Study of Combination Ruxolitinib and Decitabine Treatment for Accelerated Phase MPN or Post-MPN AML
Information source: Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Myeloproliferative Neoplasms
Intervention: Ruxolitinib (Drug); Decitabine (Drug)
Phase: Phase 1/Phase 2
Status: Recruiting
Sponsored by: John Mascarenhas Official(s) and/or principal investigator(s): John Mascarenhas, MD, Study Chair, Affiliation: Icahn School of Medicine at Mount Sinai Ronald Hoffman, MD, Principal Investigator, Affiliation: Icahn School of Medicine at Mount Sinai
Overall contact: Jill Kleczko, MPA, Phone: 212-241-0573, Email: jill.kleczko@mssm.edu
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.
Clinical Details
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
Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Maximum Tolerated Dose (MTD)Dose Limiting Toxicities (DLT)
Secondary outcome: Recommended Phase II Dose (RPTD)
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
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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.
Locations and Contacts
Jill Kleczko, MPA, Phone: 212-241-0573, Email: jill.kleczko@mssm.edu
Mayo Clinic, Scottsdale, Arizona 85289, United States; Not yet recruiting Ruben Mesa, MD, Phone: 480-301-8335, Email: mesa.ruben@mayo.edu Ruben Mesa, MD, Principal Investigator
Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States; Recruiting Jill Kleczko, MPA, Phone: 212-241-0573 Jane Lew, BS, Phone: 212-241-0481, Email: jane.lew@mssm.edu John Mascarenhas, MD, Principal Investigator
Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Not yet recruiting Raajit Rampal, MD, PhD, Phone: 212-639-2194, Email: rampalr@mskcc.org Raajit Rampal, MD, PhD, Principal Investigator
Weill Cornell Medical College, New York, New York 10065, United States; Not yet recruiting Ellen Ritchie, MD, Phone: 212-746-2856, Email: ritchie@med.cornell.edu Richard Silver, MD, Principal Investigator
Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, United States; Recruiting Dmitry Berenzon, MD, Phone: 336-716-5847, Email: dberenzo@wfubmc.edu Dmitry Berenzon, MD, Principal Investigator
University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Not yet recruiting Elizabeth Hexner, MD, Phone: 215-662-4137, Email: elizabeth.hexner@uphs.upenn.edu Elizabeth Hexner, MD, Principal Investigator
University of Utah, Salt Lake City, Utah 84132, United States; Not yet recruiting Josef Prchal, MD, Phone: 801-581-4220, Email: Josef.Prchal@hsc.utah.edu Josef Prchal, MD, Principal Investigator
Additional Information
Starting date: February 2014
Last updated: October 21, 2014
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