6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of the label:

Peripheral Neuropathy [see Warnings and Precautions (5.1)]
Infusion-Related Reactions [see Warnings and Precautions (5.2)]
Myelosuppression [see Warnings and Precautions (5.3)]
Serious and Opportunistic Infections [see Warnings and Precautions (5.4)]
Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.5)]
Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
Hepatotoxicity [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described below reflect exposure to POLIVY 1.8 mg/kg in 480 patients with large B-cell lymphoma (LBCL), including those with previously untreated LBCL (POLARIX) and relapsed or refractory DLBCL (GO29365).

Previously Untreated DLBCL, NOS or HGBL

GO39942 (POLARIX)

The safety of POLIVY in combination with R-CHP chemoimmunotherapy was evaluated in POLARIX, a randomized double-blind, placebo-controlled, multicenter study of 873 patients with previously untreated large B-cell lymphoma, 435 of whom received POLIVY plus R-CHP [see Clinical Studies (14.1)].

Patients were randomized 1:1 to receive POLIVY plus R-CHP or to receive R-CHOP for six 21-day cycles followed by two additional cycles of rituximab alone in both arms. Granulocyte colony-stimulating factor (G-CSF) primary prophylaxis was required and administered to 90% of patients in the POLIVY plus R-CHP arm and 93% of patients in the R-CHOP arm. Following premedication with an antihistamine and antipyretic, POLIVY was administered intravenously at 1.8 mg/kg on Day 1 of Cycles 1–6. R-CHP was administered starting on Day 1 of Cycles 1–6. Rituximab monotherapy was administered on Day 1 of Cycles 7–8 [see Clinical Studies (14.1)].

The trial required an absolute neutrophil count ≥1,000/µL, platelet count ≥75,000/µL, creatinine clearance (CLcr) ≥40 mL/min, hepatic transaminases ≤2.5 times the upper limit of normal (ULN), and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease. The trial excluded patients having age >80, ECOG performance status above 2, known central nervous system (CNS) lymphoma, and Grade 2 or higher peripheral neuropathy.

The median age was 65 years overall (range: 19 to 80 years); 54% of patients were male; 53% were White, 19% were Asian, 2%, Black or African American, and 5% were Hispanic or Latino.

In the POLIVY plus R-CHP group, 92% of patients received 6 cycles of POLIVY, and 94% completed 6 cycles of combination therapy.

Serious adverse reactions occurred in 34% of patients who received POLIVY plus R-CHP, including febrile neutropenia and pneumonia in ≥5% of recipients. Fatal adverse reactions occurred in 3% of recipients of POLIVY plus R-CHP within 90 days of last treatment, primarily from infection including pneumonia (0.9%) and sepsis (0.2%).

Adverse reactions led to dose reduction of POLIVY in 6% of patients, mainly from peripheral neuropathy. Adverse reactions lead to dose interruption of POLIVY in 18% of patients, most commonly from pneumonia and neutropenia, and permanent discontinuation of POLIVY in 4.4% of patients.

Table 6 summarizes adverse reactions in POLARIX. In recipients of POLIVY plus R-CHP, adverse reactions in ≥20% of patients, excluding laboratory abnormalities, were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. New or worsening Grade 3 to 4 laboratory abnormalities in ≥10% of patients were lymphopenia, neutropenia, hyperuricemia, and anemia.

