Gazyva

• Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation

  [see

  5.1 Hepatitis B Virus Reactivation

  GAZYVA can cause Hepatitis B virus (HBV) reactivation. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

  HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

  Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult healthcare providers with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

  Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

  In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with healthcare providers with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation.

  ]

  .
• Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA

  [see

  5.2 Progressive Multifocal Leukoencephalopathy

  John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, occurred in patients treated with GAZYVA for CLL and NHL. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

  ]

  .

GAZYVA is a CD20-directed cytolytic antibody indicated:

• in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). (
  1.1 Chronic Lymphocytic Leukemia (CLL)

  GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia.
  ,
  14 CLINICAL STUDIES

  14.1 Chronic Lymphocytic Leukemia

  The efficacy of GAZYVA was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (CLL11; NCT01010061) in 781 patients with previously untreated CD20+ CLL requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CLcr) < 70 mL/min. Patients with CLcr < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive; patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), GAZYVA in combination with chlorambucil (Arm 2), or rituximab product in combination with chlorambucil (Arm 3). The safety and efficacy of GAZYVA was evaluated in a Stage 1 comparison of Arm 1 vs. Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs. Arm 3 in 663 patients.

  The majority of patients received 1,000 mg of GAZYVA on days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of GAZYVA was divided between day 1 (100 mg) and day 2 (900 mg)

  [see Dosage and Administration (2.2)]

  , which was implemented in 140 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).

  In CLL11, the median age was 73 years, 62% were male, and 95% were White. Sixty-five percent had a CLcr < 70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B, and 36% were stage C. The median estimated CLcr was 62 mL/min. Eighty-one percent of patients treated with GAZYVA in combination with chlorambucil received all 6 cycles compared to 89% of patients in the rituximab product treated arm and 67% in the chlorambucil alone arm.

  In the Stage 1 analysis of CLL11, the median progression-free survival (PFS) in the GAZYVA in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm (median observation time 22.8 months) as assessed by independent review and is consistent with investigator-assessed PFS. The median overall survival (OS) was not yet reached with a total of 46 deaths: 22 (9%) in the GAZYVA in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm. The hazard ratio for OS was 0.41 (95% CI: 0.23-0.74).

  In the Stage 2 analysis of CLL11, the median PFS was 26.7 months in the GAZYVA arm and 14.9 months in the rituximab product arm with a median observation time of 18.7 months (HR: 0.42, 95% CI: 0.33-0.54, p-value < 0.0001). These results were assessed by independent review and are consistent with investigator-assessed PFS. Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was one CLL cell per 10⁴leukocytes in the sample (i.e., an MRD value of < 10^-4was considered negative). Among patients who achieved complete response (CR) and complete response with incomplete marrow recovery (CRi; 94 patients in the GAZYVA arm and 34 patients in the rituximab product arm), 18 patients (19%) had negative MRD in the bone marrow in the GAZYVA arm compared to 2 patients (6%) in the rituximab product arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the GAZYVA arm, and 4 patients (12%) in the rituximab product arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.

  Efficacy results are shown in Table 16and Figures 1and 2.

  Table 16 Efficacy Results from CLL11

  Endpoint	Stage 1 of CLL11		Stage 2 of CLL11
  	GAZYVA + ChlorambucilAll Stage 1 GClb patients (n = 238) were included in the Stage 2 GClb population (n = 333).	Chlorambucil	GAZYVA + Chlorambucil	Rituximab product + Chlorambucil
  	n = 238	n = 118	n = 333	n = 330
  Median Progression-Free SurvivalAs defined by independent review. Investigator-assessed PFS was consistent with data from independent review.	27.2 months	11.2 months	26.7 months	14.9 months
  	(HR 0.19 [0.14; 0.27], p-value < 0.0001 stratified log-rank test)		(HR 0.42 [0.33; 0.54], p-value < 0.0001 stratified log-rank test)
  Overall Response RateDefined as best overall response rate (ORR = CR + CRi + PR + nPR).	78.2%	33.1%	79.6%	66.3%
  Complete Response	28.2%	0	26.1%	8.8%
  Complete Response with Incomplete Marrow Recovery	2.5%	1.7%	2.1%	1.5%
  Partial Response	45.0%	30.5%	48.6%	54.1%
  Nodular Partial Response	2.5%	0.8%	2.7%	1.8%
  Median Duration of Response	22.4 months	4.7 months	19.6 months	9.7 months
  Overall Survival	HR 0.41 [0.23; 0.74]		Not Yet Mature

  Figure 1 Kaplan-Meier Curve of Overall Survival in Patients with CLL in CLL11 (Stage 1)

  Figure 2 Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in CLL11 (Stage 2)

  Figure 1

  Figure 2

  14.2 Follicular Lymphoma

  GADOLIN

  The efficacy of GAZYVA was evaluated in GADOLIN (NCT01059630), an open-label, multicenter, randomized study that included 335 patients with follicular lymphoma (FL) who had no response to or have progressed during or within 6 months of rituximab product or a rituximab product-containing regimen. These patients were randomized to receive either bendamustine alone (n = 171) or GAZYVA in combination with bendamustine (n = 164) for 6 cycles, each of 28 days duration. Patients in the GAZYVA plus bendamustine arm who did not have disease progression [patients with a complete response (CR), partial response (PR) or stable disease (SD)] at the end of the 6 cycles continued receiving GAZYVA monotherapy for 2 years. Patients were stratified according to the type of refractoriness to rituximab product (refractory to rituximab product monotherapy versus rituximab product in combination with chemotherapy), the number of prior therapies (≤ 2 versus > 2), and geographic region.

  GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on Day 1 of Cycles 2–6, and then every 2 months until disease progression for up to 2 years. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (1–6) at 90 mg/m²/day when given in combination with GAZYVA or 120 mg/m²/day when given alone.

  The primary analysis included 321 FL patients, including 166 patients randomized to bendamustine alone and 155 patients randomized to GAZYVA in combination with bendamustine. In the primary analysis, patients had a median age of 63 years, 88% were White and 56% were male. Thirty-four percent had bulky disease (> 6 cm), 15% had at least one B-symptom at baseline and 95% had an ECOG performance status of 0–1 at baseline. The median time since initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10). Forty-six percent of patients received 1 prior therapy and 33% of patients received 2 prior therapies. Twenty percent of patients were refractory to prior rituximab product monotherapy, 37% of patients were refractory to prior rituximab product plus chemotherapy induction treatment, and 41% of patients were refractory to rituximab product maintenance treatment received following rituximab product plus chemotherapy induction. Seventy-nine percent of patients were refractory to both rituximab product and an alkylating agent during any prior regimen (double refractory).

  The major efficacy outcome measure was PFS as determined by an independent review committee (IRC). At the time of the primary analysis, median observation time was 21.1 months. The median PFS in the bendamustine arm was 13.8 months. Median PFS was not reached in the GAZYVA plus bendamustine arm (PFS HR = 0.48, 95% CI: 0.34-0.68; stratified log-rank test p-value < 0.0001). The investigator assessed PFS result was consistent with the IRC-assessed PFS. The median investigator-assessed PFS in the bendamustine arm was 13.7 months and the median in the GAZYVA containing arm was 29.2 months (PFS HR = 0.48, 95% CI: 0.35-0.67; stratified log-rank test p-value < 0.0001).

  Efficacy results are summarized in Table 17. The Kaplan-Meier curve for IRC-PFS is shown in Figure 3.

  Table 17 Primary Analysis Efficacy Results from GADOLINBased on FL population.^,As defined by independent review.

  Endpoint	GADOLIN
  	GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 155	Bendamustine n = 166
  Median Progression-Free Survival (months)	Not Reached	13.8
  	(HR = 0.48 [0.34; 0.68], p-value < 0.0001 by stratified log-rank test)
  Best Overall ResponseBest response of PR or CR within 12 months of study start.	78.7%	74.7%
  Complete Response	15.5%	18.7%
  Partial Response	63.2%	56.0%
  Median duration of response (months)	Not Reached	11.6

  Figure 3 Kaplan-Meier Curve of IRC-Assessed Progression-Free Survival in Patients with FL

  The final analysis included a total of 335 patients with 171 randomized to bendamustine alone and 164 to GAZYVA in combination with bendamustine. With an overall median observation time of 52.2 months (range: 0-100.9 months), there were 66 deaths (40.2%) in the GAZYVA arm and 85 deaths (51.3%) in the bendamustine-alone arm (OS HR = 0.71, 95% CI: 0.51, 0.98). The Kaplan-Meier curve for OS is presented in Figure 4.

  Figure 4 Kaplan-Meier Curve of Overall Survival in Patients with FL

  Figure 3

  Figure 4

  GALLIUM

  The efficacy of GAZYVA was evaluated in GALLIUM (NCT01332968), a multicenter, open-label, randomized study that included 1202 patients with previously untreated, stage II bulky, III or IV FL. Patients were randomized 1:1 to receive either GAZYVA (n = 601) or rituximab product (n = 601) in combination with chemotherapy (CHOP, CVP, or bendamustine) for 6–8 cycles. Patients were stratified by chemotherapy (selected by each site; all patients at that site received the chosen chemotherapy regimen), FLIPI (Follicular Lymphoma International Prognostic Index) risk group and geographic region. Patients with at least PR to combination therapy received monotherapy with GAZYVA (1,000 mg) or rituximab product every two months until disease progression or for a maximum of two years. The study excluded patients with follicular lymphoma grade 3b or transformed disease; patients having an ANC < 1500 / µL, platelets < 75,000 / µL, or CLcr < 40 mL/min; and patients with hepatic transaminases > 2.5 × upper limit of normal unless attributable to lymphoma.

  GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1 and Day 1 of subsequent treatment cycles.

  GAZYVA and bendamustine were given in six 28-day cycles. Bendamustine was administered at 90 mg/m²/day on Days 1 and 2 of each cycle, with prednisone 100 mg orally or equivalent on Day 1 of Cycle 1.

  GAZYVA and CHOP were given in six 21-day cycles. Subsequently, two additional cycles of GAZYVA were given for a total of 8 GAZYVA cycles. CHOP consisted of cyclophosphamide 750 mg/m²intravenously, doxorubicin 50 mg/m², and vincristine 1.4 mg/m²(maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

  GAZYVA and CVP were given in eight 21-day cycles. CVP consisted of cyclophosphamide 750 mg/m²intravenously and vincristine 1.4 mg/m²(maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

  Patients had a median age of 59 years, 81% were White and 53% were female; 7% had Stage II, 35% had Stage III, and 56% had Stage IV disease, with 44% having bulky disease (≥ 7 cm) overall; 79% had a FLIPI score of > 2; and 97% had an ECOG performance status of 0–1. The chemotherapy was bendamustine in 57%, CHOP in 33%, and CVP in 10% of patients.

  Efficacy was based on PFS per IRC, with a median observation time of 38 months. Upon interim analysis, the risk of progression or death was significantly reduced in the GAZYVA containing arm compared to the rituximab product containing arm . Kaplan-Meier curves for PFS are shown in Figure 5. Overall response and complete remission rates were similar.

