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Study With Trabectedin in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Ovarian Cancer (MITO15)

Primary Purpose

BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype

Status

Unknown status

Phase

Phase 2

Locations

Italy

Study Type

Interventional

Intervention

Trabectedin

About this trial

This is an interventional treatment trial for BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype focused on measuring Trabectedin, BRCA1 and BRCA2, BRCAness, Ovarian cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Patients with partially platinum sensitive ovarian cancer (platinum-free interval 6-12 months) who have previously received at least two platinum based chemotherapy lines, BRCA mutated or with BRCAness phenotype.
- Definition of BRCAness phenotype: high-grade serous cancers, great initial sensitivity to platinum drugs and retention of platinum-sensitivity through multiple relapses, long history of disease, long survival, long TFIs between relapses (patients with high personal risk factors will be included after doing the analysis for BRCA 1-2 mutation before knowing the results).
- BRCA 1 and/or BRCA 2 mutation carriers (patients with established mutation will be included, patients with high personal risk factors will be included after doing the analysis before knowing the results)
Patients with platinum resistant ovarian cancer, BRCA mutated or with BRCAness phenotype who have previously received at least two previous chemotherapy lines (including platinum rechallenge).
Definition of platinum resistant: Tumor progression within 6 months of completion of platinum-based therapy (after platinum re-challenge for platinum sensitive recurrence).
Patient's written informed consent before any clinical trial-specific procedure.
18 years-of-age or older.
Measurable disease as defined in the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
Hematologic variables:
1. Hemoglobin ≥9 g/dL
2. Absolute neutrophil count (ANC) ≥1,500/μL, and
3. Platelet count ≥100,000/μL.
Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 30 mL/min
Creatinine phosphokinase (CPK) ≤ 2.5 ULN.
Hepatic function variables
1. Total bilirubin ≤ ULN.
2. Total alkaline phosphatase ≤ 2.5 ULN
3. AST (serum aspartate transaminase [SGOT]) and ALT (serum alanine transaminase [SGPT]) must be ≤2.5 x ULN.
Albumin ≥ 25 g/l.
Adequately recovered from the acute toxicity of any prior treatment. -

Exclusion Criteria:

1. Prior exposure to trabectedin. 2. Known hypersensitivity to any of the components of the trabectedin i.v. formulation or dexamethasone.
3. Less than 2 prior chemotherapy lines given in patients with partially platinum sensitive, BRCA mutated or BRCAness phenotype, ovarian cancer recurrences (including platinum rechallenge).
4. Patients with platinum refractory, BRCA mutated or with BRCAness phenotype, ovarian cancer.
5. Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy.
6. History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 3 years or longer.
7. Known clinically relevant CNS metastases. 8. Other serious illnesses, such as:
• Congestive heart failure or angina pectoris; myocardial infarction within 1 year before enrollment; 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

Sites / Locations

Catholic University of Sacred HeartRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Trabectedin

Arm Description

Trabectedin 1.3 mg/m2 q 21 days Patients will receive trabectedin until disease progression or unacceptable toxicity

Outcomes

Primary Outcome Measures

objective response

To evaluate the feasibility (in terms of objective response rate by RECIST version 1.1) of Yondelis treatment in recurrent ovarian cancer population selected for BRCA mutation or BRCAness phenotype. The response rate will be compared with an hystorical control arm of recurrent ovarian cancer patients unselected for BRCA mutation or BRCAness phenotype.

Secondary Outcome Measures

Response

-Duration of response

Progression-free survival

-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].

safety profile

Safety profile of trabectedin in this patient population

Full Information

NCT ID

NCT01772979

First Posted

November 17, 2012

Last Updated

January 17, 2013

Sponsor

Catholic University of the Sacred Heart

1. Study Identification

Unique Protocol Identification Number

NCT01772979

Brief Title

Study With Trabectedin in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Ovarian Cancer

Acronym

MITO15

Official Title

Phase II Study With Trabectedin (Yondelis®) in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Advanced Ovarian Cancer Patients

Study Type

Interventional

2. Study Status

Record Verification Date

December 2012

Overall Recruitment Status

Unknown status

Study Start Date

June 2011 (undefined)

Primary Completion Date

June 2014 (Anticipated)

Study Completion Date

June 2014 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Catholic University of the Sacred Heart

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is a multicenter phase II study on trabectedin in advanced or recurrent ovarian cancer patients with BRCA mutation and BRCAness phenotype. The purpose of this study is to determine the feasibility in terms of objective response rate by RECIST version 1.1 (Complete and Partial Response [CR + PR]) with trabectedin in patients with BRCA1 or BRCA2 mutation carrier or BRCAness phenotype advanced ovarian cancer patients.

