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

NCT04281498 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: GCO 07-0548-0008P01CA108671MPN-RC 119
• Study Type: interventional
• Target: 6
• Locations: 2 countries
• Sites: 11

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.

Conditions

Accelerated/Blast-phase Myeloproliferative Neoplasm; Chronic-phase Myelofibrosis; IDH2 Mutation

Keywords

Phase II; Myelofibrosis; Therapeutic; Ruxolitinib; Enasidenib; IDH2

Outcome Measures

Primary Outcomes (1)

• Number of MPN Participants With Response

  The number of treated accelerated-phase and blast-phase MPN patients (primary cohort) that achieve a best response per 2013 International Working Group (IWG) criteria 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. Complete Response with incomplete recovery of counts (CRi) - complete remission (\<5% marrow blasts by morphology) with incomplete count recovery (platelet count \<100 x 10\^9\^/L and/or absolute neutrophil count \< 1 x 10\^9\^/L) Complete Response (CR) - full marrow recovery; full count recovery; resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH Partial Response (PR) - morphologic remission in the peripheral blood but not necessarily in the bone marrow; resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH

  6 Months

Secondary Outcomes (2)

• Number of MPN Participants With Blast Response

  6 Months

• Number of MF-CP Participants With Any Response

  6 Months

Study Arms (1)

Patients with MPN

EXPERIMENTAL

Ruxolitinib and Enasidenib combination therapy

Drug: Ruxolitinib; Drug: Enasidenib

Interventions

Ruxolitinib DRUG

Patients who are on ruxolitinib will continue their current dose. Patients who are not on ruxolitinib will receive ruxolitinib dosing based on platelet count

Patients with MPN

Enasidenib DRUG

50mg -100mg daily

Patients with MPN

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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)
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• John Mascarenhas: lead
• Celgene Corporation: collaborator
• Incyte Corporation: collaborator
• Myeloproliferative Neoplasms Research Consortium: collaborator
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (11)

Mayo Clinic - Arizona

Scottsdale, Arizona, 85259, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

University of Kansas Cancer Center

Westwood, Kansas, 66205, United States

Location

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109-5936, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Wake Forest Baptist Health

Winston-Salem, North Carolina, 27157, United States

Location

Taussig Cancer Center Institute

Cleveland, Ohio, 44195, United States

Location

Mays Cancer Center at UT Health San Antonio

San Antonio, Texas, 78229, United States

Location

Princess Margaret Cancer Centre

Toronto, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

ruxolitinib; enasidenib

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Dr. John Mascarenhas
• Organization: Icahn School of Medicine at Mount Sinai

john.mascarenhas@mssm.edu

212-241-3417

Study Officials

• 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

  STUDY CHAIR

• Michal Bar-Natan, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Model Details: 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.

Study Record Dates

• First Submitted: February 20, 2020
• First Posted: February 24, 2020
• Study Start: January 14, 2021
• Primary Completion: May 30, 2023
• Study Completion: May 30, 2023
• Last Updated: February 4, 2025
• Results First Posted: December 18, 2024

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (10); CA (1)