A Window of Opportunity (WoO) Study Evaluating Pembrolizumab With or Without Olaparib in Tertiary Lymphoid Structures (TLS)-Positive Selected Resectable Soft Tissue Sarcoma (STS) Followed by Adjuvant Pembrolizumab
Soft tissue sarcomas represent a subtype of cancer that is both rare and very heterogeneous. When they are organized, their current treatment is essentially based on tumor resection surgery, +/- associated with treatment by chemotherapy and/or radiotherapy. The aim of this treatment is to reduce the risk of local recurrence (appearance of a tumor in the same region where it was first detected) and/or distant (appearance of a tumor in other regions, organs where it was first detected). Currently, no immunotherapy treatment has been approved for the treatment of patients with sarcoma. This research is based on the hypothesis that soft tissue sarcomas in which tertiary lymphoid structures or TLS are found, recognizable by a cluster of specific immune cells within the tumor, would be likely to respond better to the immunotherapy. Furthermore, the combination of immunotherapy and certain drugs targeting DNA repair has demonstrated some effectiveness in other types of cancers. Trial population :Adult patients with suspected / diagnosed soft tissue sarcoma of the extremities or trunk (Cohort 1: Undifferentiated pleomorphic sarcoma / Cohort 2: Dedifferentiated liposarcoma) The research will therefore focus on two experimental drugs : * Pembrolizumab (immunotherapy) and * Olaparib (DNA repair inhibitor). This research will make it possible to evaluate the effectiveness and safety of use of the two drugs.
• Male or female patients aged ≥ 18 years at time of informed consent signature
• Histologically confirmed diagnosis of high grade (FNCLCC grade 2 or 3) extremity, retroperitoneal, or trunk wall STS of selected histotypes as defined below. Diagnosis must be stated in a pathology report and confirmed by the physician investigator:
• Cohort 1: Undifferentiated Pleomorphic Sarcoma (UPS) Cohort 2: Dedifferentiated Liposarcoma (ddLPS)
• R0 resectability at time of enrollment according to expert STS surgeon
• Absence of distant metastasis on screening CT-scan (or equivalent appropriate imaging technique)
• Patients with local relapse after an initial surgical resection can be enrolled if no perioperative chemotherapy or radiation has been previously performed Identification of Tertiary Lymphoid Structures (TLSs) on tumor archival FFPE sample, as assessed by a registered STS expert senior pathologist
• Primary tumor site measurable according to RECIST v1.1 as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and suitable for repeated assessment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration from registration date
• Adequate hematologic and organ function, defined by the following laboratory results obtained within 3 days prior to the first study treatment (Cycle 0 Day 1): Absolute neutrophil count (ANC) ≥ 1500 cells/μL, Platelet count ≥ 100.000/μL, Hemoglobin ≥ 10 g/dL, Total bilirubin ≤ 1.5 ULN (subjects with documented/suspected Gilbert's disease may be enrolled with bilirubin ≤ 3 × ULN), Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit (ULN), Albumin ≥ 28g/L, Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 30 mL/min (according to Cockcroft and Gault formula), International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular weight heparin or warfarin) should be on stable dose.
• Hepatitis B and C, and HIV screening tests are not required unless
‣ Known history of HBV, HCV or HIV infection
⁃ As mandated by local health authority
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
∙ Not a woman of childbearing potential (WOCBP) OR
‣ A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for 120 to 180 days (corresponding to time needed to eliminate any study treatment(s) plus the duration of a menstruation cycle: 120 days for pembrolizumab and/or 180 days for olaparib) after the last dose of study treatment.
• Male participants:
• A male participant must agree to use a contraception - Contraceptive Guidance and Pregnancy Testing of this protocol during the treatment period and for at least 180 to 240 days, corresponding to time needed to eliminate any study treatment(s) plus the duration of a spermatogenesis cycle: 180 for pembrolizumab and/or 240 days for olaparib) after the last dose of study treatment and refrain from donating sperm during this period.
• Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
• Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
• Patient should be able and willing to comply with baseline mandatory biopsy, as well as study visits and procedures as per protocol.
• Patients must be affiliated to a social security system or beneficiary of an equivalent system.