| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic or recurrent endometrial or ovarian carcinosarcoma |
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| E.1.1.1 | Medical condition in easily understood language |
| metastatic or recurrent endometrial or ovarian carcinosarcoma |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057529 |
| E.1.2 | Term | Ovarian cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014734 |
| E.1.2 | Term | Endometrial cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10014736 |
| E.1.2 | Term | Endometrial cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase II - Selection Phase :To select the best experimental strategy between TSR-042 combined with Niraparib and Niraparib in monotherapy.
Phase III:To compare the overall survival in patients with metastatic or recurrent endometrial or ovarian carcinosarcoma after at least a first line of chemotherapy between the best experimental strategy and chemotherapy alone.
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| E.2.2 | Secondary objectives of the trial |
To further assess the overall safety profile of the best experimental arm compared to CT alone
To compare the anti-tumor activity between the best experimental strategy and chemotherapy alone
To compare the clinical benefit between the best experimental strategy and chemotherapy alone
To compare the PFS2 (time from randomization to second progression) between the best experimental strategy and chemotherapy alone
• To compare the effects of treatments on patient reported outcomes & QoL
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
To evaluate and identify predictive biomarkers of response/resistance to the TSR-042+niraparib combination therapy in tumor and blood samples from treated patients.
To correlate immune environment and benefit of the combination
To identify resistance mechanisms, with a special focus on genetic instability and EMT process
To follow the evolution of the mutations identified in circulating tumoral DNA (ctDNA) and to evaluate the correlation with efficacy endpoints.
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| E.3 | Principal inclusion criteria |
1.Progressive or recurrent uterine or ovarian carcinosarcoma (Malignant Mixed Mullerian Tumor-MMMT).
2.The primary diagnosis must be histologically confirmed and central pathological review of the initial tumor or biopsy at relapse will be done.
3.Mandatory tumor sample: Availability of tumor sample from a recently (not older than 3 months) obtained archival FFPE tumor tissue block or agreement for having a new tumor biopsy if lesion amenable.
4.Progressive disease as defined by RECIST 1.1. within 12 months from last chemotherapy cycle.
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 <2.
10.Life expectancy of > 2 months.
11.Adequate bone marrow function:
Platelet count greater than or equal to 100,000/mm3
Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3
Hemoglobin > 9g/dL
12.Adequate hepatic and renal function:
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)
Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using Cockcroft-Gault equation
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN unless liver metastases are present, in which case they must be ≤5x ULN
Alkaline phosphatase < 2.5 times ULN
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.Left ventricular ejection fraction (LVEF) > Lower Limit of Normal (LLN) as assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO), for patients planned to receive Anthracycline based therapy.
18.Patient has a negative urine or serum pregnancy test within 7 days 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.
-Non-childbearing potential is defined as follows:
-≥45 years of age and has not had menses for >1 year
-Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
-Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
-For women of childbearing potential: the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. See Section 4.3. for a list of acceptable birth control methods. Information must be captured appropriately within the site’s source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
19.Patient must agree to not breastfeed during the study and for 180 days after the last dose of study treatment.
20.Patient able to take oral medications.
21.Female aged ≥18 years at time of signing ICF.
22.Patient must have signed an approved informed consent.
23.For France only: patient affiliated to, or a beneficiary of, a social security category.
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| E.4 | Principal exclusion criteria |
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 randomization.
Patient has had radiotherapy within 4 weeks prior to randomization.
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.Previous treatment with the chemotherapy regimen selected as the control arm by the investigator.
Prior therapy with paclitaxel given on a three-weekly regimen is permitted for patients receiving weekly Paclitaxel.
Prior treatment with weekly paclitaxel is permitted where this has been used as part of first line therapy and it is greater than 6 months since the last dose of weekly paclitaxel.
Prior weekly paclitaxel for relapsed disease is not permitted.
6.Patient who have received more than 3 prior cytotoxic chemotherapies for management of uterine or ovarian carcinosarcoma.
7.Patient with persistent, clinically significant > Grade 1 toxicity.
8.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)
9.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.
10.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.
11.Patient experienced ≥ Grade 3 immune-related AE with prior immunotherapy, with the exception of non-clinically significant lab abnormalities
12.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.
13.Patient has a diagnosis of immunodeficiency or has received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to initiating protocol therapy
14.Patient has a known history of human immunodeficiency virus (type 1 or 2 antibodies).
15.Patient has known active hepatitis B or hepatitis C
16.Patient has an active autoimmune disease that has required systemic treatment in the past 2 years .Replacement therapy is not considered a form of systemic treatment
17.Patient must not have a history of interstitial lung disease.
18.Patient has received a live vaccine within 14 days of initiating protocol therapy.
19.Patient must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
20.Patient must not have received colony stimulating factors within 4 wks prior initiating protocol therapy
21.Patient has had any known Gr. 3 or 4 anemia, neutropenia or thrombocytopenia due to prior CT that persisted > 4 wks and was related to the most recent TTT
22.Patient must not have any known history of MDS or AML
23.Symptomatic CNS metastasis or leptomeningeal carcinomatosis.
24.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.
25.Known, uncontrolled hypersensitivity reactions or allergy to investigational drugs or their excipients that contraindicates the subject’s participation.
26.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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Selection Phase – Phase II
• Response Rate at 4 months (W16-RR) as per RECIST 1.1
Phase III
• Overall survival (OS).
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| E.5.2 | Secondary end point(s) |
• Safety and tolerability;
• Progression-free survival (PFS) based on Investigator assessment per RECIST v1.1;
• Time from randomization to second progression (PFS2) based on Investigator assessment per RECIST v1.1;
• Overall response rate (ORR) based on Investigator assessment per RECIST v1.1;
• Duration of response (DoR) based on Investigator assessment per RECIST v1.1;
• Time To Subsequent Therapy (TTST).
• Patient-reported Outcomes (PRO): QoL QLQ-C30 modules OV-28, HADS and PRO CTCAEs
1) Assessment of the effect of validated QOL tools to examine the effect of therapy on patients’ life, using the European Organization for Research and Treatment of Cancer (EORTC) QOL disease-specific module.
2) Concurrent evaluation of the impact of anxiety and depression on QOL and toxicity through the Hospital Anxiety and Depression Scale (HADS).
3) Definition of the reliability of the physician evaluation of the toxicity compared to patient point of view using PRO-CTCAE questionnaire, offering the unique opportunity to validate these tools in different European countries.
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| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 24 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 | Yes |
| 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 | 5 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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