MITO 25.1: 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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Mar 2021 → ongoing

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pharmaand Schweiz GmbH

External identifiers

EU CT number

2024-516632-99-00

EudraCT number

2017-002860-42

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Others, Efficacy, Therapy

Phase I Primary Objective:
To identify the Maximum Tolerated Dose (MTD) of the combination Rucaparib-Bevacizumab in stage IIIB-C-IV ovarian cancer patients.

Phase II Primary Objective:
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.

Secondary objectives 9

1. Phase I Secondary Objective: To describe the toxicity of the Rucaparib-Bevacizumab combination in terms of haematologic and non haematologic events
2. Phase I Secondary Objective: To evaluate pharmacokinetic parameter in patients receiving the combination of Rucaparib and Bevacizumab
3. Phase II Secondary Objective: To compare the overall survival (OS) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib according to HRD status;
4. Phase II Secondary Objective: To compare the progression-free survival 2 (PFS2) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib according to HRD status;
5. Phase II Secondary Objective: To compare the time from randomisation to first subsequent therapy or death (TFST) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib or Carboplatin-Paclitaxel-Rucaparib according to HRD status;To compare the time to second subsequent therapy (TSST) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib or Carboplatin-Paclitaxel-Rucaparib according to HRD status
6. Phase II Secondary Objective: To compare the response rate (Recist and/or GCIG criteria) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib according to HRD status
7. Phase II Secondary Objective: To assess the safety and tolerability of Carboplatin-Paclitaxel- Bevacizumab-Rucaparib in this populationTo evaluate alterations in DNA repair genes and genomic HRD signature and their correlation with efficacy end-points
8. Phase II Secondary Objective: To evaluate alterations in DNA repair genes and genomic HRD signature and their correlation with efficacy end-points
9. Phase II Secondary Objective: To assess changes in Quality of Life parameters in patients treated with Carboplatin-Paclitaxel-Bevacizumab compared to those treated with Carboplatin-Paclitaxel- Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib according to HRD status

Conditions and MedDRA coding

Advanced (stage III B-C-IV) ovarian, primary peritoneal and Fallopian tube cancer.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Women aged >/= 18 years at the time of study inclusion
2. Patients with newly diagnosed, histologically confirmed, high grade serous, high grade endometrioidFIGO 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. 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); - Serum creatinine ≤ 1.5 x ULN for the institution (or calculated creatinine clearance ≥ 45 mL/min/1.73 m2);
6. 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;
7. Able to understand and give written informed consent
8. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment;

Exclusion criteria 14

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 for ovarian cancer
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: - Curatively treated non-melanoma skin cancer; - Breast cancer treated curatively ≥5 years ago, or other solid tumor treated curatively ≥5 years ago, without evidence of recurrence; - 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: Maximum Tolerated Dose (MTD): defined as the maximum dose at which no limiting toxicities occurr (see belove the definition of limiting toxicities) to recommend for the Phase II randomized design of the trial
2. Phase II: Progression-free survival, defined as the time from the date of randomization to the date of documented progressive disease, recurrence or death (whichever occurs first) in patients treated according to HRD status.

Secondary endpoints 9

1. Phase I: Toxicity of the Rucaparib-Bevacizumab combination in terms of haematologic and non haematologic events. Toxicity will be evaluated according to U.S. NCI Common Toxicity Criteria version 5.0
2. Phase I: Pharmacokinetic parameter in patient receiving the combination of Rucaparib and Bevacizumab
3. Phase II: Overall survival defined as the time from the date of randomization to the date of death in patients treated accordinf to HRD status
4. Phase II: Progression-free survival 2 (PFS2) defined as time from randomisation to second objective disease progression or death in patients treated accordinf to HRD status
5. Phase II: To compare the time from randomization to first subsequent therapy or death (TFST) in patients treated according to HRD status
6. Phase II: Time to second subsequent therapy (TSST) defined as time from randomisation to the initiation of second subsequent therapy or death in patients treated according to HRD status
7. Phase II: Best target lesion response, defined as best change in sum of the target lesions from baseline to disease progression or by the modifications of CA 125 according to GCIG criteria
8. Phase II: Adverse Events and laboratory abnormalities evaluated according to CTCAE version 5.0
9. Phase II: Patient-reported outcome (PRO) of disease-related symptoms utilizing Functional Assessment of Cancer Therapy-Ovarian (FACT-O) and Euro-Quality of Life 5D (EQ-5D) tool

Investigational products

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

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Sponsor organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Address

Largo Francesco Vito 1

City

Rome

Postcode

00168

Country

Italy

Scientific contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Direzione Scientifica IRCCS Policlinico A. Gemelli

Public contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Direzione Scientifica IRCCS Policlinico A. Gemelli

Third parties 2

Locations

1 EU/EEA country · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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