  Table 18 Efficacy in Previously Untreated Follicular Lymphoma (GALLIUM)

  Endpoint per IRC	GAZYVA + chemotherapy followed by GAZYVA monotherapy n = 601	Rituximab product + chemotherapy followed by rituximab product monotherapy n = 601
  Progression-Free SurvivalInvestigator-assessed PFS was consistent with data from independent review. Number of events (%)	108 (18%)	141 (23%)
  	HR = 0.72 [95% CI: 0.56, 0.93], p-value = 0.0118Stratified log-rank test.
  Overall Response RateAfter completion of combination therapy. Assessed by CT without positron emission tomography.	91%	88%
  Complete Remission Rate	28%	27%

  Figure 5 Kaplan-Meier Curves of Progression Free Survival in Patients with Previously Untreated FL

  Figure 5

  14.3 Active Lupus Nephritis

  Study Design and Population

  The efficacy of GAZYVA was evaluated in REGENCY (NCT04221477), a Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in 271 patients with ISN/RPS 2003 Class III or IV, with or without concomitant Class V lupus nephritis (LN), treated with standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids. Patients had active or active/chronic ISN/RPS 2003 Class III or IV, with or without concomitant Class V proliferative LN determined by kidney biopsy, current or past positive antinuclear antibody (ANA), urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g, and had received at least one dose of pulse intravenous (IV) methylprednisolone (≥ 250 mg) or equivalent treatment for LN during the 6 months prior to screening or during screening.

  Patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 or in need of dialysis or transplantation, with sclerosis in > 50% of glomeruli on kidney biopsy, presence of rapidly progressive glomerulonephritis, evidence of active infection, receipt of anti-CD20 therapy < 9 months before or during screening, or receipt of cyclophosphamide, tacrolimus, ciclosporin, or voclosporin within 2 months of or during screening were excluded.

  Patients were randomized 1:1 to receive GAZYVA 1,000 mg (N=135) or placebo (N=136) intravenously, in combination with MMF 2-2.5 g/day and a tapering course of corticosteroids and were evaluated over 76 weeks. Patients randomized to receive GAZYVA were further randomized in a 1:1 ratio to receive either GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, 50, and 52 (Arm 1), or GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, and 52 (Arm 2). The totality of the GAZYVA efficacy data combining both treatment arms is shown in Table 19.

  All patients received oral prednisone 0.5 mg/kg/day (maximum 60 mg/day) and remained at this dose until Week 2. Beginning on Day 15, prednisone was tapered to achieve a target dose of 5 mg/day by Week 24. Prednisone was maintained at a low dose (5 mg/day) from Week 24 until Week 80.

  The median age of patients was 31 years, 85% were female, 58% were Hispanic or Latino, 48% were White, 19% were American Indian or Alaska Native, 15% were Black or African American and 6% were Asian. The distribution by kidney biopsy class was 39% Class III, 61% Class IV and 31% had concomitant Class V. Mean (SD) eGFR at baseline 102.3 (±30.8) mL/min/1.73 m². Mean (SD) UPCR at baseline was 3.3 (±2.9) mg/mg with 42% of patients exhibiting UPCR ≥3 mg/mg at baseline.

  Efficacy Results

  The primary endpoint measure was proportion of patients who achieved complete renal response (CRR) at Week 76, defined as meeting all of the following criteria: UPCR < 0.5 g/g; eGFR ≥ 85% of baseline, as calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; with no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal.

  Key secondary endpoint measures included: proportion of patients who achieved CRR with successful prednisone taper at Week 76 (defined as achievement of CRR at Week 76 without receiving prednisone > 7.5 mg/day or equivalent from Week 64 through Week 76), proportion of patients who achieved a proteinuric response at Week 76 (defined as achievement of UPCR < 0.8g/g and no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal) and proportion of patients who experience "renal-related events or deaths" through Week 76 (defined as occurrence of death, treatment failure, ≥ 50% increase in UPCR to a value ≥ 3 g/g and/or ≥ 30% decrease in eGFR to < 60 ml/min/1.73 m²).

  The proportion of patients achieving CRR at Week 76 was significantly greater in patients treated with GAZYVA in combination with standard therapy compared to patients who received placebo plus standard therapy. There were also a higher proportion of patients who achieved CRR with successful prednisone taper at Week 76 and proteinuric response at Week 76 in the GAZYVA plus standard therapy arm compared to the placebo plus standard therapy arm (see Table 19).

  In the REGENCY study, patients who received GAZYVA were less likely to experience the outcome of "renal-related event or death" compared with placebo. Fewer patients in the GAZYVA arm experienced worsening kidney function or doubling of serum creatinine (see Table 20).

  Table 19 Summary of Efficacy Results in Adult Patients with Active Lupus Nephritis (REGENCY Study)

  	GAZYVA + standard therapy (N=135)	Placebo + standard therapy (N=136)
  Primary Endpoint
  Complete renal response (CRR) at Week 76 (%)	46.4 (38.0, 54.9)	33.1 (25.2, 41)
  Treatment difference (95% CI)Primary and key secondary endpoints were analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusted for stratification factors race and region. Multiple Imputation handled missing data. For the primary endpoint CRR and the key secondary endpoint CRR with successful prednisone taper, missing data (not due to an Intercurrent Event (ICE)) occurred in four patients in the GAZYVA arm and one in the placebo arm. For the key secondary endpoint proteinuric response, four GAZYVA patients and two placebo patients had non-ICE-related missing data.	13.4 (2.0, 24.8)
  p-value	0.0232
  Components of CRR:
  UPCR < 0.5 g/g	64 (47.4%)	49 (36.0%)
  eGFR ≥ 85% at baseline	113 (83.7%)	103 (75.7%)
  No occurrence of intercurrent events	120 (88.9%)	102 (75%)
  Key Secondary Endpoints
  CRR with successful prednisone taper at Week 76 (%)	42.7 (34.3, 51.1)	30.9 (23.1, 38.7)
  Treatment difference (95% CI)	11.9 (0.6, 23.2)
  p-value	0.0421
  Proteinuric response at Week 76 (%)	55.5 (47.1, 64)	41.9 (33.6, 50.2)
  Treatment difference (95% CI)	13.7 (2.0, 25.4),
  p-value	0.0227

  Table 20 Renal-Related Event or Death in Adult Patients with Active Lupus Nephritis (REGENCY Study) by Week 76

  	Week 0-76		Hazard Ratio (HR) vs. Placebo (95% CI) Week 76
  	GAZYVA + standard therapy N=135 (%)	Placebo + standard therapy N=136 (%)
  Renal-Related Event or Death
  Number (%) of patients with event	24 (17.8%)	46 (33.8%)
  Time to event			0.5 (0.3, 0.8)
  Components of Renal-Related Event or Death Endpoint
  Percentage of patients with:
  Death	3 (2.2%)	1 (0.7%)
  Treatment failureTreatment failure was prospectively defined as any of the following: 1) new ESRD or need for chronic dialysis or renal transplantation, 2) clinically significant, sustained worsening in UPCR and/or eGFR from Week 24 onward that leads the investigator to conclude the patient failed the randomized treatment period, or 3) receipt of rescue therapy, except corticosteroid-only rescue	6 (4.4%)	25 (18.4%)
  End-stage renal disease (ESRD)1	0	2 (1.5%)
  Clinically significant, sustained worsening in UPCR and/or eGFR from Week 242	5 (3.7%)	22(16.2%)
  Rescue Therapy except corticosteroid-only rescue3	5 (3.7%)	22 (16.2%)
  Worsening proteinuriaWorsening proteinuria was prospectively defined as a confirmed ≥ 50% increase in UPCR to a value ≥ 3 g/g	17 (12.6%)	18 (13.2%)
  Worsening eGFRWorsening eGFR was prospectively defined as confirmed ≥ 30% decrease in eGFR to a value < 60mL/min/1.73m2	7 (5.2%)	20 (14.7%)
  Additional Renal-Related Events
  Percentage of patients with event
  Doubling of serum creatinine from baseline through Week 76	4 (3.0%)	8 (5.9%)

  Subgroup Analyses

  In pre-specified subgroup efficacy analyses, the primary endpoint in patients was examined based on 24-hour UPCR at baseline (< 3 g/g or ≥ 3 g/g), lupus nephritis class at baseline (Class III or IV), and concomitant Class V at baseline. The results are displayed in Figure 6below.

  Figure 6 Forest Plot of CRR at Week 76 on Baseline Disease Characteristics, Efficacy-Evaluable Patients

  Figure 6

  )
• in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL)who relapsed after, or are refractory to, a rituximab-containing regimen. (
  1.2 Follicular Lymphoma (FL)

  GAZYVA, in combination with bendamustine followed by GAZYVA monotherapy, is indicated for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen

  .

  GAZYVA, in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma

  .
  ,
  14 CLINICAL STUDIES

  14.1 Chronic Lymphocytic Leukemia

  The efficacy of GAZYVA was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (CLL11; NCT01010061) in 781 patients with previously untreated CD20+ CLL requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CLcr) < 70 mL/min. Patients with CLcr < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive; patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), GAZYVA in combination with chlorambucil (Arm 2), or rituximab product in combination with chlorambucil (Arm 3). The safety and efficacy of GAZYVA was evaluated in a Stage 1 comparison of Arm 1 vs. Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs. Arm 3 in 663 patients.

  The majority of patients received 1,000 mg of GAZYVA on days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of GAZYVA was divided between day 1 (100 mg) and day 2 (900 mg)

  [see Dosage and Administration (2.2)]

  , which was implemented in 140 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).

  In CLL11, the median age was 73 years, 62% were male, and 95% were White. Sixty-five percent had a CLcr < 70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B, and 36% were stage C. The median estimated CLcr was 62 mL/min. Eighty-one percent of patients treated with GAZYVA in combination with chlorambucil received all 6 cycles compared to 89% of patients in the rituximab product treated arm and 67% in the chlorambucil alone arm.

  In the Stage 1 analysis of CLL11, the median progression-free survival (PFS) in the GAZYVA in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm (median observation time 22.8 months) as assessed by independent review and is consistent with investigator-assessed PFS. The median overall survival (OS) was not yet reached with a total of 46 deaths: 22 (9%) in the GAZYVA in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm. The hazard ratio for OS was 0.41 (95% CI: 0.23-0.74).

  In the Stage 2 analysis of CLL11, the median PFS was 26.7 months in the GAZYVA arm and 14.9 months in the rituximab product arm with a median observation time of 18.7 months (HR: 0.42, 95% CI: 0.33-0.54, p-value < 0.0001). These results were assessed by independent review and are consistent with investigator-assessed PFS. Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was one CLL cell per 10⁴leukocytes in the sample (i.e., an MRD value of < 10^-4was considered negative). Among patients who achieved complete response (CR) and complete response with incomplete marrow recovery (CRi; 94 patients in the GAZYVA arm and 34 patients in the rituximab product arm), 18 patients (19%) had negative MRD in the bone marrow in the GAZYVA arm compared to 2 patients (6%) in the rituximab product arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the GAZYVA arm, and 4 patients (12%) in the rituximab product arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.

  Efficacy results are shown in Table 16and Figures 1and 2.

