An open label phase II basket trial exploring the efficacy and safety of the combination of Niraparib and Dostarlimab in patients with DNA repair-deficient or platinum-sensitive solid tumors (NIRADO)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Healthy volunteers

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

completed 25 Feb 2025

Decision date (initial)

2024-07-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-514855-13-00

EudraCT number

2020-002766-14

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of the trial is to evaluate the antitumor activity of Dostarlimab (TSR-042) and niraparib in patients with selected advanced solid tumors as measured by the Overall Response Rate at 15 weeks according to RECIST v1.1.

Secondary objectives 11

1. Efficacy Objectives • To describe the Disease Control Rate (DCR) at 15 and 21 weeks, the Overall Response Rate (ORR) at 21 weeks, the Duration Of Response (DOR), Best Overall Response Rate (BORR), Progression-Free Survival (PFS), Time To Progression (TTP), and maximum percentage of shrinkage from baseline in tumor size at 15 and 21 weeks according to RECIST v1.1.
2. Efficacy Objectives: To describe the DCR, ORR, DOR, BORR, PFS, TTP, and percentage of change from baseline in tumor size at 15 and 21 weeks according to immune-related RECIST (iRECIST).
3. Efficacy Objectives:
4. Safety objectives To evaluate the safety and tolerability of Dostarlimab (TSR-042) and niraparib in combination in patients with selected advanced solid tumors according to NCI-CTCAE v5.0.
5. Exploratory translational objectives • To explore the relationship between the tumor DNA repair deficiency, defined as bi-allelic loss-of-function alteration (mutation and/or deletion) in at least one of the following genes: ARID1A, ARID2, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, IDH1, IDH2, NBN, PALB2, PBRM1, RAD51C, RAD51D, FANCA, NBN, RAD51, RAD54L, SMARCA4 (Gustave Roussy panel) and measures of efficacy.
6. To explore the relationship between immune-related biomarkers (including but not limited to tumor tissue PD-L1 expression by IHC, RNA gene expression profiling and DNA mutation analysis) and measures of efficacy.
7. To evaluate the relationship between the tumor DNA characteristics (including but not limited to mutation of interest and γH2AX/RAD51 foci formation) and measures of efficacy.
8. To explore the relationship between immune-related biomarkers and DNA repair-related biomarkers
9. To explore the modification of immune-related and DNA repair-related biomarkers on treatment
10. To assess whether the identified biomarkers of interest are private to each tumor type or shared across histologies.
11. To evaluate Quality of Life according to EORTC-QLQ30 QoL questionnaire

Conditions and MedDRA coding

DNA repair-deficient or platinum-sensitive solid tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. 1. Age ≥ 18 years.
2. 2. Patients must have histologically or cytologically confirmed progressive metastatic or recurrent solid tumor (as defined below for each tumor type). Diagnosis must be stated in a pathology report and confirmed by the physician investigator.
3. 3. Evidence of disease progression prior to trial entry.
4. To be enrolled in this study, only the tumor types and settings described in the protocol and synopsis
5. 5. Patients must have progressed following standard of care or not eligible to effective standard therapy.
6. 6. For all cohorts: representative archival formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or 20 (ideally) freshly cut and unstained slides, with an associated pathology report, for ancillary studies and/or central testing. If less than 20 slides are available, inclusion must be discussed with the Coordinating Investigator. In all cases, recovery of the most recent tumor block or biopsy is encouraged. If no material is available (blocks or slides), a biopsy will be mandatory at baseline (before the start of the treatment).
7. 7. At least one lesion, not previously irradiated, 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. 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration from registration date.
9. 9. Estimated life expectancy of greater than 12 weeks.
10. 10. 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) (describes in the protocol and synopsis)
11. 11. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 14 days prior to the administration of the first study treatment. Pregnancy testing must be repeated within 72 hours prior to the first dose and while on study.
12. 12. Sexually active women of childbearing potential must agree to use a highly effective method of contraception supplemented by a barrier method, or to abstain from sexual activity during the study and for at least 180 days after the last study treatment administration.
13. 13. Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.
14. 14. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
15. 15. Sexually active males patients must agree to use condom during the study and for at least 180 days after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception for the same duration.
16. 16. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
17. 17. Patient should be able and willing to comply with study visits and procedures as per protocol.
18. 18. Patients must be affiliated to a social security system or beneficiary of an equivalent system.

