Carboplatin-Paclitaxel-Bevacizumab vs Carbo-Pacli-Beva-Rucaparib vs Carbo-Pacli-Ruca, Selected According to HRD Status, in Patients With Advanced Ovarian, Primary Peritoneal and Fallopian Tube Cancer, Preceded by a Phase I Dose Escalation Study on Ruca-Beva Combination (MITO25)

August 24, 2021 updated by: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

A Randomized, Molecular Driven Phase II Trial of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib, Selected According to HRD Status, in Patients With Advanced (Stage III B-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer Preceded by a Phase I Dose Escalation Study on Rucaparib-Bevacizumab Combination

This trial is a randomized, open-label Phase I-2 multi-center study designed to evaluate the effect of Carboplatin-Paclitaxel-Bevacizumab (in combination and maintenance) vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib (Rucaparib only in maintenance) vs Carboplatin-Paclitaxel-Rucaparib (Rucaparib only in maintenance) on progression-free survival in patients with advanced high grade ovarian cancer treated according to HRD status . The trial will test the hypothesis that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib and the Carboplatin-Paclitaxel-Rucaparib arms will improve the progression-free survival in comparison to standard Carboplatin-Paclitaxel-Bevacizumab in HRD negative (HR proficient) patients and that Carboplatin-Paclitaxel-Bevacizumab-Rucaparib will improve PFS with respect to Carboplatin-Paclitaxel-Rucaparib in HRD positive patients. The randomized phase of the study will be preceded by a single arm Phase I study which will be conducted only in the National Cancer Institute of Milan, aiming at evaluating the MTD of the combination Rucaparib-Bevacizumab. Once the MTD has been reached, the randomized study will start.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Phase I study design:

This is a single-centre, Phase I, open-label, dose-escalation study to evaluate the safety and tolerability of bevacizumab-rucaparib combination and determine the MTD in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The dose of bevacizumab is fixed in cohort 1, 2 and 3 of the study at 15mg/kg, q 3 weekly.

The dose of rucaparib is evaluated in three cohorts (400 mg BID; 500 mg BID; 600 mg BID).

This trial will enroll at least 3 patients in cohort 1 with dose escalation to rucaparib 500 mg from cohort 1 to 2. Cohort 2 will enroll at least 3 patients with dose escalation to rucaparib 600 mg from cohort 2 to 3.

The standard 3+3 design will be used. Patients will be enrolled in cohort of 3 patients, if no DLT event will be reported among the first 3 patients, a second cohort will be enrolled at the upper dose level. If 1 DLT event is registered in the first cohort, other 3 patients will be enrolled at the same dose.

Phase II study design:

Eligible patients with histological documented high grade Stage IIIB-IIIC-IV ovarian cancer (regardless of residual tumor) will be randomized 1:1:1 according to a molecular driven treatment.

HRD positive patients:

  • ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 for 6 cycles followed by Rucaparib 600 mg BID q 28 for 24 cycles as maintenance
  • ARM C: Carboplatin AUC 5+ Paclitaxel 175 mg/m2 q 21 + Bevacizumab 15 mg/kg for 6 cycles followed by Bevacizumab 15 mg/kg q 21 days for 16 cycles (Bevacizumab will start from Cycle 2) + Rucaparib 500 mg part BID q 28 for 24 cycles as maintenance

HRD negative patients:

  • ARM A: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 + Bevacizumab 15 mg/kg for 6 cycles followed by Bevacizumab 15 mg/kg q 21 for 16 cycles (Bevacizumab will start from Cycle 2)
  • ARM B: Carboplatin AUC 5 + Paclitaxel 175 mg/m2 q 21 for 6 cycles followed by Rucaparib 600 mg BID q 28 for 24 cycles as maintenance

Stratification factors are:

  • Residual tumor at primary surgery (RT=0 vs RT> 0)
  • Neoadiuvant chemotherapy (Yes or not)

Study Type

Interventional

Enrollment (Anticipated)

290

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Legnago, Italy
        • Recruiting
        • Ospedale Mater Salutis
      • Milan, Italy
        • Recruiting
        • Asst Grande Ospedale Metropolitano Niguarda
      • Naples, Italy
        • Recruiting
        • Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
      • Perugia, Italy
        • Recruiting
        • Azienda Ospedaliera di Perugia
      • Ponderano, Italy
        • Recruiting
        • Nuovo Ospedale degli Infermi
      • Rome, Italy, 00168
        • Recruiting
        • Fondazione Policlinico Universitario A.Gemelli IRCCS
      • Turin, Italy
        • Recruiting
        • Istituto di Candiolo - Fondazione del Piemonte per l'Oncologia - IRCCS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  1. Women aged >=18 years at the time of study inclusion;

  2. Patients with newly diagnosed, histologically confirmed, high grade serous, high grade endometrioid, FIGO stage IIIB-C-IV epithelial ovarian cancer, primary peritoneal cancer and / or Fallopian-tube cancer. Patients with mixed histology (carcinosarcoma) are eligible providing that high grade tumor represent more than 50% of the total histology.