Table 6 Select Adverse Reactions Occurring in ≥10% of Patients Treated with POLIVY Plus R-CHP in POLARIX
Adverse Reactions by Body System	POLIVY + R-CHP n = 435		R-CHOP n = 438
Adverse Reactions by Body System	All Grades, %	Grade 3–4, %	All Grades, %	Grade 3–4, %
The table includes a combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.0.
* Laboratory values are based on integrated analysis of laboratory and adverse reaction data. Reported investigations exclude electrolytes. † Febrile neutropenia includes febrile neutropenia, febrile bone marrow aplasia, and neutropenic sepsis. ‡ At last assessment, peripheral neuropathy was unresolved in 42% in the POLIVY + R-CHP arm and in 33% in the R-CHOP arm. § Peripheral neuropathy includes all terms containing "neuropathy", neuralgia, dysesthesia, paresthesia, hypoesthesia, peroneal nerve palsy, hypotonia, hyporeflexia, neuromyopathy, and hyperesthesia. ¶ Mucositis includes stomatitis, oropharyngeal pain, mucosal inflammation, mouth ulceration, oral pain, oropharyngeal discomfort, aphthous ulcer, odynophagia, oral discomfort, tongue blistering, and tongue ulceration. # Abdominal pain includes abdominal pain, abdominal discomfort, gastrointestinal pain, epigastric discomfort, and related terms. Þ Edema includes edema, face edema, swelling face, edema peripheral, fluid overload, fluid retention, pulmonary edema, peripheral swelling, and swelling. ß Infusion related reaction is reflective of the combination regimen due to same-day administration. à Rash includes rash, dermatitis, and related terms. è Musculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, myalgia, and bone pain. ð Upper respiratory tract infection incudes sinusitis, laryngitis, pharyngitis, nasopharyngitis, rhinitis, and specific infections.
Blood and Lymphatic System Disorders*
Lymphopenia	80	44	77	44
Anemia	68	14	67	11
Neutropenia	60	39	60	42
Thrombocytopenia	32	8	33	6
Febrile neutropenia†	15	15	9	9
Investigations*
Creatinine increased	66	0.7	64	0.9
Aspartate aminotransferase increased	26	0.7	23	1.1
Alanine aminotransferase increased	25	1.4	27	0.5
Alkaline phosphatase increased	23	0	22	0.5
Uric acid increased	19	18	17	16
Weight decreased	13	0.9	12	0.2
Nervous System Disorders
Peripheral neuropathy‡,§	53	1.6	54	1.1
Altered taste	14	0	16	0
Headache	13	0.2	14	0.9
Gastrointestinal Disorders
Nausea	42	1.1	37	0.5
Diarrhea	31	3.9	20	1.8
Constipation	29	1.1	29	0.2
Mucositis¶	22	1.4	19	0.5
Abdominal pain#	16	1.1	14	1.6
Vomiting	15	1.1	14	0.7
General Disorders
Fatigue	37	2.5	38	3.0
Pyrexia	16	1.4	13	0
EdemaÞ	14	0.5	11	0.2
Infusion-related reactionß	13	1.1	16	1.6
Skin and Subcutaneous Tissue Disorders
Alopecia	24	0	24	0.2
Rashà	13	0.7	11	0
Musculoskeletal Disorders
Musculoskeletal painè	19	0.5	21	1.8
Infections
Upper respiratory tract infectionð	17	0.5	16	0.5
Metabolism and Nutrition Disorders
Decreased appetite	17	1.1	14	0.7
Respiratory Disorders
Cough	15	0	14	0
Dyspnea	13	0.9	10	0.9

Other clinically relevant adverse reactions in <10% of recipients of POLIVY plus R-CHP included:

Infections: pneumonia, herpesvirus infection, sepsis, cytomegalovirus infection
Metabolic disorders: tumor lysis syndrome
Renal disorders: renal insufficiency
Respiratory disorders: pneumonitis

Relapsed or Refractory DLBCL, NOS

GO29365

The data described in this section reflect exposure to POLIVY in Study GO29365, a multicenter clinical trial for adult patients with relapsed or refractory B-cell lymphomas [see Clinical Studies (14.2)]. In patients with relapsed or refractory DLBCL, the trial included a single-arm safety evaluation of POLIVY in combination with bendamustine and a rituximab product (BR) (n = 6), followed by an open-label randomization to POLIVY in combination with BR versus BR alone (n = 39 treated per arm).

