Advanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube CancerPhase 1/2MITO25NCT03462212

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

A Phase 1/2 study testing Carboplatin, Paclitaxel and Bevacizumab in people with Advanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 7 sites in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record

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Trial summary

Who is it for?: Ages 18 years and older, women only
Conditions the study is for: Advanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer
What is being tested?: Carboplatin, Paclitaxel and Bevacizumab
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 290 participants
Where: 7 sitesItaly
Study dates: 17 Mar 2021to 1 Mar 2025
Phase: Phase 1/2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
Women only
No healthy volunteers
Adult, Older adult

Who may be able to join

Women aged >=18 years at the time of study inclusion;
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;
Archival tumor tissue available. At progression fresh biopsy is optional for patients willing to submit ;
ECOG Performance Status of 0-1;
Measurable and not measurable disease;

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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);
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;
Able to understand and give written informed consent;
Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

Who cannot join

Women who are pregnant or lactating;
Presence of brain or other central nervous system metastases, not adequately controlled by treatment;
Prior Anticancer treatment;
Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 3 weeks prior to randomization;
Another primary malignancy except for:
Curatively treated non-melanoma skin cancer;

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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);
Known active HIV, hepatitis B or C infection;
Concurrent treatment with immunosuppressive or investigational agents;
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);
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);
Serious active infection requiring i.v. antibiotics at enrolment;
Known hypersensitivity to any of the study drugs or excipients (including cremophor and hamster Ovary cell products);
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;
Prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with absorption of study drug;
Received administration of strong CYP1A2 or CYP3A4 inhibitors ≤7 days prior to first dose of Rucaparib or have on-going requirements for these medications.

Trial locations and contacts

7 sites in 1 country.

Domenica Lorusso, Prof. contact

0630158545 ext. 0039

domenica.lorusso@policlinicogemelli.it

Serena Giolitto, MSc contact

0630158545 ext. 0039

serena.giolitto@policlinicogemelli.it

City, postcode or hospital

Sites recruiting now only

7 sites in 1 country

Italy7 sites, 7 recruiting

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

Other trials in Italy

About this study

Official title: 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.

Read the 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)

Conditions: Advanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer
Being tested: Carboplatin, Paclitaxel, Bevacizumab, Rucaparib
Medical subject headings: Fallopian Tube Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

CarboplatinDrug
chemotherapy medication
PaclitaxelDrug
chemotherapy medication
BevacizumabDrug
Angiogenesis inhibitor
RucaparibDrug
PARP inhibitor

Study groups in NCT03462212
Study group	Role	What they receive
Standard treatment	Other	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) Receives: Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab
Carboplatin + Paclitaxel + Bevacizumab + Rucaparib	Experimental	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) Receives: Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab; Drug: Rucaparib
Carboplatin + Paclitaxel + Rucaparib	Experimental	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). Receives: Drug: Carboplatin; Drug: Paclitaxel; Drug: Rucaparib

What is being measured

The primary outcome is the main question the study is designed to answer.

Phase I Primary Objective: MTD
To identify the Maximum Tolerated Dose (MTD) of the combination Rucaparib-Bevacizumab in stage IIIB-C-IV ovarian cancer patients
Measured: 4 months
Phase II Primary Objective: PFS
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.
Measured: from the date of randomization to the date of documented progression disease, recurrence or death (whichever occurs first), assessed up to 64 months

Secondary outcomes (17)

