Primary Outcome
-
- Ability of PD-L1 to predict response [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
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 Outcome Measures
- Overall survival (OS) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
Kaplan-Meier curves will be generated for OS. Median OS will be estimated along with 90% confidence intervals using the method of Brookmeyer and Crowley.
- Progression free survival (PFS) [ Time Frame: Time from enrollment until disease progression or death from any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
Kaplan-Meier curves will be generated for PFS. Median PFS will be estimated along with 90% confidence intervals using the method of Brookmeyer and Crowley. - Disease control rate (CR + PR + SD) [ Time Frame: Up to 3 years ] [ Designated as safety issue:
No ] - The disease control rate (CR+PR+SD) and 90% confidence interval will also be determined.
-
Other Outcome Measures
- CD8 TILs will be assessed by percentage of tumor showing infiltration [ Time Frame: Baseline ] [ Designated as safety issue: No ]
- CD8 levels will be correlated with PD-L1 expression using Pearson or Spearman rank correlation coefficients.
- Composite measure of other immune escape mechanisms including MDSCs and other checkpoints [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
- Other immune escape mechanisms including MDSCs and other checkpoints will be assessed by immunohistochemistry (0 – 3+) or flow cytometry counting the number and percentage of positive cells. Levels will be correlated with PD-L1 expression and other biomarkers.
- PD-L1 expression by mass spectrometry [ Time Frame: Baseline ] [ Designated as safety issue: No ]
PD-L1 expression by mass spectrometry and correlation with PD-L1 expression by IHC as well as tumor response, and the T-cell inflamed phenotype will be performed. Multivariate logistic regression will be performed to determine whether these biomarkers or combinations of biomarkers are predictive of response. Exact logistic regression models will be fit given the small number of responders expected (4 from part A and 7-8 from part B). - Mass spectrometry-based flow cytometric analysis [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ] Mass spectrometry-based flow cytometric analysis (CyTOF) will be descriptive based on number and percentage of certain cell populations.
- Analysis of T-cell receptor repertoire from TILs [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ] Analysis of T-cell receptor repertoire from TILs will be descriptive looking for presence or absence of oligoclonal T-cell population.
- Duration of response [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
Will be estimated by Kaplan-Meier. - Incidence of toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ] Toxicities will be summarized in tabular form by type and severity and incidence rates generated.
-
Eligibility
- 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
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 50 mL/min for subject with creatinine levels > 1.5 X institutional ULN; creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
- 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 for subjects with liver metastases
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
- 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
- Has evidence of interstitial lung disease or active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Has received a live vaccine within 30 days prior to the first dose of trial treatment