Following premedication with an antihistamine and antipyretic, POLIVY 1.8 mg/kg was administered by intravenous infusion on Day 2 of Cycle 1 and on Day 1 of Cycles 2–6, with a cycle length of 21 days. Bendamustine 90 mg/m2 daily was administered intravenously on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2–6. A rituximab product dosed at 375 mg/m2 was administered intravenously on Day 1 of each cycle. Granulocyte colony-stimulating factor primary prophylaxis was optional and administered to 42% of recipients of POLIVY plus BR.

In POLIVY-treated patients (n = 45), the median age was 67 years (range 33 – 86) with 58% being ≥age 65, 69% were male, 69% were White, and 87% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial required an absolute neutrophil count ≥1500/µL, platelet count ≥75/µL, creatinine clearance (CLcr) ≥40 mL/min, hepatic transaminases ≤2.5 times ULN, and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease. Patients with Grade 2 or higher peripheral neuropathy or prior allogeneic hematopoietic stem cell transplantation (HSCT) were excluded.

Patients treated with POLIVY plus BR received a median of 5 cycles, with 49% receiving 6 cycles. Patients treated with BR alone received a median of 3 cycles, with 23% receiving 6 cycles.

Fatal adverse reactions occurred in 7% of recipients of POLIVY plus BR within 90 days of last treatment. Serious adverse reactions occurred in 64%, most often from infection. Serious adverse reactions in ≥5% of recipients of POLIVY plus BR included pneumonia (16%), febrile neutropenia (11%), pyrexia (9%), and sepsis (7%).

In recipients of POLIVY plus BR, adverse reactions led to dose reduction in 18%, dose interruption in 51%, and permanent discontinuation of all treatment in 31%. The most common adverse reactions leading to treatment discontinuation were thrombocytopenia and/or neutropenia.

Table 7 summarizes commonly reported adverse reactions. In recipients of POLIVY plus BR, adverse reactions in ≥20% of patients included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.

Table 7 Adverse Reactions Occurring in >10% of Patients with Relapsed or Refractory DLBCL and ≥5% More in the POLIVY Plus Bendamustine and Rituximab Product Group in Study GO29365
Adverse Reactions by Body System	POLIVY + BR n = 45		BR n = 39
Adverse Reactions by Body System	All Grades, %	Grade 3 or Higher, %	All Grades, %	Grade 3 or Higher, %
The table includes a combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.
* Includes 2 fatalities. † Includes 1 fatality.
Blood and Lymphatic System Disorders
Neutropenia	49	42	44	36
Thrombocytopenia	49	40	33	26
Anemia	47	24	28	18
Lymphopenia	13	13	8	8
Nervous System Disorders
Peripheral neuropathy	40	0	8	0
Dizziness	13	0	8	0
Gastrointestinal Disorders
Diarrhea	38	4.4	28	5
Vomiting	18	2.2	13	0
General Disorders
Infusion-related reaction	18	2.2	8	0
Pyrexia	33	2.2	23	0
Decreased appetite	27	2.2	21	0
Infections
Pneumonia	22	16*	15	2.6†
Upper respiratory tract infection	13	0	8	0
Investigations
Weight decreased	16	2.2	8	2.6
Metabolism and Nutrition Disorders
Hypokalemia	16	9	10	2.6
Hypoalbuminemia	13	2.2	8	0
Hypocalcemia	11	2.2	5	0

Other clinically relevant adverse reactions (<10% or with a <5% difference) in recipients of POLIVY plus BR included:

Blood and lymphatic system disorders: pancytopenia (7%)
Musculoskeletal disorders: arthralgia (7%)
Investigations: hypophosphatemia (9%), transaminase elevation (7%), lipase increased (7%)
Respiratory disorders: pneumonitis (4.4%)

Selected treatment-emergent laboratory abnormalities are summarized in Table 8. In recipients of POLIVY plus BR, >20% of patients developed Grade 3 or 4 neutropenia, leukopenia, or thrombocytopenia, and >10% developed Grade 4 neutropenia (13%) or Grade 4 thrombocytopenia (11%).

