Pevonedistat in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis

NCT ID: NCT03386214

Last Updated: 2022-01-06

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-23
• Study Completion Date: 2021-10-04

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

• 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.

Group Type: EXPERIMENTAL

Pevonedistat

Intervention Type: 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.

Ruxolitinib

Intervention Type: DRUG

-Standard of care outside of protocol

Peripheral blood draw

Intervention Type: 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

Skin biopsy

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

• 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.

Group Type: EXPERIMENTAL

Pevonedistat

Intervention Type: 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.

Ruxolitinib

Intervention Type: DRUG

-Standard of care outside of protocol

Peripheral blood draw

Intervention Type: 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

Skin biopsy

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

• 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.

Group Type: EXPERIMENTAL

Pevonedistat

Intervention Type: 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.

Ruxolitinib

Intervention Type: DRUG

-Standard of care outside of protocol

Peripheral blood draw

Intervention Type: 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

Skin biopsy

Intervention Type: 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.

Interventions

Pevonedistat

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.

Intervention Type: DRUG

Ruxolitinib

-Standard of care outside of protocol

Intervention Type: DRUG

Peripheral blood draw

• 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

Intervention Type: PROCEDURE

Skin biopsy

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.

Intervention Type: PROCEDURE

Other Intervention Names

MLN4924; Jakavi®

Eligibility Criteria

Inclusion Criteria

• 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
• If they are of childbearing potential:

• Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
• Male patients, even if surgically sterilized (ie, status postvasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), OR
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)

Exclusion Criteria

• 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
• Clinically significant cardiac arrhythmia

• History of polymorphic ventricular fibrillation or Torsade de Pointes
• Permanent atrial fibrillation (a fib), defined as continuous a fib for ≥ 6 months
• Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening
• Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g. pacemaker) or ablation. Patients with Paroxysmal a fib or < grade 3 a fib for a period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen.
• Implantable cardioverter defibrillator
• Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing)
• Clinically significant pulmonary hypertension requiring pharmacologic therapy
• Uncontrolled coagulopathy or bleeding disorder.
• Uncontrolled high blood pressure (i.e. systolic blood pressure > 180 mmHg, diastolic blood pressure > 95 mmHg).
• Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to institutional guidelines.
• Left ventricular ejection fraction (LVEF) < 50% as assessed by echocardiogram or radionuclide angiography.
• Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, or pulmonary fibrosis.
• Known hepatic cirrhosis or severe pre-existing hepatic impairment.
• Known CNS involvement.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
• Female patients who intend to donate eggs and male patients who intended to donate sperm during the course of this study or for 4 months after receiving the last dose of study treatment.
• Female patients who are both lactating and breastfeeding or have positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug
• Known HIV-positivity.
• Chronic, active, or acute viral hepatitis A, B, or C infection, or hepatitis B or C carrier.
• Life-threatening illness unrelated to cancer.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephen Oh, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University School of Medicine

St Louis, Missouri, United States

Countries

United States

Related Links

http://www.siteman.wustl.edu

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

Other Identifiers

IISR-2017-101916

Identifier Type: OTHER

Identifier Source: secondary_id

201802152

Identifier Type: -

Identifier Source: org_study_id