Phase I Secondary Objectives: 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 4.03
Measured: 4 months
Phase I Secondary Objectives: maximum plasma concentration (Cmax at Steady State) of Rucaparib
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.
Measured: will be evaluated during cycle 1, on days -7,1,21
Phase I Secondary Objectives: minimal plasma concentration (Cmin at Steady State) of Rucaparib
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.
Measured: will be evaluated during cycle 1, on days -7,1,21
Phase I Secondary Objectives: Area Under Curve (AUC)
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.
Measured: will be evaluated during cycle 1, on days -7,1,21
Phase I Secondary Objectives: Cmax
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.
Measured: will be evaluated during cycle 1, on day1
Phase I Secondary Objectives: Tmax
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.
Measured: will be evaluated during cycle 1, on day1
Phase I Secondary Objectives: AUC (0-24h)
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.
Measured: will be evaluated during cycle 1, on day1
Phase II Secondary Objectives: OS
Overall survival
Measured: from the date of randomization to the date of death, assessed up to 64 months
Phase II Secondary Objectives: PFS2
Progression-free survival 2
Measured: from randomisation to second objective disease progression or death, assessed up to 64 months
Phase II Secondary Objectives: TFST
Time to first subsequent therapy
Measured: from randomisation to the initiation of first subsequent therapy or death of patients, assessed up to 64 months
Phase II Secondary Objectives: TSST
Time to second subsequent therapy
Measured: from randomisation to the initiation of second subsequent therapy or death, assessed up to 64 months
Phase II Secondary Objectives: ORR
Overall response rate
Measured: 64 months
Phase II Secondary Objectives: Safety and tolerability
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
Measured: 64 months
Phase II Secondary Objectives: PRO for PHYSICAL WELL-BEING
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).
Measured: 64 months
Phase II Secondary Objectives: PRO for SOCIAL/FAMILY WELL-BEING
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).
Measured: 64 months
Phase II Secondary Objectives: PRO for EMOTIONAL WELL-BEING
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).
Measured: 64 months
Phase II Secondary Objectives: PRO for FUNCTIONAL WELL-BEING
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).
Measured: 64 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

17 Mar 20211 Mar 2025

First posted12 Mar 2018
Study start17 Mar 2021
Primary completion1 Mar 2025 (estimated)
Study completion1 Mar 2025 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (64)Papers the sponsor has linked to this study.
Other trials for Advanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube CancerStudies of the same condition, open and under way.
More trials run by Fondazione Policlinico Universitario Agostino Gemelli IRCCSThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 290 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03462212
Sponsor's protocol ID: 3329
Acronym: MITO25
Status last verified: Aug 2021
First submitted: 14 Feb 2018
Last updated: 27 Aug 2021
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Publications

De Bono JS, Mina LA, Gonzalez M, Curtin NJ, Wang E, Henshaw JW, et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. J Clin Oncol. 2013;31(suppl):2580.
Iain A. McNeish, Amit M. Oza, Robert L. Coleman, et al. Results of ARIEL2: A Phase II trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. J Clin Oncol 33, 2015 (suppl; abstr 5508)
Gourley, C. McCavigan, A Perren, T et al Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. Abstract 5502 ASC0 2014
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29. doi: 10.3322/caac.20138. Epub 2012 Jan 4.
PubMed 22237781
Chan JK, Cheung MK, Husain A, Teng NN, West D, Whittemore AS, Berek JS, Osann K. Patterns and progress in ovarian cancer over 14 years. Obstet Gynecol. 2006 Sep;108(3 Pt 1):521-8. doi: 10.1097/01.AOG.0000231680.58221.a7.
PubMed 16946210
Engel J, Eckel R, Schubert-Fritschle G, Kerr J, Kuhn W, Diebold J, Kimmig R, Rehbock J, Holzel D. Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate. Eur J Cancer. 2002 Dec;38(18):2435-45. doi: 10.1016/s0959-8049(02)00495-1.
PubMed 12460789
Harries M, Gore M. Part I: chemotherapy for epithelial ovarian cancer-treatment at first diagnosis. Lancet Oncol. 2002 Sep;3(9):529-36. doi: 10.1016/s1470-2045(02)00846-x.
PubMed 12217790
International Collaborative Ovarian Neoplasm Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet. 2002 Aug 17;360(9332):505-15. doi: 10.1016/S0140-6736(02)09738-6.
PubMed 12241653
Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006 Jan 5;354(1):34-43. doi: 10.1056/NEJMoa052985.
PubMed 16394300
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996 Jan 4;334(1):1-6. doi: 10.1056/NEJM199601043340101.
PubMed 7494563
Muggia FM, Braly PS, Brady MF, Sutton G, Niemann TH, Lentz SL, Alvarez RD, Kucera PR, Small JM. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2000 Jan;18(1):106-15. doi: 10.1200/JCO.2000.18.1.106.
PubMed 10623700
Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, Stuart G, Kaye S, Vergote I, Blom R, Grimshaw R, Atkinson RJ, Swenerton KD, Trope C, Nardi M, Kaern J, Tumolo S, Timmers P, Roy JA, Lhoas F, Lindvall B, Bacon M, Birt A, Andersen JE, Zee B, Paul J, Baron B, Pecorelli S. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000 May 3;92(9):699-708. doi: 10.1093/jnci/92.9.699.
PubMed 10793106
Spannuth WA, Sood AK, Coleman RL. Angiogenesis as a strategic target for ovarian cancer therapy. Nat Clin Pract Oncol. 2008 Apr;5(4):194-204. doi: 10.1038/ncponc1051. Epub 2008 Feb 12.
PubMed 18268546
du Bois A, Quinn M, Thigpen T, Vermorken J, Avall-Lundqvist E, Bookman M, Bowtell D, Brady M, Casado A, Cervantes A, Eisenhauer E, Friedlaender M, Fujiwara K, Grenman S, Guastalla JP, Harper P, Hogberg T, Kaye S, Kitchener H, Kristensen G, Mannel R, Meier W, Miller B, Neijt JP, Oza A, Ozols R, Parmar M, Pecorelli S, Pfisterer J, Poveda A, Provencher D, Pujade-Lauraine E, Randall M, Rochon J, Rustin G, Sagae S, Stehman F, Stuart G, Trimble E, Vasey P, Vergote I, Verheijen R, Wagner U; Gynecologic Cancer Intergroup; AGO-OVAR; ANZGOG; EORTC; GEICO; GINECO; GOG; JGOG; MRC/NCRI; NCIC-CTG; NCI-US; NSGO; RTOG; SGCTG; IGCS; Organizational team of the two prior International OCCC. 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol. 2005;16 Suppl 8:viii7-viii12. doi: 10.1093/annonc/mdi961. No abstract available.
PubMed 16239238
Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M, Ferrara N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997 Oct 15;57(20):4593-9.
PubMed 9377574

