Ruxolitinib Phosphate and Nilotinib in Treating Patients with Chronic Phase Chronic Myelogenous Leukemia Who Have Received Tyrosine Kinase Inhibitor Therapy and Achieved a Major Molecular Remission

Status: Temporarily Closed to Accrual

Description

This phase I / II trial studies the side effects and best dose of ruxolitinib phosphate when given together with nilotinib and to see how well they work in treating patients with chronic phase chronic myelogenous leukemia that is under good, but not perfect control on tyrosine kinase inhibitor therapy. Ruxolitinib phosphate and nilotinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Patients must have a diagnosis of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase by having met all of the following criteria at the time of their initial diagnosis * Cytogenetic confirmation of Philadelphia chromosome or variants of the t(9;22) translocations; patients may have secondary chromosomal abnormalities in addition to the Philadelphia chromosome * Peripheral blood or bone marrow blast count < 10% * Peripheral blood basophil count < 20% * Platelet count >= 100,000 x 10^9/L * If the peripheral blood counts are unavailable from the time of their original diagnosis, but there is no evidence of accelerated or blast-phase disease from prior clinical or other medical records, then they will be allowed to participate
  • Patients must be actively receiving treatment for their CML with a TKI: imatinib, dasatinib, nilotinib, or bosutinib * Patients must be on a stable dose of their TKI for at least 1 year prior to enrollment onto trial
  • White blood cells (WBC) =< 10 x 10^9/L
  • Platelet count =< 450,000 x 10^9/L
  • No blasts or promyelocytes in peripheral blood
  • No evidence of disease-related symptoms and extramedullary disease, including the liver and spleen
  • Patients must have an ongoing complete cytogenetic response (CCyR) on a TKI (imatinib, dasatinib, nilotinib, or bosutinib), defined as follows: * 0% Ph+ cells in metaphase, in the bone marrow and/or a negative peripheral blood fluorescence in situ hybridization (FISH) analysis for BCR-ABL1 gene fusion
  • Patients must be in a major molecular remission (MMR) on a TKI (imatinib, dasatinib, nilotinib, or bosutinib) for a minimum of 1 year leading up to enrollment; major molecular remission is defined as BCR-ABL1 transcripts =< 0.1% by quantitative real time polymerase chain reaction (QPCR) (International Scale [IS]) or >= 3-log reduction in BCR-ABL1 messenger ribonucleic acid (mRNA) from the standardized baseline, if QPCR (IS) is not available * MMR must be documented on at least 2 occasions, at least 3 months apart, in the 6 to 12 months leading up to enrollment
  • Serum creatinine =< 1.5 x ULN (upper limit of normal)
  • Direct bilirubin =< 1.5 x ULN except for i) patients with documented Gilbert’s syndrome for whom any bilirubin value is allowed and ii) for patients with asymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatase within normal range)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN
  • Serum amylase and lipase =< 2 x ULN
  • Alkaline phosphatase =< 2.5 x ULN
  • Potassium within normal limits prior to the first dose of study medication
  • Magnesium within normal limits prior to the first dose of study medication
  • Total calcium (corrected for serum albumin) within normal limits prior to the first dose of study medication
  • Patients must have a platelet count >= 100,000 x 10^9/L
  • Patients must have an absolute neutrophil count >= 1.5 x 10^9/L
  • Patients must have a hemoglobin >= 9 g/dL
  • Patients must avoid grapefruit, grapefruit juice, supplements containing grapefruit juice, star fruit, and Seville oranges during the entire study, starting 7 days prior to the first dose of study drug
  • Written informed consent obtained prior to any screening procedures

Exclusion Criteria

  • Patients in complete molecular remission (CMR) on a TKI (imatinib, dasatinib, nilotinib, or bosutinib); CMR is defined as no detectable BCR-ABL1 mRNA by QPCR (IS) using as assay with a sensitivity >= 4.5 logs below the standardized baseline
  • Atypical BCR-ABL1 mRNA transcripts that cannot be monitored with QPCR
  • Patients who have failed nilotinib or not tolerated nilotinib in the past
  • Patients with previously documented BCR-ABL Kinase Domain mutations that confer resistance to nilotinib; this includes, but is not limited to, the T315I mutation
  • Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise adherence to the protocol (e.g. uncontrolled diabetes, uncontrolled infection, etc.)
  • Cardiovascular disorders such as: * Inability to monitor the QT interval on electrocardiogram (ECG) * Complete left bundle branch block * Right bundle branch block plus left anterior or posterior hemiblock * Use of a ventricular-paced pacemaker * Congenital long QT syndrome or a known family history of long QT syndrome * Clinically significant resting bradycardia (< 50 beats per minute) * Corrected QT interval (QTc) > 450 msec on baseline ECG; if QTc > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc * Myocardial infarction within 6 months prior to starting study * History of unstable angina within 6 months prior to study entry * Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension) * History of or presence of clinically significant ventricular or atrial tachyarrhythmias
  • Patients currently receiving treatment with strong CYP3A4 inhibitors and treatment cannot be either discontinued or switched to a different medication prior to starting study drug
  • Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry; these herbal medicines may include Echinacea (including Echinacea [E.] purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John’s Wort, and Ginkgo
  • At enrollment, patients currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
  • Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery)
  • Acute or chronic pancreatic disease within the last year prior to enrollment
  • Known cytopathologically confirmed central nervous system (CNS) infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required)
  • Another primary malignant disease, which requires systemic treatment (chemotherapy or radiation)
  • Acute or chronic liver disease or severe renal disease considered unrelated to the cancer
  • History of significant congenital or acquired bleeding disorder unrelated to cancer
  • Major surgery within 4 weeks prior to day 1 of the study or who have not recovered from prior surgery
  • Treatment with ruxolitinib or other JAK inhibitor in the past
  • Treatment with other investigational agents within 30 days of day 1
  • History of non-adherence to medical regimens or inability to grant consent
  • Women who are breastfeeding
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 30 days after the final dose of nilotinib; highly effective contraception is defined as either: * Total abstinence (when this is in line with the preferred and usual lifestyle of the patient); periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Male sterilization (at least 6 months prior to enrolling); for female patients on the study the vasectomized male partner should be the sole partner for that patient * Use of a combination of any two of the following: ** Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception ** Placement of an intrauterine device (IUD) or intrauterine system (IUS) ** Barrier methods of contraception: Condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
  • Men who are unwilling to employ adequate contraception measures during the study and for 30 days after the final dose of study therapy
  • In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment; women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to enrolling; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential; if a study patient becomes pregnant or suspects being pregnant during the study or within 30 days after the final dose of nilotinib, the study doctor needs to be informed immediately and ongoing study treatment with nilotinib/ruxolitinib must be stopped immediately

Locations & Contacts

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Temporarily closed to accrual
Contact: Patrick William Burke
Phone: 734-647-8921
Email: pwburke@med.umich.edu

North Carolina

Winston-Salem
Wake Forest University Health Sciences
Status: Approved
Contact: Rupali Roy Bhave
Email: Rbhave@wakehealth.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD) of ruxolitinib phosphate (ruxolitinib) when combined with nilotinib 300 mg twice daily (BID) in treatment of patients with chronic phase chronic myelogenous leukemia (CML) who are currently in complete hematologic response (CHR), complete cytogenetic response (CCyR), and major molecular remission (MMR) but not complete molecular remission (CMR) while on tyrosine kinase inhibitor (TKI) monotherapy (imatinib, dasatinib, nilotinib, or bosutinib). (Phase I)

II. To investigate whether patients with chronic phase CML who have achieved CHR, CCyR, and MMR but not a CMR on imatinib, dasatinib, nilotinib or bosutinib monotherapy can then be treated with a combination of the TKI, nilotinib—dosed at 300 mg BID, and the JAK1/2 inhibitor, ruxolitinib, and subsequently achieve a deeper remission (CMR). (Phase II)

SECONDARY OBJECTIVES:

I. To measure the toxicity and tolerability of the combination regimen of the TKI, nilotinib, and the JAK1/2 inhibitor, ruxolitinib, in patients with chronic phase CML.

TERTIARY OBJECTIVES:

I. To determine the pharmacodynamic effect the addition of ruxolitinib to nilotinib has on STAT activation and signaling.

II. To determine what effect the addition of ruxolitinib to nilotinib has on the degree of persistent Philadelphia chromosome positive cells within the CD34+ fraction of bone marrow aspirate.

III. To determine what effect the addition of ruxolitinib to nilotinib has on patients’ CD34+ cell colony-forming ability and whether there is a depletion of BCR-ABL positive colonies.

OUTLINE: This is a phase I, dose escalation study of ruxolitinib phosphate followed by a phase II study.

Patients receive ruxolitinib phosphate orally (PO) BID on days 1-28 and nilotinib PO BID on days 1-28. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients that achieve a CMR after 12 courses may continue to receive ruxolitinib phosphate and nilotinib for up to 2 years in the absence of disease progression or unacceptable toxicity.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Patrick William Burke

Trial IDs

Primary ID UMCC 2015.103
Secondary IDs NCI-2017-02495
Clinicaltrials.gov ID NCT02973711