Durvalumab with or without Tremelimumab in Treating Participants with Resectable Malignant Pleural Mesothelioma

Status: Active

Description

This phase II trial studies how well durvalumab with or without tremelimumab works in treating participants with malignant pleural mesothelioma that can be removed by surgery. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread.

Eligibility Criteria

Inclusion Criteria

  • Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States of America [USA], European Union [EU] data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Hemoglobin ≥ 9.0 g/dL
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (≥ 1500 per mm^3)
  • Platelet count ≥ 100 x 10^9/L (≥ 100,000 per mm^3)
  • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5 x ULN
  • Serum creatinine clearance (CL) > 50 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
  • Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: ≥ 60 years old and no menses for ≥ 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
  • Surgically resectable malignant pleural mesothelioma (MPM) with no disease extension beyond the ipsilateral hemithorax
  • Planned resectional surgery for MPM (extrapleural pneumonectomy [EPP] or pleurectomy and decortication [P/D])
  • Any MPM histology (epithelial, mixed, sarcomatoid) * N0 or N1 nodal disease as present on preoperative chest computed tomography (CT) and/or positron emission tomography (PET)-CT * N2 nodule disease if no progression after 2 cycles of standard chemotherapy; progression will be considered if additional N1 or N2 disease develop during chemotherapy

Exclusion Criteria

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site); previous enrollment or randomization in the present study
  • Participation in another clinical study with an investigational product during the last 3 months
  • Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736
  • Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 30 days prior to the first dose of study drug 30 days prior to the first dose of study drug for subjects who have received prior tyrosine kinase inhibitors (TKIs) (e.g., erlotinib, gefitinib and crizotinib) and within 6 weeks for nitrosourea or mitomycin C
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
  • Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2) from previous anti-cancer therapy
  • Any prior grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved immune related adverse events (irAE) > grade 1
  • Active or prior documented autoimmune disease within the past 2 years; NOTE: subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
  • Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
  • History of primary immunodeficiency
  • History of allogeneic organ transplant
  • History of hypersensitivity to MEDI4736 or any excipient
  • History of hypersensitivity to tremelimumab or the combination of MEDI4736 + tremelimumab
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Known history of previous clinical diagnosis of tuberculosis
  • History of leptomeningeal carcinomatosis
  • Receipt of live attenuated vaccination within 30 days prior to study entry or within 6 months of receiving MEDI4736 or MEDI + tremelimumab
  • Receipt of drugs with laxative properties and herbal or natural remedies for constipation within 90 days of receiving MEDI4736 or MEDI + tremelimumab
  • Receipt of sunitinib within 3 months of receiving tremelimumab
  • Female subjects who are pregnant, breast-feeding or male or female subjects of reproductive potential who are not employing an effective method of birth control
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
  • Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids
  • Subjects with uncontrolled seizures
  • N3 nodal disease
  • History of interstitial lung disease/pneumonitis
  • No tissue is obtainable at thoracoscopy

Locations & Contacts

Texas

Houston
Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center
Status: Active
Contact: Bryan Michael Burt
Phone: 713-798-8266
Email: Bryan.Burt@bcm.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Comparison of the ratio of intratumoral cytotoxic T cells to regulatory T cells (CD8/Treg) before and after treatment with combination durvalumab (MEDI-4736) and tremelimumab checkpoint inhibitor therapy.

SECONDARY OBJECTIVES:

I. Comparison of the percentage of inducible T-cell co-stimulator (ICOS) positive intratumoral CD4 T cells before and after treatment with combination MEDI-4736 and tremelimumab checkpoint inhibitor therapy.

II. Comparison of tumor tissue expression (Ventana assay) of programmed death-ligand 1 (PD-L1) before and after treatment with combination MEDI-4736 and tremelimumab checkpoint inhibitor therapy.

III. Comparison of the ratio of the intratumoral CD8/Treg ratio in patients treated with combination therapy (MEDI-4736 and tremelimumab) compared to either patients treated with MEDI-4736 alone, and separately compare to untreated patients.

IV. Comparison of the percentage of inducible T-cell co-stimulator (ICOS) positive intratumoral CD4 T cells in patients treated with combination therapy (MEDI-4736 and tremelimumab) compared to either patients treated with MEDI-4736 alone, and separately compare to untreated patients.

V. Comparison of tumor tissue expression (Ventana assay) of programmed death-ligand 1 (PD-L1) in patients treated with combination therapy (MEDI-4736 and tremelimumab) compared to either patients treated with MEDI-4736 alone, and separately compare to untreated patients.

VI. Comparison of overall survival in patients treated with either MEDI-4736 alone or MEDI-4736 plus tremelimumab with historical untreated controls.

VII. Comparison of recurrence-free survival in patients treated with either MEDI-4736 alone or MEDI-4736 plus tremelimumab with historical untreated controls.

OUTLINE: Participants are randomized to 1 of 3 arms.

ARM I: Participants receive durvalumab intravenously (IV) over 60 minutes.

ARM II: Participants receive durvalumab IV over 60 minutes and tremelimumab IV.

ARM III: Participants do not receive durvalumab or tremelimumab.

Beginning 1 to 6 weeks after infusion, all participants undergo extrapleural pneumonectomy or pleurectomy/decortication.

After completion of study treatment, participants are followed up at 1, 2, 4 weeks, then every 4 months thereafter.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center

Principal Investigator
Bryan Michael Burt

Trial IDs

Primary ID H-36952
Secondary IDs NCI-2018-00719
Clinicaltrials.gov ID NCT02592551