  Table 16 Efficacy Results from CLL11

  Endpoint	Stage 1 of CLL11		Stage 2 of CLL11
  	GAZYVA + ChlorambucilAll Stage 1 GClb patients (n = 238) were included in the Stage 2 GClb population (n = 333).	Chlorambucil	GAZYVA + Chlorambucil	Rituximab product + Chlorambucil
  	n = 238	n = 118	n = 333	n = 330
  Median Progression-Free SurvivalAs defined by independent review. Investigator-assessed PFS was consistent with data from independent review.	27.2 months	11.2 months	26.7 months	14.9 months
  	(HR 0.19 [0.14; 0.27], p-value < 0.0001 stratified log-rank test)		(HR 0.42 [0.33; 0.54], p-value < 0.0001 stratified log-rank test)
  Overall Response RateDefined as best overall response rate (ORR = CR + CRi + PR + nPR).	78.2%	33.1%	79.6%	66.3%
  Complete Response	28.2%	0	26.1%	8.8%
  Complete Response with Incomplete Marrow Recovery	2.5%	1.7%	2.1%	1.5%
  Partial Response	45.0%	30.5%	48.6%	54.1%
  Nodular Partial Response	2.5%	0.8%	2.7%	1.8%
  Median Duration of Response	22.4 months	4.7 months	19.6 months	9.7 months
  Overall Survival	HR 0.41 [0.23; 0.74]		Not Yet Mature

  Figure 1 Kaplan-Meier Curve of Overall Survival in Patients with CLL in CLL11 (Stage 1)

  Figure 2 Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in CLL11 (Stage 2)

  Figure 1

  Figure 2

  14.2 Follicular Lymphoma

  GADOLIN

  The efficacy of GAZYVA was evaluated in GADOLIN (NCT01059630), an open-label, multicenter, randomized study that included 335 patients with follicular lymphoma (FL) who had no response to or have progressed during or within 6 months of rituximab product or a rituximab product-containing regimen. These patients were randomized to receive either bendamustine alone (n = 171) or GAZYVA in combination with bendamustine (n = 164) for 6 cycles, each of 28 days duration. Patients in the GAZYVA plus bendamustine arm who did not have disease progression [patients with a complete response (CR), partial response (PR) or stable disease (SD)] at the end of the 6 cycles continued receiving GAZYVA monotherapy for 2 years. Patients were stratified according to the type of refractoriness to rituximab product (refractory to rituximab product monotherapy versus rituximab product in combination with chemotherapy), the number of prior therapies (≤ 2 versus > 2), and geographic region.

  GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on Day 1 of Cycles 2–6, and then every 2 months until disease progression for up to 2 years. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (1–6) at 90 mg/m²/day when given in combination with GAZYVA or 120 mg/m²/day when given alone.

  The primary analysis included 321 FL patients, including 166 patients randomized to bendamustine alone and 155 patients randomized to GAZYVA in combination with bendamustine. In the primary analysis, patients had a median age of 63 years, 88% were White and 56% were male. Thirty-four percent had bulky disease (> 6 cm), 15% had at least one B-symptom at baseline and 95% had an ECOG performance status of 0–1 at baseline. The median time since initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10). Forty-six percent of patients received 1 prior therapy and 33% of patients received 2 prior therapies. Twenty percent of patients were refractory to prior rituximab product monotherapy, 37% of patients were refractory to prior rituximab product plus chemotherapy induction treatment, and 41% of patients were refractory to rituximab product maintenance treatment received following rituximab product plus chemotherapy induction. Seventy-nine percent of patients were refractory to both rituximab product and an alkylating agent during any prior regimen (double refractory).

  The major efficacy outcome measure was PFS as determined by an independent review committee (IRC). At the time of the primary analysis, median observation time was 21.1 months. The median PFS in the bendamustine arm was 13.8 months. Median PFS was not reached in the GAZYVA plus bendamustine arm (PFS HR = 0.48, 95% CI: 0.34-0.68; stratified log-rank test p-value < 0.0001). The investigator assessed PFS result was consistent with the IRC-assessed PFS. The median investigator-assessed PFS in the bendamustine arm was 13.7 months and the median in the GAZYVA containing arm was 29.2 months (PFS HR = 0.48, 95% CI: 0.35-0.67; stratified log-rank test p-value < 0.0001).

  Efficacy results are summarized in Table 17. The Kaplan-Meier curve for IRC-PFS is shown in Figure 3.

  Table 17 Primary Analysis Efficacy Results from GADOLINBased on FL population.^,As defined by independent review.

  Endpoint	GADOLIN
  	GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 155	Bendamustine n = 166
  Median Progression-Free Survival (months)	Not Reached	13.8
  	(HR = 0.48 [0.34; 0.68], p-value < 0.0001 by stratified log-rank test)
  Best Overall ResponseBest response of PR or CR within 12 months of study start.	78.7%	74.7%
  Complete Response	15.5%	18.7%
  Partial Response	63.2%	56.0%
  Median duration of response (months)	Not Reached	11.6

  Figure 3 Kaplan-Meier Curve of IRC-Assessed Progression-Free Survival in Patients with FL

  The final analysis included a total of 335 patients with 171 randomized to bendamustine alone and 164 to GAZYVA in combination with bendamustine. With an overall median observation time of 52.2 months (range: 0-100.9 months), there were 66 deaths (40.2%) in the GAZYVA arm and 85 deaths (51.3%) in the bendamustine-alone arm (OS HR = 0.71, 95% CI: 0.51, 0.98). The Kaplan-Meier curve for OS is presented in Figure 4.

  Figure 4 Kaplan-Meier Curve of Overall Survival in Patients with FL

  Figure 3

  Figure 4

  GALLIUM

  The efficacy of GAZYVA was evaluated in GALLIUM (NCT01332968), a multicenter, open-label, randomized study that included 1202 patients with previously untreated, stage II bulky, III or IV FL. Patients were randomized 1:1 to receive either GAZYVA (n = 601) or rituximab product (n = 601) in combination with chemotherapy (CHOP, CVP, or bendamustine) for 6–8 cycles. Patients were stratified by chemotherapy (selected by each site; all patients at that site received the chosen chemotherapy regimen), FLIPI (Follicular Lymphoma International Prognostic Index) risk group and geographic region. Patients with at least PR to combination therapy received monotherapy with GAZYVA (1,000 mg) or rituximab product every two months until disease progression or for a maximum of two years. The study excluded patients with follicular lymphoma grade 3b or transformed disease; patients having an ANC < 1500 / µL, platelets < 75,000 / µL, or CLcr < 40 mL/min; and patients with hepatic transaminases > 2.5 × upper limit of normal unless attributable to lymphoma.

  GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1 and Day 1 of subsequent treatment cycles.

  GAZYVA and bendamustine were given in six 28-day cycles. Bendamustine was administered at 90 mg/m²/day on Days 1 and 2 of each cycle, with prednisone 100 mg orally or equivalent on Day 1 of Cycle 1.

  GAZYVA and CHOP were given in six 21-day cycles. Subsequently, two additional cycles of GAZYVA were given for a total of 8 GAZYVA cycles. CHOP consisted of cyclophosphamide 750 mg/m²intravenously, doxorubicin 50 mg/m², and vincristine 1.4 mg/m²(maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

  GAZYVA and CVP were given in eight 21-day cycles. CVP consisted of cyclophosphamide 750 mg/m²intravenously and vincristine 1.4 mg/m²(maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

  Patients had a median age of 59 years, 81% were White and 53% were female; 7% had Stage II, 35% had Stage III, and 56% had Stage IV disease, with 44% having bulky disease (≥ 7 cm) overall; 79% had a FLIPI score of > 2; and 97% had an ECOG performance status of 0–1. The chemotherapy was bendamustine in 57%, CHOP in 33%, and CVP in 10% of patients.

  Efficacy was based on PFS per IRC, with a median observation time of 38 months. Upon interim analysis, the risk of progression or death was significantly reduced in the GAZYVA containing arm compared to the rituximab product containing arm . Kaplan-Meier curves for PFS are shown in Figure 5. Overall response and complete remission rates were similar.

  Table 18 Efficacy in Previously Untreated Follicular Lymphoma (GALLIUM)

  Endpoint per IRC	GAZYVA + chemotherapy followed by GAZYVA monotherapy n = 601	Rituximab product + chemotherapy followed by rituximab product monotherapy n = 601
  Progression-Free SurvivalInvestigator-assessed PFS was consistent with data from independent review. Number of events (%)	108 (18%)	141 (23%)
  	HR = 0.72 [95% CI: 0.56, 0.93], p-value = 0.0118Stratified log-rank test.
  Overall Response RateAfter completion of combination therapy. Assessed by CT without positron emission tomography.	91%	88%
  Complete Remission Rate	28%	27%

  Figure 5 Kaplan-Meier Curves of Progression Free Survival in Patients with Previously Untreated FL

  Figure 5

  14.3 Active Lupus Nephritis

  Study Design and Population

  The efficacy of GAZYVA was evaluated in REGENCY (NCT04221477), a Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in 271 patients with ISN/RPS 2003 Class III or IV, with or without concomitant Class V lupus nephritis (LN), treated with standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids. Patients had active or active/chronic ISN/RPS 2003 Class III or IV, with or without concomitant Class V proliferative LN determined by kidney biopsy, current or past positive antinuclear antibody (ANA), urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g, and had received at least one dose of pulse intravenous (IV) methylprednisolone (≥ 250 mg) or equivalent treatment for LN during the 6 months prior to screening or during screening.

  Patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 or in need of dialysis or transplantation, with sclerosis in > 50% of glomeruli on kidney biopsy, presence of rapidly progressive glomerulonephritis, evidence of active infection, receipt of anti-CD20 therapy < 9 months before or during screening, or receipt of cyclophosphamide, tacrolimus, ciclosporin, or voclosporin within 2 months of or during screening were excluded.

  Patients were randomized 1:1 to receive GAZYVA 1,000 mg (N=135) or placebo (N=136) intravenously, in combination with MMF 2-2.5 g/day and a tapering course of corticosteroids and were evaluated over 76 weeks. Patients randomized to receive GAZYVA were further randomized in a 1:1 ratio to receive either GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, 50, and 52 (Arm 1), or GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, and 52 (Arm 2). The totality of the GAZYVA efficacy data combining both treatment arms is shown in Table 19.

  All patients received oral prednisone 0.5 mg/kg/day (maximum 60 mg/day) and remained at this dose until Week 2. Beginning on Day 15, prednisone was tapered to achieve a target dose of 5 mg/day by Week 24. Prednisone was maintained at a low dose (5 mg/day) from Week 24 until Week 80.

  The median age of patients was 31 years, 85% were female, 58% were Hispanic or Latino, 48% were White, 19% were American Indian or Alaska Native, 15% were Black or African American and 6% were Asian. The distribution by kidney biopsy class was 39% Class III, 61% Class IV and 31% had concomitant Class V. Mean (SD) eGFR at baseline 102.3 (±30.8) mL/min/1.73 m². Mean (SD) UPCR at baseline was 3.3 (±2.9) mg/mg with 42% of patients exhibiting UPCR ≥3 mg/mg at baseline.

  Efficacy Results

  The primary endpoint measure was proportion of patients who achieved complete renal response (CRR) at Week 76, defined as meeting all of the following criteria: UPCR < 0.5 g/g; eGFR ≥ 85% of baseline, as calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; with no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal.

