Pevonedistat and Azacitidine in MDS or MDS/MPN Patients Who Fail Primary Therapy With DNA Methyl Transferase Inhibitors

NCT03238248 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: VICC HEM 16146NCI-2017-01377
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 5

Brief Summary

This study will evaluate the treatment combination of pevonedistat and azacitidine in the setting of DNA methyltransferase inhibitor(s) failure in patients with relapsed/refractory myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative neoplasm.

Conditions

Myelodysplastic Syndromes; Myeloproliferative Neoplasm

Outcome Measures

Primary Outcomes (1)

• Overall Survial Time

  Overall survival time is defined as time from day 1 in cycle 1 to death for any reason. Patiens alive at last follow up were censored. Overall survival time will be summarized using the method of Kaplan and Meier.

  up to 2 years after treatment, a maximum possible duration of 38 months.

Secondary Outcomes (3)

• Time to Progression

  Up to 24 months, or death

• Objective Response Rate

  Up to 12 months

• Rate of Hematologic Response Per IWG

  Up to 24 months

Other Outcomes (3)

• Rate of Marrow Complete Response (mCR)

  Up to 24 months.

• Change in Number of Mutations as Assessed by Next Generation Sequencing (NGS)

  Up to 24 months

• Change in Allele Frequency Assessed by Next Generation Sequencing (NGS)

  Up to 24 months

Study Arms (1)

Pevonedistat and Azacitidine

EXPERIMENTAL

Participants will receive Azacitidine (via an injection under the skin, or via an intravenous infusion (IV bag) on days 1, 2, 3, 4 and 5 of each 28-day cycle. Participants will receive Pevonedistat (through a vein in the arm) on Days 1, 3 and 5 of each 28-day cycle.

Drug: Azacitidine Subcutaneous Injection or Intravenous Infusion; Drug: Pevonedistat Infusion; Procedure: Bone Marrow Biopsy & Aspirate

Interventions

Azacitidine Subcutaneous Injection or Intravenous Infusion DRUG

75 mg/m2

Pevonedistat and Azacitidine

Pevonedistat Infusion DRUG

20 mg/m2

Pevonedistat and Azacitidine

Bone Marrow Biopsy & Aspirate PROCEDURE

Removal of a small piece of bone and bone marrow by inserting a needle into hip bone.

Pevonedistat and Azacitidine

Eligibility Criteria

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

You may qualify if:

• Signed and dated voluntary written informed consent before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• Male or female ≥ 18 years of age.
• Morphologically confirmed diagnosis of MDS or MDS/MPN in accordance with WHO diagnostic criteria.
• ECOG performance status of 0, 1 or 2.
• Expected survival ≥ 3 months after consenting.
• Refractory/relapsed disease following DNMTi failure. Refractory disease defined as either:
• failure to achieve an objective response after at least 4 cycles of DNMTi therapy, or
• failure to achieve an objective response with clear progressive disease on bone marrow biopsy after at least 2 cycles of DNMTi therapy. Relapsed disease is defined as having progressive disease after achieving an objective response after at least 2 cycles of DNMTi therapy.
• Previous DNMTi therapy may include 5'azacitidine, decitabine, or DNMTi therapy currently in clinical trials (e.g. SGI-110 (guadecitabine), ASTX727 or CC-486).To be considered DNMTi treatment failure, during each prior treatment cycle, patients must have received equivalent to minimum dosing of:
• decitabine 15mg/m2 daily x 5 days, or
• 'azacitidine 50mg/m2 IV/SC daily x 5 days,
• SGI-110 (guadecitabine) 60mg/m2 SC daily x 5 days, or
• oral DNMTi therapy with ASTX727 20/100mg daily x 5 days, or
• oral DNMTi therapy with CC-486 200mg daily x 14 days
• Recovery to ≤ Grade 1 or baseline of any toxicity due to prior systemic treatments, excluding alopecia.

You may not qualify if:

• Diagnosis of acute myeloid leukemia (i.e. ≥ 20% peripheral or marrow blasts).
• Any HSCT within 6 months prior to signing informed consent.
• Any patient who is eligible for HSCT at the time of study screening.
• Clinically significant graft versus host disease (GVHD) or GVHD requiring initiation of treatment or treatment escalation within 21 days, and/or \> Grade 1 persistent or clinically significant non-hematologic toxicity related to HSCT
• Any previous treatment with pevonedistat or other NEDD8 inhibitor.
• Treatment with any investigational products within 14 days before the first dose of protocol-indicated treatment.
• Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of any study drug.
• Major surgery requiring general anesthesia within 14 days before the first dose of any study drug or a scheduled surgery during study period. (Placement of a central line or port-a-catheter is acceptable within this time frame and does not exclude the patient.)
• Treatment with clinically significant metabolic CYP3A inducers within 14 days before the first dose of study drug. Clinically significant CYP3A inducers are not permitted during the study.
• Prolonged QTc interval \> 500 msec, calculated according to Fredericia's formula
• Known cardiopulmonary disease defined as having one or more of the following:
• Uncontrolled high blood pressure (i.e. systolic \> 180 mmHg or diastolic \> 95 mmHg);
• Symptomatic cardiomyopathy;
• Ischemic heart disease; Patients with acute coronary syndrome, myocardial infarction, and/or revascularization (e.g. coronary artery bypass graft, stent) within 6 months of first dose of study drug are excluded; Patients with a history of ischemic heart disease who have had revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll;
• Arrhythmia (e.g. history of polymorphic ventricular fibrillation or torsade de pointes). Patients with symptomatic atrial fibrillation (Afib) incompletely controlled medically, or controlled by device (e.g. pacemaker) or by ablation in the past 6 months are excluded. However, patients with stable, AFib for a period of at least 6 months, whose Afib is controlled with medication, or who have a history of paroxysmal AFib are permitted to enroll;

Sponsors & Collaborators

• Vanderbilt-Ingram Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (5)

University of Miami Miller School of Medicine

Miami, Florida, 33136, United States

Location

University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

Location

Memorial Sloan-Kettering

New York, New York, 10065, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Myeloproliferative Disorders

Interventions

Infusions, Intravenous

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Administration, Intravenous; Drug Administration Routes; Drug Therapy; Therapeutics; Infusions, Parenteral

Results Point of Contact

• Title: Teresa Melton
• Organization: Vanderbilt-Ingram Cancer Center

teresa.melton@vumc.org

615-936-7423

Study Officials

• Sanjay Mohan, MD

  Vanderbilt-Ingram Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 25, 2017
• First Posted: August 3, 2017
• Study Start: August 7, 2017
• Primary Completion: September 30, 2022
• Study Completion: November 27, 2023
• Last Updated: November 4, 2024
• Results First Posted: November 21, 2023

Record last verified: 2024-10

Locations

US (5)