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Mayo Clinic

Jeanne Palmer, MD

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Ronald Paquette, MD

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Rami Komrokji, MD

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Abdulraheem Yacoub, MD

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Moshe Talpaz, MD

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John Mascarenhas (PI), MD

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Raajit Rampal, MD, PhD

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Rupali Bhave, MD

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Aaron Gerds, MD

Ontario

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Vikas Gupta, MD

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Ruben Mesa (co-PI), MD

Clinical Research

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MPN-RC 119

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 [MPN-RC 119]

Study Status

This study Upcoming.

Myeloproliferative Neoplasms Research Consortium, July 2019

MPN-RC 119 Summary:

 

This is 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. This study will enroll up to 32 patients. Ruxolitinib and enasidenib will be given orally in 28-day cycles.  Both medications are FDA approved and are available commercially.

Enasidenib (Idhifa) gained FDA market approval in August 2017 for acute myelogenous leukemia (AML).  This was based on the clinical trial AG221-C-001 (NCT01915498), an open-label, single-arm, multicenter, clinical trial of enasidenib that included adults with relapsed or refractory AML who had an IDH2 mutation as detected by the above assay. Patients were treated with enasidenib 100 mg orally daily. Complete response (CR) and complete response with partial hematologic recovery (CRh) rates, CR/CRh duration, and conversion from transfusion dependence to transfusion independence were the basis of approval.

Ruxolitnib (Jakafi/Jakavi) first gained market approval by the FDA in November 2011 for myelofibrosis. FDA approval was based on results from two randomized Phase III trials (COMFORT-I and COMFORT-II), which demonstrated that patients treated with ruxolitinib experienced significant reductions in splenomegaly (enlarged spleen). COMFORT-I also demonstrated improvements in symptoms.

The presence of IDH mutations has prognostic significance in patients with MPNs. Clinical observations suggest that IDH mutations alter the disease biology of MPNs are associated with an increased risk of leukemic transformation. Enasidenib is a first-in-class, selective, potent inhibitor of the IDH2 mutant enzyme and has been shown to suppress pathways that may promote worsening of MPNs.  Pre-clinical studies indicate possible increased disease mitigating effects with the combination of enasidenib and ruxolitinib.

Primary Objectives

  • To estimate the efficacy of ruxolitinib and enasidenib combination therapy in patients with accelerated-phase and blast-phase disease. Efficacy will be defined as the proportion of patients who achieve a best leukemia response of: complete response (CR), Partial Response (PR), complete response with incomplete recovery of counts (CRi), as assessed by the modified 2013 International Working Group (IWG) Response Criteria.

 

 

Eligibility Criteria:

Patients with the following disease: Idiopathic myelofibrosis, or post PV-, or ET-related myelofibrosis in chronic phase and accelerated phase.

Inclusion Criteria

1. Subjects must be ≥ 18 years at the time of signing the Informed Consent Form (ICF).

2. Understanding and voluntary signing an IRB-approved informed consent form.

3. Diagnosis of:

a.  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)

b.  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.

4.  Demonstration of an IDH2 mutation.

5. Platelet count  > 75,000 X 109/L for chronic phase myelofibrosis patients.

6. Prior therapy with either ruxolitinib or enasidenib is permitted, but not a combination of ruxolitinib and enasidenib.

7. 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.

8. 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.

9. 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)

10. 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.

11. All study participants must be able to swallow oral medication.

12. Ability to adhere to the study visit schedule and all protocol requirements.

 

Exclusion Criteria

1. 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.

2. Known prior clinically relevant hypersensitivity reaction to ruxolitinib or enasidenib.

3. Prior therapy with enasidenib in combination with ruxolitinib.

4. 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, nefadozone, and telithromycin) are prohibited.  Also prohibited are CYP2C9 substrate medications that have a narrow therapeutic range: phenytoin and warfarin.

5. 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.

6. Lactating females.

7. Active uncontrolled infections.

8. 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.

9. 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 (Appendix G; 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.

10. QTc interval (Fridericia’s correction [QTcF]) > 450 ms