Study of Combination Ruxolitinib and Decitabine Treatment for Accelerated Phase MPN or Post-MPN AML

• ClinicalTrials.gov Identifier: NCT02076191
• Recruitment Status: Completed
• First Posted: March 3, 2014
• Last Update Posted: February 28, 2019
• Sponsor: John Mascarenhas
• Collaborators: Myeloproliferative Disorders-Research Consortium; National Cancer Institute (NCI); Incyte Corporation
• Information provided by (Responsible Party): John Mascarenhas, Icahn School of Medicine at Mount Sinai

Tracking Information

• First Submitted Date: February 27, 2014
• First Posted Date: March 3, 2014
• Last Update Posted Date: February 28, 2019
• Study Start Date: February 2014
• Actual Primary Completion Date: July 20, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 28, 2014)

• Maximum Tolerated Dose (MTD) [ Time Frame: up to 5 weeks ]
  Safety and efficacy of ruxolitinib when used in combination with decitabine. MTD is defined as the highest dose studied for which the incidence of (Dose Limiting Toxicities) DLT is at least 33%.
• Dose Limiting Toxicities (DLT) [ Time Frame: up to 5 weeks ]
  Safety and efficacy of ruxolitinib when used in combination with decitabine. DLTs will be defined as those adverse events occurring in the first 5 weeks after initiation of therapy that are not clearly related to disease.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 28, 2014)

Recommended Phase II Dose (RPTD) [ Time Frame: up to 20 weeks ]

Safety and tolerability of drug combination of ruxolitinib and decitabine. RPTD is that dose level below the MTD for which the incidence of DLT is <33%.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Combination Ruxolitinib and Decitabine Treatment for Accelerated Phase MPN or Post-MPN AML
• Official Title: Multicenter Phase I/II Trial of Ruxolitinib in Combination With Decitabine in Patients With Accelerated Phase Myeloproliferative Neoplasm (MPN) or Post-MPN AML
• Brief Summary: The purpose of this study is to test the safety and tolerability of ruxolitinib at different dose levels in combination with decitabine and the effectiveness of ruxolitinib in combination with decitabine in patients with accelerated or blast phase Myeloproliferative Neoplasm (MPN), which is a group of diseases of the bone marrow in which excess cells are produced. Ruxolitinib is a drug that is approved by the Federal Drug Administration (FDA) for the treatment of patients with advanced forms of myelofibrosis. It inhibits the Jak proteins that are often abnormal in MPN. A recent clinical study showed that ruxolitinib treatment could put some patients with this disease into remission. Decitabine is a chemotherapy, approved by the Federal Drug Administration (FDA), that has been used to treat acute leukemia. It works in some patients, but most patients with accelerated and blastic MPN do not respond to treatment. Ruxolitinib and decitabine will be combined in this study to find out what dose of the two medicines are safe together. Using Ruxolitinib in combination with Decitabine is experimental. The investigators want to find out what effects, good and/or bad it has on the patient and the disease.
• Detailed Description: At this time, there is no standard medical treatment for MF-BP or MF-AP. The investigators believe that the combination of ruxolitinib and DEC is a candidate approach to the treatment of MF-BP/MF-AP that is worthy of exploration based on both the current understanding of the biology of disease and emerging preclinical data. The molecular pathogenesis of MPN and progression to blast phase is almost certainly due to a complex combination of gene mutations (JAK2V617F, MPL) and epigenetic alterations (IDH1/2, IKZF1, EZH2, TET2) that culminate in the emergence of leukemic clones. Recent evidence indicates that the JAK2V617F protein can localize in the nucleus and influence global DNA methylation patterns which may lead to genomic instability and disease progression. The inhibition of JAK-STAT mediated cell proliferation and survival in conjunction with the reversal of DNA hypermethylation of tumor suppressor genes would be predicted to have at least an additive if not synergistic effect in inducing apoptosis of cells belonging to the malignant myeloid clone. Correlative studies conducted within a trial of Private and Confidential MPD-RC 109 Ruxolitinib + Decitabine combination JAK2 inhibitor and DMNT1 inhibitor in patients with MPN-BP would explore the effect on methylation status of various gene promoters as well as the influence on gene expression of chromatin related proteins and ultimately leukemic cell survival. The sequential administration of a JAK2 inhibitor followed by a DNMT inhibitor would also potentially serve to overcome the JAK2-independent effects of epigenetic lesions that lead to MPN-BP. In addition, a murine model of leukemic transformation has been described. In this model, bone marrow obtained from Tp53 null mice is retrovirally transduced with Jak2V617F, and transplanted into donor C56BL/6 mice. The transplanted mice develop an MPN which progresses to AML. In vitro drug studies utilizing bone marrow from these leukemic mice have demonstrated that exposure to decitabine or ruxolitinib inhibits colony formation in a methylcellulose colony-forming assay. Importantly, the combination of decitabine and ruxolitinib in this assay significantly reduces colony formation when compared to either drug alone (Rampal et al. ASH 2012 oral abstract 808) thus providing pre-clinical evidence for the combination study proposed here.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myeloproliferative Neoplasms

Intervention

• Drug: Ruxolitinib
  Ruxolitinib will be administered at doses of 5mg, 10mg, 15mg, or 25 mg taken orally every 12 hours throughout the treatment cycle.
• Drug: Decitabine
  Decitabine is administered intravenously at a dose of 20 mg/m2 daily for 5 days. Subsequent cycles of decitabine may be administered at 4 week intervals as clinically tolerated. Decitabine treatment may be deferred for up to 2 weeks to allow recovery from non-hematologic toxicity during the first 6 cycles and up to 2 weeks thereafter for hematologic toxicities as well. The first treatment cycle will last 35 days and will be the evaluable period for DLTs and RPTD determination for patients enrolled in the phase I portion only. Subsequent treatment cycles will be 4-6 weeks in duration as defined by decitabine administration.