Detailed Description

The main contribution to hereditary ovarian cancer comes from breast cancer (BRCA) genes mutations, which are responsible of 90% of hereditary ovarian cancer. The two susceptibility genes associated with epithelial-type OC are BRCA1 and BRCA2. The BRCA proteins play an important role in the DNA repair mechanisms and are also involved in the control of the cell cycle checkpoints, in protein ubiquitinization and chromatin remodelling. Mutations in the BRCA genes have been extensively described in families affected by breast and/or OC; mutated BRCA1 has been found in up to 75% of families with hereditary OC - Recent data suggest that dysfunction of BRCA1andBRCA2, so-called BRCAness, maybe more prevalent than originally assumed. Both genetic and epigenetic mechanisms can create the BRCAness phenotype in at least a third of all epithelial ovarian cancers. The definition of BRCAness ovarian cancer is: high-grade serous cancers, high initial sensitivity to platinum drugs and retention of platinum-sensitivity through multiple relapses, longer history of disease, longer survival, longer TFIs between relapses. Yondelis® (trabectedin) is proposed to block the transcriptional activation of a subset of inducible genes without affecting their constitutive expression. Trabectedin binds to the minor groove of DNA, bending the helix to the major groove. This binding to DNA triggers a cascade of events affecting several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in perturbation of the cell cycle. Cell cycle studies of the action of trabectedin on tumor cells in vitro reveal that it decreases the rate of progression of the cells through S phase towards G2 and causes a prolonged blockade in G2/M at biologically relevant concentrations (20-80 nM). These cell cycle blocks are p53-independent and lead to a strong apoptopic response. Cells in G1 are more sensitive to the cytotoxic effects of trabectedin. These effects appear to be related to the unique 3-subunit structure, where two of the subunits or rings are involved in binding to the minor groove of DNA in guanine-cytosine rich sequences and alkylation N2 of guanine forming adducts that distorted the DNA helix structure and they are recognized by the TC-NER mechanism. DNA repair proficiency is a major determinant for the cytotoxicity of trabectedin: human cell lines deficient for genes essential for TC-NER activity as XPA, XPB, XPD, XPF, XPG, ERCC1, CSA and CSB are resistant to trabectedin, and this resistance is reverted by complementation of the cells with the corresponding gene. Trabectedin induces double strand breaks and that the BRCA1-/- human cell line HCC1937 and BRCA2Δ22/Δ22 mice cells are more sensitive to trabectedin and this hypersensitivity is reverted by complementation by the BRCA1 or BRCA2 gene. Based in these observations it was hypothesized that the NER machinery trapped in the DNA lesion induced by trabectedin was resolved by the cells producing double strand breaks that were repaired by the HRR machinery, and synergistic action of TC-NER and HRR machinery would be necessary for maximal trabectedin cytotoxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype

Keywords

Trabectedin, BRCA1 and BRCA2, BRCAness, Ovarian cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Trabectedin

Arm Type

Experimental

Arm Description

Trabectedin 1.3 mg/m2 q 21 days Patients will receive trabectedin until disease progression or unacceptable toxicity

Intervention Type

Drug

Intervention Name(s)

Trabectedin

Other Intervention Name(s)

Yondelis

Primary Outcome Measure Information:

Title

objective response

Description

Time Frame

24 months

Secondary Outcome Measure Information:

Title

Response

Description

-Duration of response

Time Frame

36 months

Title

Progression-free survival

Description

Time Frame

36 months

Title

safety profile

Description

Safety profile of trabectedin in this patient population

Time Frame

36 months

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with partially platinum sensitive ovarian cancer (platinum-free interval 6-12 months) who have previously received at least two platinum based chemotherapy lines, BRCA mutated or with BRCAness phenotype. Definition of BRCAness phenotype: high-grade serous cancers, great initial sensitivity to platinum drugs and retention of platinum-sensitivity through multiple relapses, long history of disease, long survival, long TFIs between relapses (patients with high personal risk factors will be included after doing the analysis for BRCA 1-2 mutation before knowing the results). BRCA 1 and/or BRCA 2 mutation carriers (patients with established mutation will be included, patients with high personal risk factors will be included after doing the analysis before knowing the results) Patients with platinum resistant ovarian cancer, BRCA mutated or with BRCAness phenotype who have previously received at least two previous chemotherapy lines (including platinum rechallenge). Definition of platinum resistant: Tumor progression within 6 months of completion of platinum-based therapy (after platinum re-challenge for platinum sensitive recurrence). Patient's written informed consent before any clinical trial-specific procedure. 18 years-of-age or older. Measurable disease as defined in the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. Hematologic variables: Hemoglobin ≥9 g/dL Absolute neutrophil count (ANC) ≥1,500/μL, and Platelet count ≥100,000/μL. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 30 mL/min Creatinine phosphokinase (CPK) ≤ 2.5 ULN. Hepatic function variables Total bilirubin ≤ ULN. Total alkaline phosphatase ≤ 2.5 ULN AST (serum aspartate transaminase [SGOT]) and ALT (serum alanine transaminase [SGPT]) must be ≤2.5 x ULN. Albumin ≥ 25 g/l. Adequately recovered from the acute toxicity of any prior treatment. - Exclusion Criteria: 1. Prior exposure to trabectedin. 2. Known hypersensitivity to any of the components of the trabectedin i.v. formulation or dexamethasone. 3. Less than 2 prior chemotherapy lines given in patients with partially platinum sensitive, BRCA mutated or BRCAness phenotype, ovarian cancer recurrences (including platinum rechallenge). 4. Patients with platinum refractory, BRCA mutated or with BRCAness phenotype, ovarian cancer. 5. Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy. 6. History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 3 years or longer. 7. Known clinically relevant CNS metastases. 8. Other serious illnesses, such as: • Congestive heart failure or angina pectoris; myocardial infarction within 1 year before enrollment; 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Catholic University of Sacred Heart .

Phone

+39 0630156279

First Name & Middle Initial & Last Name or Official Title & Degree

Catholic University of Sacred Heart, .

Phone

+39 0630156279

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Giovanni Scambia, Prof

Organizational Affiliation

Catholic University of Sacred Heart

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Domenica Lorusso

Organizational Affiliation

National Cancer Institute, Milan

Official's Role

Principal Investigator

Facility Information:

Facility Name

Catholic University of Sacred Heart

City

Rome

ZIP/Postal Code

00100

Country

Italy

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Catholic University of Sacred Heart

12. IPD Sharing Statement

Learn more about this trial

Study With Trabectedin in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Ovarian Cancer

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