BRCA1 and BRCA2 Mutation Carrier and BRCAness PhenotypePhase 2MITO15NCT01772979
Study With Trabectedin in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Ovarian Cancer
A Phase 2 study testing Trabectedin in people with BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype, run by Catholic University of the Sacred Heart at 1 site in Italy.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype
- What is being tested?
- Trabectedin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 100 participants
- Where
- 1 siteItaly
- Study dates
- Jun 2011to Jun 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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. -
Who cannot join
- 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:
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- 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
Trial locations and contacts
1 site in 1 country.
Catholic University of Sacred Heart . contact
Catholic University of Sacred Heart, . contact
Italy1 site, 1 recruiting
- Recruiting
Catholic University of Sacred Heart
Rome, Rome, 00100
Catholic University of Sacred Heart
About this study
Official title: Phase II Study With Trabectedin (Yondelis®) in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Advanced Ovarian Cancer Patients
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.
Read the 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.
- Being tested
- Trabectedin
- Keywords
- Trabectedin, BRCA1 and BRCA2, BRCAness, Ovarian cancer
- Medical subject headings
- Fanconi Anemia, Complementation Group D1, Ovarian Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TrabectedinDrug
Also called Yondelis
| Study group | Role | What they receive |
|---|---|---|
| Trabectedin | Experimental | Trabectedin 1.3 mg/m2 q 21 days
Patients will receive trabectedin until disease progression or unacceptable toxicity Receives: Drug: Trabectedin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 24 months
Secondary outcomes (3)
Response
-Duration of response
Measured: 36 months
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].
Measured: 36 months
safety profile
Safety profile of trabectedin in this patient population
Measured: 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jan 2013 (estimated)
- Study startJun 2011
- Primary completionJun 2014 (estimated)
- Study completionJun 2014 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for BRCA1 and BRCA2 Mutation Carrier and BRCAness PhenotypeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Catholic University of the Sacred Heart
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. Giovanni Scambia, Catholic University of the Sacred Heart
- Investigators
- Giovanni Scambia, Prof, Principal investigator, Catholic University of Sacred HeartDomenica Lorusso, Principal investigator, National Cancer Institute, Milan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01772979
- Sponsor's protocol ID
- MITO15
- Acronym
- MITO15
- Status last verified
- Dec 2012
- First submitted
- 17 Nov 2012
- Last updated
- 21 Jan 2013
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 21 Jan 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Study With Trabectedin (Yondelis®) in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Advanced Ovarian Cancer Patients
- ClinicalTrials.gov ID
- NCT01772979
- Acronym / sponsor ID
- MITO15 / MITO15
- Keywords
- Trabectedin, BRCA1 and BRCA2, BRCAness, Ovarian cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Catholic University of the Sacred HeartUniversity, hospital or other
- Study start
- Jun 2011
- Primary completion
- Jun 2014 (estimated)
- Study completion
- Jun 2014 (estimated)
- First posted
- 21 Jan 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Trabectedin | Experimental | Drug: TrabectedinTrabectedin 1.3 mg/m2 q 21 days Patients will receive trabectedin until disease progression or unacceptable toxicity |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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.
- 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.
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TrabectedinAlso: Yondelis | Drug | Trabectedin |
Primary outcome
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.
3 secondary outcomes
Response
Time frame: 36 months
Progression-free survival
Time frame: 36 months
safety profile
Time frame: 36 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jan 2013.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Catholic University of Sacred Heart . contact
Catholic University of Sacred Heart, . contact
Giovanni Scambia, Prof principal investigator
Catholic University of Sacred Heart
Domenica Lorusso principal investigator
National Cancer Institute, Milan
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Trabectedin in people with BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype, run by Catholic University of the Sacred Heart at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Catholic University of Sacred Heart . (+39 0630156279), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
objective response (time frame: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jan 2013; AzTrials last refreshed its copy on 30 Oct 2026.