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.
Recruiting
Phase 1
| Drug | Synonyms | Arms |
|---|---|---|
| Pevonedistat | MLN4924 | Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib |
| Ruxolitinib | Jakavi® | Arm 1: Starting Dose - 5 mg/m^2 pevonedistat + ruxolitinib |
| Name | Type | Description | Interventions |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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. |
|
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Safety and tolerability of pevonedistat in combination with ruxolitinib in patients with myelofibrosis as measured by the frequency of adverse events |
| Time Frame: | Through 30 days after completion of treatment (estimated to be 42 weeks) |
| Safety Issue: | |
| Description: | -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. |
| Measure: | Spleen response with the combination of pevonedistat and ruxolitinib |
| Time Frame: | Through 12 weeks after completion of treatment (estimated to be 48 weeks) |
| Safety Issue: | |
| Description: | A baseline splenomegaly that is palpable at 5-10 cm below the left costal margin becomes not palpable OR A baseline splenomegaly that is palpable > 10 cm below the left costal margin decreases by ≥50% OR A baseline splenomegaly that is palpable < 5 cm below the left costal margin is not eligible for spleen response OR Ultrasound shows ≥35% spleen volume reduction (calculated) |
| Measure: | Improvement of constitutional symptoms with the combination of pevonedistat and ruxolitinib |
| Time Frame: | Through completion of treatment (estimated to be 36 weeks) |
| Safety Issue: | |
| Description: | A ≥50% reduction in the myeloproliferative neoplasm symptom assessment total symptom score 8 symptoms (tiredness, early satiety, abdominal discomfort, inactivity, night sweats, itching, bone pain, pain under ribs under left side) with 0 to 10 ranking where 0=no pain and 10=worst imaginable pain |
| Measure: | Hematologic response with the combination of pevonedistat and ruxolitinib as measured by anemia response |
| Time Frame: | Through 12 weeks after completion of treatment (estimated to be 48 weeks) |
| Safety Issue: | |
| Description: | -Anemia response is only applicable for patients with a baseline hemoglobin level less than 10g/dL for 8 weeks or more, and requires: ≥ 2 g/dL increase in hemoglobin level OR becoming transfusion-independent (no RBC transfusions in past 1 month) |
| Measure: | Hematologic response with the combination of pevonedistat and ruxolitinib as measured by platelet response |
| Time Frame: | Through 12 weeks after completion of treatment (estimated to be 48 weeks) |
| Safety Issue: | |
| Description: | -Platelet response is only applicable for patients with a baseline platelet count of less than 50 x 109/L for 8 weeks or more, and requires: 100% increase in platelet count AND An absolute platelet count of at least 50 x 109/L |
| Measure: | Pharmacokinetics of pevonedistat when co-administered with ruxolitinib as measured by the Cmax (peak serum concentration) |
| Time Frame: | Through Cycle 1 Day 5 |
| Safety Issue: | |
| Description: |
| Measure: | Pharmacokinetics of pevonedistat when co-administered with ruxolitinib as measured by the Tmax (time of maximum concentration observed) |
| Time Frame: | Through Cycle 1 Day 5 |
| Safety Issue: | |
| Description: |
| Measure: | Pharmacokinetics of pevonedistat when co-administered with ruxolitinib as measured by the area under the plasma drug concentration curve (AUC) |
| Time Frame: | At 24 hours |
| Safety Issue: | |
| Description: | -AUC reflects the actual body exposure to drug after administration of a dose of the drug and is expressed |
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Washington University School of Medicine |
June 18, 2021
