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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Dec 2024 → 13 Aug 2025

Decision date (initial)

2024-08-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

MSD

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

To evaluate the immunogenic potential of pembrolizumab +/- olaparib in WoO setting, in selected TLS+ selected STS subtypes. The WoO is the Windows of Opportunity, before standard surgery

Secondary objectives 11

1. To evaluate the safety and tolerability of pembrolizumab +/- olaparib in WoO setting according to the CTCAE v. 5.0
2. To evaluate the safety and tolerability of 17 cycles (approximately one-year) of adjuvant pembrolizumab in combination with radiation therapy (if indicated) according to the CTCAE v. 5.0
3. To describe the Overall Response Rate (ORR) and the Disease Control Rate (DCR) after WoO treatment according to RECIST v1.1 criteria
4. To describe the percentage of tumor shrinkage in tumor size from baseline to time of resection surgery after WoO treatment according to RECIST v1.1 criteria.
5. To assess the percentage of residual viable cells on the resection surgery specimen after WoO treatment
6. To assess the rate of complete pathological response on the resection surgery specimen after WoO treatment
7. To assess the feasibility of WoO pembrolizumab with or without olaparib in resectable TLS+ STS subtypes
8. To assess the feasibility of 17 cycles (approximately one-year) of adjuvant pembrolizumab +/- radiation therapy in TLS+ STS subtypes
9. To describe the efficacy of WoO pembrolizumab +/- olaparib and to 17 cycles (approximately one-year) of adjuvant pembrolizumab +/- radiation therapy as measured by Overall Survival (OS), recurrence-free survival (RFS), Time To Relapse (TTR), Local Recurrence Rate (LRR), and Disease Free Survival (DFS) in TLS+ selected STS subtypes.
10. Translational analyses will aim at evaluating the immunostimulatory potential of WoO pembrolizumab with or without olaparib in TLSs selected STS subtypes using the following technologies: • Tumor 5’ and TCR single-cell RNA sequencing (5’ and TCR scRNA-seq) • Tumor Bulk RNA sequencing (bulk RNA-seq) • Tumor and germline Whole Exome Sequencing (WES) • Tumor Multiplexed Immunohistochemistry (IHC), performed on sequential tumor samples at baseline and after WoO at resection surgery
11. Exploratory analyses will comprise: • Blood-based techniques, including ELISA for peripheral cytokine release assessment, peripheral TCR sequencing for the identification of TCR clonal selection, and for FACS peripheral immune cells characterization o To analyze and monitor the impact of WoO pembrolizumab +/- olaparib and of adjuvant pembrolizumab in TLS+ selected STS on peripheral biomarkers (cytokines by Elisa, PBMCs characterization by multiparametric flow cytometry and TCR sequencing) (optional; not included in the current available budget). • Radiomics analyses o To explore radiomics changes based on planned CT and MRI during WoO investigational treatment, and evaluate association of radiomics features changes and treatment efficacy evaluated by TIL density increase and tumor pathological response (optional; not included in the current budget)

Conditions and MedDRA coding

Undifferentiated pleomorphic sarcoma and Dedifferentiated liposarcoma

Regulatory references

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Male or female patients aged ≥ 18 years at time of informed consent signature
2. 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)
3. R0 resectability at time of enrollment according to expert STS surgeon and absence of indication of pre-operative chemotherapy according to best practice guidelines, or previous administration of preoperative therapy
4. Absence of distant metastasis on screening CT-scan (or equivalent appropriate imaging technique)
5. Patients with local relapse after an initial surgical resection can be enrolled if no perioperative chemotherapy or radiation has been previously performed
6. Identification of Tertiary Lymphoid Structures (TLSs) on tumor archival FFPE sample, as assessed by a registered STS expert senior pathologist
7. 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.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration from registration date
9. Adequate hematologic and organ function, defined by the following laboratory results obtained within 3 days prior to the first study treatment (Table 2):
10. Hepatitis B and C, and HIV screening tests are not required unless a. Known history of HBV, HCV or HIV infection b. As mandated by local health authority
11. 10.1. Hepatitis B positive subjects a. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. b. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
12. 10.2. Patients with history of HCV infection are eligible if HCV viral load is undetectable at screening a. Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization
13. 10.3. Patients with history of HIV infection are eligible if HIV viral load is undetectable at screening a. Participants who are HIV positive are eligible if they have received HIV antiviral therapy for at least 4 weeks and have undetectable HIV viral load prior to randomization. b. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HIV anti-viral therapy post completion of study intervention.
14. A female participant is eligible to participate if she is not pregnant (see Appendix 3 – Contraceptive Guidance and Pregnancy Testing, i.e. negative pregnancy test 72 hours prior to first dose), not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 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 for olaparib) after the last dose of study treatment. Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 – 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 days for pembrolizumab and/or 240 days for olaparib) after the last dose of study treatment and refrain from donating sperm during this period.
15. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
16. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
17. Patient should be able and willing to comply with baseline mandatory biopsy, as well as study visits and procedures as per protocol.
18. Patients must be affiliated to a social security system or beneficiary of an equivalent system.

