Olaparib beyond progression compared to platinum chemotherapy after secondary cytoreductive surgery in recurrent ovarian cancer patients. The phase III randomized, open label MITO 35b study: a project of the MITO-MANGO groups.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Jan 2025 → ongoing

Decision date (initial)

2025-01-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516842-21-00

EudraCT number

2021-000245-41

ClinicalTrials.gov

NCT05255471

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacogenetic, Safety, Pharmacogenomic

To determine the efficacy (in terms of progression-free survival) of olaparib maintenance beyond progression when compared to standard
chemotherapy in patients with recurrent ovarian cancer undergone secondary cytoreductive surgery for recurrent or progressive disease.
•To determine the efficacy of the experimental therapies on subsequent treatment (in terms of progression-free survival 2) after progression.

Secondary objectives 1

1. To compare the two arms in terms of: •Overall Survival •Safety and tolerability (CTCAE 5.0 version and PRO-CTCAE questionnaire) • Quality of Life (EORTC QLQ-C30 questionnaire) • Financial toxicity (PROFFIT questionnaire)

Conditions and MedDRA coding

Recurrent ovarian cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Inclusion criteria: • Signed informed consent prior to any study specific procedures; • Female, age = 18 years at time of signing informed consent; • Patients with high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer recurrent or progressive after first line PARPi maintenance are allowed; • Patients must have received only one previous line of a platinum containing regimen. Regimens containing bevacizumab are allowed; • Patient must have received a first-line maintenance therapy with a PARPi for at least 6 months; if the prior PARPi used was olaparib then patients must have received treatment without significant toxicity or the need for a permanent dose reduction. Patients who experience disease relapse after the end of the 24 months maintenance therapy are eligible; • Patients must have undergone secondary cytoreductive surgery. The cytoreduction must result in complete resection (absence of macroscopic residual tumor) or at least resection of the progressive lesion(s) occurring during maintenance; • Documented BRCA1/2 status. Both mutated and wild type patients are eligible. Patient with unknown status of BRCA genes agrees to undergo analysis of their germline and somatic BRCA status (testing must be completed prior to enrolment in the study); • Patients must have a life expectancy = 16 weeks; • Patients must start the experimental treatments in the current study within 3 to 8 weeks from second surgery; • ECOG performance status 0 to 1; • Patient must provide archival tumor samples formalin fixed, paraffin embedded (FFPE) from both the primary (before any treatment, chemotherapy naive)) and secondary surgeries for paired analysis. A quality control analysis of samples will be performed before patient's randomization; • Patient must be able to take oral medications; • Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: o Haemoglobin = 10.0 g/dL with no blood transfusion in the past 28 days o Absolute neutrophil count (ANC) = 1.5 x 109/L o Platelet count = 100 x 109/L o Total bilirubin = 1.5 x institutional upper limit of normal (ULN) o Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) and Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) = 2.5 x ULN for institution (or = 5x ULN if liver metastases are present). o Patients must have creatinine clearance estimated of =51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72 (a where F=0.85 for females and F=1 for males.) o For patients not receiving therapeutic anticoagulation international normalized ratio (INR) or activated partial thromboplastin time (aPTT)= 1.5xULN. Patients receiving heparin treatment should have an aPTT between 1.5 to 2.5 X ULN (or patient value before starting heparin treatment) Patients receiving coumarin derivatives should have an INR have an INR between 2.0 and 3.0 assessed in two consecutive measurements 1 to 4 days apart XML File Identifier: q1p939o9kVegPlsaSqFuuHC+alQ= Page 40/68 • Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. Postmenopausal is defined as: - Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50; - radiation-induced oophorectomy with last menses >1 year ago; - chemotherapy-induced menopause with >1-year interval since last menses; - surgical sterilisation (bilateral oophorectomy or hysterectomy). For the remaining inclusion criteria refer to the protocol

Exclusion criteria 1

1. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease and /or active, uncontrolled infection that may interfere with planned treatment, affect patient compliance or place the patient at high risk from treatment related complications [Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, New York Heart Association (NYHA) grade II or greater congestive heart failure, uncontrolled hypertension, severe peripheral vascular disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric illness ]• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication; • Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment; prior palliative radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment • Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of major surgery; Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT); • Breast feeding women; • Patients with symptomatic uncontrolled brain metastases. A TC/ RMN scan of brain is required at baseline. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days. • Other malignancy unless curatively treated with no evidence of disease for =5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma; • Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable) except for transfusion done during surgery. • Persistent toxicities >grade 2 according Common Terminology Criteria for Adverse (CTCAE) version 5.0 caused by previous cancer therapy, excluding alopecia • Resting ECG indicating uncontrolled, potentially irreversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >470 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome. • Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. • Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Patients with myelodysplastic syndrome (MSD)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML. • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV). FOR THE REMAINING EXCLUSION CRITERIA REFER TO THE PROTOCOL

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1)progression-free survival 2) progression-free survival 2

Secondary endpoints 1

1. 1) Overall Survival 2) Safety and tolerability (CTCAE 5.0 version and PRO-CTCAE questionnaire) 3) Quality of Life (EORTC QLQ-C30 questionnaire) 4) Financial toxicity (PROFFIT questionnaire

Investigational products

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

Test 2

Comparator 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Sponsor organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Address

Via Mariano Semmola 52

City

Naples

Postcode

80131

Country

Italy

Scientific contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Clorinda Schettino

Public contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Clorinda Schettino

Locations

1 EU/EEA country · 41 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 30 files

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

Application history

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