Durvalumab and Tremelimumab with or without Chemotherapy for the Treatment of Potentially Resectable Pleural Mesothelioma
This phase Ib/IIa trial tests the safety, side effects and effectiveness of durvalumab and tremelimumab with or without chemotherapy (cisplatin, carboplatin, pemetrexed) in treating patients with pleural mesothelioma that may be removed by surgery (resectable). Durvalumab and tremelimumab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by stopping cells from using folic acid to make DNA and may kill cancer cells. Durvalumab and tremelimumab with or without chemotherapy may be safe, tolerable and/or effective in treating patients with potentially resectable pleural mesothelioma.
Inclusion Criteria
- Potentially Surgically resectable suspected or confirmed MPM * Computed tomography (CT) and positron emission tomography (PET) without disease beyond ipsilateral hemithorax * CT and PET scan without obvious invasion through the chest wall and mediastinum * Surgical evaluation for resectability by experienced mesothelioma surgeons to assess whether tumor appears resectable on CT and PET. (Final resectability determination is based on intra-operative exploratory thoracotomy to assess chest wall and/or mediastinal invasion that is not apparent based on pre-operative radiological assessment. Given this assessment after enrollment, this determination will be utilized for the safety phase) * Based on the above criteria, patients will undergo planned resectional (cytoreductive) 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 CT and/or PET/CT * N2 nodal disease * Histology and subtype may be confirmed after enrollment based on thorascopic biopsy if the pathological diagnosis is not confirmed prior to referral
- Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
- Age ≥ 18 years at time of study entry
- 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) < 3.0
- Creatinine clearance > 50mL/min
- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if documented liver metastases are present)
- Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation
- 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
- The 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
- Weight > 30 Kg
Exclusion Criteria
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study sites) or 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 durvalumab
- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) < 28 days
- Clinically significant electrocardiogram (ECG) at the investigators discretion
- Current or prior use of immunosuppressive medication within 28 days before the infusion with durvalumab or durvalumab + tremelimumab 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 from diseases other than MPM
- Any prior grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1 for disease other than MPM. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids
- Known auto-immune conditions requiring systemic immune suppression therapy other than prednisone < 10 mg daily (or equivalent)
- History of interstitial pneumonitis of autoimmune etiology (including immune checkpoint pneumonitis) which has been symptomatic and/or treatment in the past
- History of primary immunodeficiency
- History of allogeneic organ transplant
- Intolerance of anti- PD-1/PD-L1 or CTLA-4 axis drug(s), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immune-stimulatory anti-tumor agents
- Concurrent severe and/or uncontrolled medical conditions which may compromise participation in the study, including impaired heart function or clinically significant heart disease
- A concurrent diagnosis of a separate malignancy is allowed if clinically stable and does not require tumor-directed therapy
- Known history of HIV seropositivity or known acquired immunodeficiency syndrome (AIDS), hepatitis C virus (allowed if received curative therapy), acute or chronic active hepatitis B infection, or other serious chronic infection requiring ongoing treatment
- Current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment on day 1 of study drug. Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract infection or chronic obstructive pulmonary disease) are eligible
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to receiving durvalumab + tremelimumab
- Female subjects who are pregnant, breastfeeding, 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 the evaluation of the study treatment or interpretation of subject safety or study results
- Presence of brain metastases regardless of whether controlled or not
- Subjects with uncontrolled seizures
- No tissue is obtainable at the time of thoracoscopy
Additional locations may be listed on ClinicalTrials.gov for NCT05932199.
Locations matching your search criteria
United States
Texas
Houston
PRIMARY OBJECTIVE:
I. To test whether the combination of platinum-based chemotherapy and pemetrexed with durvalumab / tremelimumab or durvalumab / tremelimumab alone improves recurrence-free survival for patients with resectable malignant pleural mesothelioma (MPM) compared to historical, published data for surgery with chemotherapy.
SECONDARY OBJECTIVE:
I. To determine the safety of and whether the platinum-based chemotherapy and pemetrexed with durvalumab / tremelimumab or durvalumab / tremelimumab alone improves response rate, resectability, major pathological response, and complete pathological response.
EXPLORATORY OBJECTIVE:
I. To determine the safety of and whether the platinum-based chemotherapy and pemetrexed with durvalumab / tremelimumab or durvalumab / tremelimumab alone improves response rate, resectability, major pathological response, and complete pathological response for patients with epithelioid and non-epithelioid histologies.
SCIENTIFIC EXPLORATORY OBJECTIVES:
I. Develop an next-generation sequencing (NGS) plasma assay of common mutations identified from our previous grant cycle to prospectively measure minimal residual disease (MRD) after resection as a potential, novel biomarker test in mesothelioma.
II. Determine the predictive role of BH3 profiling in patients undergoing neoadjuvant immune-checkpoint inhibitor (ICI) followed by surgery.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive durvalumab intravenously (IV) over 1 hour and tremelimumab IV over 1 hour on day 1 of each cycle. Cycles repeat every 21 days for 3 cycles. Patients then undergo surgical resection 4-8 weeks later. Within two months of surgery, patients receive durvalumab IV and tremelimumab IV on day 1 of each cycle. Cycles repeat every 28 days for up to an additional 2 cycles of tremelimumab and up to a total of 12 months of durvalumab in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo computed tomography (CT) or magnetic resonance imaging (MRI), and blood sample collection on study.
ARM II: Patients receive durvalumab IV over 1 hour, tremelimumab IV over 1 hour, cisplatin IV or carboplatin IV, and pemetrexed IV over 10 minutes on day 1 of each cycle. Cycles repeat every 21 days for 3 cycles. Patients then undergo surgical resection 4-8 weeks later. Within two months of surgery, patients receive durvalumab IV and tremelimumab IV on day 1 of each cycle. Cycles repeat every 28 days for up to 2 additional cycles of tremelimumab and up to a total of 12 months of durvalumab in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT or MRI, and blood sample collection on study.
After completion of study treatment, patients are followed up every 3 months.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationBaylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Principal InvestigatorRobert Taylor Ripley
- Primary IDNEMO
- Secondary IDsNCI-2024-04597, H-51512
- ClinicalTrials.gov IDNCT05932199