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

Study Overview
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Brief Summary
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This is an open-label, prospective, multicenter, randomized Phase III, clinical trial evaluating the efficacy and safety of trabectedin in BRCA1 and BRCA2 mutation carrier and BRCAness phenotype advanced ovarian cancer patients in comparison to physician' choice chemotherapy. Arm A: Trabectedin 1.3 mg/mq d1 q 21 in 3 hours (central line) Arm B: Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Topotecan 4 mg/mq dd 1,8,15 q 28 or Gemcitabine 1000 mg/mq dd 1, 8, 15 q 28 Weekly Paclitaxel 80 mg/mq gg 1, 8, 15 q 28 Carboplatin AUC 5-6 q 21 or 28 Patients will be randomly assigned in a 1:1 ratio to treatment arms. During the randomization process, patients will be stratified by Platinum sensitivity Measurable disease Number of previous chemotherapy lines > vs < 3 BRCA mutational status

Detailed Description
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Subjects will be randomized in a 1:1 ratio to receive one of the following treatments: Arm A: Trabectedin 1.3 mg/m2 d1 q 21 in 3 hours (central line) Arm B: Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Topotecan 4 mg/ m2 dd 1,8,15 q 28 or Gemcitabine 1000 mg/mq dd 1, 8, 15 q 28 Weekly Paclitaxel 80 mg/ m2 dd 1, 8, 15 q 28 Carboplatin AUC 5-6 q 21 or 28 Randomization will be stratified based on platinum-free interval (PFI) (PFI ≥ 0 and ≤ 6 months vs. PFI > 6 months), presence / absence of measurable disease/number of previous chemotherapy lines, germline BRCA mutational status vs BRCAness phenotype. Platinum-free interval (PFI) is defined as the time from the last dose of the platinum containing regimen until the first date progression. Subjects will continue to receive chemotherapy treatment until disease progression (clinical progression meant as global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression is considered progression of disease), intolerability, patient refusal, investigator decision or death from any cause. Subjects will be evaluated every 12 weeks ± 1 week by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for objective radiographic response and radiographic disease progression.

Official Title
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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

Conditions
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Ovarian Neoplasms

Intervention / Treatment
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* Drug: Trabectedin
* Drug: Pegylated Liposomal Doxorubicin
* Drug: Topotecan
* Drug: Gemcitabine
* Drug: Weekly Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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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: Hematopoietic: Absolute neutrophil count ≥ 1,500/mm3; Platelet count ≥ 100,000/mm3; 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 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin<br>Trabectedin 1.3 mg/m2 d1 q 21 in 3 hours (central line) | Drug: Trabectedin<br> <br> * Other names: Yondelis;|
| Other: Standard Treatment<br>Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Topotecan 4 mg/ m2 dd 1,8,15 q 28 or Gemcitabine 1000 mg/mq dd 1, 8, 15 q 28 Weekly Paclitaxel 80 mg/ m2 dd 1, 8, 15 q 28 Carboplatin AUC 5-6 q 21 or 28 | Drug: Pegylated Liposomal Doxorubicin<br> <br> Drug: Topotecan<br> <br> Drug: Gemcitabine<br> <br> Drug: Weekly Paclitaxel<br> <br> Drug: Carboplatin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The primary objective is to compare the Trabectedin versus physician' choice chemotherapy in terms of overall survival (OS). | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Progression-free survival [the diagnosis of progression will be assessed by radiological criteria; CA 125 increases alone (GCIG criteria of progression) will not be considered as progression of disease without a radiological confirmation of progression]. | 4 years | 
| Duration of Response | Duration of response | 4 years | 
| Adverse events | Incidence of adverse events, according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0. | 4 years |