Clinical Trials /

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

NCT04281498

Description:

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.

Related Conditions:
  • Myeloproliferative Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: GCO 07-0548-0008
  • SECONDARY ID: P01CA108671
  • SECONDARY ID: MPN-RC 119
  • NCT ID: NCT04281498

Conditions

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

Interventions

DrugSynonymsArms
RuxolitinibPatients with MPN
EnasidenibPatients with MPN

Purpose

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.

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.

      Ruxolitnib (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.
    

Trial Arms

NameTypeDescriptionInterventions
Patients with MPNExperimentalRuxolitinib and Enasidenib combination therapy
  • Ruxolitinib
  • Enasidenib

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:Proportion of MPN participants with response
Time Frame:6 Months
Safety Issue:
Description: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

Measure:Proportion of MPN participants with blast response
Time Frame:6 Months
Safety Issue:
Description:The proportion of treated accelerated-phase and blast-phase MPN patients that achieve complete (CBR) and partial blast response (PBR).
Measure:Proportion of MF-CP participants with any response
Time Frame:6 Months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Michal Bar-Natan

Trial Keywords

  • Phase II
  • Myelofibrosis
  • Therapeutic
  • Ruxolitnib
  • Enasidenib
  • IDH2

Last Updated

February 20, 2020