Description:
This is a multicenter, double-blind, randomized, placebo-controlled study designed to compare
overall survival in participants with relapsed or refractory AML treated with idasanutlin in
combination with cytarabine versus participants treated with placebo and cytarabine.
Participants will receive induction treatment with idasanutlin/placebo and cytarabine (Cycle
1). Responding participants may continue to receive a maximum of further two cycles of
consolidation (Cycle 2 and Cycle 3). Complete remission (CR), CR with incomplete platelet
count recovery (CRp), overall remission rate (ORR), event-free survival (EFS), leukemia-free
survival (LFS) and percentage of participants with an allogeneic hematopoietic stem cell
transplant (HSCT) will also be compared between treatment arms. This study will include
participants with and without TP53 wild type (TP53 WT) mutations.
Title
- Brief Title: A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML)
- Official Title: A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase III Study of Idasanutlin, an MDM2 Antagonist, With Cytarabine Versus Cytarabine Plus Placebo in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)
Clinical Trial IDs
- ORG STUDY ID:
WO29519
- SECONDARY ID:
2014-003065-15
- NCT ID:
NCT02545283
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Cytarabine | | Idasanutlin plus Cytarabine |
| Idasanutlin | | Idasanutlin plus Cytarabine |
Purpose
This is a multicenter, double-blind, randomized, placebo-controlled study designed to compare
overall survival in participants with relapsed or refractory AML treated with idasanutlin in
combination with cytarabine versus participants treated with placebo and cytarabine.
Participants will receive induction treatment with idasanutlin/placebo and cytarabine (Cycle
1). Responding participants may continue to receive a maximum of further two cycles of
consolidation (Cycle 2 and Cycle 3). Complete remission (CR), CR with incomplete platelet
count recovery (CRp), overall remission rate (ORR), event-free survival (EFS), leukemia-free
survival (LFS) and percentage of participants with an allogeneic hematopoietic stem cell
transplant (HSCT) will also be compared between treatment arms. This study will include
participants with and without TP53 wild type (TP53 WT) mutations.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Idasanutlin plus Cytarabine | Experimental | Participants will receive induction therapy idasanutlin and cytarabine for 5 days followed by 23 days of rest in Cycle 1 (treatment cycle length=28 days). Responding participants may continue with consolidation therapy for a maximum of 2 additional cycles including idasanutlin and cytarabine for 5 days followed by 23 days of rest in each cycle (treatment cycle length=28 days). After each cycle, for participants achieving CRp or complete remission with incomplete blood count recovery (CRi), up to 28 additional days are allowed for blood count recovery, if needed. | |
| Placebo plus Cytarabine | Placebo Comparator | Participants will receive induction therapy idasanutlin matching placebo and cytarabine for 5 days followed by 23 days of rest in Cycle 1 (treatment cycle length=28 days). Responding participants may continue with consolidation therapy for a maximum of 2 additional cycles including idasanutlin matching placebo and cytarabine for 5 days followed by 23 days of rest in each cycle (treatment cycle length=28 days). After each cycle, for participants achieving CRp or CRi, up to 28 additional days are allowed for blood count recovery, if needed. | |
Eligibility Criteria
Inclusion Criteria:
- Documented/confirmed first/second refractory/relapsed AML using World Health
Organization classification, except acute promyelocytic leukemia
- No more than 2 prior induction regimens (excluding prior HSCT) in their first line
treatment and one must have included cytarabine with an anthracycline (or
anthracenedione)
- Eastern Cooperative Oncology Group performance status of 0 to 1
- Adequate hepatic and renal function
- White blood cell (WBC) count at randomization less than or equal to (</=) 50000 cells
per cubic millimeter (/mm^3)
Exclusion Criteria:
- First relapsed participants aged less than (<) 60 years with first CR duration greater
than (>) 1 year
- Participants with prior documented antecedent hematological disorder (AHD)
- AML secondary to any prior chemotherapy unrelated to leukemia
- Participants who are either refractory to or relapsed within 90 days of receiving a
regimen containing a cumulative dose of greater than or equal to (>/=) 18 g/m^2 of
cytarabine
- Participants who have received allogeneic HSCT within 90 days prior to randomization
- Participants who have received immunosuppressive therapy for graft versus host disease
within 2 weeks prior to randomization
- Prior treatment with an Murine Double Minute 2 (MDM2) antagonist
- Participants receiving any other investigational or commercial agents or therapies
administered with the intention to treat their malignancy within 30 days from first
receipt of study drug
- Participants with a history of other malignancy within 5 years prior to screening
- Participants who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study
