Mylotarg

Newly-Diagnosed De Novo CD33-positive AML (Combination Regimen)

Newly-Diagnosed CD33-positive AML (Single-agent Regimen)

A treatment course of MYLOTARG as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy [see Clinical Studies (14.1)].

For the induction cycle, the recommended dose of MYLOTARG is 6 mg/m2 (not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m2 (not limited to one 4.5 mg vial) on Day 8.

For continuation, the recommended dose of MYLOTARG is 2 mg/m2 (not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.

Relapsed or Refractory CD33-positive AML (Single-agent Regimen)

           The recommended dose of MYLOTARG as a single agent for treatment for adults and pediatric patients 2 years and older with relapsed or refractory CD33-positive AML is 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of MYLOTARG [see Clinical Studies (14.2)].           

Reconstitution

• MYLOTARG is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
• Calculate the dose (mg) and number of vials of MYLOTARG required.
• Prior to reconstitution, allow drug product vials to reach room temperature (up to 30°C) for approximately 5 minutes.
• Reconstitute each vial with 5 mL of Sterile Water for Injection, USP to obtain a concentration of 1 mg/mL of MYLOTARG that delivers 4.5 mL (4.5 mg).
• Gently swirl the vial to aid dissolution. DO NOT SHAKE.
• Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fiber-like particles.
• MYLOTARG contains no bacteriostatic preservatives.
• If the reconstituted solution cannot be used immediately, it may be stored in the original vial for up to 16 hours in a refrigerator (2°C to 8°C; 36°F to 46°F) or up to 3 hours at room temperature (up to 30°C). PROTECT FROM LIGHT. DO NOT FREEZE.

Dilution

• Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area. Withdraw this amount from the vial(s) using a syringe. PROTECT FROM LIGHT. Discard any unused reconstituted solution left in the vial.

Doses must be mixed to a concentration between 0.075 mg/mL to 0.234 mg/mL according to the following instructions:

• Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted MYLOTARG solution to a syringe with 0.9% Sodium Chloride Injection to a final concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT.
• Doses greater than or equal to 3.9 mg are to be diluted in a syringe or a polyvinyl chloride (PVC) with di(2-ethylhexyl)phthalate (DEHP), non-PVC polyolefin, or ethylene vinyl acetate intravenous infusion bag in an appropriate volume of 0.9% Sodium Chloride Injection to ensure a final concentration between 0.075 mg/mL to 0.234 mg/mL. PROTECT FROM LIGHT.
• Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE.
• Following dilution with 0.9% Sodium Chloride Injection, MYLOTARG solution should be infused immediately. If not used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C to 8°C; 36°F to 46°F) and for up to 6 hours at room temperature (up to 30°C). The allowed time at room temperature (up to 30°C) includes the time required for preparation of the diluted solution, equilibration, if needed, and the 2 hours needed to administer to the patient. PROTECT FROM LIGHT and DO NOT FREEZE.

Administration

• Use an in-line 0.2 micron polyethersulfone (PES) filter for infusion of MYLOTARG.
• Protect the intravenous bag from light using a light-blocking cover during infusion. The infusion line does not need to be protected from light.
• Infuse the diluted solution over 2 hours using an infusion set made of polyvinyl chloride (PVC) with DEHP, PVC non-DEHP, polyethylene, or polyurethane. The infusion must be completed prior to the end of the allowed 6-hour storage of the diluted solution at room temperature (up to 30°C).
• Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products.

Risk Summary

Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)], MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on MYLOTARG use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, gemtuzumab ozogamicin caused embryo-fetal toxicity, including structural abnormalities and alterations to growth, at maternal systemic exposures that were greater than or equal to 0.4 times the exposure in patients at the maximum recommended dose based on AUC (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Risk Summary

There are no data on the presence of gemtuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise women not to breastfeed during treatment with MYLOTARG and for at least 1 month after the final dose.

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating MYLOTARG.

Contraception

Infertility

Combination Therapy in Newly-Diagnosed De Novo CD33-positive AML

The safety of MYLOTARG in first-line combination therapy was evaluated in two prospective clinical trials, Study ALFA-0701 in adults and Study AAML0531 in pediatric patients.

Monotherapy for Newly-Diagnosed CD33-positive AML

The safety evaluation of MYLOTARG (6 mg/m2 then 3 mg/m2, with 7 days between the doses) as monotherapy is based on a randomized, open-label, Phase 3 trial of MYLOTARG (N=118) versus best supportive care (BSC) (N=119) in patients with previously untreated AML who were considered ineligible for intensive chemotherapy in Study AML-19 [see Clinical Studies (14.1)].

