A Study of Pevonedistat in Adult East Asian Participants

Millennium Pharmaceuticals

Status and phase: Completed; Phase 1

Conditions: Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Treatments: Drug: Azacitidine 75 mg/m^2; Drug: Pevonedistat 25 mg/m^2; Drug: Pevonedistat 44 mg/m^2; Drug: Pevonedistat 10 mg/m^2; Drug: Pevonedistat 20 mg/m^2

Study type: Interventional

Funder types: Industry

Identifiers

NCT02782468

U1111-1166-8630 (Registry Identifier)

Pevonedistat-1012

Details and patient eligibility

About

The purpose of this study is to evaluate the safety and tolerability of pevonedistat administered as a single agent and in combination with azacitidine in adult east Asian participants with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).

Full description

The drug being tested in this study is called Pevonedistat. Pevonedistat is being tested to treat people with myelodysplastic syndromes MDS (including nonproliferative chronic myelomonocytic leukemia [CMML]) and AML (acute myeloid leukaemia) as a single-agent and in combination treatment with azacitidine. This study will look at the safety and tolerability, the recommended phase 2/phase 3 dose of pevonedistat administered in combination with azacitidine, pharmacokinetics and response to treatment in participants who take single agent pevonedistat compared to participants who take pevonedistat and azacitidine.

The study will enroll approximately 37 participants. Participants will be assigned into one of the four treatment groups which will remain disclosed to the patient and study doctor during the study. Participants will be first enrolled at single-agent low dose level (25 mg/m^2). If this dose is tolerable, participants will be enrolled in parallel at single-agent higher dose level (44 mg/m^2) and in combination treatment cohorts.

• Pevonedistat 25 mg/m^2
• Pevonedistat 44 mg/m^2
• Pevonedistat 10 mg/m^2 and azacitidine 75 mg/m^2 combination
• Pevonedistat 20 mg/m^2 and azacitidine 75 mg/m^2 combination Participants will receive pevonedistat infusion intravenously and azacitidine via intravenous or subcutaneous route.

This multi-center trial will be conducted in Japan, Korea and Taiwan. The overall time to participate in this study is approximately 24 months. Participants will attend the End of Study (EOS) visit for safety, 30 days after receiving their last dose of study drug or before the start of subsequent antineoplastic therapy (other than hydroxyurea).

Enrollment: 23 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria include, in part:

1. East Asian patients aged 18 years or older (or minimum age of legal consent consistent with local regulations) when written study informed consent is obtained must meet 1 of the following diagnosis criteria for either the Single-Agent Arm or the Combination Arm (additional restrictions apply to the Single Agent Arm):

   a. Are male and female participants with WHO-defined AML, including leukemia secondary to prior chemotherapy or resulting from an antecedent hematologic disorder, who have failed to achieve CR or who have relapsed after prior therapy (R/R) and are not candidates for potentially curative treatment, or ii. Are male and female participants aged 60 years or older with previously untreated AML who have bone marrow blasts <30% and who are not candidates for standard induction chemotherapy, or iii. Are male and female participants with WHO-defined MDS that meets the IPSS-R criteria for the very high, high, or intermediate risk group, for whom standard curative, life-prolonging treatment does not exist or is no longer effective (R/R), or iv. Are male and female participants with previously untreated MDS that meets the IPSS-R criteria for the very high, high, or intermediate risk group, or vi. Are male and female participants with WHO-defined CMML-2 or CMML-1 that meets the IPSS-R criteria for the very high, high, or intermediate risk group CMML-1 participants must have bone marrow blasts >=5%

2. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

3. Able to undergo bone marrow aspiration and biopsy at Screening.

Exclusion Criteria include, in part:

1. Acute promyelocytic leukemia (as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics [t (15:17)] of peripheral blood or bone marrow, or by other accepted analysis) or AML associated with t (9;22) karyotypes or molecular.
2. More than 3 prior lines of therapy (Combination Arm only).
3. Prior therapy with hypomethylating agents (example, azacitidine, decitabine). (Combination Arm only).
4. Is eligible for a hematopoietic stem cell transplant.
5. Is a female participant who is lactating and breastfeeding or who have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.
6. Had treatment with any investigational products within 14 days before the first dose of any study drug.
7. Has known hypersensitivity to azacitidine or mannitol (Combination Arm only).
8. Has known central nervous system involvement.
9. Had systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of any study drug, except for hydroxyurea.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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23 participants in 4 patient groups

Arm 1, Cohort 1: Pevonedistat 25 mg/m^2

Experimental group

Description:

Pevonedistat, 25 milligram per square meter (mg/m\^2), 60-minute infusion, intravenously, on Days 1, 3 and 5, followed by a rest period of 16 days, in 21-day treatment cycles.

Treatment:

Drug: Pevonedistat 25 mg/m^2

Arm 1, Cohort 2: Pevonedistat 44 mg/m^2

Experimental group

Description:

Pevonedistat, 44 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5, followed by a rest period of 16 days, in 21-day treatment cycles.

Treatment:

Drug: Pevonedistat 44 mg/m^2

Arm 2, Cohort 1: Pevonedistat 10 mg/m^2+ Azacitidine 75 mg/m^2

Experimental group

Description:

Pevonedistat 10 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m\^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.

Treatment:

Drug: Azacitidine 75 mg/m^2

Drug: Pevonedistat 10 mg/m^2

Arm 2, Cohort 2: Pevonedistat 20 mg/m^2+ Azacitidine 75 mg/m^2

Experimental group

Description:

Pevonedistat 20 mg/m\^2, 60-minute infusion, intravenously, on Days 1, 3, and 5 and azacitidine 75 mg/m\^2, on Days 1 to 5, and Days 8 and 9, intravenously or subcutaneously, followed by a rest period of 19 days, in 28-day treatment cycles.

Treatment:

Drug: Azacitidine 75 mg/m^2

Drug: Pevonedistat 20 mg/m^2