Study Arms

Experimental: Myeloproliferative neoplasms

In phase I, increasing doses of ruxolitinib in combination with decitabine at a dose of 20 mg/m2 daily intravenously over 5 days. An initial dose of ruxolitinib of 10 mg orally twice daily is anticipated with planned, dose escalations of 15 mg orally twice daily, 25 mg orally twice daily and 50 mg orally twice daily. The dose can also be de-escalated to 5mg orally twice daily if dose limiting toxicities (DLTs) are observed at the initial 10mg dose. Patients will receive ruxolitinib as a single agent for the first 7 days followed by the administration of decitabine on day 8 for a total of 5 consecutive days. Patients will continue ruxolitinib at the assigned dose through the first cycle and may reduce the dose for specified toxicity beginning with the second cycle. Patients in Phase II will start at the recommended phase II dose (RPTD) of ruxolitinib in combination with decitabine at a dose of 20 mg/m2 daily intravenously over 5 days.

Interventions:

• Drug: Ruxolitinib
• Drug: Decitabine

• Publications *: Mascarenhas JO, Rampal RK, Kosiorek HE, Bhave R, Hexner E, Wang ES, Gerds A, Abboud CN, Kremyanskaya M, Berenzon D, Odenike O, Farnoud N, Krishnan A, Weinberg RS, McGovern E, Salama ME, Najfeld V, Medina-Martinez JS, Arango Ossa JE, Levine MF, Zhou Y, Sandy L, Heaney ML, Levine RL, Mesa RA, Dueck AC, Hoffman R. Phase 2 study of ruxolitinib and decitabine in patients with myeloproliferative neoplasm in accelerated and blast phase. Blood Adv. 2020 Oct 27;4(20):5246-5256. doi: 10.1182/bloodadvances.2020002119.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2018): 49
• Original Estimated Enrollment (submitted: February 28, 2014): 60
• Actual Study Completion Date: July 20, 2018
• Actual Primary Completion Date: July 20, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Accelerated phase MPN as defined by 10%-19% blasts in the peripheral blood or bone marrow and evidence of dysplastic marrow features with a concomitant diagnosis of essential thrombocythemia (ET), polycythemia vera (PV) or primary myelofibrosis (PMF) or a diagnosis of acute myelogenous leukemia as defined by 20% blasts in the blood or bone marrow following a previous diagnosis of ET, PV or PMF.
• >18 years of age
• Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2. Patients with ECOG performance status of 3 will be eligible if the lower performance status is deemed by the investigator to be due entirely to accelerated or blastic phase MPN and not due to another comorbidity.
• Acceptable pre-study organ function during screening as defined as: Total bilirubin < 1.5 times the upper limit of normal (ULN) unless due to Gilbert's disease or hemolysis, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN, Serum creatinine ≤ 1.5 x ULN
• Women of childbearing potential and males must agree to use adequate contraception (i.e., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform the treating physician immediately.
• Patients who are not candidates for or have declined an allograft.
• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Have had chemotherapy or investigational therapy, with the exception of hydroxyurea, within 4 weeks of study entry. Previous treatment with either ruxolitinib or decitabine as single agents will not exclude eligibility. Previous stem cell transplant will also not exclude eligibility as long as other inclusion/exclusion criteria have been met.
• Patients with acute myelofibrosis are excluded.
• Uncontrolled intercurrent illness including, but not limited to hepatitis, human immunodeficiency virus (HIV)-positive subjects receiving combination antiretroviral therapy, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Other medications, severe acute/chronic medical or psychiatric conditions, or laboratory abnormalities that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, that in the judgment of the Investigator would make the subject inappropriate for entry into this study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02076191
• Other Study ID Numbers: GCO 13-1816; MPD-RC 109 ( Other Identifier: Myeloproliferative Disorders-Research Consortium ); P01CA108671 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: John Mascarenhas, Icahn School of Medicine at Mount Sinai
• Original Responsible Party: John Mascarenhas, Icahn School of Medicine at Mount Sinai, Assistant Professor
• Current Study Sponsor: John Mascarenhas
• Original Study Sponsor: Same as current

Collaborators

• Myeloproliferative Disorders-Research Consortium
• National Cancer Institute (NCI)
• Incyte Corporation

Investigators

• Study Chair: John Mascarenhas, MD; Icahn School of Medicine at Mount Sinai
• Principal Investigator: Ronald Hoffman, MD; Icahn School of Medicine at Mount Sinai

• PRS Account: Icahn School of Medicine at Mount Sinai
• Verification Date: February 2019