The overall incidence of any Grade adverse reactions reported in AML-19 was 87% in the MYLOTARG arm and 90% in the BSC arm. The incidence of Grade greater than or equal to 3 adverse reactions was 61% in the MYLOTARG arm and 68% in the BSC arm. Death due to any Adverse Event was reported in the MYLOTARG arm of 19 (17%) compared to the BSC arm of 23 (20%).

Monotherapy for Relapsed or Refractory CD33-positive AML

The adverse reactions described in this section reflect exposure to MYLOTARG 3 mg/m2 on Days 1, 4 and 7 as monotherapy in 57 patients with relapsed AML treated on MyloFrance-1 [see Clinical Studies (14.1)]. All 57 (100%) patients received the 3 planned doses of MYLOTARG.

During the treatment period, Grade 3 treatment-emergent adverse events (TEAEs) that occurred in greater than 1% patients included sepsis (32%), fever (16%), rash (11%), pneumonia (7%), bleeding (7%), mucositis (4%), pain (4%), diarrhea (2%), headaches (2%), tachycardia (2%), and lung edema (2%). No Grade 4 toxicity was observed. All grade TEAEs that occurred in greater than 15% of patients included fever (79%), infection (42%), increased AST (40%), bleeding (23%), nausea and vomiting (21%), constipation (21%), mucositis (21%), headache (19%), increased ALT (16%), and rash (16%). No infectious deaths occurred. Grade 1 or 2 hyperbilirubinemia developed in 4 (7%) patients. No episodes of VOD occurred. Seven patients received HSCT after MYLOTARG treatment. Three patients received an allogeneic BMT and 4 patients were treated with autologous BMT. No patients developed VOD following HSCT.

Distribution

N-acetyl gamma calicheamicin dimethyl hydrazide is approximately 97% bound to human plasma proteins in vitro. Population PK analyses found the total volume of distribution of hP67.6 antibody (sum of V1 [6.31 L] and V2 [15.1 L]) to be approximately 21.4 L in patients.

Elimination

The clearance (CL) value of hP67.6 from plasma was 0.35 L/h after the first dose and 0.15 L/h after the second dose, a decrease of roughly 60%. The terminal plasma half-life (t½) for hP67.6 was 62 hours after the first dose and 90 hours after the second dose.

Metabolism

In vitro studies demonstrated that N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolized, primarily via nonenzymatic reduction of the disulfide moiety.

Specific Populations

Age, race, sex, mild or moderate renal impairment (creatinine clearance [CLcr] 30–89 mL/min calculated by the Cockcroft-Gault equation) or mild hepatic impairment had no clinically significant effect on the pharmacokinetics of gemtuzumab ozogamicin. The pharmacokinetics of gemtuzumab ozogamicin in patients with severe renal impairment (CLcr 15–29 mL/min) or moderate (total bilirubin greater than 1.5× to 3.0× ULN) and severe hepatic impairment (total bilirubin greater than 3× ULN) is unknown.

Drug Interaction Studies

No clinical drug interaction studies have been performed.

In Vitro Studies

At clinically relevant concentrations, gemtuzumab ozogamicin had a low potential to:

• Inhibit CYP450 Enzymes: CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.

At clinically relevant concentrations, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to:

• Inhibit CYP450 Enzymes: CYP1A2, CYP2B6 , CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.
• Induce CYP450 Enzymes: CYP1A2, CYP2B6, and CYP3A4.
• Inhibit UGT Enzymes: UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7.
• Inhibit Drug Transporters: P-gp (P-glycoprotein), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3.

Study ALFA-0701

MYLOTARG in combination with chemotherapy was evaluated in ALFA-0701 (NCT00927498), a multicenter, randomized, open-label Phase 3 study of 271 patients with newly-diagnosed de novo AML ages 50 to 70 years. Patients were randomized (1:1) to receive induction therapy consisting of daunorubicin (60 mg/m2 on Days 1 to 3) and cytarabine (200 mg/m2 on Days 1 to 7) (DA) with (n=135) or without (n=136) MYLOTARG 3 mg/m2 (up to maximum of one vial) on Days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with daunorubicin and cytarabine alone (daunorubicin 35 mg/m2/day on Days 1 and 2, and cytarabine 1 g/m2 every 12 hours, on Day 1 to Day 3 without MYLOTARG). Patients with response received consolidation therapy with 2 courses of treatment including daunorubicin (60 mg/m2 on Day 1 of consolidation course 1; 60 mg/m2 on Days 1 and 2 of consolidation course 2) and cytarabine (1 g/m2 every 12 hours on Days 1 to 4) with or without MYLOTARG 3 mg/m2 (up to a maximum of one vial) on Day 1 according to their initial randomization. Patients who experienced remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of MYLOTARG and transplantation was recommended.