  Key secondary endpoint measures included: proportion of patients who achieved CRR with successful prednisone taper at Week 76 (defined as achievement of CRR at Week 76 without receiving prednisone > 7.5 mg/day or equivalent from Week 64 through Week 76), proportion of patients who achieved a proteinuric response at Week 76 (defined as achievement of UPCR < 0.8g/g and no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal) and proportion of patients who experience "renal-related events or deaths" through Week 76 (defined as occurrence of death, treatment failure, ≥ 50% increase in UPCR to a value ≥ 3 g/g and/or ≥ 30% decrease in eGFR to < 60 ml/min/1.73 m²).

  The proportion of patients achieving CRR at Week 76 was significantly greater in patients treated with GAZYVA in combination with standard therapy compared to patients who received placebo plus standard therapy. There were also a higher proportion of patients who achieved CRR with successful prednisone taper at Week 76 and proteinuric response at Week 76 in the GAZYVA plus standard therapy arm compared to the placebo plus standard therapy arm (see Table 19).

  In the REGENCY study, patients who received GAZYVA were less likely to experience the outcome of "renal-related event or death" compared with placebo. Fewer patients in the GAZYVA arm experienced worsening kidney function or doubling of serum creatinine (see Table 20).

  Table 19 Summary of Efficacy Results in Adult Patients with Active Lupus Nephritis (REGENCY Study)

  	GAZYVA + standard therapy (N=135)	Placebo + standard therapy (N=136)
  Primary Endpoint
  Complete renal response (CRR) at Week 76 (%)	46.4 (38.0, 54.9)	33.1 (25.2, 41)
  Treatment difference (95% CI)Primary and key secondary endpoints were analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusted for stratification factors race and region. Multiple Imputation handled missing data. For the primary endpoint CRR and the key secondary endpoint CRR with successful prednisone taper, missing data (not due to an Intercurrent Event (ICE)) occurred in four patients in the GAZYVA arm and one in the placebo arm. For the key secondary endpoint proteinuric response, four GAZYVA patients and two placebo patients had non-ICE-related missing data.	13.4 (2.0, 24.8)
  p-value	0.0232
  Components of CRR:
  UPCR < 0.5 g/g	64 (47.4%)	49 (36.0%)
  eGFR ≥ 85% at baseline	113 (83.7%)	103 (75.7%)
  No occurrence of intercurrent events	120 (88.9%)	102 (75%)
  Key Secondary Endpoints
  CRR with successful prednisone taper at Week 76 (%)	42.7 (34.3, 51.1)	30.9 (23.1, 38.7)
  Treatment difference (95% CI)	11.9 (0.6, 23.2)
  p-value	0.0421
  Proteinuric response at Week 76 (%)	55.5 (47.1, 64)	41.9 (33.6, 50.2)
  Treatment difference (95% CI)	13.7 (2.0, 25.4),
  p-value	0.0227

  Table 20 Renal-Related Event or Death in Adult Patients with Active Lupus Nephritis (REGENCY Study) by Week 76

  	Week 0-76		Hazard Ratio (HR) vs. Placebo (95% CI) Week 76
  	GAZYVA + standard therapy N=135 (%)	Placebo + standard therapy N=136 (%)
  Renal-Related Event or Death
  Number (%) of patients with event	24 (17.8%)	46 (33.8%)
  Time to event			0.5 (0.3, 0.8)
  Components of Renal-Related Event or Death Endpoint
  Percentage of patients with:
  Death	3 (2.2%)	1 (0.7%)
  Treatment failureTreatment failure was prospectively defined as any of the following: 1) new ESRD or need for chronic dialysis or renal transplantation, 2) clinically significant, sustained worsening in UPCR and/or eGFR from Week 24 onward that leads the investigator to conclude the patient failed the randomized treatment period, or 3) receipt of rescue therapy, except corticosteroid-only rescue	6 (4.4%)	25 (18.4%)
  End-stage renal disease (ESRD)1	0	2 (1.5%)
  Clinically significant, sustained worsening in UPCR and/or eGFR from Week 242	5 (3.7%)	22(16.2%)
  Rescue Therapy except corticosteroid-only rescue3	5 (3.7%)	22 (16.2%)
  Worsening proteinuriaWorsening proteinuria was prospectively defined as a confirmed ≥ 50% increase in UPCR to a value ≥ 3 g/g	17 (12.6%)	18 (13.2%)
  Worsening eGFRWorsening eGFR was prospectively defined as confirmed ≥ 30% decrease in eGFR to a value < 60mL/min/1.73m2	7 (5.2%)	20 (14.7%)
  Additional Renal-Related Events
  Percentage of patients with event
  Doubling of serum creatinine from baseline through Week 76	4 (3.0%)	8 (5.9%)

  Subgroup Analyses

  In pre-specified subgroup efficacy analyses, the primary endpoint in patients was examined based on 24-hour UPCR at baseline (< 3 g/g or ≥ 3 g/g), lupus nephritis class at baseline (Class III or IV), and concomitant Class V at baseline. The results are displayed in Figure 6below.

  Figure 6 Forest Plot of CRR at Week 76 on Baseline Disease Characteristics, Efficacy-Evaluable Patients

  Figure 6

  )
• in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma. (
  1.2 Follicular Lymphoma (FL)

  GAZYVA, in combination with bendamustine followed by GAZYVA monotherapy, is indicated for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen

  .

  GAZYVA, in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma

  .
  ,
  14 CLINICAL STUDIES

  14.1 Chronic Lymphocytic Leukemia

  The efficacy of GAZYVA was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (CLL11; NCT01010061) in 781 patients with previously untreated CD20+ CLL requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CLcr) < 70 mL/min. Patients with CLcr < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive; patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), GAZYVA in combination with chlorambucil (Arm 2), or rituximab product in combination with chlorambucil (Arm 3). The safety and efficacy of GAZYVA was evaluated in a Stage 1 comparison of Arm 1 vs. Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs. Arm 3 in 663 patients.

  The majority of patients received 1,000 mg of GAZYVA on days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of GAZYVA was divided between day 1 (100 mg) and day 2 (900 mg)

  [see Dosage and Administration (2.2)]

  , which was implemented in 140 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).

  In CLL11, the median age was 73 years, 62% were male, and 95% were White. Sixty-five percent had a CLcr < 70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B, and 36% were stage C. The median estimated CLcr was 62 mL/min. Eighty-one percent of patients treated with GAZYVA in combination with chlorambucil received all 6 cycles compared to 89% of patients in the rituximab product treated arm and 67% in the chlorambucil alone arm.

  In the Stage 1 analysis of CLL11, the median progression-free survival (PFS) in the GAZYVA in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm (median observation time 22.8 months) as assessed by independent review and is consistent with investigator-assessed PFS. The median overall survival (OS) was not yet reached with a total of 46 deaths: 22 (9%) in the GAZYVA in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm. The hazard ratio for OS was 0.41 (95% CI: 0.23-0.74).

  In the Stage 2 analysis of CLL11, the median PFS was 26.7 months in the GAZYVA arm and 14.9 months in the rituximab product arm with a median observation time of 18.7 months (HR: 0.42, 95% CI: 0.33-0.54, p-value < 0.0001). These results were assessed by independent review and are consistent with investigator-assessed PFS. Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was one CLL cell per 10⁴leukocytes in the sample (i.e., an MRD value of < 10^-4was considered negative). Among patients who achieved complete response (CR) and complete response with incomplete marrow recovery (CRi; 94 patients in the GAZYVA arm and 34 patients in the rituximab product arm), 18 patients (19%) had negative MRD in the bone marrow in the GAZYVA arm compared to 2 patients (6%) in the rituximab product arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the GAZYVA arm, and 4 patients (12%) in the rituximab product arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.

  Efficacy results are shown in Table 16and Figures 1and 2.

  Table 16 Efficacy Results from CLL11

  Endpoint	Stage 1 of CLL11		Stage 2 of CLL11
  	GAZYVA + ChlorambucilAll Stage 1 GClb patients (n = 238) were included in the Stage 2 GClb population (n = 333).	Chlorambucil	GAZYVA + Chlorambucil	Rituximab product + Chlorambucil
  	n = 238	n = 118	n = 333	n = 330
  Median Progression-Free SurvivalAs defined by independent review. Investigator-assessed PFS was consistent with data from independent review.	27.2 months	11.2 months	26.7 months	14.9 months
  	(HR 0.19 [0.14; 0.27], p-value < 0.0001 stratified log-rank test)		(HR 0.42 [0.33; 0.54], p-value < 0.0001 stratified log-rank test)
  Overall Response RateDefined as best overall response rate (ORR = CR + CRi + PR + nPR).	78.2%	33.1%	79.6%	66.3%
  Complete Response	28.2%	0	26.1%	8.8%
  Complete Response with Incomplete Marrow Recovery	2.5%	1.7%	2.1%	1.5%
  Partial Response	45.0%	30.5%	48.6%	54.1%
  Nodular Partial Response	2.5%	0.8%	2.7%	1.8%
  Median Duration of Response	22.4 months	4.7 months	19.6 months	9.7 months
  Overall Survival	HR 0.41 [0.23; 0.74]		Not Yet Mature

  Figure 1 Kaplan-Meier Curve of Overall Survival in Patients with CLL in CLL11 (Stage 1)

  Figure 2 Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in CLL11 (Stage 2)

  Figure 1

  Figure 2

  14.2 Follicular Lymphoma

  GADOLIN

  The efficacy of GAZYVA was evaluated in GADOLIN (NCT01059630), an open-label, multicenter, randomized study that included 335 patients with follicular lymphoma (FL) who had no response to or have progressed during or within 6 months of rituximab product or a rituximab product-containing regimen. These patients were randomized to receive either bendamustine alone (n = 171) or GAZYVA in combination with bendamustine (n = 164) for 6 cycles, each of 28 days duration. Patients in the GAZYVA plus bendamustine arm who did not have disease progression [patients with a complete response (CR), partial response (PR) or stable disease (SD)] at the end of the 6 cycles continued receiving GAZYVA monotherapy for 2 years. Patients were stratified according to the type of refractoriness to rituximab product (refractory to rituximab product monotherapy versus rituximab product in combination with chemotherapy), the number of prior therapies (≤ 2 versus > 2), and geographic region.

  GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on Day 1 of Cycles 2–6, and then every 2 months until disease progression for up to 2 years. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (1–6) at 90 mg/m²/day when given in combination with GAZYVA or 120 mg/m²/day when given alone.

  The primary analysis included 321 FL patients, including 166 patients randomized to bendamustine alone and 155 patients randomized to GAZYVA in combination with bendamustine. In the primary analysis, patients had a median age of 63 years, 88% were White and 56% were male. Thirty-four percent had bulky disease (> 6 cm), 15% had at least one B-symptom at baseline and 95% had an ECOG performance status of 0–1 at baseline. The median time since initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10). Forty-six percent of patients received 1 prior therapy and 33% of patients received 2 prior therapies. Twenty percent of patients were refractory to prior rituximab product monotherapy, 37% of patients were refractory to prior rituximab product plus chemotherapy induction treatment, and 41% of patients were refractory to rituximab product maintenance treatment received following rituximab product plus chemotherapy induction. Seventy-nine percent of patients were refractory to both rituximab product and an alkylating agent during any prior regimen (double refractory).