Exclusion criteria 28

1. Has a visceral STS primary site.
2. Has a non resectable or marginally resectable locally advanced STS as assessed by expert STS surgeon.
3. Has evidence of metastatic disease on CT-scan (or equivalent imaging technique).
4. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
5. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids.
6. Has had previous exposure to anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an agent directed to another stimulatory or co inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
7. Had had previous exposure to olaparib or any other PARP inhibitor.
8. Has received a live vaccine or live-attenuated vaccine received within 4 weeks prior to Cycle 0 Day 1 or anticipation that such a live attenuated vaccine will be required during the study. Administration of killed vaccines is allowed.
9. Has received treatment with systemic immunostimulatory agents (e.g., IFN and IL-2) within 4 weeks prior to Cycle 0 Day 1.
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
11. Has had an administration of colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior to Cycle 0 Day 1.
12. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization (see Appendix 3 – Contraceptive Guidance and Pregnancy Testing). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
13. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
14. Has a history of severe allergic, anaphylactic, or other hypersensitivity reactions to the components of excipients in pembrolizumab and/or olaparib.
15. Has any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) or immunodeficiency
16. Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid)
17. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
18. Has a history of allogeneic tissue/organ or hematopoietic stem cell transplantation.
19. Has a history of another primary malignancy within 2 years prior to Cycle 0 Day 1 except for: • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease • Adequately treated carcinoma in situ without evidence of disease (e.g., carcinoma in situ of the cervix, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent, carcinoma in situ of the bladder that have undergone potentially curative therapy)
20. Has a serious, uncontrolled medical disorder including, but not limited to: • Ongoing or active infection or severe infection requiring hospitalization or IV antibiotics within 2 weeks of starting treatment (with the exception of prophylactic antibiotics) • Any of the following cardiac conditions: o Symptomatic uncontrolled congestive heart failure > NYHA II o Left ventricular ejection fraction (LVEF) < 40%; patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable cardiologic treatment. o Presence of uncontrolled, potentially reversible cardiac conditions: uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, pericardial effusion, myocardial infarction within 90 days o QTcF prolongation >500 ms, or participant has congenital long QT syndrome • Active peptic ulcer disease or gastritis • Active bleeding diatheses • Major seizure disorder • Extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan
21. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption).
22. Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA), Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection, HIV (defined as detectable viral load). Note: HIV, Hepatitis B and C screening tests are not required unless: • Known history of HBV, HCV or HIV infection • As mandated by local health authority
23. Has any active infection requiring systemic therapy.
24. Major surgical procedure within 20 days prior ty Cycle 0 Day 1 or anticipation of need for a major surgical procedure during the course of the study.
25. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
26. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
27. Participant is currently receiving either strong (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks. The medication can be restarted as soon as olaparib has been halted.
28. Participant is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents. The medication can be restarted as soon as olaparib has been halted.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary clinical evaluation criterion will be 50% increase in CD8+ T-cell tumor infiltration density between baseline biopsy and resection surgery specimen as defined by expert pathologist who will be blinded for treatment arm and patient outcome

Secondary endpoints 9

1. Percentage of residual viable cells on the resection surgery specimen as assessed by expert pathologist after WoO treatment
2. Proportion of patients with 70% pathological response on the resection surgery specimen as assessed by expert pathologist after WoO treatment
3. Objective Response Rate (ORR) at 4 weeks of WoO treatment defined as the rate of patients with Complete Response (CR) or Partial Response (PR) according to RECIST v1.1Disease Control Rate (DCR) at 4 weeks of WoO according to RECIST v1.1
4. Maximum percentage of shrinkage from baseline in the sum of the reference diameters of the target lesions (selected according to RECIST)
5. Local Recurrence Rate (LRR) at 2-year post-surgery
6. Time To Relapse (TTR)
7. Disease Free Survival (DFS) at 2-year post-surgery
8. Overall Survival (OS)
9. Quality of resection and amputation rate

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications