DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more



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

Page last updated: August 23, 2015

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017