Phase I/II Trial of Pembrolizumab in Combination With Binimetinib in Unresectable Locally Advanced or Metastatic Triple Negative Breast Cancer
Overview
- Phase
- Phase 1
- Intervention
- Binimetinib
- Conditions
- Breast Adenocarcinoma
- Sponsor
- Mayo Clinic
- Enrollment
- 23
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD) of Pembrolizumab in Combination With Binimetinib Using the Standard 3+3 Design (Phase I)
- Status
- Completed
- Last Updated
- 10 months ago
Overview
Brief Summary
This phase I/II trial studies the best dose of pembrolizumab and binimetinib and how well it works when given together with pembrolizumab in treating patients with triple negative breast cancer that has spread to other parts of the body (metastatic). 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. Binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and binimetinib may work better in treating patients with triple negative breast cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of binimetinib in combination with pembrolizumab. (Phase I) II. To evaluate the objective response rate (ORR) of binimetinib in combination with pembrolizumab in patients with unresectable locally advanced or metastatic triple negative breast cancer by Response Evaluation Criteria in Solid Tumors (RECIST). (Phase II) SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of binimetinib in combination with pembrolizumab. II. To evaluate the ORR by immune-related RECIST criteria (irRECIST). III. To evaluate the progression free survival (PFS), duration of response (DoR), and disease control rate (DCR) by RECIST and irRECIST. IV. To assess overall survival (OS). CORRELATIVE RESEARCH OBJECTIVES: I. To assess the correlation between ORR, PFS, or OS and baseline and/or change in tumor infiltrating lymphocytes (TILs). II. To assess the correlation between ORR, PFS, or OS and baseline and/or change in immune related gene signature and PDJ amplification. III. To assess the change in immunoregulatory cells (IRC). IV. To assess the change in the cytokine profile. V. To assess the change in circulating tumor cells (CTC). OUTLINE: This is phase I, dose-escalation study of binimetinib followed by a phase II study. Patients receive binimetinib orally (PO) twice daily (BID) on days 1-14 of cycle 1 and on days 1-21 of cycle 2 and subsequent cycles. Beginning cycle 2, patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycle 1 equals 14 days. Cycles 2 and beyond repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months until progressive disease, then every 6 months for up to 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age \>= 18 years
- •Histological confirmation of adenocarcinoma of the breast
- •Estrogen receptor (ER) and progesterone receptor (PR) negative; defined as ER =\< 10% and PR =\< 10% staining by immunohistochemistry (IHC)
- •HER2 negative in the primary or metastatic tumor tissue defined as:
- •Immunohistochemistry (IHC) grade 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within =\< 10% of the invasive tumor cell; OR
- •IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within \> 10% of the invasive tumor cell; OR
- •IHC grade 2+ staining intensity by means of IHC analysis with no gene amplification below; OR
- •No gene amplification on in situ hybridization (ISH) based on:
- •Single-probe average HER2 copy number \< 4.0 signals/cell OR
- •Dual-probe HER2/CEP17 ratio \< 2.0 with an average HER2 copy number \< 4.0 signals/cell
Exclusion Criteria
- •Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
- •Pregnant women
- •Nursing women
- •Men or women of childbearing potential who are unwilling to employ adequate contraception
- •Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm OR participated in a study of an investigational agent, received study therapy or used an investigational device =\< 4 weeks prior to registration
- •Immunocompromised patients and patients with known immunodeficiency; or receiving systemic steroid therapy or any other immunosuppressive therapy =\< 7 days prior to registration; NOTE: inhaled steroids and low-dose corticosteroids are allowed
- •History of active tuberculosis (TB), human immunodeficiency virus (HIV), active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) and/or active hepatitis C infection (e.g. hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] qualitative is detected)
- •Received a live vaccine =\< 30 days prior to registration; NOTE: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines, and are not allowed
- •Hypersensitivity to pembrolizumab, binimetinib, or any excipients of either drug
- •Prior anti-cancer therapy with a monoclonal antibody (mAb) =\< 4 weeks prior to registration OR failure to recover (to =\< grade 1) from adverse events (AE) attributable to agents received \> 4 weeks prior to registration
Arms & Interventions
Treatment (binimetinib, pembrolizumab)
Patients receive binimetinib PO BID on days 1-14 of cycle 1 and on days 1-21 of cycle 2 and subsequent cycles. Beginning cycle 2, patients also receive pembrolizumab IV over 30 minutes on day 1. Cycle 1 equals 14 days. Cycles 2 and beyond repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Binimetinib
Treatment (binimetinib, pembrolizumab)
Patients receive binimetinib PO BID on days 1-14 of cycle 1 and on days 1-21 of cycle 2 and subsequent cycles. Beginning cycle 2, patients also receive pembrolizumab IV over 30 minutes on day 1. Cycle 1 equals 14 days. Cycles 2 and beyond repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (binimetinib, pembrolizumab)
Patients receive binimetinib PO BID on days 1-14 of cycle 1 and on days 1-21 of cycle 2 and subsequent cycles. Beginning cycle 2, patients also receive pembrolizumab IV over 30 minutes on day 1. Cycle 1 equals 14 days. Cycles 2 and beyond repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) of Pembrolizumab in Combination With Binimetinib Using the Standard 3+3 Design (Phase I)
Time Frame: 35 days
Will be assessed by Common Terminology Criteria for Adverse Events version 4.0. Safety/adverse events data will be tabulated, including adverse events of all grades.
Objective Response Rate (ORR) as (Phase II)
Time Frame: 3 years
Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Will utilize Simon's Two-Stage Optimal Design to test the null hypothesis. Will be estimated using the approach of Jung and Kim. The 90% lower confidence bound will be calculated using the approach of Koyama and Chen. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Secondary Outcomes
- ORR by Immune-related RECIST Criteria (irRECIST)(Up to 3 years)
- Progression Free Survival (PFS)(The time from study enrollment to date of progression, assessed up to 3 years)
- Overall Survival (OS)(The time from study enrollment to death attributable to any cause, assessed up to 3 years)