  The major efficacy outcome measure was PFS as determined by an independent review committee (IRC). At the time of the primary analysis, median observation time was 21.1 months. The median PFS in the bendamustine arm was 13.8 months. Median PFS was not reached in the GAZYVA plus bendamustine arm (PFS HR = 0.48, 95% CI: 0.34-0.68; stratified log-rank test p-value < 0.0001). The investigator assessed PFS result was consistent with the IRC-assessed PFS. The median investigator-assessed PFS in the bendamustine arm was 13.7 months and the median in the GAZYVA containing arm was 29.2 months (PFS HR = 0.48, 95% CI: 0.35-0.67; stratified log-rank test p-value < 0.0001).

  Efficacy results are summarized in Table 17. The Kaplan-Meier curve for IRC-PFS is shown in Figure 3.

  Table 17 Primary Analysis Efficacy Results from GADOLINBased on FL population.^,As defined by independent review.

  Endpoint	GADOLIN
  	GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 155	Bendamustine n = 166
  Median Progression-Free Survival (months)	Not Reached	13.8
  	(HR = 0.48 [0.34; 0.68], p-value < 0.0001 by stratified log-rank test)
  Best Overall ResponseBest response of PR or CR within 12 months of study start.	78.7%	74.7%
  Complete Response	15.5%	18.7%
  Partial Response	63.2%	56.0%
  Median duration of response (months)	Not Reached	11.6

  Figure 3 Kaplan-Meier Curve of IRC-Assessed Progression-Free Survival in Patients with FL

  The final analysis included a total of 335 patients with 171 randomized to bendamustine alone and 164 to GAZYVA in combination with bendamustine. With an overall median observation time of 52.2 months (range: 0-100.9 months), there were 66 deaths (40.2%) in the GAZYVA arm and 85 deaths (51.3%) in the bendamustine-alone arm (OS HR = 0.71, 95% CI: 0.51, 0.98). The Kaplan-Meier curve for OS is presented in Figure 4.

  Figure 4 Kaplan-Meier Curve of Overall Survival in Patients with FL

  Figure 3

  Figure 4

  GALLIUM

  The efficacy of GAZYVA was evaluated in GALLIUM (NCT01332968), a multicenter, open-label, randomized study that included 1202 patients with previously untreated, stage II bulky, III or IV FL. Patients were randomized 1:1 to receive either GAZYVA (n = 601) or rituximab product (n = 601) in combination with chemotherapy (CHOP, CVP, or bendamustine) for 6–8 cycles. Patients were stratified by chemotherapy (selected by each site; all patients at that site received the chosen chemotherapy regimen), FLIPI (Follicular Lymphoma International Prognostic Index) risk group and geographic region. Patients with at least PR to combination therapy received monotherapy with GAZYVA (1,000 mg) or rituximab product every two months until disease progression or for a maximum of two years. The study excluded patients with follicular lymphoma grade 3b or transformed disease; patients having an ANC < 1500 / µL, platelets < 75,000 / µL, or CLcr < 40 mL/min; and patients with hepatic transaminases > 2.5 × upper limit of normal unless attributable to lymphoma.

  GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1 and Day 1 of subsequent treatment cycles.

  GAZYVA and bendamustine were given in six 28-day cycles. Bendamustine was administered at 90 mg/m²/day on Days 1 and 2 of each cycle, with prednisone 100 mg orally or equivalent on Day 1 of Cycle 1.

  GAZYVA and CHOP were given in six 21-day cycles. Subsequently, two additional cycles of GAZYVA were given for a total of 8 GAZYVA cycles. CHOP consisted of cyclophosphamide 750 mg/m²intravenously, doxorubicin 50 mg/m², and vincristine 1.4 mg/m²(maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

  GAZYVA and CVP were given in eight 21-day cycles. CVP consisted of cyclophosphamide 750 mg/m²intravenously and vincristine 1.4 mg/m²(maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

  Patients had a median age of 59 years, 81% were White and 53% were female; 7% had Stage II, 35% had Stage III, and 56% had Stage IV disease, with 44% having bulky disease (≥ 7 cm) overall; 79% had a FLIPI score of > 2; and 97% had an ECOG performance status of 0–1. The chemotherapy was bendamustine in 57%, CHOP in 33%, and CVP in 10% of patients.

  Efficacy was based on PFS per IRC, with a median observation time of 38 months. Upon interim analysis, the risk of progression or death was significantly reduced in the GAZYVA containing arm compared to the rituximab product containing arm . Kaplan-Meier curves for PFS are shown in Figure 5. Overall response and complete remission rates were similar.

  Table 18 Efficacy in Previously Untreated Follicular Lymphoma (GALLIUM)

  Endpoint per IRC	GAZYVA + chemotherapy followed by GAZYVA monotherapy n = 601	Rituximab product + chemotherapy followed by rituximab product monotherapy n = 601
  Progression-Free SurvivalInvestigator-assessed PFS was consistent with data from independent review. Number of events (%)	108 (18%)	141 (23%)
  	HR = 0.72 [95% CI: 0.56, 0.93], p-value = 0.0118Stratified log-rank test.
  Overall Response RateAfter completion of combination therapy. Assessed by CT without positron emission tomography.	91%	88%
  Complete Remission Rate	28%	27%

  Figure 5 Kaplan-Meier Curves of Progression Free Survival in Patients with Previously Untreated FL

  Figure 5

  14.3 Active Lupus Nephritis

  Study Design and Population

  The efficacy of GAZYVA was evaluated in REGENCY (NCT04221477), a Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in 271 patients with ISN/RPS 2003 Class III or IV, with or without concomitant Class V lupus nephritis (LN), treated with standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids. Patients had active or active/chronic ISN/RPS 2003 Class III or IV, with or without concomitant Class V proliferative LN determined by kidney biopsy, current or past positive antinuclear antibody (ANA), urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g, and had received at least one dose of pulse intravenous (IV) methylprednisolone (≥ 250 mg) or equivalent treatment for LN during the 6 months prior to screening or during screening.

  Patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 or in need of dialysis or transplantation, with sclerosis in > 50% of glomeruli on kidney biopsy, presence of rapidly progressive glomerulonephritis, evidence of active infection, receipt of anti-CD20 therapy < 9 months before or during screening, or receipt of cyclophosphamide, tacrolimus, ciclosporin, or voclosporin within 2 months of or during screening were excluded.

  Patients were randomized 1:1 to receive GAZYVA 1,000 mg (N=135) or placebo (N=136) intravenously, in combination with MMF 2-2.5 g/day and a tapering course of corticosteroids and were evaluated over 76 weeks. Patients randomized to receive GAZYVA were further randomized in a 1:1 ratio to receive either GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, 50, and 52 (Arm 1), or GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, and 52 (Arm 2). The totality of the GAZYVA efficacy data combining both treatment arms is shown in Table 19.

  All patients received oral prednisone 0.5 mg/kg/day (maximum 60 mg/day) and remained at this dose until Week 2. Beginning on Day 15, prednisone was tapered to achieve a target dose of 5 mg/day by Week 24. Prednisone was maintained at a low dose (5 mg/day) from Week 24 until Week 80.

  The median age of patients was 31 years, 85% were female, 58% were Hispanic or Latino, 48% were White, 19% were American Indian or Alaska Native, 15% were Black or African American and 6% were Asian. The distribution by kidney biopsy class was 39% Class III, 61% Class IV and 31% had concomitant Class V. Mean (SD) eGFR at baseline 102.3 (±30.8) mL/min/1.73 m². Mean (SD) UPCR at baseline was 3.3 (±2.9) mg/mg with 42% of patients exhibiting UPCR ≥3 mg/mg at baseline.

  Efficacy Results

  The primary endpoint measure was proportion of patients who achieved complete renal response (CRR) at Week 76, defined as meeting all of the following criteria: UPCR < 0.5 g/g; eGFR ≥ 85% of baseline, as calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; with no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal.

  Key secondary endpoint measures included: proportion of patients who achieved CRR with successful prednisone taper at Week 76 (defined as achievement of CRR at Week 76 without receiving prednisone > 7.5 mg/day or equivalent from Week 64 through Week 76), proportion of patients who achieved a proteinuric response at Week 76 (defined as achievement of UPCR < 0.8g/g and no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal) and proportion of patients who experience "renal-related events or deaths" through Week 76 (defined as occurrence of death, treatment failure, ≥ 50% increase in UPCR to a value ≥ 3 g/g and/or ≥ 30% decrease in eGFR to < 60 ml/min/1.73 m²).

  The proportion of patients achieving CRR at Week 76 was significantly greater in patients treated with GAZYVA in combination with standard therapy compared to patients who received placebo plus standard therapy. There were also a higher proportion of patients who achieved CRR with successful prednisone taper at Week 76 and proteinuric response at Week 76 in the GAZYVA plus standard therapy arm compared to the placebo plus standard therapy arm (see Table 19).

  In the REGENCY study, patients who received GAZYVA were less likely to experience the outcome of "renal-related event or death" compared with placebo. Fewer patients in the GAZYVA arm experienced worsening kidney function or doubling of serum creatinine (see Table 20).

  Table 19 Summary of Efficacy Results in Adult Patients with Active Lupus Nephritis (REGENCY Study)

  	GAZYVA + standard therapy (N=135)	Placebo + standard therapy (N=136)
  Primary Endpoint
  Complete renal response (CRR) at Week 76 (%)	46.4 (38.0, 54.9)	33.1 (25.2, 41)
  Treatment difference (95% CI)Primary and key secondary endpoints were analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusted for stratification factors race and region. Multiple Imputation handled missing data. For the primary endpoint CRR and the key secondary endpoint CRR with successful prednisone taper, missing data (not due to an Intercurrent Event (ICE)) occurred in four patients in the GAZYVA arm and one in the placebo arm. For the key secondary endpoint proteinuric response, four GAZYVA patients and two placebo patients had non-ICE-related missing data.	13.4 (2.0, 24.8)
  p-value	0.0232
  Components of CRR:
  UPCR < 0.5 g/g	64 (47.4%)	49 (36.0%)
  eGFR ≥ 85% at baseline	113 (83.7%)	103 (75.7%)
  No occurrence of intercurrent events	120 (88.9%)	102 (75%)
  Key Secondary Endpoints
  CRR with successful prednisone taper at Week 76 (%)	42.7 (34.3, 51.1)	30.9 (23.1, 38.7)
  Treatment difference (95% CI)	11.9 (0.6, 23.2)
  p-value	0.0421
  Proteinuric response at Week 76 (%)	55.5 (47.1, 64)	41.9 (33.6, 50.2)
  Treatment difference (95% CI)	13.7 (2.0, 25.4),
  p-value	0.0227

  Table 20 Renal-Related Event or Death in Adult Patients with Active Lupus Nephritis (REGENCY Study) by Week 76

