1. MITO 25
A randomized phase II trial of Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib in advanced (stage III B-C-IV) ovarian, primary peritoneal and fallopian tube cancer

2. Presented By Iain McNeish at 2015 ASCO Annual Meeting
Results of ARIEL2:<br />A phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis
Presented By Iain McNeish at 2015 ASCO Annual Meeting

3. Presented By Iain McNeish at 2015 ASCO Annual Meeting
ARIEL2 designed to assess rucaparib efficacy in three prospectively defined molecular subgroups
Pazienti con carcinomi sierosi ed endometroidi dell’ovaio ad alto grado, con recidiva platino sensibile che avessero ricevuto e risposto ad almeno una precedente linea di chemioterapia abase di platino sono state arruolate e stratificate nei 3 gruppi: BRCA mutate, BRCA like e negative per BRCA e trattate con Rucaparib 600 mg due volte al giorno fino a progressione o tossicita’ inaccettabile
Presented By Iain McNeish at 2015 ASCO Annual Meeting

4. ARIEL2 patient characteristics
204 pz sono state arruolate, il 43% aveva ricevuto piu’ di 2 precedenti linee di terapia a base di platino, il 20% era BRCA mutata, e il 40% era BRCA like secondo la signature LOH
Presented By Iain McNeish at 2015 ASCO Annual Meeting

5. Presented By Iain McNeish at 2015 ASCO Annual Meeting
Primary efficacy analysis: PFS in BRCAmut and BRCA-like versus Biomarker Negative patients
Rucaparib e’ molto attivo nelle pzienti BRCA mutate con una PFS mediana di 9.4 mesi ma altrettanto lo e’ nelle BRCA LIKE con una PFS di 7.1 mesi
Presented By Iain McNeish at 2015 ASCO Annual Meeting

6. Presented By Iain McNeish at 2015 ASCO Annual Meeting
In BRCAwt tumors, the BRCA-like subgroup derives enhanced benefit from rucaparib
In termini di risposte nelle pazienti mutate Rucaparib registra 82% di RR e nelle BRCA like 45%
Presented By Iain McNeish at 2015 ASCO Annual Meeting

7. Rucaparib is generally well tolerated<br />
Il trattamento e’ risultato molto ben tollerato: le principali tossicita’ sono anemia (16% grado 3), alterazioni delle transaminasi (11) e astenia (6%)
Presented By Iain McNeish at 2015 ASCO Annual Meeting

8. Study design Stratification Factor: Residual tumor at primary surgery;
ARM A: Carboplatin AUC 5+Paclitaxel 175 mg/mq q 21 for 6 cycles + Bevacizumab 15 mg/kg q 21 for 22 cycles
N= 225 R A N D O M I Z T
FIGO stage IIIB-IV high grade serous or endometrioid ovarian cancer, primary peritoneal and / or fallopian-tube cancer.
ARM B: Carboplatin AUC 5+ Paclitaxel 175 mg/mq q Bevacizumab 15 mg/kg for 22 cycles + Rucaparib 600 mg bid q 28 for 24 cycles (Rucaparib only in maintenance)
ARM C: Carboplatin AUC 5+ Paclitaxel 175 mg/mq q 21 + Rucaparib 600 bid q 28 mg for 24 cycles as maintenance
1:1:1
Stratification Factor:
Residual tumor at primary surgery;
Stage of disease;
HRD status (BRCA mutated vs BRCA like vs biomarker negative)
MITO 25

9. Objectives Primary: Progression free survival (PFS)
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 arm.
MITO 25

10. Objectives Secondary:
To compare the overall survival (OS) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib;
To compare the post progression survival (PFS2) of patients receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-Paclitaxel-Bevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib;
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;
To assess the safety and tolerability of Carboplatin-Paclitaxel- Bevacizumab-Rucaparib in this population;
To evaluate LOH signature and its correlation with efficacy end-points;
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.
MITO 25

11. Inclusion Criteria MITO 25
Female aged  18 years at the time of study inclusion;
Patients with newly diagnosed, histologically confirmed, FIGO stage IIIB-IV high grade (based on local histopathological findings) serous or endometrioid ovarian cancer, primary peritoneal and / or fallopian-tube cancer. Patients with mixed histology are eligible providing that high grade tumor represent more than 70% 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;
Archivial 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;
CA-125 be <ULN at the time of maintenance treatment initiation;
Adequate renal and hepatic function;
Adequate bone marrow function, defined as:
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.
MITO 25

12. Exclusion Criteria MITO 25 Women who are pregnant or lactating;
Presence of brain or other central nervous system metastases, not adequately controlled;
Prior Anticancer treatment;
Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 4 weeks prior to randomization;
Another primary malignancy except for: Curatively treated non-melanoma skin cancer; Breast cancer treated curatively >3 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;
Clinically significant (i.e. active) cardiovascular disease;
Serious active infection requiring i.v. antibiotics at enrolment.
Known hypersensitivity to any of the study drugs or excipients;
Evidence of any other medical conditions, physical examination or laboratory findings that may interfere with the planned treatment,;
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.
MITO 25

13. Statistical consideration
In this patient population the median time to PFS is projected to be in the range of 15 months, expected median PFS in the experimental arms (B and C) is 21 months (HR 0.71). Approximately 225 patients (including 15% drop out) will be randomized to study treatment in a 1:1:1 ratio. It is projected that approximately 135 events (recurrence, progression or death) will need to be observed in order to provide approximately 80% power to detect a 30% improvement based on a 0.71 hazard ratio. The power projection is based on a one-sided log-rank test at an alpha = 0.20 significance level.
Study duration: The total estimated duration of the trial is 60 months, including 30 months to accrue patients, and follow-up of 30 months from randomization of last patient for survival.
MITO 25

14. Study design IDMC for safety
Due to the absence of phase I trial on Bevacizuamb -Rucaparib combination a rapid reporting, monitoring and analysis of all Significant Safety Events (SSEs) (defined below) will be performed during the first three treatment cycles of the first 20 patients randomized in the experimental arm.
Information regarding the occurrence of all SSEs will be reported by the Investigator to the Coordinator Centre and to the IDMC within 48 hours from the time the event becomes evident to the investigator.
A SSE is defined as any of the following:
• General Toxicity (NCI-CTC AE, v4.03): grade 3 and grade 4 adverse events,
including hospitalization;
• A patient death (grade 5).
The starting dose of Rucaparib in this study will be 600 mg bid.
MITO 25

15. Study Drug Study drug: Rucaparib 600 mg bid q 28 for 15 months;
Bevacizumab 15 mg/kg q 21 for 22 months ;
Carboplatin and Paclitaxel standard dose for 6 cycles.
Reference Therapy:
Carboplatin AUC 5 + Paclitaxel 175 mg/mq q 21 for 6 cycles + Bevacizumab 15 mg/kg q 21 for 22 cycles
Dosage and Administration:
Rucaparib 600 mg bid per os will be administered in a 28 days cycle until disease progression or unacceptable toxicity or patient refusal which ever occurs first up to 24 months or 12 months (?).
MITO 25

16. Administrative Information
Academic trial
NCI of Milan sponsor (insurance)
Data center: NCI of Milan (MITO center)
Planned study start: January 2016
Clovis will provide Rucaparib
To participate please contact:
MITO 25