| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with DNA repair-deficient or platinum-sensitive solid tumors |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the antitumor activity of Dostarlimab and niraparib in patients with selected advanced solid tumors as measured by the Overall Response Rate |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy Objectives
•To describe the Disease Control Rate (DCR), the Overall Response Rate (ORR), 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
•To evaluate the Overall Survival (OS).
Safety objectives
To evaluate the safety and tolerability of Dostarlimab and niraparib in combination in patients with selected advanced solid tumors |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years.
2. Patients must have histologically or cytologically confirmed progressive metastatic or recurrent solid tumor (as defined below for each tumor type).
3. Evidence of disease progression prior to trial entry.
4. To be enrolled in this study, only the tumor types and settings described below are allowed:
4.1.1 – Cohort 1A: Urothelial Bladder Cancer
4.1.2– Cohort 1B: Gastric or gastro-esophageal junction adenocarcinoma
4.1.3– Cohort 1C: Head and Neck Cancer
4.1.4– Cohort 1D: Biliary Tract Cancer
4.1.5- Cohort 1E Others
4.2 - Cohorts 2: Platinum-sensitive urothelial bladder cancer
4.3 - Cohort 3: Clear cell Renal Cell Carcinoma
5. 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.
6. 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.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration from registration date.
8. Estimated life expectancy of greater than 12 weeks.
9. 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):
o Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks before cycle 0 day 1).
o Lymphocyte count ≥ 500/μL.
o Platelet count ≥ 100.000/μL (without platelets transfusion within 2 weeks before Cycle 0 Day 1).
o Hemoglobin ≥ 9g/dL (patients are not allowed to be transfused with RBC or receive erythropoietic treatment to meet this criterion).
o Total bilirubin ≤ 1.5 ULN (subjects with documented/suspected Gilbert’s disease or liver metastases may be enrolled with bilirubin ≤ 3 × ULN).
o Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit (ULN) or ≤ 5 × ULN in case of liver involvement.
o Albumin ≥ 28g/L.
o Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min (according to Cockroft and Gault formula).
o 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.
10. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior to the administration of the first study treatment.
11. 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.
12. Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.
13. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.
14. 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.
15. Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
16. Patient should be able and willing to comply with study visits and procedures as per protocol.
17. Patients must be affiliated to a social security system or beneficiary of an equivalent system.
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| E.4 | Principal exclusion criteria |
1. Participation in another clinical study with an investigational product simulteanously and/or during the last 4 weeks
2. Receipt of the last dose of anti-cancer therapy 28 days prior to the first dose of study drug, or five half lives of the previous agent, whichever is the shorter.
3. Prior 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. History of another primary malignancy within 5 years prior to Cycle 0 Day 1 except for:
5. Treatment with systemic corticosteroids or other immunosuppressive medications within 7 days prior to Cycle 0 Day 1, or anticipated requirements for systemic immunosuppressive medications during the trial:
6. Acute toxicities from previous therapies that have not resolved to Grade ≤ 1, with the exception of alopecia.
7. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
8. Participant must not have received a platelet transfusion ≤ 4 weeks prior to Cycle 0 Day 1.
9. Participants must not have received colony stimulating factors within 4 weeks prior to Cycle 0 Day 1.
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. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia
12. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
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. History of autoimmune disease
15. Active or prior documented inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis).
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. History of allogeneic organ transplant or prior bone marrow transplantation of double umbilical cord blood transplantation.
18. Uncontrolled intercurrent illness including, but not limited to:
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. 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. Known positive test for HIV.
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. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
24. Active tuberculosis.
25. Administration of attenuated or live vaccine within 2 weeks prior to Cycle 0 Day 1 or anticipation that such a live attenuated vaccine will be required during the study.
26. Major surgical procedure within 20 days prior ty Cycle 0 Day 1 with recovery from any surgical effects or anticipation of need for a major surgical procedure during the course of the study.
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. 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. 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.
30. History of leptomeningeal disease
31. Previous treatment with PARP inhibitors.
32. Treatment with systemic immunostimulatory agents (e.g. INF-α and IL-2) within 4 weeks prior to Cycle 0 Day 1.
33. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose galactose malabsorption
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. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Response Rate (ORR) according to RECIST v1.1 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Overall Reponse Rate (ORR) at 21 weeks according to RECIST v1.1
• Overall response rate (ORR) at 15 and 21 weeks according to iRECIST.
• Best overall response (BOR) according to RECIST v1.1
• Duration of response (DOR) according to RECIST v1.1
• Progression-free survival (PFS) according to RECIST v1.1
• Time to tumor progression (TTP) according to RECIST v1.1
• iTTP according iRECIST
• iPFS according to iRECIST
• Best overall response (iBOR) according to iRECIST
• Duration of response (iDOR) according to iRECIST.
• Disease control rate (DCR) according to RECIST v1.1 and iRECIST
• Maximum percentage of shrinkage from baseline in the sum of the reference diameters of the target lesions (selected according to RECIST and iRECIST)
• Overall Survival
• Safety according to CTCAE v. 5.0
• Quality of life according to EORTC-QLQ30
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At 15 and 21 weeks and at the end of the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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