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Combined Ruxolitinib and Enasidenib in Patients With Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis With an IDH2 Mutation

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ClinicalTrials.gov Identifier: NCT04281498
Recruitment Status : Recruiting
First Posted : February 24, 2020
Last Update Posted : May 21, 2021
Sponsor:
Collaborators:
Celgene Corporation
Incyte Corporation
Myeloproliferative Neoplasms Research Consortium
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
John Mascarenhas, Icahn School of Medicine at Mount Sinai

Brief Summary:
The presence of IDH mutation is associated with worse survival in patients with myelofibrosis. Moreover IDH mutations are among the most frequently encountered events in MPNs that have progressed to acute myeloid leukemia. Ruxolitinib, a JAK1/2 inhibitor, and enasidenib an IDH2 inhibitor are effective and tolerable treatments for patients with myelofibrosis (MF) and acute myeloid leukemia (AML), respectively. The study team hypothesize that the combination of these agents in patients with MPN with an IDH2 mutation will improve the overall clinical response to therapy.

Condition or disease Intervention/treatment Phase
Accelerated/Blast-phase Myeloproliferative Neoplasm Chronic-phase Myelofibrosis IDH2 Mutation Drug: Ruxolitinib Drug: Enasidenib Phase 2

Detailed Description:

At this time, there is no standard medical treatment for MPN-AP/BP and most patients with accelerated and blast phase MPN do not respond well to treatment This is a phase II open-label study to evaluate the safety and efficacy of combined ruxolitinib and enasidenib in patients with accelerated/blast-phase myeloproliferative neoplasm or chronic phase myelofibrosis with high risk features and IDH2 mutation.

Ruxolitinib (Jakafi/Jakavi) is FDA approved for myelofibrosis and was shown to reduce splenomegaly and improve symptoms. Enasidenib is a potent inhibitor of the IDH2 mutant enzyme and is FDA approved for relapsed refractory AML where it showed effectivity.

Pre-clinical studies indicate increased disease mitigating effects with the combination of enasidenib and ruxolitinib.

This study will enroll up to 32 patients. Ruxolitinib and enasidenib will be given orally in 28-day cycles.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Single Arm open-label Study of Combined Ruxolitinib and Enasidenib in Patients with Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis with an IDH2 Mutation, Simons minimax design.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Open-label Study of Combined Ruxolitinib and Enasidenib in Patients With Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis With an IDH2 Mutation
Actual Study Start Date : January 20, 2021
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: Patients with MPN
Ruxolitinib and Enasidenib combination therapy
Drug: Ruxolitinib
Patients who are on ruxolitinib will continue their current dose. Patients who are not on ruxolitinib will receive ruxolitinib dosing based on platelet count

Drug: Enasidenib
50mg -100mg daily




Primary Outcome Measures :
  1. Proportion of MPN participants with response [ Time Frame: 6 Months ]
    The proportion of treated accelerated-phase and blast-phase MPN patients (primary cohort) that achieve a best response of either complete response (CR), Partial Response (PR), or complete response with incomplete recovery of counts (CRi), when treated with the combination of ruxolitinib with enasidenib within 6 cycles of combined therapy.


Secondary Outcome Measures :
  1. Proportion of MPN participants with blast response [ Time Frame: 6 Months ]
    The proportion of treated accelerated-phase and blast-phase MPN patients that achieve complete (CBR) and partial blast response (PBR).

  2. Proportion of MF-CP participants with any response [ Time Frame: 6 Months ]
    The proportion of treated patients with MF-CP and 4%-9% circulating blasts that achieve complete response (CR) Partial Response (PR), clinical improvement (CI) with the combination of ruxolitinib and enasidenib within 6 cycles of combined therapy.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

INCLUSION CRITERIA:

  • Subjects must be ≥ 18 years at the time of signing the Informed Consent Form (ICF).
  • Understanding and voluntary signing an IRB-approved informed consent form.
  • Diagnosis of:

    1. Accelerated-phase (≥ 10% blasts in PB or BM) or blast-phase (≥ 20% blasts in PB or BM) myeloproliferative neoplasm (with history of prior myelofibrosis, polycythemia vera, or essential thrombocythemia)
    2. Previously treated patients with myelofibrosis with persistent disease or progressive disease (persistent or progressive splenomegaly, leukocytosis, anemia, or thrombocytopenia) with intermediate-1 or greater risk disease according to 2013 International Working Group (IWG) criteria, and 4-9% circulating blasts.
  • Demonstration of an IDH2 mutation.
  • Platelet count > 75,000 X 109/L for chronic phase myelofibrosis patients.
  • Prior therapy with either ruxolitinib or enasidenib is permitted, but not a combination of ruxolitinib and enasidenib.
  • Patients with chronic phase myelofibrosis on ruxolitinib must be on the drug for at least 3 months and on a stable dose for at least one month.
  • Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. ECOG 3 status will be allowed if attributable to MPN.
  • Patients must have adequate organ function as demonstrated by the following: a. Direct bilirubin < 2.0mg/dL, unless due to Gilbert's disease or current elevations in direct bilirubin associated with existing enasidenib use. b. Serum creatinine< 2.0 mg/dL. c. ALT and AST ≤ 3x upper limit of normal (unless transaminitis is considered to be related to MF).
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to starting enasidenib and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking enasidenib. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a condom during sexual contact with a female of child bearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
  • All study participants must be able to swallow oral medication.
  • Ability to adhere to the study visit schedule and all protocol requirements.