  	Week 0-76		Hazard Ratio (HR) vs. Placebo (95% CI) Week 76
  	GAZYVA + standard therapy N=135 (%)	Placebo + standard therapy N=136 (%)
  Renal-Related Event or Death
  Number (%) of patients with event	24 (17.8%)	46 (33.8%)
  Time to event			0.5 (0.3, 0.8)
  Components of Renal-Related Event or Death Endpoint
  Percentage of patients with:
  Death	3 (2.2%)	1 (0.7%)
  Treatment failureTreatment failure was prospectively defined as any of the following: 1) new ESRD or need for chronic dialysis or renal transplantation, 2) clinically significant, sustained worsening in UPCR and/or eGFR from Week 24 onward that leads the investigator to conclude the patient failed the randomized treatment period, or 3) receipt of rescue therapy, except corticosteroid-only rescue	6 (4.4%)	25 (18.4%)
  End-stage renal disease (ESRD)1	0	2 (1.5%)
  Clinically significant, sustained worsening in UPCR and/or eGFR from Week 242	5 (3.7%)	22(16.2%)
  Rescue Therapy except corticosteroid-only rescue3	5 (3.7%)	22 (16.2%)
  Worsening proteinuriaWorsening proteinuria was prospectively defined as a confirmed ≥ 50% increase in UPCR to a value ≥ 3 g/g	17 (12.6%)	18 (13.2%)
  Worsening eGFRWorsening eGFR was prospectively defined as confirmed ≥ 30% decrease in eGFR to a value < 60mL/min/1.73m2	7 (5.2%)	20 (14.7%)
  Additional Renal-Related Events
  Percentage of patients with event
  Doubling of serum creatinine from baseline through Week 76	4 (3.0%)	8 (5.9%)

  Subgroup Analyses

  In pre-specified subgroup efficacy analyses, the primary endpoint in patients was examined based on 24-hour UPCR at baseline (< 3 g/g or ≥ 3 g/g), lupus nephritis class at baseline (Class III or IV), and concomitant Class V at baseline. The results are displayed in Figure 6below.

  Figure 6 Forest Plot of CRR at Week 76 on Baseline Disease Characteristics, Efficacy-Evaluable Patients

  Figure 6

  )
• for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy (
  1.3 Lupus Nephritis (LN)

  GAZYVA is indicated for the treatment of adult patients with active lupus nephritis who are receiving standard therapy.
  ,
  14 CLINICAL STUDIES

  14.1 Chronic Lymphocytic Leukemia

  The efficacy of GAZYVA was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (CLL11; NCT01010061) in 781 patients with previously untreated CD20+ CLL requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CLcr) < 70 mL/min. Patients with CLcr < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive; patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), GAZYVA in combination with chlorambucil (Arm 2), or rituximab product in combination with chlorambucil (Arm 3). The safety and efficacy of GAZYVA was evaluated in a Stage 1 comparison of Arm 1 vs. Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs. Arm 3 in 663 patients.

  The majority of patients received 1,000 mg of GAZYVA on days 1, 8 and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of GAZYVA was divided between day 1 (100 mg) and day 2 (900 mg)

  [see Dosage and Administration (2.2)]

  , which was implemented in 140 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).

  In CLL11, the median age was 73 years, 62% were male, and 95% were White. Sixty-five percent had a CLcr < 70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B, and 36% were stage C. The median estimated CLcr was 62 mL/min. Eighty-one percent of patients treated with GAZYVA in combination with chlorambucil received all 6 cycles compared to 89% of patients in the rituximab product treated arm and 67% in the chlorambucil alone arm.

  In the Stage 1 analysis of CLL11, the median progression-free survival (PFS) in the GAZYVA in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm (median observation time 22.8 months) as assessed by independent review and is consistent with investigator-assessed PFS. The median overall survival (OS) was not yet reached with a total of 46 deaths: 22 (9%) in the GAZYVA in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm. The hazard ratio for OS was 0.41 (95% CI: 0.23-0.74).

  In the Stage 2 analysis of CLL11, the median PFS was 26.7 months in the GAZYVA arm and 14.9 months in the rituximab product arm with a median observation time of 18.7 months (HR: 0.42, 95% CI: 0.33-0.54, p-value < 0.0001). These results were assessed by independent review and are consistent with investigator-assessed PFS. Minimal residual disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was one CLL cell per 10⁴leukocytes in the sample (i.e., an MRD value of < 10^-4was considered negative). Among patients who achieved complete response (CR) and complete response with incomplete marrow recovery (CRi; 94 patients in the GAZYVA arm and 34 patients in the rituximab product arm), 18 patients (19%) had negative MRD in the bone marrow in the GAZYVA arm compared to 2 patients (6%) in the rituximab product arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the GAZYVA arm, and 4 patients (12%) in the rituximab product arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.

  Efficacy results are shown in Table 16and Figures 1and 2.

  Table 16 Efficacy Results from CLL11

  Endpoint	Stage 1 of CLL11		Stage 2 of CLL11
  	GAZYVA + ChlorambucilAll Stage 1 GClb patients (n = 238) were included in the Stage 2 GClb population (n = 333).	Chlorambucil	GAZYVA + Chlorambucil	Rituximab product + Chlorambucil
  	n = 238	n = 118	n = 333	n = 330
  Median Progression-Free SurvivalAs defined by independent review. Investigator-assessed PFS was consistent with data from independent review.	27.2 months	11.2 months	26.7 months	14.9 months
  	(HR 0.19 [0.14; 0.27], p-value < 0.0001 stratified log-rank test)		(HR 0.42 [0.33; 0.54], p-value < 0.0001 stratified log-rank test)
  Overall Response RateDefined as best overall response rate (ORR = CR + CRi + PR + nPR).	78.2%	33.1%	79.6%	66.3%
  Complete Response	28.2%	0	26.1%	8.8%
  Complete Response with Incomplete Marrow Recovery	2.5%	1.7%	2.1%	1.5%
  Partial Response	45.0%	30.5%	48.6%	54.1%
  Nodular Partial Response	2.5%	0.8%	2.7%	1.8%
  Median Duration of Response	22.4 months	4.7 months	19.6 months	9.7 months
  Overall Survival	HR 0.41 [0.23; 0.74]		Not Yet Mature

  Figure 1 Kaplan-Meier Curve of Overall Survival in Patients with CLL in CLL11 (Stage 1)

  Figure 2 Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in CLL11 (Stage 2)

  Figure 1

  Figure 2

  14.2 Follicular Lymphoma

  GADOLIN

  The efficacy of GAZYVA was evaluated in GADOLIN (NCT01059630), an open-label, multicenter, randomized study that included 335 patients with follicular lymphoma (FL) who had no response to or have progressed during or within 6 months of rituximab product or a rituximab product-containing regimen. These patients were randomized to receive either bendamustine alone (n = 171) or GAZYVA in combination with bendamustine (n = 164) for 6 cycles, each of 28 days duration. Patients in the GAZYVA plus bendamustine arm who did not have disease progression [patients with a complete response (CR), partial response (PR) or stable disease (SD)] at the end of the 6 cycles continued receiving GAZYVA monotherapy for 2 years. Patients were stratified according to the type of refractoriness to rituximab product (refractory to rituximab product monotherapy versus rituximab product in combination with chemotherapy), the number of prior therapies (≤ 2 versus > 2), and geographic region.

  GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1, on Day 1 of Cycles 2–6, and then every 2 months until disease progression for up to 2 years. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (1–6) at 90 mg/m²/day when given in combination with GAZYVA or 120 mg/m²/day when given alone.

  The primary analysis included 321 FL patients, including 166 patients randomized to bendamustine alone and 155 patients randomized to GAZYVA in combination with bendamustine. In the primary analysis, patients had a median age of 63 years, 88% were White and 56% were male. Thirty-four percent had bulky disease (> 6 cm), 15% had at least one B-symptom at baseline and 95% had an ECOG performance status of 0–1 at baseline. The median time since initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10). Forty-six percent of patients received 1 prior therapy and 33% of patients received 2 prior therapies. Twenty percent of patients were refractory to prior rituximab product monotherapy, 37% of patients were refractory to prior rituximab product plus chemotherapy induction treatment, and 41% of patients were refractory to rituximab product maintenance treatment received following rituximab product plus chemotherapy induction. Seventy-nine percent of patients were refractory to both rituximab product and an alkylating agent during any prior regimen (double refractory).

  The major efficacy outcome measure was PFS as determined by an independent review committee (IRC). At the time of the primary analysis, median observation time was 21.1 months. The median PFS in the bendamustine arm was 13.8 months. Median PFS was not reached in the GAZYVA plus bendamustine arm (PFS HR = 0.48, 95% CI: 0.34-0.68; stratified log-rank test p-value < 0.0001). The investigator assessed PFS result was consistent with the IRC-assessed PFS. The median investigator-assessed PFS in the bendamustine arm was 13.7 months and the median in the GAZYVA containing arm was 29.2 months (PFS HR = 0.48, 95% CI: 0.35-0.67; stratified log-rank test p-value < 0.0001).

  Efficacy results are summarized in Table 17. The Kaplan-Meier curve for IRC-PFS is shown in Figure 3.

  Table 17 Primary Analysis Efficacy Results from GADOLINBased on FL population.^,As defined by independent review.

  Endpoint	GADOLIN
  	GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 155	Bendamustine n = 166
  Median Progression-Free Survival (months)	Not Reached	13.8
  	(HR = 0.48 [0.34; 0.68], p-value < 0.0001 by stratified log-rank test)
  Best Overall ResponseBest response of PR or CR within 12 months of study start.	78.7%	74.7%
  Complete Response	15.5%	18.7%
  Partial Response	63.2%	56.0%
  Median duration of response (months)	Not Reached	11.6

  Figure 3 Kaplan-Meier Curve of IRC-Assessed Progression-Free Survival in Patients with FL

  The final analysis included a total of 335 patients with 171 randomized to bendamustine alone and 164 to GAZYVA in combination with bendamustine. With an overall median observation time of 52.2 months (range: 0-100.9 months), there were 66 deaths (40.2%) in the GAZYVA arm and 85 deaths (51.3%) in the bendamustine-alone arm (OS HR = 0.71, 95% CI: 0.51, 0.98). The Kaplan-Meier curve for OS is presented in Figure 4.

  Figure 4 Kaplan-Meier Curve of Overall Survival in Patients with FL

  Figure 3

  Figure 4

  GALLIUM

  The efficacy of GAZYVA was evaluated in GALLIUM (NCT01332968), a multicenter, open-label, randomized study that included 1202 patients with previously untreated, stage II bulky, III or IV FL. Patients were randomized 1:1 to receive either GAZYVA (n = 601) or rituximab product (n = 601) in combination with chemotherapy (CHOP, CVP, or bendamustine) for 6–8 cycles. Patients were stratified by chemotherapy (selected by each site; all patients at that site received the chosen chemotherapy regimen), FLIPI (Follicular Lymphoma International Prognostic Index) risk group and geographic region. Patients with at least PR to combination therapy received monotherapy with GAZYVA (1,000 mg) or rituximab product every two months until disease progression or for a maximum of two years. The study excluded patients with follicular lymphoma grade 3b or transformed disease; patients having an ANC < 1500 / µL, platelets < 75,000 / µL, or CLcr < 40 mL/min; and patients with hepatic transaminases > 2.5 × upper limit of normal unless attributable to lymphoma.

