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) 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 | RG7388 | 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) 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 2
- 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
or for engraftment syndrome after autologous stem cell transplantation 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
except for malignancy that has been in remission without treatment for at least 2
years prior to randomization
- 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: | From randomization to death from any cause (up to approximately 5.5 years) |
| Safety Issue: | |
| Description: | |
Secondary Outcome Measures
| Measure: | Percentage of Participants in Complete Response (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: | Event-Free Survival (EFS) According to HMRA in TP53 WT Population |
| Time Frame: | From randomization up to treatment failure, relapse, or death from any cause (up to approximately 5.5 years) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants with Overall Remission (CR, CRp, and CRi) 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: | Duration of Remission Following CR (DOR) in TP53 WT Population |
| Time Frame: | From achieving CR until relapse or death from any cause (up to approximately 5.5 years) |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population |
| Time Frame: | Baseline up to approximately 5.5 years |
| Safety Issue: | |
| Description: | |
| Measure: | Percentage of Participants with Complete Response (CR) in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population |
| Time Frame: | At the end of induction (up to Day 56) |
| Safety Issue: | |
| Description: | |
| Measure: | Overall Survival in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population |
| Time Frame: | From randomization to death from any cause (up to approximately 5.5 years) |
| Safety Issue: | |
| Description: | |
| Measure: | Number of Participants who Experienced at Least One Adverse Event by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v4.03) |
| Time Frame: | Baseline up to approximately 5.5 years |
| Safety Issue: | |
| Description: | |
| Measure: | Number of Participants with Adverse Events Leading to Discontinuation |
| Time Frame: | Baseline up to approximately 5.5 years |
| Safety Issue: | |
| Description: | |
| Measure: | Number of Participants with Adverse Events Leading to Death up to Day 30 |
| Time Frame: | Up to Day 30 |
| Safety Issue: | |
| Description: | |
| Measure: | Number of Participants with Adverse Events Leading to Death up to Day 60 |
| Time Frame: | Up to Day 60 |
| Safety Issue: | |
| Description: | |
| Measure: | Number of Participants with Clinical Laboratory Abnormalities in Biochemistry Tests at the Greatest Severity, According to NCI-CTCAE v4.03 |
| Time Frame: | Baseline; Cycles 1-3 Days 1, 2, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) |
| Safety Issue: | |
| Description: | Laboratory parameters for blood biochemistry will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment. |
| Measure: | Number of Participants with Clinical Laboratory Abnormalities in Hematology Tests at the Greatest Severity, According to NCI-CTCAE v4.03 |
| Time Frame: | Baseline; Cycles 1-3 Days 1, 2, 8, 15, 22, and 28 (1 cycle is 28 days); and, 30 Days after CR or CRp in Cycle 1, or if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) |
| Safety Issue: | |
| Description: | Laboratory parameters for hematology will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment. |
| Measure: | Body Temperature Over Time |
| Time Frame: | Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Systolic Blood Pressure Over Time |
| Time Frame: | Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Diastolic Blood Pressure Over Time |
| Time Frame: | Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Pulse Rate Over Time |
| Time Frame: | Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Respiratory Rate Over Time |
| Time Frame: | Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Change from Baseline in Heart Rate, as Measured by Electrocardiogram |
| Time Frame: | Baseline, Days 1, 2, and 5 of Cycle 1, Days 1, 2 of Cycles 2 and 3 (1 cycle is 28 days), Treatment Discontinuation Visit (28 days after last dose of study drug) |
| Safety Issue: | |
| Description: | |
| Measure: | Change from Baseline in Electrocardiogram Parameters: PQ, PR, RR, QRS, QT and QTcF Intervals |
| Time Frame: | Baseline, Days 1, 2, and 5 of Cycle 1, Days 1, 2 of Cycles 2 and 3 (1 cycle is 28 days), Treatment Discontinuation Visit (28 days after last dose of study drug) |
| Safety Issue: | |
| Description: | |
| Measure: | Total Duration of Study Treatment |
| Time Frame: | Up to 3 cycles (1 cycle is 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Number of Treatment Cycles Started |
| Time Frame: | Up to 3 cycles (1 cycle is 28 days) |
| Safety Issue: | |
| Description: | |
| Measure: | Cumulative Dose of Idasanutlin and Cytarabine |
| Time Frame: | Up to 3 cycles (1 cycle is 28 days) |
| 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 (Ctrough) 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: | 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: | Terminated |
| Lead Sponsor: | Hoffmann-La Roche |
Last Updated
March 3, 2021
