Study With Trabectedin in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Ovarian Cancer (MITO15)
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|ClinicalTrials.gov Identifier: NCT01772979|
Recruitment Status : Unknown
Verified December 2012 by Prof. Giovanni Scambia, Catholic University of the Sacred Heart.
Recruitment status was: Recruiting
First Posted : January 21, 2013
Last Update Posted : January 21, 2013
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.
|Condition or disease||Intervention/treatment||Phase|
|BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype||Drug: Trabectedin||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||100 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study With Trabectedin (Yondelis®) in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Advanced Ovarian Cancer Patients|
|Study Start Date :||June 2011|
|Estimated Primary Completion Date :||June 2014|
|Estimated Study Completion Date :||June 2014|
Trabectedin 1.3 mg/m2 q 21 days
Patients will receive trabectedin until disease progression or unacceptable toxicity
Other Name: Yondelis
- objective response [ Time Frame: 24 months ]
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.
- Response [ Time Frame: 36 months ]-Duration of response
- Progression-free survival [ Time Frame: 36 months ]-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 [ Time Frame: 36 months ]Safety profile of trabectedin in this patient population
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01772979
|Contact: Catholic University of Sacred Heart .||+39 0630156279|
|Contact: Catholic University of Sacred Heart, .||+39 0630156279|
|Catholic University of Sacred Heart||Recruiting|
|Rome, Italy, 00100|
|Contact: Catholic University of Sacred Heart|
|Principal Investigator:||Giovanni Scambia, Prof||Catholic University of Sacred Heart|
|Principal Investigator:||Domenica Lorusso||National Cancer Institute, Milan|