A Phase II Study of the Anti-PD-1 Antibody Pembrolizumab in Patients With Malignant Mesothelioma
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Biphasic Mesothelioma
- Sponsor
- University of Chicago
- Enrollment
- 65
- Locations
- 1
- Primary Endpoint
- Ability of PD-L1 to predict response
- Status
- Active, Not Recruiting
- Last Updated
- 10 months ago
Overview
Brief Summary
This phase II trial studies how well pembrolizumab works in treating patients with malignant mesothelioma, a cancer of the linings around the lungs (pleura) or abdomen (peritoneum). Monoclonal antibodies, such as pembrolizumab, work by blocking a protein called programmed cell death 1 (PD-1) which may stimulate an immune response and kill tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the objective response rate of patients with malignant mesothelioma treated with pembrolizumab in A) an unselected patient population, as well as B) in a programmed cell death ligand 1 (PD-L1) positive population (should the trial proceed to Part B, and PD-L1 expression correlate with improved efficacy). II. To determine the optimal threshold for PD-L1 expression using the 22C3 antibody based immunohistochemistry (IHC) assay in correlation to tumor response. SECONDARY OBJECTIVES: I. To determine the progression-free survival of patients with malignant mesothelioma in A) an unselected patient population and B) a PD-L1 positive population when treated with pembrolizumab. II. To determine the overall survival of patients with malignant mesothelioma in A) an unselected patient population and B) a PD-L1 positive population when treated with pembrolizumab. III. To determine the disease control rate (complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]) of patients with malignant mesothelioma who are treated with pembrolizumab in A) an unselected patient population and B) a PD-L1 positive population. IV. To determine toxicity in patients with malignant mesothelioma who are treated with pembrolizumab. V. To determine percentage of patients with mesothelioma who have PD-L1 tumor expression, and the distribution of PD-L1 expression (percent positivity of tumor cells/stroma staining). TERTIARY OBJECTIVES: I. To characterize the T-cell inflamed phenotype in mesothelioma patients via presence of cluster of differentiation (CD)8 tumor infiltrating lymphocytes (TILs) and/or use of a gene expression signature (Nanostring). II. To evaluate other immune escape mechanisms including indoleamine-pyrrole 2,3-dioxygenase (IDO) expression, regulatory T cells (Tregs) (forkhead box P3 \[FOXP3\] expression), myeloid-derived suppressor cells (MDSCs) and other checkpoints by immunohistochemistry (or other methods e.g. flow cytometry). III. To determine PD-L1 expression by mass spectrometry and correlate with tumor response, PD-L1 expression by IHC, and the T-cell inflamed phenotype. IV. To determine the immune cell populations present in fresh tumor (when available), via tumor digests and mass spectrometry-based flow cytometric analysis (e.g. using CyTOF) in a multiplex fashion in patients with fresh tumor tissue. V. To characterize the T-cell receptor repertoire of TILs compared to circulating T-cells in mesothelioma patients with available fresh frozen tissue (spectrotyping, T-cell repertoire sequencing \[e.g. using the Adaptive platform\]). OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab. After completion of study treatment, patients are followed up for 30 days (up to 90 days for serious adverse events), every 8 weeks until patient experiences confirmed disease progression or starts a new anti-cancer therapy, and then every 12 weeks for 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed pleural or peritoneal malignant mesothelioma, epithelial, sarcomatoid, or biphasic subtypes
- •Disease progression on or after pemetrexed and cis- or carboplatin
- •ONLY FOR PART B - PD-L1 selection should a PD-L1 expression threshold have been defined in Part A and potentially additional mesothelioma trial data; there will be no PD-L1/biomarker selection for Part A
- •No more than 2 prior lines of cytotoxic therapy, which should have included pemetrexed and a platinum
- •Enrollment of treatment naïve patients who refuse standard chemotherapy or are intolerant may be permissible if reviewed and deemed clinically appropriate by the principal investigator (PI)
- •Be willing and able to provide written informed consent for the trial
- •Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for peritoneal mesothelioma, and modified RECIST for pleural mesothelioma
- •Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion; while 20 unstained slides or a tumor block are preferred, at least 14 unstained slides are requested for analysis; PI approval for a lower number of slides is acceptable
- •Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- •Absolute neutrophil count (ANC) \>= 1,500/mcL
Exclusion Criteria
- •Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks (4 weeks for monoclonal antibodies) of the first dose of treatment
- •Side effects from prior treatment have not resolved to =\< grade 1 (or baseline due to previously administered agent/pre-existing conditions)
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- •Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent
- •Note: Subjects with =\< grade 2 neuropathy are an exception to this criterion and may qualify for the study
- •Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- •Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or other indolent cancers which either have undergone curative-intent therapy or inactive (i.e. not expected to limit life expectancy or interfere with therapy)
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment
- •Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study
Arms & Interventions
Treatment (pembrolizumab)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab.
Intervention: Pembrolizumab
Treatment (pembrolizumab)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab.
Intervention: Laboratory Biomarker Analysis
Treatment (pembrolizumab)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab.
Intervention: Pharmacogenomic Study
Outcomes
Primary Outcomes
Ability of PD-L1 to predict response
Time Frame: Up to 3 years
Based on the results from Part A, the Youden Index methodology will be used to determine the optimal threshold for PD-L1 expression in correlation with tumor response, and if a correlation is identified this threshold will be used for Part B. The overall ability of PD-L1 to predict response will be assessed using the area under the receiver operating characteristic curve (area under the curve). If the area is significantly greater than 0.5, part B will begin using the optimum cutpoint as determined from the Youden index.
Secondary Outcomes
- Disease control rate (CR + PR + SD)(Up to 3 years)
- Progression free survival (PFS)(Time from enrollment until disease progression or death from any cause, assessed up to 3 years)
- Overall survival (OS)(Up to 3 years)