    Stage III patients should have had one attempt at optimal debulking surgery (upfront or interval debulking). Stage IV patients must have had either a biopsy and/or upfront or interval debulking surgery;

  3. Archival tumor tissue available. At progression fresh biopsy is optional for patients willing to submit ;
  4. ECOG Performance Status of 0-1;
  5. Measurable and not measurable disease;

  6. Adequate renal and hepatic function, defined as:

    • Total serum bilirubin ≤ 1.5 institutional ULN unless patient has Gilbert's syndrome in which case total serum bilirubin must be <2 ULN for the institution AST and/or ALT ≤ 2.5 x ULN for the institution. (or ≤ 5 x ULN if liver metastases are present);
    • Alkaline phosphatase < 1.5 x ULN for the institution (if > 1.5 x ULN, then alkaline phosphatase liver fraction must be < 1.5 ULN)
    • Serum creatinine ≤ 1.5 x ULN for the institution (or calculated creatinine clearance ≥ 45 mL/min/1.73 m2);

  7. Adequate bone marrow function, defined as:

    • Total leukocytes 2.5 x 109/L;
    • ANC 1.5 x 109/L;
    • Platelet count 100 x 109/L;
  8. Able to understand and give written informed consent;
  9. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

Exclusion Criteria:

  1. Women who are pregnant or lactating;
  2. Presence of brain or other central nervous system metastases, not adequately controlled by treatment;
  3. Prior Anticancer treatment;
  4. Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 3 weeks prior to randomization;

  5. Another primary malignancy except for:

    1. Curatively treated non-melanoma skin cancer;
    2. Breast cancer treated curatively ≥5 years ago, or other solid tumor treated curatively ≥5 years ago, without evidence of recurrence;
    3. Synchronous endometrioid endometrial cancer (except for Stage 1A G1/G2);
  6. Known active HIV, hepatitis B or C infection;
  7. Concurrent treatment with immunosuppressive or investigational agents;
  8. History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or subarachnoid haemorrhage within _6 months prior to the first study treatment);

  9. Clinically significant (i.e. active) cardiovascular disease, including:

    • Myocardial infarction or unstable angina within _6 months prior to the first study treatment;
    • New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF);
    • Serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia);
    • Peripheral vascular disease > grade 3 (i.e.symptomatic and interfering with activities of daily living requiring repair or revision);
  10. Serious active infection requiring i.v. antibiotics at enrolment;
  11. Known hypersensitivity to any of the study drugs or excipients (including cremophor and hamster Ovary cell products);
  12. Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment related complications;
  13. Prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with absorption of study drug;
  14. Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first dose of Rucaparib or have on-going requirements for these medications.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: Standard treatment
Carboplatin AUC 5 + Paclitaxel 175 mg/mq d 1 q 21 for 6 cycles + Bevacizumab 15 mg/kg d 1 q 21 days for 22 cycles (in combination and maintenance)
Drug: Carboplatin
chemotherapy medication
Drug: Paclitaxel
chemotherapy medication
Drug: Bevacizumab
Angiogenesis inhibitor
EXPERIMENTAL: Carboplatin + Paclitaxel + Bevacizumab + Rucaparib
Carboplatin AUC 5 + Paclitaxel 175 mg/mq d1 q 21 days for 6 cycles + Bevacizumab 15 mg/kg d1 q 21 for 22 cycles (in combination and maintenance) + Rucaparib at the dose defined by the Phase I study continuously for 2 years (Rucaparib only in maintenance)
Drug: Rucaparib
PARP inhibitor
Drug: Carboplatin
chemotherapy medication
Drug: Paclitaxel
chemotherapy medication
Drug: Bevacizumab
Angiogenesis inhibitor
EXPERIMENTAL: Carboplatin + Paclitaxel + Rucaparib
Carboplatin AUC 5 + Paclitaxel 175 mg/mq d1 q 21 days for 6 cycles + Rucaparib 600 mg BID continuously for 2 years (Rucaparib only as maintenance).
Drug: Rucaparib
PARP inhibitor
Drug: Carboplatin
chemotherapy medication
Drug: Paclitaxel
chemotherapy medication