  GAZYVA was given by intravenous infusion as a flat dose of 1,000 mg on Days 1, 8 and 15 of Cycle 1 and Day 1 of subsequent treatment cycles.

  GAZYVA and bendamustine were given in six 28-day cycles. Bendamustine was administered at 90 mg/m²/day on Days 1 and 2 of each cycle, with prednisone 100 mg orally or equivalent on Day 1 of Cycle 1.

  GAZYVA and CHOP were given in six 21-day cycles. Subsequently, two additional cycles of GAZYVA were given for a total of 8 GAZYVA cycles. CHOP consisted of cyclophosphamide 750 mg/m²intravenously, doxorubicin 50 mg/m², and vincristine 1.4 mg/m²(maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

  GAZYVA and CVP were given in eight 21-day cycles. CVP consisted of cyclophosphamide 750 mg/m²intravenously and vincristine 1.4 mg/m²(maximum dose, 2 mg) on Day 1 and prednisone 100 mg orally on Days 1-5.

  Patients had a median age of 59 years, 81% were White and 53% were female; 7% had Stage II, 35% had Stage III, and 56% had Stage IV disease, with 44% having bulky disease (≥ 7 cm) overall; 79% had a FLIPI score of > 2; and 97% had an ECOG performance status of 0–1. The chemotherapy was bendamustine in 57%, CHOP in 33%, and CVP in 10% of patients.

  Efficacy was based on PFS per IRC, with a median observation time of 38 months. Upon interim analysis, the risk of progression or death was significantly reduced in the GAZYVA containing arm compared to the rituximab product containing arm . Kaplan-Meier curves for PFS are shown in Figure 5. Overall response and complete remission rates were similar.

  Table 18 Efficacy in Previously Untreated Follicular Lymphoma (GALLIUM)

  Endpoint per IRC	GAZYVA + chemotherapy followed by GAZYVA monotherapy n = 601	Rituximab product + chemotherapy followed by rituximab product monotherapy n = 601
  Progression-Free SurvivalInvestigator-assessed PFS was consistent with data from independent review. Number of events (%)	108 (18%)	141 (23%)
  	HR = 0.72 [95% CI: 0.56, 0.93], p-value = 0.0118Stratified log-rank test.
  Overall Response RateAfter completion of combination therapy. Assessed by CT without positron emission tomography.	91%	88%
  Complete Remission Rate	28%	27%

  Figure 5 Kaplan-Meier Curves of Progression Free Survival in Patients with Previously Untreated FL

  Figure 5

  14.3 Active Lupus Nephritis

  Study Design and Population

  The efficacy of GAZYVA was evaluated in REGENCY (NCT04221477), a Phase III, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in 271 patients with ISN/RPS 2003 Class III or IV, with or without concomitant Class V lupus nephritis (LN), treated with standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids. Patients had active or active/chronic ISN/RPS 2003 Class III or IV, with or without concomitant Class V proliferative LN determined by kidney biopsy, current or past positive antinuclear antibody (ANA), urine protein-to-creatinine ratio (UPCR) ≥ 1 g/g, and had received at least one dose of pulse intravenous (IV) methylprednisolone (≥ 250 mg) or equivalent treatment for LN during the 6 months prior to screening or during screening.

  Patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 or in need of dialysis or transplantation, with sclerosis in > 50% of glomeruli on kidney biopsy, presence of rapidly progressive glomerulonephritis, evidence of active infection, receipt of anti-CD20 therapy < 9 months before or during screening, or receipt of cyclophosphamide, tacrolimus, ciclosporin, or voclosporin within 2 months of or during screening were excluded.

  Patients were randomized 1:1 to receive GAZYVA 1,000 mg (N=135) or placebo (N=136) intravenously, in combination with MMF 2-2.5 g/day and a tapering course of corticosteroids and were evaluated over 76 weeks. Patients randomized to receive GAZYVA were further randomized in a 1:1 ratio to receive either GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, 50, and 52 (Arm 1), or GAZYVA 1,000 mg IV on Day 1, Weeks 2, 24, 26, and 52 (Arm 2). The totality of the GAZYVA efficacy data combining both treatment arms is shown in Table 19.

  All patients received oral prednisone 0.5 mg/kg/day (maximum 60 mg/day) and remained at this dose until Week 2. Beginning on Day 15, prednisone was tapered to achieve a target dose of 5 mg/day by Week 24. Prednisone was maintained at a low dose (5 mg/day) from Week 24 until Week 80.

  The median age of patients was 31 years, 85% were female, 58% were Hispanic or Latino, 48% were White, 19% were American Indian or Alaska Native, 15% were Black or African American and 6% were Asian. The distribution by kidney biopsy class was 39% Class III, 61% Class IV and 31% had concomitant Class V. Mean (SD) eGFR at baseline 102.3 (±30.8) mL/min/1.73 m². Mean (SD) UPCR at baseline was 3.3 (±2.9) mg/mg with 42% of patients exhibiting UPCR ≥3 mg/mg at baseline.

  Efficacy Results

  The primary endpoint measure was proportion of patients who achieved complete renal response (CRR) at Week 76, defined as meeting all of the following criteria: UPCR < 0.5 g/g; eGFR ≥ 85% of baseline, as calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; with no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal.

  Key secondary endpoint measures included: proportion of patients who achieved CRR with successful prednisone taper at Week 76 (defined as achievement of CRR at Week 76 without receiving prednisone > 7.5 mg/day or equivalent from Week 64 through Week 76), proportion of patients who achieved a proteinuric response at Week 76 (defined as achievement of UPCR < 0.8g/g and no occurrence of the following intercurrent events: rescue therapy, treatment failure, death or early study withdrawal) and proportion of patients who experience "renal-related events or deaths" through Week 76 (defined as occurrence of death, treatment failure, ≥ 50% increase in UPCR to a value ≥ 3 g/g and/or ≥ 30% decrease in eGFR to < 60 ml/min/1.73 m²).

  The proportion of patients achieving CRR at Week 76 was significantly greater in patients treated with GAZYVA in combination with standard therapy compared to patients who received placebo plus standard therapy. There were also a higher proportion of patients who achieved CRR with successful prednisone taper at Week 76 and proteinuric response at Week 76 in the GAZYVA plus standard therapy arm compared to the placebo plus standard therapy arm (see Table 19).

  In the REGENCY study, patients who received GAZYVA were less likely to experience the outcome of "renal-related event or death" compared with placebo. Fewer patients in the GAZYVA arm experienced worsening kidney function or doubling of serum creatinine (see Table 20).

  Table 19 Summary of Efficacy Results in Adult Patients with Active Lupus Nephritis (REGENCY Study)

  	GAZYVA + standard therapy (N=135)	Placebo + standard therapy (N=136)
  Primary Endpoint
  Complete renal response (CRR) at Week 76 (%)	46.4 (38.0, 54.9)	33.1 (25.2, 41)
  Treatment difference (95% CI)Primary and key secondary endpoints were analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusted for stratification factors race and region. Multiple Imputation handled missing data. For the primary endpoint CRR and the key secondary endpoint CRR with successful prednisone taper, missing data (not due to an Intercurrent Event (ICE)) occurred in four patients in the GAZYVA arm and one in the placebo arm. For the key secondary endpoint proteinuric response, four GAZYVA patients and two placebo patients had non-ICE-related missing data.	13.4 (2.0, 24.8)
  p-value	0.0232
  Components of CRR:
  UPCR < 0.5 g/g	64 (47.4%)	49 (36.0%)
  eGFR ≥ 85% at baseline	113 (83.7%)	103 (75.7%)
  No occurrence of intercurrent events	120 (88.9%)	102 (75%)
  Key Secondary Endpoints
  CRR with successful prednisone taper at Week 76 (%)	42.7 (34.3, 51.1)	30.9 (23.1, 38.7)
  Treatment difference (95% CI)	11.9 (0.6, 23.2)
  p-value	0.0421
  Proteinuric response at Week 76 (%)	55.5 (47.1, 64)	41.9 (33.6, 50.2)
  Treatment difference (95% CI)	13.7 (2.0, 25.4),
  p-value	0.0227

  Table 20 Renal-Related Event or Death in Adult Patients with Active Lupus Nephritis (REGENCY Study) by Week 76

  	Week 0-76		Hazard Ratio (HR) vs. Placebo (95% CI) Week 76
  	GAZYVA + standard therapy N=135 (%)	Placebo + standard therapy N=136 (%)
  Renal-Related Event or Death
  Number (%) of patients with event	24 (17.8%)	46 (33.8%)
  Time to event			0.5 (0.3, 0.8)
  Components of Renal-Related Event or Death Endpoint
  Percentage of patients with:
  Death	3 (2.2%)	1 (0.7%)
  Treatment failureTreatment failure was prospectively defined as any of the following: 1) new ESRD or need for chronic dialysis or renal transplantation, 2) clinically significant, sustained worsening in UPCR and/or eGFR from Week 24 onward that leads the investigator to conclude the patient failed the randomized treatment period, or 3) receipt of rescue therapy, except corticosteroid-only rescue	6 (4.4%)	25 (18.4%)
  End-stage renal disease (ESRD)1	0	2 (1.5%)
  Clinically significant, sustained worsening in UPCR and/or eGFR from Week 242	5 (3.7%)	22(16.2%)
  Rescue Therapy except corticosteroid-only rescue3	5 (3.7%)	22 (16.2%)
  Worsening proteinuriaWorsening proteinuria was prospectively defined as a confirmed ≥ 50% increase in UPCR to a value ≥ 3 g/g	17 (12.6%)	18 (13.2%)
  Worsening eGFRWorsening eGFR was prospectively defined as confirmed ≥ 30% decrease in eGFR to a value < 60mL/min/1.73m2	7 (5.2%)	20 (14.7%)
  Additional Renal-Related Events
  Percentage of patients with event
  Doubling of serum creatinine from baseline through Week 76	4 (3.0%)	8 (5.9%)

  Subgroup Analyses

  In pre-specified subgroup efficacy analyses, the primary endpoint in patients was examined based on 24-hour UPCR at baseline (< 3 g/g or ≥ 3 g/g), lupus nephritis class at baseline (Class III or IV), and concomitant Class V at baseline. The results are displayed in Figure 6below.

  Figure 6 Forest Plot of CRR at Week 76 on Baseline Disease Characteristics, Efficacy-Evaluable Patients

  Figure 6

  )

• Premedicate for infusion-related reactions and tumor lysis syndrome. (
  2.1 Important Dosing Information

  • Premedicate before each infusion
    [see Dosage and Administration (2.4)]
    .
  • Provide prophylactic hydration and anti-hyperuricemics to patients at high risk of tumor lysis syndrome
    [see Dosage and Administration (2.4)and Warnings and Precautions (5.4)].
  • Administer only as an intravenous infusion through a dedicated line
    [see Dosage and Administration (2.6)]
    .
  • Do not administer as an intravenous push or bolus.
  • Monitor blood counts at regular intervals.
  • GAZYVA should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur
    [see Warnings and Precautions (5.3)].
  ,
  5.3 Infusion-Related Reactions

  GAZYVA can cause severe and life-threatening infusion-related reactions (IRRs). Sixty-five percent of patients with CLL experienced a reaction to the first 1,000 mg of GAZYVA infused. Thirty-seven percent of patients with relapsed or refractory NHL and 60% of patients with previously untreated NHL experienced a reaction on Day 1 of GAZYVA infusion. In patients with CLL and NHL , IRRs have occurred within 24 hours of receiving GAZYVA. IRRs can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). The most frequently reported IRR symptoms in patients with CLL and NHL include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills

  [see Adverse Reactions (6.1)]

  .

