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Recurrent Ovarian CarcinoSarcoma Anti-pd-1 Niraparib (ROCSAN)

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ClinicalTrials.gov Identifier: NCT03651206
Recruitment Status : Not yet recruiting
First Posted : August 29, 2018
Last Update Posted : August 29, 2018
Sponsor:
Collaborator:
Tesaro, Inc.
Information provided by (Responsible Party):
ARCAGY/ GINECO GROUP

Brief Summary:
Carcinosarcomas (CS) (malignant mixed Müllerian tumors) are highly aggressive and rare tumors with a worldwide annual incidence between 0.5-3.3 cases/100.000 women. Gynecological CS, i.e. ovarian CS (OCS) and uterine CS (UCS), have a 5-year overall survival (OS) < 10% and a poor prognosis. After initial treatment (surgery +/- adjuvant radiotherapies +/- chemotherapies (CT)), vast majority of patients relapsed and received diverse CT producing modest benefits, and nearly all patients will die. After first line CT including platinum salt, monotherapy (doxorubicin or paclitaxel) is frequently used for relapsed patients, but the response rate (RR) is <20%, progression-free survival (PFS) <4 months, and OS <1 year. In this unmet need situation, a better knowledge of these aggressive neoplasms is essential to propose new therapeutic options.

Condition or disease Intervention/treatment Phase
Ovarian Carcinosarcoma Endometrial Carcinosarcoma Drug: Niraparib Combination Product: Niraparib plus TSR-042 Drug: Chemotherapy Drugs Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 196 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Phase 2 :

Arm A - Niraparib

Arm B - Niraparib plus TSR-042

Arm C - Chemotherapy drugs

Peak the winner between the Arm A or the arm B

Phase 3:

Arm A: The best arm of the phase 2

Arm B: Chemotherapy drugs

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicentric Randomized Phase 2/3 Evaluating TSR-042 in Combination With Niraparib Versus Niraparib Alone Compared to Chemotherapy in the Treatment of Metastatic or Recurrent Endometrial or Ovarian Carcinosarcoma After First Line Chemotherapy
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023


Arm Intervention/treatment
Experimental: Arm A - Niraparib
Niraparib, 200 mg or 300 mg, daily dose
Drug: Niraparib
PARP Inhibitor

Experimental: Arm B - Niraparib plus TSR-042

Niraparib, 200 mg or 300 mg, daily dose

TSR042, intravenous infusion on Day 1 of every 21-day cycle at 400 mg for the 4 first cycles, followed by 1,000 mg on Day 1 of every 42-day cycle thereafter

Combination Product: Niraparib plus TSR-042
Combination of 2 drugs, a PARP Inhibitor and a Anti-PD-1

Active Comparator: Arm C - Chemotherapy drugs

Chemotherapies (Standard of care)

For Ovarian Cancer Patients Paclitaxel, 80 mg/m², Intravenous, Day 1, 8, 15 every 28 days Pegylated Liposomal Doxorubicin, 40 mg/m², Intravenous, every 28 days Topotecan, 4mg/m², Intravenous, Day 1, 8, 15 every 28 days

For Endometrial Cancer Patients Doxorubicin, 60 mg/m², Intravenous, every 21 days Paclitaxel, 80 mg/m², Intravenous, Day 1, 8, 15 every 28 days Gemcitabine, 800 mg/m², Intravenous, Day 1, 8 every 21 days

Drug: Chemotherapy Drugs
Chemotherapies given in standard of care




Primary Outcome Measures :
  1. Response Rate (RR) at 4 months [ Time Frame: 4 months after the last patient included ]
    RR is defined as the proportion of patients with a partial response or complete response 4 months after randomization

  2. Overall survival (OS) [ Time Frame: 1 year after the last patient included ]
    OS is the time from the date of the randomization until death due to any cause


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 1 year after the last patient included ]
    PFS is the time from randomization to the date of event defined as the first documented progression (RECIST 1.1) or death due to any cause.

  2. Time To Subsequent Treatment (TTST) [ Time Frame: 1 year after the last patient included ]
    TTST is the time from the date of randomization to the earliest date of anti-cancer therapy start following study treatment discontinuation, or death by any cause in the absence of start of new anti-cancer therapy

  3. Progression-Free Survival 2 (PFS2) [ Time Frame: 1 year after the last patient included ]
    PFS2 is the time from the date of randomization to the second objective disease progression, or death from any cause, whichever occurs first.

  4. Objective Response Rate (ORR) [ Time Frame: 1 year after the last patient included ]
    ORR is the proportion of patients with a best response of Complete Response or Partial Response.

  5. Adverse events [ Time Frame: 1 year after the last patient included ]
    Assessed by CTCAE 5.0

  6. Patient-reported outcomes (PROs) [ Time Frame: 1 year after the last patient included ]
    Assessed with questionnaires to be completed by patient and collected frequently during the study



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 Formalin-Fixed Paraffin-Embedded (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 radiotherapy, 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 Eastern Cooperative Oncology Group (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 for 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 150 days after the last dose of study treatment or is of non-childbearing 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.
  19. Patient must agree to not breastfeed during the study or for 150 days after the last dose of study treatment.
  20. Patient able to take oral medications.
  21. Female, aged at least 18 years.
  22. Patient must have signed an approved informed consent.

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 Poly Adenosine diphosphate Ribose Polymerase Inhibitors (PARPi) therapy or Programmed Death-1 (PD-1) / Programmed Death Ligand 1 (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. Patient must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effect.
  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. Patients who have received more than 3 prior cytotoxic chemotherapy for management of uterine or ovarian carcinosarcoma.
  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, New York Heart Association (NHYA) 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. Patients with persistent, clinically significant > Grade 1 toxicity.
  9. Patients 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 abnormality.
  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 Adverse Events (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; 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 (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus (HCV) ribonucleic acid (qualitative) is detected).
  16. 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.
  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 (eg, granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
  21. Patient 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.
  22. Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
  23. Symptomatic Central Nervous System (CNS) metastasis or leptomeningeal carcinomatosis.
  24. Patients with a history of other invasive malignancies or with a concomitant invasive malignancy, with the exception of non-melanoma skin cancer, if there is any evidence of other malignancy being present within the last 3 years; 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.
  27. For France only: A patient will be eligible for randomization only if either affiliated to, or a beneficiary of, a social security category.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03651206


Contacts
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Contact: Isabelle RAY-COQUARD, Professor +33142348323 lmauline@arcagy.org
Contact: Bénédicte VOTAN +33142348323 lmauline@arcagy.org

Sponsors and Collaborators
ARCAGY/ GINECO GROUP
Tesaro, Inc.

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Responsible Party: ARCAGY/ GINECO GROUP
ClinicalTrials.gov Identifier: NCT03651206     History of Changes
Other Study ID Numbers: ENGOT-en8
First Posted: August 29, 2018    Key Record Dates
Last Update Posted: August 29, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No sharing plan

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ARCAGY/ GINECO GROUP:
Malignant mixed Mullerian tumors
Metastatic ovarian carcinosarcoma
Recurrent ovarian carcinosarcoma
Metastatic endometrial carcinosarcoma
Recurrent endometrial carcinosarcoma
Niraparib
TSR-042

Additional relevant MeSH terms:
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Carcinosarcoma
Mixed Tumor, Mullerian
Ovarian Neoplasms
Neoplasms, Complex and Mixed
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Neoplasms, Connective and Soft Tissue
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Niraparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents