## Protocol Section
### Identification Module
**NCT ID:** NCT01772979

**Acronym:** MITO15

**Brief Title:** Study With Trabectedin in BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype Ovarian Cancer

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

#### Organization Study ID Info
**ID:** MITO15
#### Organization
**Class:** OTHER
**Full Name:** Catholic University of the Sacred Heart
### Status Module
#### Completion Date
**Date:** 2014-06

**Type:** ESTIMATED

#### Expanded Access Info
**Last Known Status:** RECRUITING
#### Last Update Post Date
**Date:** 2013-01-21

**Type:** ESTIMATED

**Last Update Submit Date:** 2013-01-17

**Overall Status:** UNKNOWN

#### Primary Completion Date
**Date:** 2014-06

**Type:** ESTIMATED

#### Start Date
**Date:** 2011-06

**Status Verified Date:** 2012-12

#### Study First Post Date
**Date:** 2013-01-21
**Type:** ESTIMATED
**Study First Submit Date:** 2012-11-17
**Study First Submit QC Date:** 2013-01-17
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Catholic University of the Sacred Heart

#### Responsible Party

**Investigator Affiliation:** Catholic University of the Sacred Heart

**Investigator Full Name:** Prof. Giovanni Scambia

**Investigator Title:** Professor Giovanni Scambia

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Oversight Has DMC:** True

### Description Module

**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.

### Conditions Module

**Conditions:**

- BRCA1 and BRCA2 Mutation Carrier and BRCAness Phenotype

**Keywords:**

- Trabectedin

- BRCA1 and BRCA2

- BRCAness

- Ovarian cancer

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 100

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Trabectedin 1.3 mg/m2 q 21 days

Patients will receive trabectedin until disease progression or unacceptable toxicity

**Intervention Names:**

- Drug: Trabectedin

**Label:** Trabectedin

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Trabectedin

**Name:** Trabectedin

**Other Names:**

- Yondelis

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**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.

**Measure:** objective response

**Time Frame:** 24 months

#### Secondary Outcomes

**Description:** -Duration of response

**Measure:** Response

**Time Frame:** 36 months

**Description:** -Progression-free survival \[the diagnosis of progression will be assessed by radiological criteria; CA 125 increases alone (GCIG criteria of progression) will not be considered as progression of disease without a radiological confirmation of progression\].

**Measure:** Progression-free survival

**Time Frame:** 36 months

**Description:** Safety profile of trabectedin in this patient population

**Measure:** safety profile

**Time Frame:** 36 months

### Eligibility Module

**Eligibility Criteria:** 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 recurrence).
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 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

**Minimum Age:** 18 Years

**Sex:** FEMALE

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Name:** Catholic University of Sacred Heart .

**Phone:** +39 0630156279

**Role:** CONTACT

**Contact 2:**

**Name:** Catholic University of Sacred Heart, .

**Phone:** +39 0630156279

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Rome

**Contacts:**

***Contact 1:***

- **Name:** Catholic University of Sacred Heart

- **Role:** CONTACT

**Country:** Italy

**Facility:** Catholic University of Sacred Heart

**Status:** RECRUITING

**Zip:** 00100

#### Overall Officials

**Official 1:**

**Affiliation:** Catholic University of Sacred Heart

**Name:** Giovanni Scambia, Prof

**Role:** PRINCIPAL_INVESTIGATOR

**Official 2:**

**Affiliation:** National Cancer Institute, Milan

**Name:** Domenica Lorusso

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000004701

- Term: Endocrine Gland Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000010049

- Term: Ovarian Diseases

- ID: D000000291

- Term: Adnexal Diseases

- ID: D000005831

- Term: Genital Diseases, Female

- ID: D000052776

- Term: Female Urogenital Diseases

- ID: D000005261

- Term: Female Urogenital Diseases and Pregnancy Complications

- ID: D000091642

- Term: Urogenital Diseases

- ID: D000005833

- Term: Genital Neoplasms, Female

- ID: D000014565

- Term: Urogenital Neoplasms

- ID: D000091662

- Term: Genital Diseases

- ID: D000004700

- Term: Endocrine System Diseases

- ID: D000006058

- Term: Gonadal Disorders

- ID: D000002277

- Term: Carcinoma

- ID: D000009375

- Term: Neoplasms, Glandular and Epithelial

- ID: D000009370

- Term: Neoplasms by Histologic Type

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BXS

- Name: Urinary Tract, Sexual Organs, and Pregnancy Conditions

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M12974

- Name: Ovarian Neoplasms

- Relevance: HIGH

- As Found: Ovarian Cancer

- ID: M1704

- Name: Carcinoma, Ovarian Epithelial

- Relevance: HIGH

- As Found: Ovarian Cancer

- ID: M5534

- Name: Carcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M7863

- Name: Endocrine Gland Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M12972

- Name: Ovarian Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M3643

- Name: Adnexal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M8943

- Name: Genital Diseases, Female

- Relevance: LOW

- As Found: Unknown

- ID: M2876

- Name: Genital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M2875

- Name: Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M27093

- Name: Female Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14127

- Name: Pregnancy Complications

- Relevance: LOW

- As Found: Unknown

- ID: M8399

- Name: Female Urogenital Diseases and Pregnancy Complications

- Relevance: LOW

- As Found: Unknown

- ID: M8945

- Name: Genital Neoplasms, Female

- Relevance: LOW

- As Found: Unknown

- ID: M17315

- Name: Urogenital Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M9163

- Name: Gonadal Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M12320

- Name: Neoplasms, Glandular and Epithelial

- Relevance: LOW

- As Found: Unknown

- ID: M12315

- Name: Neoplasms by Histologic Type

- Relevance: LOW

- As Found: Unknown

- ID: T4352

- Name: Ovarian Cancer

- Relevance: HIGH

- As Found: Ovarian Cancer

- ID: T4354

- Name: Ovarian Epithelial Cancer

- Relevance: HIGH

- As Found: Ovarian Cancer

### Condition Browse Module - Meshes

- ID: D000010051

- Term: Ovarian Neoplasms

- ID: D000077216

- Term: Carcinoma, Ovarian Epithelial

### Intervention Browse Module - Ancestors

- ID: D000018906

- Term: Antineoplastic Agents, Alkylating

- ID: D000000477

- Term: Alkylating Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000000970

- Term: Antineoplastic Agents

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M1862

- Name: Trabectedin

- Relevance: HIGH

- As Found: Excluded

- ID: M20942

- Name: Antineoplastic Agents, Alkylating

- Relevance: LOW

- As Found: Unknown

- ID: M3820

- Name: Alkylating Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000077606

- Term: Trabectedin

### Misc Info Module

- Version Holder: 2024-05-24