The median age of the patients was 62 years (range, 50–70), 137 female and 134 male, and 88% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at baseline. Baseline characteristics were balanced between treatment arms with the exception of gender as a higher percentage of males were enrolled in the MYLOTARG arm (55%) than in the DA alone arm (44%). Overall, 59%, 65%, and 70% of patients had documented favorable/intermediate risk and 33%, 27%, and 21% had poor/adverse disease by the National Comprehensive Cancer Network (NCCN), European LeukemiaNet (ELN), and cytogenetic risk classifications, respectively. CD33 expression on AML blasts by flow cytometry harmonized from local laboratory results was determined in 194/271 (72%) patients overall. Few patients (14%) had low CD33 expression (less than 30% of blasts), and none had no expression of CD33.

Efficacy was established on the basis of event-free survival (EFS), measured from the date of randomization until induction failure, relapse, or death by any cause. Per protocol, induction failure was defined as failure to achieve CR or CRp in induction, and date of induction failure was defined as date of marrow evaluation after the last course of induction. Median EFS was 17.3 months in the MYLOTARG arm versus 9.5 months in the control arm; hazard ratio (HR) 0.56 (95% CI: 0.42–0.76); 2-sided p less than 0.001 by log-rank test.

In an exploratory analysis of EFS defined as failure to achieve CR in induction, relapse, or death from any cause and using the date of randomization as the date of induction failure, median EFS was 13.6 months for MYLOTARG + DA and 8.8 months for DA with HR 0.68 (95% CI: 0.51–0.91).

The Kaplan-Meier plot for per-protocol EFS is shown in Figure 1. There was no statistically significant difference between treatment arms in overall survival.

Figure 1. Kaplan-Meier Plot of Event-Free Survival (mITT Population) ALFA-0701 Trial

Abbreviations: C=cytarabine; D=daunorubicin; GO=gemtuzumab ozogamicin; mITT=modified intent-to-treat.

Study AAML0531

MYLOTARG in combination with chemotherapy was evaluated in AAML0531 (NCT00372593), a multicenter, randomized study of 1,063 patients with newly-diagnosed AML ages 0 to 29 years. Patients were randomized to 5-cycle chemotherapy alone or with a single dose of MYLOTARG (3 mg/m2/dose) administered once on Day 6 in Induction 1 and once on Day 7 in Intensification 2. All patients proceeded to Induction 2 regardless of remission status after Induction 1. In the absence of active disease, a neutrophil count (ANC) >1 Gi/L and a platelet count >75 Gi/L was recommended before proceeding with subsequent cycles of therapy. Patients not in remission after Induction 2 discontinued protocol therapy permanently. All other patients proceeded to Intensification 1. Patients with high- and intermediate-risk disease with 5/6 or 6/6 matched family donors (MFD) proceeded to HSCT following Intensification 1. Patients with high-risk disease proceeded to HSCT with an alternative donor if no MFD was available. All patients with low-risk disease and any high- and intermediate-risk patients without appropriate donors proceeded with Intensification 2 with or without MYLOTARG according to their initial randomization, followed by Intensification 3. All patients in remission were to proceed on to Intensification 2 or allogeneic HSCT. In Intensification 2, patients received MYLOTARG according to the initial randomization. Patients in remission after Intensification 2 proceeded to Intensification 3.

There were 532 patients randomized to treatment with MYLOTARG + chemotherapy and 531 to chemotherapy alone. Overall, 94% of patients were <18 years of age, and 6% were adults; median age was 9.0 years (range: 0–29 years). The patients were 49% male, 51% female, 73% White, 11% Black, 5% Asian, 11% other or missing race, and 18% Hispanic. The proportion of patients in each disease risk group: low risk (23% vs 23%), intermediate risk (57% vs 57%), and high risk (15% vs 17%).

