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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Mount Sinai School of Medicine
Sponsor:
Collaborators:
Myeloproliferative Disorders-Research Consortium
Incyte Corporation
Information provided by (Responsible Party):
John Mascarenhas, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT02076191
First received: February 27, 2014
Last updated: August 13, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Myeloproliferative Neoplasms
Drug: Ruxolitinib
Drug: Decitabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Mount Sinai School of Medicine:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: up to 5 weeks ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Recommended Phase II Dose (RPTD) [ Time Frame: up to 20 weeks ] [ Designated as safety issue: Yes ]
    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%.


Estimated Enrollment: 60
Study Start Date: February 2014
Estimated Study Completion Date: February 2018
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02076191

Contacts
Contact: Jill Kleczko, MPA 212-241-0573 jill.kleczko@mssm.edu
Contact: John Mascarenhas, MD 212-241-3417 john.mascarenhas@mssm.edu

Locations
United States, Arizona
Mayo Clinic Not yet recruiting
Scottsdale, Arizona, United States, 85289
Contact: Ruben Mesa, MD    480-301-8335    mesa.ruben@mayo.edu   
Principal Investigator: Ruben Mesa, MD         
United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Jill Kleczko, MPA    212-241-0573      
Contact: Jane Lew, BS    212-241-0481    jane.lew@mssm.edu   
Principal Investigator: John Mascarenhas, 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         
Weill Cornell Medical College Not yet recruiting
New York, New York, United States, 10065
Contact: Ellen Ritchie, MD    212-746-2856    ritchie@med.cornell.edu   
Principal Investigator: Richard Silver, MD         
United States, North Carolina
Wake Forest University Baptist Medical Center Not yet recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Dmitry Berenzon, MD    336-716-5847    dberenzo@wfubmc.edu   
Principal Investigator: Dmitry Berenzon, MD         
United States, Pennsylvania
University of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Elizabeth Hexner, MD    215-662-4137    elizabeth.hexner@uphs.upenn.edu   
Principal Investigator: Elizabeth Hexner, MD         
United States, Utah
University of Utah Not yet recruiting
Salt Lake City, Utah, United States, 84132
Contact: Josef Prchal, MD    801-581-4220    Josef.Prchal@hsc.utah.edu   
Principal Investigator: Josef Prchal, MD         
Sponsors and Collaborators
John Mascarenhas
Myeloproliferative Disorders-Research Consortium
Incyte Corporation
Investigators
Study Chair: John Mascarenhas, MD Mount Sinai School of Medicine
Principal Investigator: Ronald Hoffman, MD Mount Sinai School of Medicine
  More Information

No publications provided

Responsible Party: John Mascarenhas, Assistant Professor, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT02076191     History of Changes
Other Study ID Numbers: GCO 13-1816, MPD-RC 109, P01CA108671
Study First Received: February 27, 2014
Last Updated: August 13, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Mount Sinai School of Medicine:
Ruxolitinib
Decitabine
Myeloproliferative Neoplasms
Combination Therapy

Additional relevant MeSH terms:
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 16, 2014