A Phase 1 Study of PD-1 Inhibition With Pembrolizumab Combined With JAK2 Inhibition in Triple Negative Breast Cancer
Overview
- Phase
- Phase 1
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Metastatic Malignant Neoplasm in the Bone
- Sponsor
- Mayo Clinic
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of ruxolitinib phosphate when given together with pembrolizumab in treating patients with stage IV triple negative breast cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and ruxolitinib phosphate together may work better in treating patients with stage IV triple negative breast cancer.
Detailed Description
PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) of ruxolitinib phosphate (ruxolitinib) (JAK2 inhibition) in combination with fixed dosing of pembrolizumab (anti PD-1) in patients with advanced/metastatic triple negative breast cancer (TNBC). SECONDARY OBJECTIVES: I. To determine the safety profile of pembrolizumab in combination with ruxolitinib. II. To estimate clinical tumor response in women with TNBC treated with pembrolizumab in combination with ruxolitinib as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. EXPLORATORY/CORRELATIVE OBJECTIVES: I. To assess tumor response with immune related (ir)RECIST and associations with PDJ amplification, PD-L1, PD-L2, JAK2 and phosphorylated (p)STAT3 expression. II. To determine the effect of combination targeted blockade on T- and B- cell immunity to breast cancer tumor antigens. OUTLINE: This is a dose-escalation study of ruxolitinib phosphate. Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and ruxolitinib phosphate orally (PO) twice daily (BID) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study, patients are followed up every 3 or 6 months for up to 2 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age \>= 18 years
- •Metastatic (stage IV) triple negative breast cancer that has progressed after at least one prior chemotherapy regimen in the metastatic setting or refusal of chemotherapy in the metastatic setting; non-measurable disease (i.e. bone metastases) is permitted
- •Histological confirmation of triple negative breast cancer defined as:
- •Her2/neu by fluorescence in situ hybridization (FISH) (ratio =\< 1.8) or immunohistochemistry (IHC) (0 or 1+)
- •Estrogen receptor (ER) and progesterone receptor (PR) expression \< 10%
- •Absolute neutrophil count (ANC) \>= 1500/mm\^3 (obtained =\< 7 days prior to registration)
- •Platelet count \>= 100,000/mm\^3 (obtained =\< 7 days prior to registration)
- •Total bilirubin =\< 1.5 x upper limit normal (ULN) (obtained =\< 7 days prior to registration)
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN or \< 5 x ULN if organ involvement (obtained =\< 7 days prior to registration)
- •Alkaline phosphatase \< 5 x ULN (obtained =\< 7 days prior to registration)
Exclusion Criteria
- •Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, known positive for active infectious hepatitis, type A, B or C (past infection allowed), or psychiatric illness/social situations that would limit compliance with study requirements; Note: ongoing infection controlled on antibiotics/antifungal/antiviral medications are allowed
- •Any of the following prior therapies:
- •Cytotoxic chemotherapy =\< 14 days prior to registration
- •Immunotherapy =\< 14 days prior to registration
- •Biologic therapy (i.e. antibody therapies) =\< 28 days prior to registration
- •Radiation therapy =\< 14 days prior to registration
- •Targeted therapies (i.e. PARP inhibitors, =\< 7 days or 5 half-lives whichever is shorter)
- •Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =\< 14 days prior to registration
- •Active uncontrolled central nervous system (CNS) metastases
- •Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive
Arms & Interventions
Treatment (pembrolizumab, ruxolitinib phosphate)
Patients receive pembrolizumab IV over 30 minutes on day 1 and ruxolitinib phosphate PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (pembrolizumab, ruxolitinib phosphate)
Patients receive pembrolizumab IV over 30 minutes on day 1 and ruxolitinib phosphate PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pembrolizumab
Treatment (pembrolizumab, ruxolitinib phosphate)
Patients receive pembrolizumab IV over 30 minutes on day 1 and ruxolitinib phosphate PO BID on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Ruxolitinib Phosphate
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Up to 28 days after last dose of study drug
Assessed by NCI CTCAE version 4.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns (by cohort and overall). Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The rate of grade 3 or higher non-hematologic adverse events, and the rate of grade 4 or higher adverse event (hematologic and non-hematologic) will be computed each with a 95% exact binomial confidence.
Maximum tolerated dose
Time Frame: Up to 21 days
Defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients. Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Secondary Outcomes
- Best response(Up to 2 years)