Download mito-23 - Mito Group

Randomized phase III trial on Trabectedin
(ET 743) vs clinician’s choice
chemotherapy in recurrent ovarian,
primary peritoneal or fallopian tube cancers
of BRCA mutated or BRCAness phenotype
patients
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STUDY DESIGN
Randomized phase III
STRATIFICATION CRITERIA:
Measurable Disease
Platinum Sensitivity
Number of Previous CHT Lines
Mutational status
Recurrent ovarian,
primary peritoneal or
fallopian tube cancers
of BRCA mutated or
BRCAness phenotype
patients
II line chemotherapy
(physician choice):
- PLD 40 mg/mq d1 q28;
- Topotecan 4 mg/mq d1,8,15 q 28
- Weekly Paclitaxel 80 mg/mq d1,8,15 q28
-Gemcitabine 1000 mg/mq gg1,8,15 q28
-Carboplatin AUC 5 g 1 q 21
Random
1.1
Trabectedin 1.3 mg/mq d1 q
21 in 3 hours (central line)
STUDY OBJECTIVES
Primary:
The primary objective is to compare the treatment groups in terms
of progression free survival (PFS) according to Recist v1.1 criteria.
Secondary:
•Overall survival (OS)
•Radiological response rate (in patients with measurable disease)
•Duration of response
•CA-125 response rate per GCIG
•Toxicity profile
• Quality of life using the EORTC C30 and EORTC 0V28
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INCLUSION CRITERIA
•
•
Female of age 18 years or older;
Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or
fallopian tube cancer (Subjects with borderline ovarian cancer are excluded; subjects with ovarian
carcinosarcoma are included);
•
Platinum resistant or sensitive patients with:
- BRCA mutated patients;
- BRCAness phenotype patients: patients who have received at least two previous platinum based
chemotherapy lines reporting CR or PR or SD lasting at least 6 months;
- Platinum sensitive patients not able to receive or not willing to receive platinum treatments.
•
Measurable and evaluable disease per RECIST 1.1;
•
Subjects with isolated rising CA-125 without radiographically visible disease are excluded;
•
ECOG performance status 0 or 1;
•
Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit of normal;
•
Life expectancy of at least 3 months ;
•
Adequate organ functions:
- Hematopoietic; Absolute neutrophil count ≥ 1,500/mm^3; Platelet count ≥ 100,000/mm^3; Hemoglobin ≥ 9
g/dl;
- Hepatic; AST and ALT ≤ 1.5 times upper limit of normal (ULN)* ; Alkaline Phosphatase ≤ 2.5 times ULN* ;
Bilirubin ≤ 1.5 times;
- ULN NOTE: * ≤ 3 times ULN if liver metastases are present ;
- Renal; Creatinine Clearance ≥ 45 ml/min or Serum Creatinine ≤1.5 x ULN;
- Serum Albumin >2.5 g/dl;
•
No other invasive malignancy within the past 3 years except non-melanoma skin cancer or in situ cervical
cancer (patients with
previous cancers may be enrolled providing that no recurrences have be reported in the last 3 years);
•
Written Informed Consent.
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EXCLUSION CRITERIA
•
•
•
•
•
•
•
Prior exposure to trabectedin;
Known hypersensitivity to any of the components of the trabectedin i.v. formulation or
dexamethasone;
Less than 2 previous responses to platinum (i.e. subsequent recurrences at least 6
months after the first and the second platinum based treatment), unless BRCA mutation
is documented;
Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy ;
History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ
adequately treated) unless in remission for 3 years or longer ;
Known clinically relevant CNS metastases, unless treated and asymptomatic;
Other serious illnesses, such as:
- Congestive heart failure or angina pectoris; myocardial infarction within 1 year before
enrolment; uncontrolled arterial
hypertension or arrhythmias.
- Psychiatric disorder that prevents compliance with protocol;
- Active viral hepatitis; or chronic liver disease;
- Active infection;
- Any other unstable medical conditions.
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Assessment
Written Informed Consent
Screening
Day
Before study
procedures
Cycle
Day 1
Day 8
End of Treatment
Day 15
Day 16-21
Demographic Data
- 28 to 0
Medical History
- 28 to 0
Prior surgical and/or
chemotherapy treatments
- 14 to 0
Vital Signs (heart rate, blood
pressure, temperature)
- 14 to 0
X
Complete Physical
Examination (assessment of
signs and symptoms of
desease)
- 14 to 0
X
X
X
X
Performance Status (ECOG)
- 14 to 0
X
X
X
X
ECG
- 28 to 0
Repeat if clinically indicated
Echocardiogram
-28 to 0
Repeat every 3 cycle only in case of PLD and T treatments, in all
other cases repeat only if clinically indicated
Concomitant Disease and
Medication
- 14 to 0
Throughout the study
Adverse Events
- 14 to 0
Throughout the study
Hematology
Coagulation Test
-7 to 0
-7 to 0
X
Xa
Xa
X
X
Chemistry and Liver Panel
-7 to 0
X
Xa
Xa
X
QoL assessments
X
Radiologic evaluations
- 28 to 0
CA 125
-7 to 0
X
Every 3 chemotherapy cycles
Every 12 +/- 1 week
X
Follow Up
X
X
X
X
Xb
STATISTICS PROTOCOL
Phase 3
The primary endpoint is PFS
Hazard Ratio: 0.71
Median PFS expected in the control arm: 17 weeks
Median PFS hoped for the experimental arm : 24 weeks
Type I one-side error α: 0.025
Statistical Power 80%
288 events are required
Overall 344 patients will be enrolled in 3 years (10
patients/months)
Interim futility analysis at 172 events
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MITO-23: TRANSLATIONAL STUDIES
• Evaluating the impact of altered gene and microRNA
(miRNA) expression on trabectedin efficacy with the
aim of identify which genes are involved in the so
called BRCAness phenotype;
• Analysis of cellular infiltrate present on tumor
specimens of patients treated with trabectedin;
• DNA sequencing in order to evaluate
mutation/genetic aberration profile in selected panels
of genes associated to tumor sensibility to trabectedin
(BROCA panel).
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TRANSLATIONAL STUDIES:
Specimens
Tumor histological blocks (FFPE material): samples will be collected at primary surgery
and/or interval debulking surgery (or before trabectedin treatment by dedicated biopsies).
Storage and analysis will be centralized at Fondazione Istituto Nazionale dei Tumori.
•Characterization of tumor infiltrate by IHC (2 slides per marker & 1 HE slide & 3 backup
slides);
•Extraction of RNA from tissue sections for gene expression by DASL microarray analysis;
•Extraction of DNA from tissue sections for targeted sequencing of “Panel cancer related
genes” (in collaboration with Istituto Mario Negri, Milan).
Blood samples: Blood samples will be collected at baseline (registration), at third cycle of
treatment and at progression. Storage and analyses will be centralized at Istituto Mario Negri,
Milan. 10 ml blood sample will be taken at each time point, centrifuged in EDTA, processed to
obtain 5 ml plasma collected and stored at -20°C or at -80°C when possible.
•Analysis of miRNA profile by Agilen microarrays or evaluation of selected miRNA by RT-qPCR
(in collaboration with Fondazione Istituto Nazionale dei Tumori)
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ADMINISTRATIVE INFORMATION
•Academic trial
•NCI of Milan sponsor
•Data center: NCI of Milan (MITO center)
•Planned study start: March 2015
•Pharma-Mar support: Trabectedin supply , financial support for
insurance,
translational studies and data management.
To participate please contact:
[email protected]
[email protected]
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