NCT03709576

Pevonedistat and Azacitidine as Maintenance Therapy After Allogeneic Stem Cell Transplantation for Non-Remission AML

A Phase II Study of Pevonedistat (MLN4924, TAK924) and Azacitidine as Maintenance Therapy After Allogeneic Stem Cell Transplantation for Non-Remission Acute Myelogenous Leukemia

• Status: Terminated
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 3 (actual)
• Sponsor: Milton S. Hershey Medical Center · Academic / Other
• Sex: All
• Age: 18 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

This research is being done to find out the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML and to see the overall diseases free survival, relapse, and GVHD after treatment.

Detailed description

In preclinical studies Pevonedistat has shown significant single agent activity against mouse xenograft models of AML cell Line HL-60. Also this effect seemed to be synergistically enhanced by combining it with Azacitidine. In clinical arena, Pevonedistat has shown single agent activity in heavily pretreated patients with AML. In Study C15003, responses (complete responses \[CRs\] and partial responses \[PRs\]) were observed in a variety of patient settings, including post allogeneic transplant, therapy-related AML, and primary refractory AML, although some of the responses were of relatively short duration. Study C15009 is an ongoing phase 1b study evaluating the MTD of Pevonedistat on Days 1, 3, and 5 in combination with 75 mg/m2 Azacitidine (administered on a 5-on/2-off \[weekend\]/2-on schedule) in a 28-day treatment cycle in patients 60 years of age or older with treatment naïve AML who are unlikely to benefit from standard induction therapy. As of 22 June 2017, enrollment had completed and 15 patients remained on study. As of 22 January 2017, preliminary data are available for 64 patients enrolled in the study who received at least 1 dose of Pevonedistat in combination with Azacitidine; these patients had completed a total of approximately 360 cycles, with a median of 4 cycles of treatment In the dose escalation cohorts, 6 patients received 20 mg/m2 Pevonedistat, and 3 patients received 30 mg/m2. The most common events (reported by ≥ 25% of patients) were constipation (45%), nausea (42%), fatigue (39%), anemia (34%), febrile neutropenia (30%), decreased appetite (28%), and thrombocytopenia (27%). The MTD in this study was determined to be 20 mg/m2 Pevonedistat given on Days 1, 3, and 5, in combination with 75 mg/m2 Azacitidine given on Days 1 through 5, 8, and 9, in 28 day treatment cycles. A total of 45 (70%) patients experienced at least 1 SAE A total of 14 SAEs were reported for more than 1 patient, including: febrile neutropenia (16 patients); pneumonia (8 patients); pyrexia (4 patients); AML and sepsis (3 patients); and acute myocardial infarction, cellulitis, diverticulitis, dyspnea, embolism, hypoxia, mental status changes, multi-organ failure, and transaminase increased (2 patients each). A total of 19 patients treated with Pevonedistat (either 20 mg/m2 or 30 mg/m2), discontinued from Study participation because of a TEAE. No other events leading to discontinuation were assessed by study investigators as at least possibly related to study drug treatment. 11 on-study deaths had been reported; none assessed as related to study treatment. A total of 31 patients experienced PR or better. Eighteen patients had a best response of CR, 4 patients had a best response of CRi, and 9 patients had a best response of PR. One patient in the 30 mg/m2 dose level group achieved a CR; all other responses occurred in patients treated with 20 mg/m2. The following studies are currently enrolling. * Study 2001: A Phase 2, randomized, controlled Open-Label Clinical study of the efficacy and safety of Pevonedistat plus Azacitidine versus single-agent Azacitidine in patients with higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia and low-blast acute myelogenous leukemia. * Study 1012: A phase 1/1b, Open-label Study of Pevonedistat (MLN4924, TAK-924) as Single Agent and in Combination with Azacitidine in adult East Asian patients with acute myeloid leukemia or myelodysplastic syndromes Hence owing to the current knowledge of clinical and preclinical experience with Azacitidine and Pevonedistat alone and in combination, this combination appears feasible for testing in patients post-transplant with at very high risk of relapse. The Investigator proposes a study using a combination of Pevonedistat and Azacitidine for maintenance therapy after allogeneic HSCT for non-remission. Patients will receive up to five 28 day cycles of the investigational maintenance therapy. Maintenance therapy will begin between days +30 to +45 post-transplant.

Conditions

• Acute Myeloid Leukemia (AML)

Interventions

Type	Name	Description
DRUG	Pevonedistat	To assess the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML.
PROCEDURE	transplant	Although hematopoietic stem cell transplantation (HSCT) is curative for many patients with AML, AML in relapse at the time of transplant is still a major challenge with low rates of leukemia-free survival even with an intensive myeloablative conditioning.
DRUG	Azacitidine	To assess the toxicity and efficacy of a combination of Pevonedistat and Azacitidine as post allogeneic hematopoietic stem cell transplant maintenance therapy for non-remission AML.

Timeline

• Start date: 2018-07-18
• Primary completion: 2019-07-22
• Completion: 2019-07-22
• First posted: 2018-10-17
• Last updated: 2020-12-16
• Results posted: 2020-10-29

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study