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase I Primary Objective: MTD
Time Frame: 4 months
To identify the Maximum Tolerated Dose (MTD) of the combination Rucaparib-Bevacizumab in stage IIIB-C-IV ovarian cancer patients
4 months
Phase II Primary Objective: PFS
Time Frame: from the date of randomization to the date of documented progression disease, recurrence or death (whichever occurs first), assessed up to 64 months
To compare progression-free survival (PFS) of patients with advanced ovarian, primary peritoneal and Fallopian tube cancer when treated with Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs carboplatin-Paclitaxel-Rucaparib according to Homologous Recombination Deficient (HRD) status.
from the date of randomization to the date of documented progression disease, recurrence or death (whichever occurs first), assessed up to 64 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase I Secondary Objectives: toxicity of the Rucaparib-Bevacizumab combination in terms of haematologic and non haematologic events
Time Frame: 4 months
Toxicity will be evaluated according to U.S. NCI Common Toxicity Criteria version 4.03
4 months
Phase I Secondary Objectives: maximum plasma concentration (Cmax at Steady State) of Rucaparib
Time Frame: will be evaluated during cycle 1, on days -7,1,21
The evaluation of the effect of bevacizumab on rucaparib Cmax at SS will be performed by comparing (in each individual patient) the Cmax during cycle 1, on days 1 and 21, with the Cmax obtained on day -7 in which only Rucaparib will be administered. For these parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean.
will be evaluated during cycle 1, on days -7,1,21
Phase I Secondary Objectives: minimal plasma concentration (Cmin at Steady State) of Rucaparib
Time Frame: will be evaluated during cycle 1, on days -7,1,21
The evaluation of the effect of bevacizumab on rucaparib Cmin at SS will be performed by comparing (in each individual patient) the Cmin during cycle 1, on days 1 and 21, with the Cmax obtained on day -7 in which only Rucaparib will be administered. For these parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean.
will be evaluated during cycle 1, on days -7,1,21
Phase I Secondary Objectives: Area Under Curve (AUC)
Time Frame: will be evaluated during cycle 1, on days -7,1,21
The evaluation of the effect of bevacizumab on rucaparib AUC will be performed by comparing (in each individual patient) during cycle 1, on days 1 and 21, rucaparib AUC with AUC obtained on day -7 in which only Rucaparib will be administered. For this parameters, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean.
will be evaluated during cycle 1, on days -7,1,21
Phase I Secondary Objectives: Cmax
Time Frame: will be evaluated during cycle 1, on day1
The evaluation of the effect of bevacizumab on rucaparib Cmax will be performed by measuring the maximum seric concentration of drug. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean.
will be evaluated during cycle 1, on day1
Phase I Secondary Objectives: Tmax
Time Frame: will be evaluated during cycle 1, on day1
The evaluation of the effect of bevacizumab on rucaparib will be performed by measuring the amount of time that the drug is present at the maximum concentration in serum. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean.
will be evaluated during cycle 1, on day1
Phase I Secondary Objectives: AUC (0-24h)
Time Frame: will be evaluated during cycle 1, on day1
The evaluation of the effect of bevacizumab on rucaparib will be performed by measuring the AUC during 24 h. For this parameter, the following descriptive statistics will be calculated: mean, standard deviation, coefficient of variation, median, and geometric mean.
will be evaluated during cycle 1, on day1
Phase II Secondary Objectives: OS
Time Frame: from the date of randomization to the date of death, assessed up to 64 months
Overall survival
from the date of randomization to the date of death, assessed up to 64 months
Phase II Secondary Objectives: PFS2
Time Frame: from randomisation to second objective disease progression or death, assessed up to 64 months
Progression-free survival 2
from randomisation to second objective disease progression or death, assessed up to 64 months
Phase II Secondary Objectives: TFST
Time Frame: from randomisation to the initiation of first subsequent therapy or death of patients, assessed up to 64 months
Time to first subsequent therapy
from randomisation to the initiation of first subsequent therapy or death of patients, assessed up to 64 months
Phase II Secondary Objectives: TSST
Time Frame: from randomisation to the initiation of second subsequent therapy or death, assessed up to 64 months
Time to second subsequent therapy
from randomisation to the initiation of second subsequent therapy or death, assessed up to 64 months
Phase II Secondary Objectives: ORR
Time Frame: 64 months
Overall response rate
64 months
Phase II Secondary Objectives: Safety and tolerability
Time Frame: 64 months
Safety and tolerability will be evaluated by U.S. National Cancer Institute Common Toxicity Criteria Adverse Event (NCI CTCAE) version 4.03 and the number of dose reductions
64 months
Phase II Secondary Objectives: PRO for PHYSICAL WELL-BEING
Time Frame: 64 months
Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A).
64 months
Phase II Secondary Objectives: PRO for SOCIAL/FAMILY WELL-BEING
Time Frame: 64 months
Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A).
64 months
Phase II Secondary Objectives: PRO for EMOTIONAL WELL-BEING
Time Frame: 64 months
Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A).
64 months
Phase II Secondary Objectives: PRO for FUNCTIONAL WELL-BEING
Time Frame: 64 months
Patient-reported outcome (PRO) of disease-related symptoms will be recorded utilizing the disease-related symptoms - physical (DRS-P) subscale of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) FACT-Ovarian Symptom Index 18 (FOSI-18) changes and using Euro-Quality of Life 5D (EQ-5D) tool (Appendix A).
64 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Collaborators

Istituto Di Ricerche Farmacologiche Mario Negri
Foundation Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 17, 2021

Primary Completion (ANTICIPATED)

March 1, 2025

Study Completion (ANTICIPATED)

March 1, 2025

Study Registration Dates

First Submitted

February 14, 2018

First Submitted That Met QC Criteria

March 9, 2018

First Posted (ACTUAL)

March 12, 2018

Study Record Updates

Last Update Posted (ACTUAL)

August 27, 2021

Last Update Submitted That Met QC Criteria

August 24, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3329

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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