Ruxolitinib Phosphate and Decitabine in Treating Patients with Myeloproliferative Neoplasms
This phase I/II trial studies the side effects and best dose of ruxolitinib phosphate when given together with decitabine and to see how well they work in treating patients with myeloproliferative neoplasms, a group of diseases of the bone marrow in which excess cells are produced. Ruxolitinib phosphate may stop the growth of cancer cells by blocking one of the proteins needed for cell growth. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ruxolitinib phosphate with decitabine may be an effective treatment for myeloproliferative neoplasms.
Inclusion Criteria
- Accelerated phase myeloproliferative neoplasm (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
- 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
- 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 at any time 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02076191.
PRIMARY OBJECTIVES:
I. Establish the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) of ruxolitinib (ruxolitinib phosphate) in combination with decitabine by identifying the highest dose of ruxolitinib that can be administered with decitabine with an incidence of < 33% non-hematologic grade 3 or higher toxicities as assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0. The RPTD will be one dose level below the MTD. (Phase I)
II. Estimate therapeutic response in the Phase II trial by the overall rate of partial response (leukemia response-partial) or better by 6 months in patients treated at the RPTD. (Phase II)
SECONDARY OBJECTIVES:
I. Characterize the safety and tolerability of ruxolitinib given in combination with decitabine. (Phase I)
II. Characterize the tolerability and safety of ruxolitinib given at the RPTD in combination with decitabine. (Phase II)
TERTIARY OBJECTIVES:
I. Quantitate ruxolitinib levels at steady-state on day 8 with subsequent levels to determine whether decitabine administration affects ruxolitinib pharmacokinetics. (Incyte) (Phase I)
II. Examine the mutational status of a panel of genes that are commonly mutated in patients with de novo or secondary acute myeloid leukemia (AML). (Memorial Sloan-Kettering Cancer Center [MSKCC]) (Phase I)
III. Investigate the pattern of cluster of differentiation (CD)34+ cell engraftment and clonal evolution in a murine xenotransplantation system as a predictor of treatment response. (Mount Sinai School of Medicine [MSSM]) (Phase I)
IV. Explore somatic mutations that may be more expressed in leukemic blasts using whole exome sequencing. (MSKCC) (Phase I)
V. Explore novel transcripts, alternative splicing, gene fusion events, single nucleotide variants (SNVs), and insertion or deletion (indels) as identified by ribonucleic acid sequencing (RNAseq). (MSKCC) (Phase I)
VI. Explore the effect of ruxolitinib and decitabine combination therapy on cytokine expression at specified time points. (Phase I)
VII. Compare the janus kinase 2 (JAK2) allele burden prior to and during treatment with ruxolitinib in both the granulocyte and mononuclear cells. (Freiburg) (Phase I)
VIII. Assess the change in global deoxyribonucleic acid (DNA) methylation status of leukemic blasts after combination therapy and evaluate the association with therapeutic response. (Cornell) (Phase II)
IX. Assess the inhibition of the janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway after decitabine treatment. (MSKCC) (Phase II)
X. Examine the mutational status of a panel of genes that are commonly mutated in patients with de novo or secondary AML. (MSKCC) (Phase II)
XI. Explore somatic mutations that may be more expressed in leukemic blasts using whole exome sequencing. (MSKCC) (Phase II)
XII. Compare the JAK2 allele burden prior to and after completion of 6 cycles of treatment with ruxolitinib in both the granulocyte and mononuclear cells. (Freiburg) (Phase II)
XIII. Investigate the pattern of CD34+ cell engraftment and clonal evolution in a murine xenotransplantation system as a predictor of treatment response. (MSSM) (Phase II)
XIV. Explore novel transcripts, alternative splicing, gene fusion events, SNVs, and indels as identified by RNAseq. (MSKCC) (Phase II)
XV. Explore the effect of ruxolitinib and decitabine combination therapy on cytokine expression at specified time points. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of ruxolitinib phosphate followed by a phase II study.
Patients receive ruxolitinib phosphate orally (PO) every 12 hours on days 1-28 (days 1-35 of course 1) and decitabine intravenously (IV) over 2-3 hours on days 1-5 (days 8-12 of course 1). Treatment repeats every 28 days (35 days for course 1) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationMount Sinai Hospital
Principal InvestigatorJohn Omar Mascarenhas
- Primary IDMPD-RC 109
- Secondary IDsNCI-2014-01264, GCO 13-1816, MPD-RC 107
- ClinicalTrials.gov IDNCT02076191