- Participants with extramedullary AML with no evidence of systemic involvement
- Pregnant or breastfeeding participants
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Overall Survival in TP53 WT Population |
| Time Frame: | Baseline up to approximately 3.5 years |
| Safety Issue: | |
| Description: | |
Secondary Outcome Measures
| Measure: | Overall Survival in the Overall Population |
| Time Frame: | Baseline up to approximately 3.5 years |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants in CR at the End of Induction According to Hematologic Malignancy Response Assessment (HMRA) in TP53 WT Population |
| Time Frame: | At the end of induction (up to Day 56) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants in CRp at the End of Induction According to HMRA in TP53 WT Population |
| Time Frame: | At the end of induction (up to Day 56) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants with Overall Remission at the End of Induction According to HMRA in TP53 WT Population |
| Time Frame: | At the end of induction (up to Day 56) |
| Safety Issue: | |
| Description: | |
| Measure: | EFS According to HMRA in TP53 WT Population |
| Time Frame: | Baseline up to treatment failure, relapse or death from any cause (up to approximately 3.5 years) |
| Safety Issue: | |
| Description: | |
| Measure: | LFS According to HMRA in TP53 WT Population |
| Time Frame: | Date of remission to date of relapse or death (up to approximately 3.5 years) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants Undergoing HSCT Following Response, in TP53 WT Population |
| Time Frame: | Baseline up to approximately 3.5 years |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants in CR at the End of Induction According to HMRA in Overall Population |
| Time Frame: | At the end of induction (up to Day 56) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants in CRp at the End of Induction According to HMRA in Overall Population |
| Time Frame: | At the end of induction (up to Day 56) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants with Overall Remission at the End of Infusion According to HMRA in Overall Population |
| Time Frame: | At the end of induction (up to Day 56) |
| Safety Issue: | |
| Description: | |
| Measure: | EFS According to HMRA in Overall Population |
| Time Frame: | Baseline up to treatment failure, relapse or death from any cause (up to approximately 3.5 years) |
| Safety Issue: | |
| Description: | |
| Measure: | LFS According to HMRA in Overall Population |
| Time Frame: | Date of remission to date of relapse or death (up to approximately 3.5 years) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants Undergoing HSCT Following Response, in Overall Population |
| Time Frame: | Baseline up to approximately 3.5 years |
| Safety Issue: | |
| Description: | |
| Measure: | Apparent Clearance (CL/F) of Idasanutlin |
| Time Frame: | Cycle 1: Predose (0 hour [Hr]), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Apparent Volume of Distribution (Vd/F) of Idasanutlin |
| Time Frame: | Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Maximum Concentration Observed (Cmax) of Idasanutlin |
| Time Frame: | Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Steady-State Concentration (C trough) of Idasanutlin |
| Time Frame: | Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin |
| Time Frame: | Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | AUC from Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin |
| Time Frame: | Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Half-Life (t 1/2) of Idasanutlin |
| Time Frame: | Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Total Clearance (CL) of Cytarabine |
| Time Frame: | Cycle 1: Within 2 Hr pre-cytarabine dose, end of 1-3 Hr cytarabine infusion, 6 Hr post idasanutlin morning dose on Days 1, 5; Within 2 Hr pre-cytarabine dose on Day 2; Cycle 2, 3: Within 2 Hr pre-cytarabine dose on Day 2 (Cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Volume of Distribution (Vd) of Cytarabine |
| Time Frame: | Cycle 1: Within 2 Hr pre-cytarabine dose, end of 1-3 Hr cytarabine infusion, 6 Hr post idasanutlin morning dose on Days 1, 5; Within 2 Hr pre-cytarabine dose on Day 2; Cycle 2, 3: Within 2 Hr pre-cytarabine dose on Day 2 (Cycle length= 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants with Adverse Events |
| Time Frame: | Baseline up to approximately 3.5 years |
| Safety Issue: | |
| Description: | |
| Measure: | Change from Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score |
| Time Frame: | Cycle 1 Day 1 (Baseline), Days 8, 15, 28 of Cycle 1, Days 1, 8, 15, 28 of Cycles 2, 3, 28 days after last dose (last dose on Cycle 3 Day 5), thereafter every 3 months until relapse (maximum up to 3.5 years) |
| Safety Issue: | |
| Description: | |
| Measure: | Change from Baseline in EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire Score |
| Time Frame: | Cycle 1 Day 1 (Baseline), Days 8, 15, 28 of Cycle 1, Days 1, 8, 15, 28 of Cycles 2, 3, 28 days after last dose (last dose on Cycle 3 Day 5), thereafter every 3 months until relapse (maximum up to 3.5 years) |
| Safety Issue: | |
| Description: | |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Hoffmann-La Roche |
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