Pevonedistat and Ruxolitinib Phosphate in Treating Participants with Myelofibrosis

Status: Active

Description

This phase I trial studies the side effects and best dose of pevonedistat when given together with ruxolitinib phosphate in treating participants with myelofibrosis. Pevonedistat and ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

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 International Prognostic Scoring System (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 complete response (CR) by International Working Group (IWG) criteria
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • 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
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x IULN
  • Creatinine clearance ≥ 50 mL/min
  • Hemoglobin > 8 g/dL; patients may be transfused to achieve this value; elevated indirect bilirubin due to post transfusion hemolysis is allowed
  • 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 [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception)
  • Male patients, even if surgically sterilized (i.e., 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 [e.g., 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 Institutional Review Board (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 inducers within 14 days before the first dose of study drug; clinically significant metabolic 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 (New York Heart Association [NYHA] class III or IV) * Myocardial infarction within 6 months prior to first dose (patients who had ischemic heart disease such as acute coronary syndrome (ACS), myocardial infarction (MI), and/or revascularization more than 6 months prior to enrollment and who are without cardiac symptoms may enroll) * 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) * Pulmonary hypertension
  • 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 central nervous system (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 human immunodeficiency virus (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

Locations & Contacts

Missouri

Saint Louis
Siteman Cancer Center at Washington University
Status: Active
Contact: Stephen T. Oh
Phone: 314-362-8846
Email: stoh@wustl.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of pevonedistat in combination with ruxolitinib phosphate (ruxolitinib) in patients with myelofibrosis.

SECONDARY OBJECTIVES:

I. To assess spleen response with the combination of pevonedistat and ruxolitinib.

II. To assess improvement of constitutional symptoms with the combination of pevonedistat and ruxolitinib.

III. To assess hematologic response with the combination of pevonedistat and ruxolitinib.

IV. To evaluate the pharmacokinetics of pevonedistat when co-administered with ruxolitinib.

EXPLORATORY OBJECTIVES:

I. To explore the effects of the combination therapy of pevonedistat and ruxolitinib on downstream signaling pathways (including nuclear factor kappa-light-chain-enhancer of activated B cells [NF-kappaB]) using mass cytometry.

II. To measure cytokine levels as biomarkers of inflammatory cytokine signaling and their response to treatment with pevonedistat and ruxolitinib.

III. To identify genetic alterations associated with response to pevonedistat and ruxolitinib therapy and to determine the effect of the combination therapy on clonal hierarchy via genomic analysis.

OUTLINE: This is a phase I, dose-escalation study of pevonedistat.

Participants receive pevonedistat intravenously (IV) over 60 minutes on days 1, 3, and 5, and ruxolitinib phosphate per standard of care. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, 12 weeks, and then every 6 months for up to 5 years.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Siteman Cancer Center at Washington University

Principal Investigator
Stephen T. Oh

Trial IDs

Primary ID 201802152
Secondary IDs NCI-2018-00369
Clinicaltrials.gov ID NCT03386214