Study at a glance

From the registry record, last updated by the sponsor on 27 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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
ClinicalTrials.gov ID: NCT03462212
Acronym / sponsor ID: MITO25 / 3329
Conditions: Advanced (Stage IIIB-C-IV) Ovarian, Primary Peritoneal and Fallopian Tube Cancer
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Unknown status
Enrolment: 290 participants (estimated)
Lead sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCSUniversity, hospital or other
Collaborators: Istituto Di Ricerche Farmacologiche Mario Negri, Foundation Medicine
Study start: 17 Mar 2021 (actual)
Primary completion: 1 Mar 2025 (estimated)
Study completion: 1 Mar 2025 (estimated)
First posted: 12 Mar 2018 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Phase I study design:

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).

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 design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 3

Arm	Type	Receives
Standard treatment	Other	Drug: Carboplatin, Drug: Paclitaxel, Drug: BevacizumabCarboplatin 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)
Carboplatin + Paclitaxel + Bevacizumab + Rucaparib	Experimental	Drug: Carboplatin, Drug: Paclitaxel, Drug: Bevacizumab, Drug: RucaparibCarboplatin 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)
Carboplatin + Paclitaxel + Rucaparib	Experimental	Drug: Carboplatin, Drug: Paclitaxel, Drug: RucaparibCarboplatin 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).

Who may qualify

Ages: 18 years and older
Sex: Female only
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (16 listed)

Women aged >=18 years at the time of study inclusion;
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;
Archival tumor tissue available. At progression fresh biopsy is optional for patients willing to submit ;
ECOG Performance Status of 0-1;

Key exclusion criteria (21 listed)

Women who are pregnant or lactating;
Presence of brain or other central nervous system metastases, not adequately controlled by treatment;
Prior Anticancer treatment;
Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 3 weeks prior to randomization;
Another primary malignancy except for:

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Carboplatinchemotherapy medication	Drug	Carboplatin + Paclitaxel + Bevacizumab + Rucaparib, Carboplatin + Paclitaxel + Rucaparib, Standard treatment
Paclitaxelchemotherapy medication	Drug	Carboplatin + Paclitaxel + Bevacizumab + Rucaparib, Carboplatin + Paclitaxel + Rucaparib, Standard treatment
BevacizumabAngiogenesis inhibitor	Drug	Carboplatin + Paclitaxel + Bevacizumab + Rucaparib, Standard treatment
RucaparibPARP inhibitor	Drug	Carboplatin + Paclitaxel + Bevacizumab + Rucaparib, Carboplatin + Paclitaxel + Rucaparib

Primary outcome

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
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.

