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

Phase 2
18 Years
Open (Enrolling)
BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype

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Trial Information

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

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

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.

Inclusion Criteria:

1. 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)

2. 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

3. Patient's written informed consent before any clinical trial-specific procedure.

4. 18 years-of-age or older.

5. Measurable disease as defined in the Response Evaluation Criteria in Solid Tumors
(RECIST) Guidelines

6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.

7. Hematologic variables:

1. Hemoglobin ≥9 g/dL

2. Absolute neutrophil count (ANC) ≥1,500/μL, and

3. Platelet count ≥100,000/μL.

8. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 30 mL/min

9. Creatinine phosphokinase (CPK) ≤ 2.5 ULN.

10. 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.

11. Albumin ≥ 25 g/l.

12. 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

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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

objective response

Outcome Description:

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.

Outcome Time Frame:

24 months

Safety Issue:


Principal Investigator

Giovanni Scambia, Prof

Investigator Role:

Principal Investigator

Investigator Affiliation:

Catholic University of Sacred Heart


Italy: Ethics Committee

Study ID:




Start Date:

June 2011

Completion Date:

June 2014

Related Keywords:

  • BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype
  • Trabectedin
  • BRCA1 and BRCA2
  • BRCAness
  • Ovarian cancer
  • Ovarian Neoplasms