An international multicentric randomized phase II evaluating dostarlimab in combination with niraparib versus niraparib alone compared to chemotherapy in the treatment of metastatic or recurrent endometrial or ovarian carcinosarcoma after at least one line of chemotherapy : ROCSAN study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Asso De Recherche Cancers Gynecologiques

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

15 Oct 2024 → ongoing

Decision date (initial)

2024-10-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-516782-36-00

EudraCT number

2019-002662-12

ClinicalTrials.gov

NCT03651206

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Phase II – Step 1 : Selection Phase
To select the best experimental strategy between dostarlimab combined with niraparib and niraparib in monotherapy.

Phase II – Step 2 : Extension phase
To evaluate the efficacy of the best experimental strategy in patients with metastatic or recurrent endometrial or ovarian carcinosarcoma after at least a first line of chemotherapy

Secondary objectives 7

1. To evaluate the median overall survival in the best experimental strategy
2. To further assess the overall safety profile of the best experimental arm
3. To evaluate the anti-tumor activity of the best experimental strategy (including ORR and DoR rate)
4. To assess the clinical benefit of the best experimental strategy
5. To further assess the PFS and the PFS2 (time from randomization to second progression in the selection phase, time from treatment initiation to second progression in extension phase) in the best experimental strategy
6. To evaluate the effects of treatments on patient reported outcomes & QoL
7. To explore biology mechanism of response and resistance (see exploratory objectives)

Conditions and MedDRA coding

metastatic or recurrent endometrial or ovarian carcinosarcoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 22

1. Progressive or recurrent uterine carcinosarcoma (Malignant Mixed Mullerian Tumor-MMMT).
2. The primary diagnosis must be histologically confirmed by pathological expert review of the initial tumor or biopsy at relapse.
3. Mandatory tumor samples: Availability of an archival FFPE tumor sample(s) from diagnosis, or if not available from relapse setting.
4. Progressive disease as defined by RECIST 1.1.
5. Failure after ≥1 prior platinum containing regimen, which may have been given in the adjuvant setting.
6. Patient must have had 1 prior chemotherapeutic regimen for management of carcinosarcoma that may have included chemotherapy, chemotherapy and radio-chemotherapy, and/or consolidation/maintenance therapy.
7. Patient must be free of active infection requiring antibiotics.
8. Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to beginning protocol chemotherapy; continuation of hormone replacement therapy is permitted.
9. Patient must have ECOG Performance Status ≤1.
10. Life expectancy of > 2 months.
11. Adequate bone marrow function:o Platelet count greater than or equal to 100,000/mm3 o Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 o Hemoglobin > 9g/dL
12. Adequate hepatic and renal function/ o Total bilirubin ≤1.5x Upper Limit of Normal (ULN) unless liver metastases are present, in which case they must be ≤3x ULN (≤2.0 in patients with known Gilberts syndrome OR direct bilirubin ≤ 1 x ULN) o Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN unless liver metastases are present, in which case they must be ≤5x ULN o Alkaline phosphatase < 2.5 times ULN o Serum albumin > 3 g/dL
13. International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
14. Patient must have normal BP or adequately treated and controlled hypertension (systolic BP≤140 mmHg and/or diastolic BP ≤90 mmHg)
15. Patient receiving corticosteroids may continue as long as their dose is stable and ≤10mg/day (prednisone equivalent) for at least 4 weeks prior to initiating protocol therapy.
16. Patient must agree to not donate blood during the study or for 90 days after the last dose of study treatment
17. Patient has a negative urine or serum pregnancy test within 72 hours prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of nonchildbearing potential.
18. Patient must agree to not breastfeed during the study and for 180 days after the last dose of study treatment.
19. Patient able to take oral medications
20. Female aged ≥18 years at time of signing ICF.
21. Patient must have signed an approved informed consent.
22. For France only: patient affiliated to, or a beneficiary of, a social security category.

