A Phase 1b, Open-Label, Dose-Escalation Study of MLN4924 Plus Azacitidine in Treatment-Naïve Patients With Acute Myelogenous Leukemia Who Are 60 Years or Older

Millennium Pharmaceuticals, Inc.8 sites in 1 country64 target enrollmentApril 10, 2013

ConditionsAcute Myelogenous Leukemia

InterventionsMLN4924 Azacitidine

DrugsMLN4924 Azacitidine

Overview

Phase: Phase 1
Intervention: MLN4924
Conditions: Acute Myelogenous Leukemia
Sponsor: Millennium Pharmaceuticals, Inc.
Enrollment: 64
Locations: 8
Primary Endpoint: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Status: Completed
Last Updated: 6 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of this study is to establish the maximum tolerated dose (MTD), and to assess the safety and tolerability of MLN4924 (pevonedistat) in combination with azacitidine in treatment naive participants with AML who were 60 years of age or older.

Registry

clinicaltrials.gov

Start Date

April 10, 2013

End Date

April 8, 2018

Last Updated

6 years ago

Study Type

Interventional

Study Design

Sequential

Sex

All

Investigators

Sponsor

Millennium Pharmaceuticals, Inc.

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Participants with world health organization (WHO)-defined AML, 60 years of age or older, who are unlikely to benefit from standard induction therapy, defined as having at least 1 of the following:
•Greater than or equal to 75 years of age.
•Antecedent hematologic disease.
•Known adverse cytogenetic risk.
•Eastern Cooperative Oncology Group (ECOG) PS =
•Participant must not have received definitive treatment for AML, defined as any prior chemotherapy with antileukemic activity.
•ECOG PS 0 to
•Expected survival longer than 3 months from enrollment in the study.
•Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to practice true abstinence.
•Male participants who agree to practice effective barrier contraception or agree to practice true abstinence.

Exclusion Criteria

•Previous treatment with azacitidine or decitabine.
•Known favorable cytogenetic risk.
•Any serious medical or psychiatric illness.
•Treatment with any investigational products.
•Known hypersensitivity to azacitidine or mannitol.
•Acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
•Active uncontrolled infection or severe infectious disease.
•Major surgery within 14 days before the first dose of study drug.
•Life-threatening illness unrelated to cancer.
•Clinically uncontrolled central nervous system (CNS) involvement.

Arms & Interventions

MLN4924 and Azacitidine

Intervention: MLN4924

MLN4924 and Azacitidine

Intervention: Azacitidine

Outcomes

Primary Outcomes

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Time Frame: Baseline up to 30 days after the last dose of study drug (up to 5 years)

Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings

Time Frame: Baseline up to 30 days after the last dose of study drug (up to 5 years)

Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings

Time Frame: Baseline up to 30 days after the last dose of study drug (up to 5 years)

Secondary Outcomes

Dose-escalation Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length is equal to [=] 28 days))
Maximum Tolerated Dose (MTD) Expansion Phase, Cmax: Maximum Observed Plasma Concentration for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, Ctrough: Observed Plasma Concentration at the End of the Dosing Interval for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, AUC0-tau: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (Tau) for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, AUC0-tau: Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (Tau) for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, AUC24hours: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Post-Dose for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, AUCinf: Area Under the Plasma Concentration-time Curve Extrapolated to Infinity for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, Lambdaz: Terminal Disposition Phase Rate Constant for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, t1/2: Terminal Disposition Phase Half-life for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, Rac: Observed Accumulation Ratio for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, Rac: Observed Accumulation Ratio for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, CLp: Systemic Clearance for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, CLp: Systemic Clearance for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Dose-escalation Phase, Vss: Volume of Distribution at Steady-state for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
MTD Expansion Phase, Vss: Volume of Distribution at Steady-state for MLN4924(Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose; Cycle 1 Day 5 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length = 28 days))
Best Overall Response Rate(Cycle(C)1Day(D)22 and at C2 between D20 and 28 and at C4 and beyond C4 after completion of every 3rd C between D15 and 28 up to 30 days after last dose of study drug/before start of subsequent antineoplastic therapy, if that occurred sooner(up to 5 years))
Duration of Response(From the date of first documented CR, PR or CRi up to the date of first disease progression (Up to 5 years))
Overall Survival(From the first dose of study drug up to date of death (up to 5 years))
Thirty-day Mortality Rate(30 days after the first dose of study drug in Cycle 1 (Cycle Length=28 days))
Sixty-day Mortality Rate(60 days after the first dose of study drug on Cycle 1 (Cycle Length=28 days))