  In patients with LN, IRRs occurred predominantly during infusion of the first 1,000 mg. IRRs were generally mild to moderate and could be managed by the slowing or temporarily halting the infusion

  [see Dosage and Administration (2.6)]

  . Severe and life-threatening IRRs requiring symptomatic treatment were also reported. The most common IRR signs or symptoms reported in the REGENCY study included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia

  [see Adverse Reactions (6.2)]

  .

  Premedicate patients with acetaminophen, anti-histamine, and a glucocorticoid

  [see Dosage and Administration (2.4)].

  Closely monitor patients during the entire infusion. Reduce infusion rate, interrupt infusion or permanently discontinue GAZYVA for IRRs based on severity

  [see Dosage and Administration (2.5)]

  . Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for IRRs as needed.

  For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the IRR to GAZYVA. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication as is suggested here.
  ,
  5.4 Hypersensitivity Reactions Including Serum Sickness

  Hypersensitivity reactions have been reported in patients treated with GAZYVA. Signs of immediate-onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria and tachycardia. Late-onset hypersensitivity diagnosed as serum sickness has also been reported, with symptoms that include chest pain, diffuse arthralgia and fever. Hypersensitivity reactions may be difficult to clinically distinguish from IRRs. However, hypersensitivity very rarely occurs with the first infusion and, when observed, often occurs after previous exposure.

  If a hypersensitivity reaction is suspected during or after an infusion, stop the infusion and permanently discontinue treatment. GAZYVA is contraindicated in patients with known hypersensitivity reactions to GAZYVA, including serum sickness with prior GAZYVA use

  [see Contraindications (4)]

  .
  )
• Administer only as intravenous infusion. Do not administer as an intravenous push or bolus. (
  2.1 Important Dosing Information

  • Premedicate before each infusion
    [see Dosage and Administration (2.4)]
    .
  • Provide prophylactic hydration and anti-hyperuricemics to patients at high risk of tumor lysis syndrome
    [see Dosage and Administration (2.4)and Warnings and Precautions (5.4)].
  • Administer only as an intravenous infusion through a dedicated line
    [see Dosage and Administration (2.6)]
    .
  • Do not administer as an intravenous push or bolus.
  • Monitor blood counts at regular intervals.
  • GAZYVA should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur
    [see Warnings and Precautions (5.3)].
  )
• The recommended dosage for chronic lymphocytic leukemia is 100 mg on day 1 and 900 mg on day 2 of Cycle 1, 1,000 mg on day 8 and 15 of Cycle 1, and 1,000 mg on day 1 of Cycles 2–6. (
  2.2 Recommended Dosage for Chronic Lymphocytic Leukemia

  Each dose of GAZYVA is 1,000 mg administered intravenously with the exception of the first infusions in Cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg) according to Table 1.

  Table 1 Dose of GAZYVA to be Administered During Six 28-Day Treatment Cycles for Patients with CLL

  Day of treatment cycle		Dose of GAZYVA	Rate of infusion
  Cycle 1 (loading doses)	Day 1	100 mg	Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate.
  	Day 2	900 mg	If no infusion-related reaction (IRR) occurred during the previous infusion, administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. If an IRR occurred during the previous infusion, administer at 25 mg/hr. The rate of infusion can be escalated in increments of up to 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
  	Day 8	1,000 mg	If no IRR occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If an infusion-related reaction occurred during the previous infusion, administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
  	Day 15	1,000 mg
  Cycles 2 – 6	Day 1	1,000 mg

  If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible and adjust dosing schedule to maintain the time interval between doses. If appropriate, patients who do not complete the Day 1 Cycle 1 dose may proceed to the Day 2 Cycle 1 dose.
  )
• The recommended dosage for follicular lymphoma is 1,000 mg on day 1, 8 and 15 of Cycle 1, 1,000 mg on day 1 of Cycles 2-6 or Cycles 2-8, and then 1,000 mg every 2 months for up to 2 years. (
  2.3 Recommended Dosage for Follicular Lymphoma

  Each dose of GAZYVA is 1,000 mg administered intravenously according to Table 2.

  For patients with relapsed or refractory FL, administer GAZYVA in combination with bendamustine in six 28-day cycles. Patients who achieve stable disease, complete response, or partial response to the initial 6 cycles should continue on GAZYVA 1,000 mg as monotherapy for up to two years.

  For patients with previously untreated FL, administer GAZYVA with one of the following chemotherapy regimens:

  • Six 28-day cycles in combination with bendamustine
  • Six 21-day cycles in combination with CHOP, followed by 2 additional 21-day cycles of GAZYVA alone
  • Eight 21-day cycles in combination with CVP

  Patients with previously untreated FL who achieve a complete response or partial response to the initial 6 or 8 cycles should continue on GAZYVA 1,000 mg as monotherapy for up to two years.

  GAZYVA should be administered at the standard infusion rate in Cycle 1 (see Table 2). In patients with FL who do not experience a Grade 3 or higher IRR during Cycle 1, GAZYVA may be administered as a shorter, approximately 90-minute infusion from Cycle 2 onwards (see Table 3) with continued premedication.

  Table 2 Dose and Standard Infusion Rate of GAZYVA to be Administered During 6–8 Treatment Cycles, Followed by GAZYVA Monotherapy for Patients with FL

  Day of treatment cycle		Dose of GAZYVA	Rate of infusion
  Cycle 1 (loading doses)	Day 1	1,000 mg	Administer at 50 mg/hr. The rate of the infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
  	Day 8	1,000 mg	If no infusion-related reaction or an infusion-related reaction of Grade 1 occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If an infusion-related reaction of Grade 2 or higher occurred during the previous infusion, administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
  	Day 15	1,000 mg
  Cycles 2 – 6 or 2–8	Day 1	1,000 mg
  Monotherapy	Every two months for up to two years	1,000 mg

  Table 3 Dose and Infusion Rate of a GAZYVA 90-Minute Infusion for Patients with FL

  Day of treatment cycle		Dose of GAZYVA	Rate of infusion
  Cycle 1	Days 1, 8, 15	1,000 mg	See Table 2
  Cycles 2–6Consider an approximately 90-minute infusion in patients with FL who do not experience a Grade 3 or higher infusion-related reaction to GAZYVA in Cycle 1 and subsequent cycles.or 2-8	Day 1	1,000 mg	If no Grade 3 or higher IRR occurred during Cycle 1: 100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes. If an IRR of Grade 1-2 with ongoing symptoms or a Grade 3 or higher IRR occurred during the previous approximately 90-minute infusion, administer all subsequent GAZYVA infusions at the standard infusion rate (see Table 2).
  Monotherapy	Every two months for up to two years	1,000 mg

  If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible. During GAZYVA and chemotherapy treatment, adjust the dosing schedule accordingly to maintain the time interval between chemotherapy cycles. During monotherapy, maintain the original dosing schedule for subsequent doses. Initiate monotherapy approximately two months after the last dose of GAZYVA administered during the induction phase.
  )
• The recommended dosage for active lupus nephritis is 1,000 mg at the initial infusion, on Week 2, 24, 26, and every 6 months thereafter. (
  2.4 Recommended Dosage for Active Lupus Nephritis

  Each recommended dose of GAZYVA is 1,000 mg administered intravenously according to Table 4.

  Table 4 Dose and Infusion Rate for Standard Infusion of GAZYVA in Adults with Active Lupus Nephritis

  Dose number	Timing of treatment	Dose of GAZYVA	Rate of infusion
  1	Initial infusion	1,000 mg	Administer at a rate of 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. For management of IRRs that occur during infusion, see Dosage Modifications for Adverse Reactions (2.6) .
  2	Week 2 (two weeks after Dose 1)	1,000 mg	Administer at a rate of 100 mg/hr. The rate of infusion can be escalated at a rate of 100 mg/hr every 30 minutes to a maximum of 400 mg/hr.
  3	Week 24	1,000 mg
  4	Week 26 (two weeks after Dose 3)	1,000 mg
  5 Dose 5 should be administered six months after Dose 4and thereafter	Every 6 months	1,000 mg

  Patients who do not experience Grade ≥ 3 infusion related reactions during the previous infusion may receive GAZYVA over approximately 90 minutes from Dose 2 onwards (see Table 5), with continued premedication.

  Table 5 Dose and Infusion Rate for a 90-Minute Infusion of GAZYVA in Adults with Active Lupus Nephritis

  Dose number	Rate of infusion
  1	See Table 4
  2 and thereafter (if no Grade 3 or higher IRR during previous infusion)	100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes. If an IRR of Grade 1-2 with ongoing symptoms or a Grade 3 or higher IRR occurs during the previous approximately 90-minute infusion, administer GAZYVA at the standard infusion rate (see Table 4).

  If a planned dose of GAZYVA is missed, it should be administered as soon as possible – do not wait until the next planned dose. The schedule of administration should be adjusted to maintain the appropriate interval between doses.
  )

Injection: 1,000 mg/40 mL (25 mg/mL) clear, colorless to slightly brown solution in a single-dose vial.

• Lactation
  : Advise not to breastfeed. (
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action, GAZYVA can cause fetal B-cell depletion

  [see Clinical Pharmacology (12.1)]

  . There are no data with GAZYVA use in pregnant women to inform a drug-associated risk. Monoclonal antibodies are transferred across the placenta. In animal reproduction studies, weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1,000 mg monthly produced opportunistic infections and immune complex mediated hypersensitivity reactions. No embryo-toxic or teratogenic effects were observed in the monkeys

  (see Data)

  . Advise pregnant women of the potential risk to the fetus.

  The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

  Clinical Considerations

  Disease-Associated Maternal and/or Embryo/Fetal Risk

  Pregnant women with systemic lupus erythematosus (SLE) are at increased risk of adverse pregnancy outcomes, including worsening of the underlying disease, premature birth, miscarriage, and intrauterine growth restriction. Maternal LN increases the risk of hypertension and preeclampsia/eclampsia. Passage of maternal autoantibodies across the placenta may result in adverse neonatal outcomes, including neonatal lupus and congenital heart block.

  Fetal/Neonatal Adverse Reactions

  GAZYVA is likely to cause fetal B-cell depletion

  (see Data)

  . Avoid administering live vaccines to neonates and infants exposed to GAZYVA in utero until B-cell recovery occurs

  [see Warnings and Precautions (5.11)and Clinical Pharmacology (12.2)]

  .

  Data

  Animal Data

  In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition, which includes the period of organogenesis. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. There were no embryo-toxic or teratogenic effects in animals. Secondary opportunistic infections, immune complex mediated hypersensitivity reactions, or a combination of both were observed in exposed dams. When first measured on day 28 postpartum, obinutuzumab was detected in offspring at levels in the range of maternal serum levels on the same day, and B-cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.
  )