Exclusion criteria 35

1. 1. Participation in another clinical study with an investigational product simultaneously and/or during the last 4 weeks (excepting observational or noninterventional clinical studies).
2. 2. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 28 days prior to the first dose of study drug, or five half lives of the previous agent, whichever is the shorter.
3. 3. Participant has had radiation therapy encompassing >20% of the bone marrow within 2 weeks prior to Cycle 0 Day 1; or any radiation therapy within 1 week prior to Cycle 0 Day 1.
4. 4. History of another primary malignancy within 5 years prior to Cycle 0 Day 1 except for: o 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. o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. o Adequately treated carcinoma in situ without evidence of disease (eg, carcinoma in situ of the cervix, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
5. 5. Treatment with systemic corticosteroids or other immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents) within 2 weeks prior to Cycle 0 Day 1, or anticipated requirements for systemic immunosuppressive medications during the trial: o The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids for patients with orthostatic hypotension, low-dose supplemental corticosteroids for adrenocortical insufficiency and topical steroids for cutaneous diseases are allowed.
6. 6. Acute toxicities from previous therapies that have not resolved to Grade ≤ 1, with the exception of alopecia.
7. 7. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
8. 8. Participant must not have received a platelet transfusion ≤ 4 weeks prior to Cycle 0 Day 1.
9. 9. Participants must not have received colony stimulating factors (eg, granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior to Cycle 0 Day 1.
10. 10. Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
11. 11. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
12. 12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
13. 13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the TSR-042 formulation, or to niraparib or its components.
14. 14. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis. o Patients with autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible. o Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible.
15. 15. Active or prior documented inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis).
16. 16. History of interstitial lung disease, idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis on screening chest CT scan.
17. 17. History of allogeneic organ transplant or prior bone marrow transplantation of double umbilical cord blood transplantation.
18. 18. Uncontrolled intercurrent illness including, but not limited to: o ongoing or active infection or severe infection requiring hospitalization or IV antibiotics within 2 weeks of starting treatment (with the exception of prophylactic antibiotics). o symptomatic congestive heart failure > NYHA II, superior vena cava syndrome, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, pericardial effusion, myocardial infarction within 90 days. o active peptic ulcer disease or gastritis. o active bleeding diatheses. o major seizure disorder
19. 19. Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
20. 20. Patients with known 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.
21. 21. Known positive test for HIV.
22. 22. Patients with active hepatitis B (defined as positive HBsAg test at screening) or hepatitis C (HCV).Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen anti-HBc) are eligible.
23. 23. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
24. 24. Active tuberculosis
25. 25. Administration of attenuated or live vaccine within 4 weeks prior to Cycle 0 Day 1 or anticipation that such a live attenuated vaccine will be required during the study.
26. 26. 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.
27. 27. Uncontrolled tumor-related pain: patients requiring pain medication must be on a stable regimen at study entry and symptomatic lesions amenable to palliative radiotherapy should be treated prior to enrolment.
28. 28. Uncontrolled effusion (pleural, pericardial or ascites) requiring recurrent drainage procedures (once a month or more frequently); patients with indwelling catheters (e.g. PleurX) are allowed.
29. 29. Uncontrolled hypercalcemia (>1.5mmol/L ionized calcium or Ca > 12mg/dL or corrected serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. o Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history or clinically significant hypercalcemia are eligible. o Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while on study.
30. 30. History of leptomeningeal disease o Symptomatic CNS metastasis or uncontrolled CNS metastasis, requiring increasing doses of steroids or stable dose of steroids > 10mg prednisone qd. o Spinal cord compression without evidence that disease has been clinically stable for ≥ 2 weeks prior to Cycle 0 Day 1.
31. 31. Previous treatment with PARP inhibitors.
32. 32. Treatment with systemic immunostimulatory agents (e.g. INF-a and IL-2) within 4 weeks prior to Cycle 0 Day 1.
33. 33. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose galactose malabsorption
34. 34. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study result.
35. 35. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall Response Rate (ORR) at 15 weeks according to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1).

Secondary endpoints 15

1. Overall Reponse Rate (ORR) at 21 weeks according to RECIST v1.1
2. Overall response rate (ORR) at 15 and 21 weeks according to iRECIST.
3. Best overall response (BOR) according to RECIST v1.1
4. Duration of response (DOR) according to RECIST v1.1
5. Progression-free survival (PFS) according to RECIST v1.1
6. Time to tumor progression (TTP) according to RECIST v1.1
7. iTTP according iRECIST
8. iPFS according to iRECIST
9. Best overall response (iBOR) according to iRECIST
10. Duration of response (iDOR) according to iRECIST.
11. Disease control rate (DCR) according to RECIST v1.1 and iRECIST
12. Maximum percentage of shrinkage from baseline in the sum of the reference diameters of the target lesions (selected according to RECIST and iRECIST)
13. Overall Survival
14. Safety according to CTCAE v. 5.0
15. Quality of life according to EORTC-QLQ30

Investigational products

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

Test 2

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 · 7 investigational sites

By country

Investigational sites

Application history

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