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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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)
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STUDY OBJECTIVES
Primary:
The primary objective is to compare the treatment groups in terms
of overall survival (OS)
Secondary:
•Progression free survival (PFS)
•Radiological response rate (in patients with measurable disease)
•Duration of response
•CA-125 response rate per GCIG
•Toxicity profile
•Quality of life using the QLQ-C30 and QLQ-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
• Platinum resistant or sensitive patients with either:
BRCA mutated patients
BRCAness phenotype patients: patients who have received and responded (subsequent PFI>6 months) to at
least 2 previous platinum based chemotherapy lines
Platinum sensitive patients who are not able to receive or not willing to receive other platinum treatments
• Measurable and evaluable disease per RECIST 1.1(Subjects with isolated rising CA-125 without radiologically
visible disease are excluded)
• ECOG performance status 0 or 1
• No limits in the number of previous chemotherapy lines, previous treatment with parp inhibitors is allowed
• Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit normal
• Life expectancy of at least 3 months
• Adequate organ functions
• 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
• Adequately recovered from the acute toxicity of any prior treatment
• For agents in the standard arm, also refer to the local prescribing information with regards to warnings,
precautions, and contraindications
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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
• Subjects with borderline ovarian cancer, ie. Subject with low malignant potential tumors are excluded
• Less than 2 reported 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 III
The primary endpoint is OS
Hazard Ratio: 0.67
Median OS expected in the control arm: 10 months
Median OS hoped for the experimental arm : 15 months
Two-sided log-rank test at the error alfa= 0.05
Statistical Power 80%
198 events are required
Overall 244 patients will be enrolled in 30 months (8 patients/months)
Interim futility analysis at ~ 99 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
(BRCA test).
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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 Fondazione IRCCS
Istituto Nazionale Tumori, 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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Site
Principal Investigator
Status
Ethical Committee
Francesco Raspagliesi/ Domenica Lorusso
In approvazione
26.11.2015
Fondazione Policlinico Universitario A. Gemelli - Roma
Giovanni Scambia
In valutazione
03.12.2015
Istituto Nazionale Tumori Pascale - Napoli
Carmen Pisano
In valutazione
16.12.2015
Ospedale San Raffaele – Milano
Giorgia Mangili
In istruttoria
Fondazione del Piemonte per l'Oncologia - Istituto di Candiolo
Giorgio Valabrega
In istruttoria
Ospedale Fatebenefratelli - Roma
Enrico Breda
In compilazione
ULLS 13 - Mirano
Grazia Artioli
In istruttoria
IRST - Meldola
Ugo De Giorgi
In istruttoria
A.O. di Perugia - Ospedale Santa Maria Misericordia - Perugia
Anna Maria Mosconi
In valutazione
Sapienza Università di Roma-Policlinico Umberto I - Roma
Pierluigi Benedetti Panici
In istruttoria
CRO IRCCS - Aviano
Roberto Sorio
In istruttoria
IRE-Istituto Nazionale Tumori REGINA ELENA - Roma
Patrizia Vici
In istruttoria
AOU Federico II
Sabino De Placido
In compilazione
Fondazione IRCCS Policlinico S.Matteo di Pavia
Stefano Bogliolo
In istruttoria
U.O.Oncologia Medica - Ospedale Vito Fazzi - Lecce
Graziana Ronzino
In istruttoria
Ospedale degli Infermi - Faenza
Stefano Tamberi
In istruttoria
AULSS 21 Regione Veneto - Legnago
Filippo Greco
In valutazione
Ospedale Civile SS. Trinità - Sora
Teresa Gamucci
In istruttoria
A.O. S.Giuseppe Moscati - Avellino
Cesare Gridelli
In istruttoria
Ospedale Santa Croce - Fano
Rodolfo Mattioli
In istruttoria
A.O. Carlo Poma - Mantova
Maria Giovanna Cavazzini
In istruttoria
Ospedale S.Maria delle Croci - Ravenna
Claudia Casanova
In istruttoria
A.O.U. Santa Maria della Misericordia - Udine
Claudia Andreetta
In istruttoria
Centro Sociale Oncologico AAS1 Triestina - Trieste
Rita Ceccherini
In istruttoria
IRCCS AOU San Martino - IST - Genova
Serafina Mammoliti
In istruttoria
Ospedale Civile G.Fornaroli - Magenta
Silvia Elvira Negretti
In istruttoria
Istituto Europeo di Oncologia - Milano
Nicoletta Colombo
In istruttoria
Arcispedale sant'anna - Cona, Ferrara
Antonio Frassoldati
In istruttoria
Spedali Civili di Brescia - Brescia
Germana Tognon
In istruttoria
AOU Maggiore della Carità - Novara
Roberta Buosi
IRCCS Istituto Nazionale Tumori – Milano
COORDINATING CENTER
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In istruttoria
16.12.2015
02.12.2015
ADMINISTRATIVE INFORMATION
•Academic trial
•NCI of Milan sponsor
•Data center: NCI of Milan (MITO center)
•Planned study start: February 2016
•Pharma-Mar support: Trabectedin supply , financial support for insurance,
translational studies and data management.
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