Trial Title:
Neoadjuvant Durvalumab and Tremelimumab With and Without Chemotherapy for Mesothelioma
NCT ID:
NCT05932199
Condition:
Mesothelioma
Conditions: Official terms:
Mesothelioma
Mesothelioma, Malignant
Carboplatin
Pemetrexed
Durvalumab
Tremelimumab
Antibodies, Monoclonal
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Durvalumab / tremelimumab
Description:
Durvalumab concentrate for solution for infusion will be supplied in glass vials
containing 500 mg durvalumab at a concentration of 50 mg/mL.
Tremelimumab concentrate for solution for infusion will be supplied in glass vials
containing 400 mg or 25 mg tremelimumab at a concentration of 20 mg/mL.
Arm group label:
Induction dual immunotherapy with durvalumab / tremelimumab
Intervention type:
Drug
Intervention name:
Platinum cisplatin or carboplatin and pemetrexed chemotherapy plus durvalumab/tremelimumab
Description:
Cisplatin 75mg/ m2 (or carboplatin AUC 5-6) + pemetrexed 500 mg/m2 will be provided as
per standard of care.
Durvalumab concentrate for solution for infusion will be supplied in glass vials
containing 500 mg durvalumab at a concentration of 50 mg/mL.
Tremelimumab concentrate for solution for infusion will be supplied in glass vials
containing 400 mg or 25 mg tremelimumab at a concentration of 20 mg/mL.
Arm group label:
Platinum cisplatin or carboplatin and pemetrexed chemotherapy plus durvalumab/tremelimumab
Summary:
Objectives: The investigators will test whether combination of chemoimmunotherapy or dual
agent immunotherapy alone improves efficacy for patients with MPM.
Primary Objectives:
The primary objective is 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 MPM compared to historical,
published data for surgery with chemotherapy.
Secondary Objective(s):
The secondary objectives are 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(s):
The exploratory objectives are 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.
The scientific exploratory objectives include:
1. Develop an 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.
2. Determine the predictive role of BH3 profiling in patients undergoing neoadjuvant
ICI followed by surgery: With patient samples collected from our neoadjuvant ICI
trial, the investigators will test whether BH3 profiling from pre-treatment tumor
biopsies and PBMC predicts clinical, radiological, and pathological responses to
ICIs. The investigators will identify TAMs from the TiME in MPM tumor samples before
and after treatment to compare differences in polarization induced by ICI in
clinical and pathologically responding versus non-responding patients.
Detailed description:
Study Design:
The study will be a two-arm, randomized non-comparative Phase Ib/IIa study of induction
dual immunotherapy with durvalumab/tremelimumab OR platinum chemotherapy (cisplatin or
carboplatin) and pemetrexed chemotherapy plus dual immunotherapy with
durvalumab/tremelimumab for 3 cycles in untreated, potentially resectable malignant
pleural mesothelioma for all histologic subtypes and regardless PDL1 score. Patients will
continue adjuvant durvalumab for up to 12 months following surgery. Tremelimumab will be
given up to cycle 5 on treatment protocol. The investigators will enroll 6 patients to
each arm to assess safety and resectability. If differences are not noted between the two
arms, the investigators will expand enrollment to 23 patients per arm. To account for up
to 10% unevaluable patients, the investigators will enroll at total of 52 patients.
Safety in the first 6 patients in the chemotherapy plus immunotherapy arm will be
determined by rate of attempted surgical resection. If 4 or more patients undergo
surgical resection, then the study will proceed to enroll the full 23 patient cohort. If
3 or less than 3 patients undergo surgical resection, the study will be paused for PI
review of the enrolled patients to determine causality of the safety events.
Criteria for 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
Duke Cancer Institute
Address:
City:
Durham
Zip:
27710
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Jeffrey Clarke, MD
Phone:
919-660-9674
Email:
Jeffrey.clarke@duke.edu
Facility:
Name:
Baylor St Lukes
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Monica Vilchis
Phone:
713-798-5530
Email:
Monica.vilchis@bcm.edu
Contact backup:
Last name:
Robert Ripley, MD
Phone:
713-798-6376
Email:
ripley@bcm.edu
Investigator:
Last name:
Robert Ripley, MD
Email:
Principal Investigator
Start date:
July 3, 2024
Completion date:
May 31, 2028
Lead sponsor:
Agency:
Baylor College of Medicine
Agency class:
Other
Collaborator:
Agency:
Duke Cancer Institute
Agency class:
Other
Source:
Baylor College of Medicine
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05932199
