Combination of immunotherapy and chemotherapy for mesothelioma treatment

Combination of Induction Durvalumab and Tremelimumab Alone Versus Durvalumab and Tremelimumab With Chemotherapy for Potentially Resectable Pleural Mesothelioma

This study is testing whether combining two immunotherapy drugs with chemotherapy can help people with a type of lung cancer called mesothelioma live longer without their cancer coming back.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 52 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Baylor College of Medicine (Academic / other)
• Drugs / interventions: durvalumab, tremelimumab, chemotherapy, immunotherapy, radiation, prednisone
• Locations: 2 sites (Durham, North Carolina and 1 other locations)
• Trial ID: NCT05932199 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the effectiveness of combining durvalumab and tremelimumab with platinum-based chemotherapy and pemetrexed in patients with resectable malignant pleural mesothelioma (MPM). The study will be conducted in two arms, one receiving dual immunotherapy alone and the other receiving the combination with chemotherapy. The primary goal is to improve recurrence-free survival compared to historical data, while secondary objectives focus on safety and response rates. The trial will enroll a total of 52 patients, with an initial safety assessment based on surgical resection rates.

Who should consider this trial

Good fit: Ideal candidates are patients with potentially resectable MPM of any histology and without significant disease spread beyond the ipsilateral hemithorax.

Not a fit: Patients with unresectable MPM or those with extensive disease spread may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly improve survival outcomes for patients with malignant pleural mesothelioma.

How similar studies have performed: Other studies have shown promise with similar immunotherapy approaches, but this specific combination is being evaluated for the first time.

Eligibility criteria

Inclusion Criteria:

1. Potentially Surgically resectable 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 or mediastinum. Surgical evaluation for resectability by an experienced mesothelioma surgeon 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 above criteria, patients will undergo planned resectional surgery for MPM \[extrapleural pneumonectomy (EPP) or pleurectomy and decortication (P/D)\]
2. Any MPM histology (epithelial, mixed, sarcomatoid)

   1. N0 or N1 nodal disease, as present on preoperative chest CT and/or PET/CT
   2. N2 nodal disease.
3. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
4. Age \> 18 years at time of study entry
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. Adequate normal organ and marrow function as defined below: Hemoglobin ≥ 9.0 g/dL; Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (\> 1500 per mm3); Platelet count ≥ 100 × 109/L (\>100,000 per mm3); Serum bilirubin ≤ 1.5× institutional upper limit of normal (ULN)AST \<3.0; Creatinine clearance \>50mL/miN; Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (≤ 5 × 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.

   Males:

   Creatinine CL (mL/min) = Weight (kg) × (140 - Age) 72 × serum creatinine (mg/dL)

   Females:

   Creatinine CL (mL/min) = Weight (kg) × (140 - Age) × 0.85 72 × serum creatinine (mg/dL)
7. 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.
8. 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.
9. Weight \>30 Kg

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) or previous enrollment or randomization in the present study.
2. Participation in another clinical study with an investigational product during the last 3 months.
3. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.
4. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, or other investigational agent) \<28 days
5. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.
6. 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.
7. Any unresolved toxicity (\>CTCAE grade 2) from previous anti-cancer therapy from diseases other than MPM.
8. 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.
9. Known auto-immune conditions requiring systemic immune suppression therapy other than prednisone \< 10 mg daily (or equivalent).
10. History of interstitial pneumonitis of autoimmune etiology (including immune checkpoint pneumonitis) which has been symptomatic and/or treatment in the past. Any evidence of current ILD or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids.
11. History of primary immunodeficiency.
12. History of allogeneic organ transplant.
13. 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.
14. Concurrent severe and/or uncontrolled medical conditions which may compromise participation in the study, including impaired heart function or clinically significant heart disease.
15. A concurrent diagnosis of a separate malignancy is allowed if clinically stable and does not require tumor-directed therapy.
16. 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.
17. 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.
18. History of leptomeningeal carcinomatosis.
19. Receipt of live attenuated vaccination within 30 days prior to receiving durvalumab or + tremelimumab.
20. Female subjects who are pregnant, breastfeeding, or male or female subjects of reproductive potential who are not employing an effective method of birth control.
21. 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.
22. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids.
23. Subjects with uncontrolled seizures.
24. No tissue is obtainable at the time of thoracoscopy.

Where this trial is running

Durham, North Carolina and 1 other locations

• Duke Cancer Institute — Durham, North Carolina, United States (Not_yet_recruiting)
• Baylor St Lukes — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Robert Ripley, MD — Baylor College of Medicine
• Study coordinator: Monica Vilchis

Conditions Mesothelioma