Table 8 Select Laboratory Abnormalities Worsening from Baseline in Patients with Relapsed or Refractory DLBCL and ≥5% More in the POLIVY Plus Bendamustine and Rituximab Product Group
Laboratory Parameter*	POLIVY + BR n = 45		BR n = 39
Laboratory Parameter*	All Grades, (%)	Grade 3–4, (%)	All Grades, (%)	Grade 3–4, (%)
* Includes laboratory abnormalities that are new or worsening in grade or with worsening from baseline unknown.
Hematologic
Lymphocyte count decreased	87	87	90	82
Neutrophil count decreased	78	61	56	33
Hemoglobin decreased	78	18	62	10
Platelet count decreased	76	31	64	26
Chemistry
Creatinine increased	87	4.4	77	5
Calcium decreased	44	9	26	0
SGPT/ALT increased	38	0	8	2.6
SGOT/AST increased	36	0	26	2.6
Lipase increased	36	9	13	5
Phosphorus decreased	33	7	28	8
Amylase increased	24	0	18	2.6
Potassium decreased	24	11	28	5

Safety was also evaluated in 173 adult patients with relapsed or refractory lymphoma who received POLIVY, bendamustine, and either a rituximab product or obinutuzumab in Study GO29365, including the 45 patients with DLBCL described above. In the expanded safety population, the median age was 66 years (range 27 – 86), 57% were male, 91% had an ECOG performance status of 0-1, and 32% had a history of peripheral neuropathy at baseline.

Fatal adverse reactions occurred in 4.6% of recipients of POLIVY within 90 days of last treatment, with infection as a leading cause. Serious adverse reactions occurred in 60%, most often from infection.

Table 9 summarizes the most common adverse reactions in the expanded safety population. The overall safety profile was similar to that described above. Adverse reactions in ≥20% of patients were diarrhea, neutropenia, peripheral neuropathy, fatigue, thrombocytopenia, pyrexia, decreased appetite, anemia, and vomiting. Infection-related adverse reactions in >10% of patients included upper respiratory tract infection, febrile neutropenia, pneumonia, and herpesvirus infection.

Table 9 Most Common Adverse Reactions (≥20% Any Grade or ≥5% Grade 3 or Higher) in Recipients of POLIVY and Chemoimmunotherapy for Relapsed or Refractory Lymphoma
Adverse Reaction by Body System	POLIVY + Bendamustine + Rituximab Product or Obinutuzumab n = 173
Adverse Reaction by Body System	All Grades, %	Grade 3 or Higher, %
The table includes a combination of grouped and ungrouped terms.
* Primary prophylaxis with granulocyte colony-stimulating factor was given to 46% of all patients. † Includes 5 fatalities. ‡ Includes 4 fatalities.
Blood and Lymphatic System Disorders
Neutropenia	44	39
Thrombocytopenia	31	23
Anemia	28	14
Febrile neutropenia*	13	13
Leukopenia	13	8
Lymphopenia	12	12
Nervous System Disorders
Peripheral neuropathy	40	2.3
Gastrointestinal Disorders
Diarrhea	45	8
Vomiting	27	2.9
General Disorders
Fatigue	40	5
Pyrexia	30	2.9
Decreased appetite	29	1.7
Infections
Pneumonia	13	10†
Sepsis	6	6‡
Metabolism and Nutrition Disorders
Hypokalemia	18	6

Other clinically relevant adverse reactions (<20% any grade) included:

General disorders: infusion-related reaction (7%)
Infection: upper respiratory tract infection (16%), lower respiratory tract infection (10%), herpesvirus infection (12%), cytomegalovirus infection (1.2%)
Respiratory: dyspnea (19%), pneumonitis (1.7%)
Nervous system disorders: dizziness (10%)
Investigations: weight decrease (10%), transaminase elevation (8%), lipase increase (3.5%)
Musculoskeletal disorders: arthralgia (7%)
Eye disorders: blurred vision (1.2%)