This phase I/II tests the safety, side effects and best dose of ruxolitinib in combination with enzalutamide and how well it works in treating patients with prostate cancer that remains despite blocking hormone production (castration-resistant) and that has spread from where it first started to other places in the body (metastatic). Ruxolitinib, a kinase inhibitor, slows down the growth of the tumor by blocking the proteins, JAK1 and JAK2, tumors use to grow. Enzalutamide, an androgen receptor inhibitor, works by blocking the effects of androgen (a male reproductive hormone). This may help stop the growth and spread of tumor cells that need testosterone to grow. Giving ruxolitinib in combination with enzalutamide may be safe, tolerable, and/or effective in treating metastatic castration-resistant prostate cancer.
Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration
Males age ≥ 18 years with progressive metastatic, castration-resistant prostate cancer, previous adenocarcinoma histology confirmation required
Ability to understand a written informed consent document, as determined by the study physician or designee
Surgical castration or continuous medical castration ≥ 8 weeks prior to screening; serum testosterone < 50 ng/dL
History of untreated (with radiotherapy and/or surgery) brain metastasis is not allowed (stable and treated metastases are allowed)
History of seizures or known hypersensitivity to enzalutamide, ruxolotinib or any of the excipients in the product
Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with the absorption of the study medications
Uncontrolled hypertension as indicated by systolic blood pressure (SBP) > 170 mmHg or diastolic blood pressure (DBP) > 105 mmHg on 2 consecutive measurements at screening visit unless known to have white coat hypertension syndrome
Single group
Biopsy
Procedure/SurgeryUndergo tissue biopsy
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Bone Scan
Procedure/SurgeryUndergo bone scan
Computed Tomography
Procedure/SurgeryUndergo CT
Enzalutamide
DrugGiven PO
Ruxolitinib
DrugGiven PO
Dose-limiting toxicity (DLT)
DLT will be defined based on the rate of drug-related grade 3-5 adverse events (AEs) experienced. AEs will be assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The proportion of patients at each dose level experiencing each grade level of toxicity will be described. To estimate the frequency and severity of AEs associated with treatment, the proportion of subjects encountering toxicity at each dose level will be reported with exact 95% binomial confidence intervals.
Maximum tolerated dose (MTD)
MTD will be defined based on the rate of drug-related grade 3-5 adverse events (AEs) experienced. MTD will be the highest dose level at which the probability of a subject experiencing a DLT during cycle 1 falls between 0.23 and 0.33.
Rate of response
To assess rate of response by PSA50 and/or RECIST 1.1 criteria of ruxolitinib in combination with enzalutamide in patients with mCRPC within the first 6 months of therapy (PSA50 confirmation not required).
Pharmacokinetics (PK) Cmax
PK will be assessed via measurement in plasma at pre-specified timepoints. PK analysis will be performed on individual serum concentration data. Serum concentrations will be listed and summarized using descriptive statistics.
Phosphorylated STAT3 (pSTAT3) percentage
Pharmacodynamics will be assessed through measurement of pSTAT3 percentage in whole blood at pre-specified timepoints.
Objective progression free survival (PFS)
PFS will be defined by Prostate Cancer Working Group 3 criteria. Median PFS will be estimated by the Kaplan-Meier method and corresponding 95% confidence interval will be derived.
Rate of response (PSA and/or radiographic)
To assess rate of response by PSA50 and/or RECIST 1.1 criteria of ruxolitinib in combination with enzalutamide in patients with mCRPC
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University of Michigan Rogel Cancer Center
Lead sponsor
Incyte Corporation
Collaborator
