Download MITO 25 - Mito Group

MITO 25
A randomized phase II trial of CarboplatinPaclitaxel-Bevacizumab vs CarboplatinPaclitaxel-Bevacizumab-Rucaparib vs
Carboplatin-Paclitaxel-Rucaparib in
advanced (stage III B-C-IV) ovarian,
primary peritoneal and fallopian tube
cancer
Study design
ARM A: Carboplatin AUC 5+Paclitaxel 175
mg/mq q 21 for 6 cycles + Bevacizumab 15
mg/kg q 21 for 22 cycles
N= 216
FIGO stage IIIB-IV
high grade serous
or endometrioid
ovarian cancer,
primary peritoneal
and / or fallopiantube cancer, HRD
positive
R
A
N
D
O
M
I
Z
A
T
I
O
N
ARM B: Carboplatin AUC 5+ Paclitaxel 175
mg/mq q 21 + Bevacizumab 15 mg/kg for 22
cycles + Rucaparib 600 mg bid q 28 until
progression or unacceptable toxicity
1:1:1
Stratification Factor:
•Residual tumor at primary surgery;
•Stage of disease;
•HRD status (BRCA mutated vs BRCA like)
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ARM C: Carboplatin AUC 5+ Paclitaxel 175
mg/mq q 21 + Rucaparib 600 bid q 28 mg
until progression or unacceptable toxicity
Study design
Dose modification:
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 bevacizumab/rucaparib 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:
• Any form of Grade 3-4 Toxicity (NCI-CTC AE, v4.03) including hospitalization;
• A patient death (grade 5).
The starting dose of Rucaparib in this study will be 600 mg bid.
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Objectives
Primary:
Progression free survival (PFS)
The trial will test the hypothesis that Carboplatin-PaclitaxelBevacizumab-Rucaparib and the Carboplatin-Paclitaxel–Rucaparib
arms will improve the progression-free survival in comparison to
standard Carboplatin-Paclitaxel-Bevacizumab arm.
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Objectives
Secondary:
•To compare the overall survival (OS) of patients receiving CarboplatinPaclitaxel-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-BevacizumabRucaparib vs Carboplatin-Paclitaxel-Rucaparib;
•To compare the response rate (Recist and/or GCIG criteria) of patients
receiving Carboplatin-Paclitaxel-Bevacizumab vs Carboplatin-PaclitaxelBevacizumab-Rucaparib vs Carboplatin-Paclitaxel-Rucaparib;
•To assess the safety and tolerability of Carboplatin-Paclitaxel- BevacizumabRucaparib 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-PaclitaxelRucaparib.
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Inclusion Criteria
•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.
•HRD positive patients
•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.
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Exclusion Criteria
•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.
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Statistical consideration
The final analysis of the primary endpoint will be performed using a stratified logrank test to determine whether treatment with Carboplatin-PaclitaxelBevacizumab-Rucaparib or treatments with Carboplatin-Paclitaxel-Rucaparib will
prolong PFS relative to patients treated with Carboplatin-Paclitaxel-Bevacizumab.
All patients randomized will be included in the Intent-to-Treat analysis. Success is
defined as the rejection of the Null Hypothesis of no difference when comparing
Carboplatin-Paclitaxel-Bevacizumab-Rucaparib and Carboplatin-PaclitaxelRucaparib treatment groups with the Carboplatin-Paclitaxel-Bevacizumab control
group in which a statistically significant result favoring treatment with CarboplatinPaclitaxel-Bevacizumab-Rucaparib and Carboplatin-Paclitaxel-Rucaparib for PFS is
demonstrated. The statistical test of the null hypothesis will be carried out using a
one-sided level of significance for which the overall alpha type 1 error is ≤ 0.20.
All patients receiving at least one dose of study drug will be considered
evaluable for safety. The adverse event incidence rates as well as the
frequency of occurrence of overall toxicity, categorized by toxicity grades
(severity) will be described for each arm of the trial.
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Rationale for Number of Patients
The study is dimensioned considering two parallel
comparisons (Arm B vs Arm A and Arm C vs Arm A).
For each comparison, considering a prolongation in
term of PFS of 7 months expected with the
experimental Arm (from 17 months to 24 months)
corresponding to an HR of 0.71, 96 events are
needed to perform the final analysis with an 80%
power and a one-tailed alpha of 0.2. Overall, 216
patients will be randomized with a 1:1:1 ratio into
one of the study arms.
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Study Drug
Study drug:
•Rucaparib 600 mg bid q 28 until progression or unacceptable toxicity;
•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
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Administrative Information
•Academic trial
•NCI of Milan sponsor
•Data center: NCI of Milan (MITO center)
•Planned study start: October 2016
• HRD EVALUATION CENTRALIZED BY Clovis (14 days)
• Assurance and Rucaparib provided
To participate please contact:
[email protected]
[email protected]
MITO 25
MITO 25: STATE OF THE ART
• Approved by EC of NCI Milan on January 2017
• Suspended by AIFA:
• Cemtralized revision of imaging for primary
end point PFS
• Phase 1 data of Rucaparib-Bevacizumab
combinaton
INTERESTED CENTRES
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