EXCLUSION CRITERIA:

  • Use of any other standard anti-neoplastic drug or growth factor (e.g., anagrelide, G-CSF, lenalidomide, thalidomide clofarabine) except hydroxyurea or experimental drugs, with the exception of ruxolitinib or enasidenib, less than 14 days or 5-half-lives, whichever is longer, prior to starting study therapy and/or lack of recovery from all toxicity (except for alopecia) from previous therapy to Grade 1 or better.

    a. Patients will be permitted to receive hydroxyurea while on study for up to a total of 3 cycles of combined therapy.

  • Known prior clinically relevant hypersensitivity reaction to ruxolitinib or enasidenib.
  • Prior therapy with enasidenib in combination with ruxolitinib.
  • Concurrent use of strong inducers of CYP3A4 (Rifampin, St. John's Wort, Carbamazepine, Phenytoin) and/or the following strong inhibitors of CYP3A4 (protease inhibitor containing HIV anti-retrovirals, cobicistat, clarithromycin, itraconazole, ketoconazole, nefazodone, and telithromycin) are prohibited. Also prohibited are CYP2C9 substrate medications that have a narrow therapeutic range: phenytoin and warfarin.
  • Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form, which places the subject at unacceptable risk if he/she were to participate in the study or which confounds the ability to interpret data from the study.
  • Lactating females.
  • Active uncontrolled infections.
  • Patients with active malignancy of other type than required for this study are not eligible with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast. Patients with malignancies with indolent behavior such as prostate cancer treated with radiation or surgery can be enrolled in the study as long as they have a reasonable expectation to have been cured with the treatment modality received.
  • Subject has significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) Class III or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke; or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment.
  • QTc interval (Fridericia's correction [QTcF]) > 450 ms

All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee to ensure that the patient qualifies for the trial.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04281498


Contacts
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Contact: Michal Bar-Natan, MD 212-241-6772 michal.bar-natan@mssm.edu
Contact: Raajit Rampal, MD, PhD 212-639-2194 rampalr@mskcc.org

Locations
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United States, Arizona
Mayo Clinic - Arizona Not yet recruiting
Scottsdale, Arizona, United States, 85259
Contact: Jeanne Palmer, MD       Palmer.Jeanne@mayo.edu   
Principal Investigator: Jeanne Palmer, MD         
United States, California
Cedars-Sinai Medical Center Not yet recruiting
Los Angeles, California, United States, 90048
Contact: Ronald Paquette, MD    310-423-1160    ronald.paquette@cshs.org   
Principal Investigator: Ronald Paquette, MD         
United States, Florida
Moffitt Cancer Center Not yet recruiting
Tampa, Florida, United States, 33612
Contact: Andrew T. Kuykendall, MD    813-745-6841    Andrew.Kuykendall@moffitt.org   
Principal Investigator: Andrew T. Kuykendall, MD         
United States, Kansas
University of Kansas Cancer Center Not yet recruiting
Westwood, Kansas, United States, 66205
Contact: Abdulraheem Yacoub, MD    913-588-6029    ayacoub@kumc.edu   
Principal Investigator: Abdulraheem Yacoub, MD         
United States, Michigan
University of Michigan Rogel Cancer Center Not yet recruiting
Ann Arbor, Michigan, United States, 48109-5936
Contact: Kristen Pettit, MD    734-764-8195    krpettit@med.umich.edu   
Principal Investigator: Kristen Pettit, MD         
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Lonette Sandy    212-241-4546    Lonette.Sandy@mssm.edu   
Contact: Amelia Gabler, BS         
Principal Investigator: Michal Bar-Natan, MD         
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Contact: Raajit Rampal, MD, PhD    212-639-2194    rampalr@mskcc.org   
Principal Investigator: Raajit Rampal, MD, PhD         
United States, North Carolina
Wake Forest Baptist Health Not yet recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Rupali Roy Bhave, MD    336-716-1808    rbhave@wakehealth.edu   
Principal Investigator: Rupali Roy Bhave, MD         
United States, Ohio
Taussig Cancer Center Institute Recruiting
Cleveland, Ohio, United States, 44195
Contact: Aaron Gerds, MD, MS    216-445-9840    gerdsa@ccf.org   
Principal Investigator: Aaron Gerds, MD, MS         
United States, Texas
Mays Cancer Center at UT Health San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Ruben Mesa, MD         
Principal Investigator: Ruben Mesa, MD         
Canada
Princess Margaret Cancer Centre Not yet recruiting
Toronto, Canada, M5G 2M9
Contact: Vikas Gupta, MD, FRCP, FRCPath    (416) 946-4521    vikas.gupta@uhn.ca   
Principal Investigator: Vikas Gupta, MD, FRCP, FRCPath         
Sponsors and Collaborators
John Mascarenhas
Celgene Corporation
Incyte Corporation
Myeloproliferative Neoplasms Research Consortium
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Investigators
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Study Chair: John Mascarenhas, MD Icahn School of Medicine at Mount Sinai
Study Chair: Ruben Mesa, MD Mays Cancer Center at UT Health
Study Chair: Ronald Hoffman, MD Icahn School of Medicine at Mount Sinai
Principal Investigator: Michal Bar-Natan, MD Icahn School of Medicine at Mount Sinai
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Responsible Party: John Mascarenhas, Associate Professor, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT04281498    
Other Study ID Numbers: GCO 07-0548-0008
P01CA108671 ( U.S. NIH Grant/Contract )
MPN-RC 119 ( Other Identifier: Myeloproliferative Neoplasms Research Consortium )
First Posted: February 24, 2020    Key Record Dates
Last Update Posted: May 21, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by John Mascarenhas, Icahn School of Medicine at Mount Sinai:
Phase II
Myelofibrosis
Therapeutic
Ruxolitinib
Enasidenib
IDH2
Additional relevant MeSH terms:
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Neoplasms
Blast Crisis
Primary Myelofibrosis
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Pathologic Processes