17 secondary outcomes

Phase I Secondary Objectives: toxicity of the Rucaparib-Bevacizumab combination in terms of haematologic and non haematologic events
Time frame: 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
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
Phase I Secondary Objectives: Area Under Curve (AUC)
Time frame: 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
Phase I Secondary Objectives: Tmax
Time frame: 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
Phase II Secondary Objectives: OS
Time frame: 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
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
Phase II Secondary Objectives: TSST
Time frame: 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
Phase II Secondary Objectives: Safety and tolerability
Time frame: 64 months
Phase II Secondary Objectives: PRO for PHYSICAL WELL-BEING
Time frame: 64 months
Phase II Secondary Objectives: PRO for SOCIAL/FAMILY WELL-BEING
Time frame: 64 months
Phase II Secondary Objectives: PRO for EMOTIONAL WELL-BEING
Time frame: 64 months
Phase II Secondary Objectives: PRO for FUNCTIONAL WELL-BEING
Time frame: 64 months

Results and safety

Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2021.
BackgroundDe Bono JS, Mina LA, Gonzalez M, Curtin NJ, Wang E, Henshaw JW, et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. J Clin Oncol. 2013;31(suppl):2580.
BackgroundIain A. McNeish, Amit M. Oza, Robert L. Coleman, et al. Results of ARIEL2: A Phase II trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. J Clin Oncol 33, 2015 (suppl; abstr 5508)
BackgroundGourley, C. McCavigan, A Perren, T et al Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. Abstract 5502 ASC0 2014
Results publication: PubMed 22237781Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29. doi: 10.3322/caac.20138. Epub 2012 Jan 4.
Results publication: PubMed 16946210Chan JK, Cheung MK, Husain A, Teng NN, West D, Whittemore AS, Berek JS, Osann K. Patterns and progress in ovarian cancer over 14 years. Obstet Gynecol. 2006 Sep;108(3 Pt 1):521-8. doi: 10.1097/01.AOG.0000231680.58221.a7.
Results publication: PubMed 12460789Engel J, Eckel R, Schubert-Fritschle G, Kerr J, Kuhn W, Diebold J, Kimmig R, Rehbock J, Holzel D. Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate. Eur J Cancer. 2002 Dec;38(18):2435-45. doi: 10.1016/s0959-8049(02)00495-1.
Results publication: PubMed 12217790Harries M, Gore M. Part I: chemotherapy for epithelial ovarian cancer-treatment at first diagnosis. Lancet Oncol. 2002 Sep;3(9):529-36. doi: 10.1016/s1470-2045(02)00846-x.
Results publication: PubMed 12241653International Collaborative Ovarian Neoplasm Group. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet. 2002 Aug 17;360(9332):505-15. doi: 10.1016/S0140-6736(02)09738-6.
Results publication: PubMed 16394300Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006 Jan 5;354(1):34-43. doi: 10.1056/NEJMoa052985.
Results publication: PubMed 7494563McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996 Jan 4;334(1):1-6. doi: 10.1056/NEJM199601043340101.
Results publication: PubMed 10623700Muggia FM, Braly PS, Brady MF, Sutton G, Niemann TH, Lentz SL, Alvarez RD, Kucera PR, Small JM. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2000 Jan;18(1):106-15. doi: 10.1200/JCO.2000.18.1.106.
Results publication: PubMed 10793106Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, Stuart G, Kaye S, Vergote I, Blom R, Grimshaw R, Atkinson RJ, Swenerton KD, Trope C, Nardi M, Kaern J, Tumolo S, Timmers P, Roy JA, Lhoas F, Lindvall B, Bacon M, Birt A, Andersen JE, Zee B, Paul J, Baron B, Pecorelli S. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000 May 3;92(9):699-708. doi: 10.1093/jnci/92.9.699.
Related InfoLink provided by the sponsor.
Individual participant dataSharing planned: No

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Domenica Lorusso, Prof. contact

0630158545 ext. 0039

domenica.lorusso@policlinicogemelli.it

Serena Giolitto, MSc contact

0630158545 ext. 0039

serena.giolitto@policlinicogemelli.it

Domenica Lorusso, Prof. principal investigator

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

7 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 27 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Domenica Lorusso, Prof. (0630158545 ext. 0039, domenica.lorusso@policlinicogemelli.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase I Primary Objective: MTD (time frame: 4 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03462212, which also lists 64 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Aug 2021.