Exclusion criteria 27

1. Not enrolled in any interventional clinical trial (except to biological trials that must be validated by the sponsor)
2. Prior treatment with niraparib or other PARPi therapy or PD1/PDL-1 inhibitors.
3. Patient has had investigational therapy, immunotherapy, chemotherapy or biological therapy administered within 4 weeks or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to treatment initiation. Patient has had radiotherapy within 4 weeks prior to treatment initiation.
4. Patients must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects
5. Patient who has received more than 3 prior cytotoxic chemotherapies for management of uterine carcinosarcoma.
6. Patient with persistent, clinically significant > Grade 1 toxicity.
7. Patient has clinically significant cardiovascular disease (eg, significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, uncontrolled cardiac arrhythmia or unstable angina < 6 months to enrollment, NYHA grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, and history of cerebrovascular accident within 6 months)
8. Patient with any other severe concurrent disease, which may increase the risk associated with study participation or study drug administration and, in the judgment of the investigator, would make the patient inappropriate for entry into this study, including significant neurologic, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormalities. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
9. Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption.
10. Patient experienced ≥ Grade 3 immune-related AE with prior immunotherapy, with the exception of non-clinically significant lab abnormalities
11. Participant has had radiation therapy encompassing >20% of the bone marrow within 2 weeks prior to Day 1 of protocol therapy or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
12. Patient has a diagnosis of immunodeficiency or has received systemic steroid therapy >10mg/day (prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to initiating protocol therapy
13. Participants with known HIV infection are allowed with the following requirements: Documented evidence of plasma HIV-1 RNA persistently <50 copies/mL ≤3 months prior to AND at Screening. In the >3 to 12 months prior to Screening, plasma HIV-1 RNA consistently <50 c/mL required; if single increases ≥50 c/mL occurred, they cannot have been persistent nor associated with antiretroviral resistance per investigator assessment AND CD4 cell count >350 cells/mm3 over past 12 months and at Screening (and no measurement ≤350 cells/mm3 during that time period) AND Must be on an uninterrupted combination antiretroviral therapy regimen for at least 3 months prior to Screening, with combination antiretroviral therapy regimen consistent with locally recommended guidelines Participants with history of CDC Stage 3 AIDS-defining disease (CDC, 2014; also known as acquired immunodeficiency syndrome - defining disease) are allowed if AIDS-defining disease has been treated and cured or is stable for ≥3 months prior to study entry. Cutaneous Kaposi’s sarcoma not requiring systemic therapy is allowed. No history of HIV-associated non-Hodgkin lymphoma ≤5 years prior to study entry. No treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
14. Patient has known active hepatitis B (e. g., hepatitis B surface antigen [HBsAg] reactive and HBcAb reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative] is detected).
15. Patient has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
16. Patient must not have a history of interstitial lung disease.
17. Patient has received a live vaccine within 30 days of initiating protocol therapy.
18. Patient must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
19. Patient must not have received colony-stimulating factors (e.g, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
20. Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
21. Symptomatic CNS metastasis or leptomeningeal carcinomatosis.
22. Patients with a history of other invasive malignancies (any evidence of other malignancy being present within the last 3 years) or with a concomitant invasive malignancy, with the exception of non-melanoma skin cancer; patients are also ineligible if their previous cancer treatment contraindicates this protocol therapy.
23. Known hypersensitivity reactions or allergy to investigational drugs or their excipients that contraindicates the subject’s participation.
24. Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the study protocol and follow up schedule; those considerations should be discussed with the patient before registration in the trial.
25. Patients under psychiatric care and patients admitted to a health or social institution.
26. Patients deprived of their liberty by judicial or administrative decision.
27. Patients under a legal protection measure or unable to express their consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Step 1 - Selection Phase : Response Rate at 4 months (W16-RR) as per RECIST 1.1
2. Step 2 – Extension phase :6-months Overall survival (OS) rate.

Secondary endpoints 9

1. Progression-Free Survival (PFS)
2. Time To Subsequent Treatment or Death
3. Progression-Free Survival 2 (PFS2)
4. Overall Survival
5. Objective Response Rate (ORR)
6. Disease Control Rate (DCR)
7. Duration of response
8. Safety and Tolerability
9. QoL & symptom benefit evaluation

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Asso De Recherche Cancers Gynecologiques

Sponsor organisation

Asso De Recherche Cancers Gynecologiques

Address

8 Rue Lamennais

City

Paris

Postcode

75008

Country

France

Scientific contact point

Organisation

Asso De Recherche Cancers Gynecologiques

Contact name

Isabelle RAY-COQUARD

Public contact point

Organisation

Asso De Recherche Cancers Gynecologiques

Contact name

Isabelle RAY-COQUARD

Third parties 1

Locations

3 EU/EEA countries · 39 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 38 files

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

Application history

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