Ruxolitinib and Thalidomide in Treating Patients with Newly Diagnosed, Relapsed, or Refractory Myelofibrosis

This phase II trial studies how well ruxolitinib and thalidomide work in treating patients with myelofibrosis that is newly diagnosed, has come back (relapsed), or does not respond to treatment (refractory). Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Thalidomide may shrink cancer and reduce the number of blood transfusion needed. Giving ruxolitinib and thalidomide may work better in treating patients with myelofibrosis.

Inclusion Criteria

• Diagnosis of myelofibrosis (either primary or post essential thrombocythemia/polycythemia vera) requiring therapy, including those previously treated and relapsed or refractory, or if newly diagnosed, with intermediate-1 or -2 or high risk according to International Working Group (IWG) criteria
• Patients taking ruxolitinib at the time of enrollment must have been taking ruxolitinib for a minimum of 3 months, and must have been on a stable dose of ruxolitinib for a minimum of 4 weeks immediately prior to enrollment
• Patients taking ruxolitinib at the time of enrollment must be deemed to have had a suboptimal response (less than partial response per IWG criteria) to ruxolitinib single-agent therapy or deemed to have progression of disease (per IWG criteria)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Total bilirubin =< 2.0 mg/dL, unless due to Gilbert’s disease
• Serum creatinine =< 2.0 mg/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit of normal (unless the transaminitis is considered to be related to MF)
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 14 days prior to and again within 24 hours of starting thalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking thalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a condom during sexual contact with a female of child bearing potential even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure * A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) * Pregnancy test within 24 hours of thalidomide is a pre-treatment parameter
• All study participants must be registered into the mandatory Risk Evaluation and Mitigation Strategies (REMS) program, and be willing and able to comply with the requirements of REMS
• Platelets >= 50000/uL
• Absolute neutrophil count (ANC) >= 1000
• All study participants must be able to swallow oral medication

Exclusion Criteria

• Use of any other standard anti-neoplastic drug or growth factor (e.g., anagrelide, granulocyte colony-stimulating factor [G-CSF], Revlimid, clofarabine) except hydroxyurea or experimental drugs, with the exception of ruxolitinib, less than 14 days or 5-half lives prior to starting study therapy and/or lack of recovery from all toxicity from previous therapy to grade 1 or better
• Known prior clinically relevant hypersensitivity reaction to thalidomide, including the development of erythema nodosum if characterized by a desquamating rash
• Prior therapy with thalidomide in combination with ruxolitinib
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form, which places the subject at unacceptable risk if he/she were to participate in the study or which confounds the ability to interpret data from the study
• Lactating females
• Known positive for human immunodeficiency virus (HIV) or hepatitis B or C per institutional standard of care
• Participants with prior history of thromboembolic disease (i.e. deep venous thrombosis [DVT]) or pulmonary embolism [PE] within the last six months, as thalidomide has demonstrated an increased risk of DVT or PE
• Known to have a hypercoagulability syndrome (e.g.: antithrombin III, deficiency, anticardiolipin syndrome etc)
• Concurrent use of any strong inducers or strong inhibitors of CYP3A4
• Patients with active malignancy of other type than required for this study are not eligible with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast; patients with malignancies with indolent behavior such as prostate cancer treated with radiation or surgery can be enrolled in the study as long as they have a reasonable expectation to have been cured with the treatment modality received

PRIMARY OBJECTIVE:

I. To determine the efficacy of the combination of ruxolitinib with thalidomide in patients with myelofibrosis (MF) (primary myelofibrosis, post polycythemia vera myelofibrosis, or post essential thrombocythemia myelofibrosis [PMF, post-PV MF, or post-ET MF]), in achieving objective improvements in disease status.

SECONDARY OBJECTIVES:

I. To estimate the efficacy by the proportion of patients who achieve a complete response, partial response, clinical improvement, or platelet response.

II. To explore the effect of the combination on anemia and transfusion dependence in patients with MF.

III. To determine the safety of the combination in patients with MF.

EXPLORATORY OBJECTIVES:

I. To explore time to response (TTR) and duration of response (DOR).

II. To explore changes in JAK2V617F allele burden.

OUTLINE: This is dose-escalation study of ruxolitinib.

RUN-IN: Patients receive ruxolitinib orally (PO) daily on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

COMBINATION PHASE: Patients receive ruxolitinib PO daily and thalidomide PO daily on days 1-28. Treatment repeats every 28 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 60 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Raajit Kumar Rampal

• Primary ID 16-1498
• Secondary IDs NCI-2017-00448
• Clinicaltrials.gov ID NCT03069326