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Pembrolizumab in Treating Patients with Malignant Pleural Mesothelioma That Can Be Removed by Surgery

Trial Status: Active

This pilot phase I trial studies pembrolizumab in treating patients malignant pleural mesothelioma that can be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread.

Inclusion Criteria

  • Histologically or cytologically confirmed pleural malignant mesothelioma, epithelial or biphasic subtypes
  • Disease amenable to maximal surgical debulking via extended pleurectomy/decortication as determined by a surgeon specializing in mesothelioma
  • No prior chemotherapy, targeted therapy, or immunotherapy for mesothelioma
  • Be willing and able to provide written informed consent for the trial
  • Have measurable or evaluable disease based on modified Response Evaluation Criteria in Solid Tumors (RECIST) for mesothelioma
  • If they have not previously had a video assisted thoracoscopic surgery, and they have a free pleural space to allow for a video assisted thoracoscopy surgery (VATS) procedure, then they must be willing to undergo a VATS for adequate histologic staging
  • If they have previously undergone a VATS, or they do not have a free pleural space to allow for a VATS procedure, then they must be able to undergo a computed tomography (CT) or ultrasound guided needle biopsy to obtain baseline tissue if it is feasible; if this is not anatomically feasible, then they must be able to provide at least 15 unstained slides or a tumor block from their prior biopsy
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Have adequate cardiac function as assessed by echocardiogram, with an ejection fraction (EF) > 45%
  • Have adequate pulmonary function to tolerate surgery; patients must have a diffusing lung capacity for carbon monoxide (DLCO) > 35% of predicted post operative forced expiratory volume in 1 second (FEV1) (ppoFEV1) > 35% of predicted
  • Arterial blood gas partial pressure carbon dioxide (pCO2) < 50 mmHg
  • 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]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (IULN); creatinine clearance should be calculated per institutional standard
  • Serum total bilirubin =< 1.5 X ULN
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
  • International normalized ratio (INR) or prothrombin time (PT) activated partial thromboplastin time (aPTT) =< 1.5 X ULN; patients on anticoagulation are expected to hold anticoagulation for at least 5 days prior to surgery
  • Have no extrathoracic disease by best surgical staging
  • 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 a study of an investigational agent and received an investigational agent within 4 weeks of the first dose of treatment
  • Has received any prior anticancer therapy for mesothelioma (no prior chemotherapy, immunotherapy, or targeted therapy)
  • 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 during the neoadjuvant pembrolizumab and optional adjuvant pembrolizumab stages
  • Has a known history of active TB (bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Has a known additional malignancy that is progressing or requires active treatment within the past 3 years; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids [with higher than physiologic doses] or immunosuppressive drugs); replacement therapy (e.g.: thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Has known history of, or any evidence of active, non-infectious pneumonitis that required steroids, or active pneumonitis
  • Has evidence of interstitial lung disease
  • 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 screening visit through 120 days after the last dose of trial treatment
  • 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] RNA [qualitative] is detected)
  • Is on anticoagulation that cannot be discontinued in the perioperative stage
  • Has received a live vaccine within 30 days of planned start of study therapy * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: ACTIVE
Contact: Hedy Lee Kindler
Phone: 773-702-0360

PRIMARY OBJECTIVES:

I. To determine the rate of induction of a gamma-interferon gene expression profile (GEP) using a Clinical Laboratory Improvement Act (CLIA) Nanostring nCounter based assay (performed in Merck’s CLIA laboratory) in patients with malignant pleural mesothelioma treated with pembrolizumab.

II. To determine the safety and feasibility of neoadjuvant pembrolizumab in patients with malignant pleural mesothelioma.

SECONDARY OBJECTIVES:

I. To determine 1-year progression-free survival (PFS) in patients treated with pembrolizumab via a multimodality approach (including neoadjuvant pembrolizumab, extended pleurectomy/decortication, adjuvant pemetrexed/cisplatin and if applicable adjuvant pembrolizumab).

II. To determine the median overall survival (OS) for malignant mesothelioma (MM) patients treated with pembrolizumab via a multimodality approach (including neoadjuvant pembrolizumab, extended pleurectomy/decortication, adjuvant pemetrexed/cisplatin and if applicable adjuvant pembrolizumab).

III. To determine the 1-year PFS, disease free survival (DFS) and OS for programmed cell death-ligand 1 (PD-L1) positive or TCIP-positive MM patients treated with a multimodality approach.

IV. To determine safety of adjuvant pembrolizumab treatment after surgery and adjuvant chemotherapy.

V. To determine the objective response rate to single-agent pembrolizumab via positron emission tomography (PET)/computed tomography (CT) in previously untreated MM patients, and to correlate this response with changes in the immune microenvironment.

VI. To determine the pathologic complete response rate to single agent pembrolizumab in previously untreated MM patients.

EXPLORATORY OBJECTIVES:

I. To determine changes in the density of tumor infiltrating lymphocytes (= TIL response).

II. To determine the immune micro-environmental changes induced by pembrolizumab comparing pre- and on-treatment biopsies.

III. To perform multicolor immunohistochemistry staining for PD-L1, programmed cell death 1 (PD-1), cluster of differentiation (CD)8, forkhead box P3 (FOXP3), CD163, and indoleamine 2,3-dioxygenase (IDO) on baseline tissue and surgical (on-treatment) tissue; additional immunohistochemistry (IHC) markers may be added including CD206, CD11a, CD163, inducible T-cell co-stimulator (ICOS) and related markers if appropriate based on assay availability.

IV. To provide a detailed analysis of the immune microenvironment in fresh tissue tumor samples, by performing tissue digesting and freezing of single cell suspension for analysis by flow cytometry/ CyTOF, or comparable single cell based analysis method.

V. To characterize the T-cell receptor repertoire of TILs compared to circulating T cells (spectrotyping, T-cell repertoire sequencing (e.g. using the Nakamura lab established T cell receptor [TCR] pipeline).

VI. To characterize immunogenic tumor-private mutations based on tumor and normal tissue exome sequencing, and tumor ribonucleic acid sequencing (RNAseq) analysis using an established computational pipeline for prediction and validation.

VII. To determine changes in PD-L1 expression (using the Merck developed 22C3 antibody) between baseline and after pembrolizumab (pre-/on treatment with pembrolizumab) and using established interpretation guidelines.

VIII. To determine blood based changes with pembrolizumab treatment before and during treatment, including peripheral blood mononuclear cell (PBMC) inflammation expression profile.

IX. To determine blood based changes with pembrolizumab treatment before and during treatment, including serum mesothelin (SMRP) and osteopontin.

X. To determine blood based changes with pembrolizumab treatment before and during treatment, including to collect lymphocytes to potentially react against tumor private antigens determined by immunogenic mutation testing.

XI. To explore the role of image-based textural analysis in assessing therapy-induced changes in tumor composition.

XII. To correlate tumor volume measurements based on CT with true tumor volume in pathologic specimens and to characterize the histologic subtypes based on CT imaging parameters.

XIII. To explore the role of PET/CT in differentiating tumor inflammation versus tumor progression and compare with pathologic findings.

OUTLINE:

NEOADJUVANT PEMBROLIZUMAB: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

SURGICAL INTERVENTION: Beginning 4 weeks after last dose of pembrolizumab, patients undergo surgical debulking with an extended pleurectomy/decortication.

ADJUVANT CHEMOTHERAPY: Beginning 6-8 weeks following surgery, patients receive standard of care cisplatin IV and pemetrexed IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

OPTIONAL ADJUVANT PEMBROLIZUMAB: Patients with the absence of disease progression and no residual grade 3/4 toxicities, may continue to receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks thereafter.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Hedy Lee Kindler

  • Primary ID IRB15-1149
  • Secondary IDs NCI-2016-00460
  • Clinicaltrials.gov ID NCT02707666