14 CLINICAL STUDIES
14.1 Newly-Diagnosed CD33-positive AML
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.
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.
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.
14.2 Relapsed or refractory CD33-positive AML
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.