This is a prospective, open-label, multi-site Phase II trial of pembrolizumab in combination with pemetrexed and cisplatin or carboplatin as neo-adjuvant therapy followed by surgery and adjuvant pembrolizumab in patients affected by resectable stage I-IIIa chemonaïve epithelioid/biphasic pleural mesothelioma.
This is a prospective, open-label, multi-site Phase II trial of pembrolizumab in combination with pemetrexed and cisplatin or carboplatin as neo-adjuvant therapy followed by surgery and adjuvant pembrolizumab in patients affected by resectable stage I-IIIa chemonaïve epithelioid/biphasic pleural mesothelioma. The neoadjuvant systemic treatment will be based on three cycles of pembrolizumab 200 mg flat dose in combination with standard doses of cisplatin (75 mg/sm) or carboplatin (AUC 5) and pemetrexed (500 mg/sm) administered intra-venous every 3 weeks. The surgical intervention of pleurectomy/decortication will be planned to occur within 6 weeks after the completion of neoadjuvant treatment. The adjuvant systemic treatment will be based on 14 cycles of pembrolizumab 200 mg flat dose administered intra-venous every 3 weeks. Patients should be able to start pembrolizumab following surgery as soon as clinically feasible and within 10 weeks from surgery. All participating centers will enroll eligible patients and administer neoadjuvant and adjuvant systemic treatment. Thoracic surgery will be centralized in two reference centres (AOUPD PADOVA AND HUMANITAS CANCER CENTER). All eligible patients will undergo two multidisciplinary team discussions, before and after induction systemic treatment. The primary objective of this trial is to determine the pathological complete response rate of pembrolizumab in combination with standard doses of cisplatin or carboplatin and pemetrexed administered intra-venous every 3 weeks for three cycles. Pathological response will be centrally assessed by a blinded pathologist. Radiological and metabolic assessment through CT-scan and PET-CT will be performed at the baseline and at the end of neoadjuvant chemo-immunotherapy. Radiological CT-scan will be then performed every 9 weeks (+/- 1 week) during the adjuvant treatment. Further radiological follow-up after the end of study treatment (or for those patients with early treatment discontinuation without disease relapse) will be performed every 12 weeks until a two-year period from surgery, followed by every 18 weeks until the fifth year. Radiological response will be centrally assessed by a blinded radiologist. Adverse events will be monitored throughout the trial and graded in severity according to the guidelines outlined in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
41
The neoadjuvant systemic treatment will be based on three cycles of pembrolizumab 200 mg flat dose in combination with standard doses of cisplatin (75 mg/sm) or carboplatin (AUC 5) and pemetrexed (500 mg/sm) administered intra-venous every 3 weeks. The surgical intervention of pleurectomy/decortication will be planned to occur within 6 weeks after the completion of neoadjuvant treatment. The adjuvant systemic treatment will be based on 14 cycles of pembrolizumab 200 mg flat dose administered intra-venous every 3 weeks. Patients should be able to start pembrolizumab following surgery as soon as clinically feasible and within 10 weeks from surgery.
Humanitas Gavazzeni
Bergamo, Italia/Bergamo, Italy
IFO - Istituto Tumori Regina Elena, Roma
Roma, Italia/Roma, Italy
Istituto Clinico Humanitas
Rozzano, Milano, Italy
Centro di Riferimento Oncologico (CRO) IRCCS
Aviano, Pordenone, Italy
Primary endpoint - To evaluate the activity of neo-adjuvant treatment by the determination of pathological complete response rate (pCR)
Pathological complete response defined as 0% residual viable tumor cells in the primary tumor and in sampled lymph nodes, following neoadjuvant treatment as assessed by central pathology assessment. Patients who are not evaluable per central pathology assessment (this includes patients with R2 margins) or who do not have a surgical specimen will be considered as non-pCR (eg, pathology assessments captured as "non-evaluable" or "missing," as appropriate). Patients who received less than 2 cycles out of the planned 3 cycles of neoadjuvant therapy due to unacceptable toxicity will not be considered in the pCR evaluation.
Time frame: Pathological complete response will be evaluated following neoadjuvant treatment and within 6 weeks after the last dose of study intervention.
Secondary endpoint - To further evaluate the activity of neo-adjuvant treatment in terms of major pathological response.
Major pathological response defined as ≤10% residual viable tumor cells in the primary tumor and sampled lymph nodes after neoadjuvant treatment at the time of resection as assessed per central pathology laboratory. Patients who are not evaluable per central pathology assessment (including patients with R2 margins) or who do not have a surgical specimen will be considered as having non-mPR (eg, response captured as "non-evaluable" or "missing," as appropriate).
Time frame: Major pathological response will be evaluated at the time of surgery that will be performed within 6 weeks after the last dose of study intervention.
Secondary endpoint - To further evaluate the activity of neo-adjuvant treatment in terms of overall response rate (ORR).
Overall response rate defined as the sum of partial and complete response according to modified RECIST 1.1 criteria for Malignant Pleural Mesothelioma.
Time frame: The ORR will be evaluated: at the time of the screening (within 4 weeks before the neoadjuvant treatment); within 6 weeks after neoadjuvant treatment; within 10 weeks after surgery; at every radiological assessment with CT-scan up to 24 months
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Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo
Alessandria, Italy
Azienda Ospedaliero-Universitaria S. Anna
Ferrara, Italy
Istituto Oncologico Veneto IRCCS
Padua, Italy
Azienda Ospedaliera-Universitaria di Parma
Parma, Italy
Secondary endpoint - To evaluate the efficacy of neo-adjuvant treatment in terms of overall survival (OS).
Overall survival defined as the time from the start of treatment to all-cause death.
Time frame: From the start of treatment to death from any cause, up to 24 months.
Secondary endpoint - To evaluate the efficacy of neo-adjuvant treatment in terms of event free survival (EFS).
Event free survival defined as the time from the start of treatment to any progression of disease precluding surgery, progression or recurrence of disease after surgery, progression of disease in the absence of surgery, or death from any cause.
Time frame: From the start of treatment to any progression of disease precluding surgery, progression or recurrence of disease after surgery, progression of disease in the absence of surgery, or death from any cause, up to 24 months.
Secondary endpoint - To evaluate the feasibility of neo-adjuvant treatment in terms of resection rate and rate of patients who complete all cycles of neoadjuvant treatment and following surgery.
Feasibility in terms of: i) Resection rate: defined as the percentage of patients finally eligible for radical surgery, among those who receive at least one cycle of neoadjuvant treatment; ii) rate of patients who complete three cycles of neoadjuvant chemo-immunotherapy followed by radical surgery.
Time frame: From the screening to the surgery which is performed within 6 weeks after the neoadjuvant treatment, up to 22 weeks.
Secondary endpoint - To evaluate the safety profile of neoadjuvant treatment
Safety profile in terms of incidence and grade of adverse events; incidence of adverse events and serious adverse events; incidence of definitive interruptions of treatment because of any-cause adverse events and treatment-related adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Time frame: Safety profile will be evaluated during the entire duration of the study, up to 24 months.