Pevonedistat in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis

NCT03386214 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: 201802152IISR-2017-101916
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Based on the investigators' preclinical data, the combination of pevonedistat and ruxolitinib may provide greater clinical responses in patients with myelofibrosis compared to ruxolitinib monotherapy via inhibition of NFκB in addition to JAK-STAT signaling.

Conditions

Myelofibroses

Outcome Measures

Primary Outcomes (2)

• Safety and tolerability of pevonedistat in combination with ruxolitinib in patients with myelofibrosis as measured by the frequency of adverse events

  -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

  Through 30 days after completion of treatment (estimated to be 42 weeks)

• Safety and tolerability of pevonedistat in combination with ruxolitinib in patients with myelofibrosis as measured by the maximum tolerated dose (MTD)

  -MTD: The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. Dose escalations will proceed until the MTD has been reached.

  28 days after enrollment of last participant (estimated to be 25 months)

Secondary Outcomes (7)

• Spleen response with the combination of pevonedistat and ruxolitinib

  Through 12 weeks after completion of treatment (estimated to be 48 weeks)

• Improvement of constitutional symptoms with the combination of pevonedistat and ruxolitinib

  Through completion of treatment (estimated to be 36 weeks)

• Hematologic response with the combination of pevonedistat and ruxolitinib as measured by anemia response

  Through 12 weeks after completion of treatment (estimated to be 48 weeks)

• Hematologic response with the combination of pevonedistat and ruxolitinib as measured by platelet response

  Through 12 weeks after completion of treatment (estimated to be 48 weeks)

• Pharmacokinetics of pevonedistat when co-administered with ruxolitinib as measured by the Cmax (peak serum concentration)

  Through Cycle 1 Day 5

Study Arms (3)

Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib

EXPERIMENTAL

* Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle. * Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.

Drug: Pevonedistat; Drug: Ruxolitinib; Procedure: Peripheral blood draw; Procedure: Skin biopsy

Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib

EXPERIMENTAL

* Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle. * Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.

Drug: Pevonedistat; Drug: Ruxolitinib; Procedure: Peripheral blood draw; Procedure: Skin biopsy

Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib

EXPERIMENTAL

* Pevonedistat will be given as an IV infusion at the assigned dose over the course of 60 minutes on Days 1, 3, and 5 of each 28-day cycle. * Ruxolitinib will be continued at the same dose as prior to enrollment and will be administered as standard of care outside the study protocol.

Drug: Pevonedistat; Drug: Ruxolitinib; Procedure: Peripheral blood draw; Procedure: Skin biopsy

Interventions

Pevonedistat DRUG

The amount of pevonedistat to be administered will be based on body surface area (BSA). BSA will be calculated using a standard formula on Cycle 1 Day 1, and on Day 1 of subsequent cycles if the patient experiences a \> 5% change in body weight from the weight used for the most recent BSA calculation.

Also known as: MLN4924

Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib; Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib; Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib

Ruxolitinib DRUG

-Standard of care outside of protocol

Also known as: Jakavi®

Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib; Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib; Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib

Peripheral blood draw PROCEDURE

* Baseline or Cycle 1 Day 1 (prior to study treatment administration) * Cycle 2 Day 1 (prior to study treatment administration) * Cycle 4 Day 1 (prior to study treatment administration) * End of treatment

Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib; Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib; Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib

Skin biopsy PROCEDURE

A skin punch biopsy specimen will be collected at the baseline visit. One 6 mm punch biopsy of normal skin will be performed using standard techniques and local anesthesia.

Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib; Arm 2: Dose Level 2 - 10 mg/m^2 pevonedistat + ruxolitinib; Arm 3: Dose Level 3 - 20 mg/m^2 pevonedistat + ruxolitinib

Eligibility Criteria

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

You may qualify if:

• Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera/essential thrombocythemia myelofibrosis classified as high risk, intermediate-2 risk, or intermediate 1 risk by IPSS.
• On treatment with ruxolitinib for at least 3 months and have been on a stable dose for at least 8 weeks and have not achieved a CR by IWG criteria.
• At least 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Adequate bone marrow and organ function as defined below:
• Absolute neutrophil count ≥ 500/mcL, and have not received any growth factor support for at least 4 weeks prior to screening
• Platelets ≥ 50,000/mcL
• Peripheral blood blasts ≤ 10%
• Albumin \> 2.7 g/dL
• Total bilirubin ≤ institutional upper limit of normal (IULN); patients with Gilbert's syndrome may enroll if direct bilirubin ≤ 1.5 x IULN
• ALT and AST ≤ 2.5 x IULN
• Creatinine clearance ≥ 50 mL/min
• Female patients who:
• Are postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR

You may not qualify if:

• History of allogeneic stem cell transplant.
• Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during the study period.
• Received hydroxyurea therapy within 28 days (4 weeks) before the first dose of any study drug.
• Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug.
• Currently receiving any other investigational agents.
• Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of study drug. Clinically significant metabolic enzyme inducers are not permitted during the study.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pevonedistat, ruxolitinib, or other agents used in the study.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures.
• Diagnosis or treated for another malignancy within 2 years before enrollment, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any time are not excluded if they have undergone resection.
• Ongoing or active infection.
• Known cardiopulmonary disease defined as:
• Unstable angina pectoris
• Congestive heart failure (NYHA class III or IV)
• Myocardial infarction within 6 months prior to first dose (patients who had ischemic heart disease such as ACS, MI, and/or revascularization more than 6 months prior to enrollment and who are without cardiac symptoms may enroll)
• Symptomatic cardiomyopathy

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Takeda: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

pevonedistat; ruxolitinib

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Stephen Oh, M.D., Ph.D.

  Washington University School of Medicine

  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: SPONSOR

Study Record Dates

• First Submitted: December 21, 2017
• First Posted: December 29, 2017
• Study Start: April 23, 2018
• Primary Completion: September 12, 2021
• Study Completion: October 4, 2021
• Last Updated: January 6, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)