Supportive evidence of efficacy was provided by event-free survival (EFS), measured from the date of study entry until induction failure, relapse, or death by any cause. Induction failure was defined as failure to achieve CR by the end of Induction 2 period, and date of induction failure was defined as Day 1 on study. The EFS hazard ratio was 0.84 (95% CI: 0.71–0.99). The estimated percentage of patients free of induction failure, relapse, or death at five years was 48% (95% CI: 43%–52%) in the MYLOTARG + chemotherapy arm versus 40% (95% CI: 36%–45%) in the chemotherapy alone arm.

The Kaplan-Meier plot for EFS is shown in Figure 2. No difference between treatment arms in overall survival was demonstrated.

Figure 2. Kaplan-Meier Plot of Event-Free Survival (Full Analysis Set) Study AAML0531 Trial

Abbreviations: GO=gemtuzumab ozogamicin.

Study AML-19

MYLOTARG single-agent therapy was evaluated in Study AML-19 (NCT00091234), a multicenter, randomized, open-label Phase 3 study comparing MYLOTARG to best supportive care (BSC) for patients with newly-diagnosed AML who were a) greater than 75 years of age or b) 61 to 75 years of age with a World Health Organization performance status (WHO PS) greater than 2 or were unwilling to receive intensive chemotherapy. Patients were randomized 1:1 and stratified by age (61–75 vs 76–80 years vs ≥81 years), CD33 positivity of bone marrow blasts (less than 20 % vs 20–80% vs greater than 80% vs unknown), initial white blood cell count (less than 30 vs greater than or equal to 30 × 109/L), WHO PS (0–1 vs 2 vs 3–4), and institution.

During induction, MYLOTARG 6 mg/m2 was given on Day 1 and MYLOTARG 3 mg/m2 was given on Day 8. Patients with no evidence of disease progression or significant toxicities after MYLOTARG induction received continuation therapy as outpatients with up to 8 courses of treatment including MYLOTARG 2 mg/m2 on Day 1 every 4 weeks. Patients continued therapy if they did not experience significant toxicities, relapse, or disease progression. BSC included standard supportive care measures and hydroxyurea or other anti-metabolites for palliative purposes.

In total, 118 patients were randomized to treatment with MYLOTARG and 119 patients to BSC. Overall, the median age of patients was 77 years (range, 62–88 years), and most patients (65%) had a WHO PS of 0 to 1 at baseline. Baseline characteristics were balanced between treatment arms with the exception of gender and cytogenetics. Compared to the BSC arm, the MYLOTARG arm had a higher percentage of females (52% vs 39%) and patients with favorable/intermediate risk cytogenetics (50% vs 38%). The proportion with adverse cytogenetics was similar between arms (28% vs 27%). Fewer patients on the MYLOTARG arm had missing cytogenetics data (22% vs 35%). CD33 expression on AML blasts by flow cytometry at a centralized location was determined in 235/237 (99%) patients; 10% had CD33 expression less than 20%.

The efficacy of MYLOTARG was established on the basis of improvement in overall survival (OS). The hazard ratio (HR) for OS was 0.69 (95% CI: 0.53–0.90) (2-sided p=0.005 by log-rank test). Median OS was 4.9 months in the MYLOTARG arm versus 3.6 months in the control arm.

Study MyloFrance-1

The efficacy of MYLOTARG as a single agent was evaluated in MyloFrance-1 a phase 2, single-arm, open-label study in adults with CD33-positive AML in first relapse. Patients with secondary leukemia or a prior autologous or allogeneic stem cell transplantation were excluded. Study treatment included a single course of MYLOTARG 3 mg/m2 on Days 1, 4, and 7. Consolidation therapy consisted of cytarabine intravenously every 12 hours for 3 days. The cytarabine dose was 3 g/m2 for patients less than 55 years old and 1 g/m2 for patients 55 years or older and/or patients with a creatinine clearance below 50 mL/minute. Hematopoietic stem cell transplantation (HSCT) was allowed after treatment with MYLOTARG, but it was recommended to delay HSCT by at least 90 days following MYLOTARG.

There were 57 patients treated with MYLOTARG. Overall, the median age of patients was 64 years (range 22–80 years). The median duration of first remission was 10 months. Forty-four (78%) patients had intermediate-risk and 12 (22%) poor-risk cytogenetics.

The efficacy of MYLOTARG was established on the basis of complete remission (CR) rate and duration of remission. Fifteen (26%; 95% CI 16% – 40%) patients achieved CR following a single course of MYLOTARG. Median relapse-free survival, measured from the first documentation of CR to the date of relapse or death, was 11.6 months.