Pevonedistat, Azacitidine (or Decitabine), and Venetoclax for the Treatment of Patients With Acute Myelogenous Leukemia

NCT04172844 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: PRO36496
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

Brief Summary

This is a phase Ib study with a 3 + 3 dose escalation design followed by a dose-expansion phase.

Conditions

Acute Myelogenous Leukemia

Keywords

leukemia; acute myeloid leukemia

Outcome Measures

Primary Outcomes (2)

• Recommended phase 2 dose of pevonedistat when co-administered with azacitidine and venetoclax in patients with AML.

  The maximum-tolerated dose is defined as the highest dose level at which none of the first three treated subjects, or no more than one of the first six treated subjects, experiences a dose-limiting toxicity.

  Up to 28 days (one cycle) for each dosing cohort.

• The toxicity profile of pevonedistat, azacitidine, and venetoclax combination therapy.

  The number of serious adverse events will be measured using NCI-CTCAE v5 criteria.

  Up to 30 days after last dose of study drugs.

Secondary Outcomes (5)

• Complete Remission Rate

  Up to five years.

• Complete Remission with Partial Hematological Recovery

  Up to five years.

• Partial Remission Marrow

  Up to five years.

• Morphologic Leukemia Free State

  Up to five years.

• Complete Remission without Minimal Residual Disease

  Up to five years.

Study Arms (2)

Pevonedistat Dose Escalation

EXPERIMENTAL

This study uses a varied 3 + 3 design. Three patients will be started at a dose of 10 mg/m\^2 days 1, 3 and 5. If no DLTs are observed in the first 3 participants, then a new cohort will be enrolled at the next planned dose level of 15 mg/m\^2 days 1, 3 and 5. If two out of three subjects experience a DLT, then they will de-escalate one dose level. If one subject in three experiences a DLT, then expand up to three subjects at 20 mg/m\^2 day 1, 3 and 5. If two out of six subjects experience a DLT, de-escalate one level. All subjects will receive Azacitidine and Venetoclax at the indicated dosages and timing.

Drug: Azacitidine; Drug: Venetoclax; Drug: Pevonedistat

Dose Expansion Phase

EXPERIMENTAL

Patients will receive the recommended phase 2 dose (RP2D) identified from dose-escalation phase.

Drug: Azacitidine; Drug: Venetoclax; Drug: Pevonedistat

Interventions

Azacitidine DRUG

75mg/m\^2 Days 1-7 given IV

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Dose Expansion Phase; Pevonedistat Dose Escalation

Venetoclax DRUG

100 mg on cycle 1 day 1, 200 mg daily on cycle 1 day 2, 400 mg on cycle 1 day 3 and thereafter from cycle 1. Venetoclax is given for a minimum of 21 days and a maximum of 28 days. Administered orally.

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Dose Expansion Phase; Pevonedistat Dose Escalation

Pevonedistat DRUG

The doses for the 3 + 3 design (dose escalation phase) are listed in the arm description. The dose-expansion phase will use the maximum-tolerated dose.

Also known as: MLN4924, Nedd8-Activating Enzyme Inhibitor MLN4924

Dose Expansion Phase; Pevonedistat Dose Escalation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Male or female subjects 18 years or older.
• Patients must have a diagnosis of morphologically documented AML or secondary AML \[from prior conditions, such as myelodysplastic syndrome (MDS), or therapy-related AML (t-AML), as defined by World Health Organization (WHO) criteria.
• During the dose-escalation phase, only subjects with relapsed/refractory AML will be eligible.
• During the expansion phase, subjects with relapsed/refractory AML will be eligible OR subjects with newly diagnosed AML unable or unwilling to receive intensive induction chemotherapy will be eligible.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Clinical laboratory values within the following parameters:
• Albumin \>2.7 g/dL.
• Total bilirubin ≤ institutional upper limit of normal (ULN). Patient with total bilirubin \> ULN may enroll if direct bilirubin ≤1.5 x institutional ULN of the direct bilirubin.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × institutional ULN.
• Creatinine clearance ≥ 30 mL/min (calculated by Cockcroft-Gault formula).
• White blood cell (WBC) count \< 25,000/μL before administration of pevonedistat on cycle 1 day 1. (Note: Hydroxyurea may be used to meet this criterion.)
• Prothrombin time (PT) and partial thromboplastin time (PTT) \< 1.5 institutional ULN.
• Female subjects who:
• Are postmenopausal for at least one year before the screening visit, OR

You may not qualify if:

• Acute promyelocytic leukemia.
• Extramedullary only relapse AML.
• Treatment with systemic antineoplastic therapy or radiation within 14 days before the study enrollment. The use of hydroxyurea for leukoreduction is permitted. Subjects must have recovered from the side effects of prior therapy per treating physician discretion.
• Hematopoietic Stem Cell Transplantation (HCT) within 100 days of enrollment, or evidence of veno-occlusive disease (VOD) at any time post-transplant, or active acute graft-versus-host disease requiring systemic immunosuppressive therapy.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures.
• Current systemic treatment with strong or moderate cytochrome P3A (CYP3A) inducers within seven days prior to enrollment.
• Any evidence of spontaneous tumor lysis syndrome (TLS).
• Active, significant, uncontrolled infection or severe infectious disease requiring therapy (bacterial, viral or fungal) as per the discretion of the treating physician.
• Presence of another active malignancy (requiring treatment) diagnosed within 12 months with the exception of
• adequately treated non-melanoma skin cancer.
• adequately treated melanoma grade 2 or less.
• cervical intraepithelial neoplasia.
• adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast.
• basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin.
• adequately treated prostate cancer.

Sponsors & Collaborators

• Medical College of Wisconsin: lead

Study Sites (2)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Murthy GSG, Saliba AN, Szabo A, Harrington A, Abedin S, Carlson K, Michaelis L, Runaas L, Baim A, Hinman A, Maldonado-Schmidt S, Venkatachalam A, Flatten KS, Peterson KL, Schneider PA, Litzow M, Kaufmann SH, Atallah E. A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia. Haematologica. 2024 Sep 1;109(9):2864-2872. doi: 10.3324/haematol.2024.285014.

  PMID: 38572562 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia

Interventions

Azacitidine; venetoclax; pevonedistat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Ehab Atallah, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 20, 2019
• First Posted: November 21, 2019
• Study Start: January 13, 2020
• Primary Completion: December 12, 2021
• Study Completion: February 27, 2022
• Last Updated: June 4, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)