Analysis of Olaparib Response in Patients With BRCA1 and/or 2 Promoter Methylation Diagnosed of Advanced Breast Cancer

NCT03205761 | Completed Phase 2 Results

• 3 other identifiers: GEICAM/2015-062016-001407-23ESR-15-11274
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 16

Brief Summary

This is a multicenter single-arm phase II clinical trial to evaluate the efficacy and safety of olaparib in patients diagnosed of advanced triple negative breast cancer (TNBC) with methylation of BRCA1 and/or BRCA2 promoters assessed in DNA from metastatic lesions and absence of BRCA1 and 2 germline mutations.

Conditions

Advanced Breast Cancer

Keywords

Advanced Breast Cancer; Triple Negative; olaparib; lynparza; BRCA; Methylation

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR)

  ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions. Tumor response will be assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). Efficacy population is a subset of the intend to treat population that has received at least one dose of study medication and has performed at least one tumor response assessment according to RECIST v.1.1 (unless a progression, death or unacceptable toxicity is seen before the first tumor response assessment).

  Through study treatment, and average of 8 weeks

Secondary Outcomes (7)

• Clinical Benefit Rate (CBR)

  Through study treatment, and average of 8 weeks

• Response Duration (RD)

  Through study treatment, up to 19 months

• Progression Free Survival (PFS)

  Through study treatment, and average of 8 weeks

• Overall Survival (OS)

  Up to 14 months

• The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment

  Through study treatment, and average of 8 weeks

Study Arms (1)

Olaparib

EXPERIMENTAL

Patients with a positive methylation status on at least one of the two genes and lacking of known deleterious or suspected deleterious mutations in both genes could be included in the study to receive olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first.

Drug: Olaparib

Interventions

Olaparib DRUG

Olaparib tablet formulation at 600 mg total daily dose (given in two oral administrations of 300 mg every 12 hours approximately). Patients will continue to receive their treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death or withdrawal of consent, whichever occurs first.

Also known as: Lynparza

Olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \*The patient has signed and dated the informed consent document and it has been obtained before conducting any procedure specifically for the study.
• Female ≥ 18 years of age on day of signing informed consent.
• Patient with histological confirmation of breast cancer with evidence of advanced disease not amenable to resection or radiation therapy with curative intent.
• Documented Triple Negative (TN) disease by immunohistochemistry (IHC) and/or in situ hybridization based on local testing (preferably assessed on the most recent tumour biopsy available). TN is defined as negative hormone receptor status (\< 1% of tumour cells with Estrogen Receptor (ER) and Progesterone Receptor (PgR) expression) and Human Epidermal growth factor Receptor 2 (HER2) negative status (defined as IHC score 0/1+ or negative by in situ hybridization defined according to local criteria).
• Patient must have received at least one previous regimen in the advance disease setting.
• Absence of deleterious or suspected deleterious germline mutations in BRCA1 and BRCA2. Germinal BRCA mutational status will be centrally assessed in Myriad laboratories to check eligibility unless the test has been previously performed at Myriad and absence of mutations has been determined.
• Availability of a tumour tissue sample from the metastatic lesions (every effort should be done to obtain the sample after the previous therapeutic regimen for advanced disease) for central testing.
• Documented methylation of BRCA1 and/or 2 promoters based on central testing by analysis on the most recent tumour from metastatic lesions available.
• At least one lesion measurable not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) or clinical examination and which is suitable for accurate repeated measurements according to RECIST v.1.1.
• Patient must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
• Haemoglobin ≥ 10.0 g/dL with no blood transfusions in the past 28 days.
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase, SGOT) /Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase, SGPT) \] ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5 x ULN

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to the sponsor and/or study site staff).
• Previous enrolment in the present study.
• Participation in another clinical study with an investigational product during the last 4 weeks.
• \*Any previous treatment with a Poly Adenosine diphosphate-Ribose Polymerase (PARP) inhibitor, including olaparib.
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons), within 3 weeks prior to study treatment (or a longer period depending on the defined characteristics of the agents used).
• Resting ECG with corrected QT interval (QTc) \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
• \*Concomitant use of known strong Cytochrome P3A (CYP3A) inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. Please refer to section 5.5.2.1 about strong and moderate CYP3A inhibitors.
• \*Concomitant use of known strong CYP3A inducers (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Please refer to section 5.5.2.2 about strong and moderate CYP3A inducers.
• \*Persistent toxicities (\> NCI-CTCAE grade 2) caused by previous cancer therapy (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion).
• \*Patients with myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) or with features suggestive of MDS/AML.
• \*Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. Patients with brain metastases may be eligible for the study only if more than 4 weeks from treatment completion for these metastases (including radiation and/or surgery), are clinically stable at the time of study entry. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
• Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
• \*Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• \*Breast feeding women.
• \*Immunocompromised patients, e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV).

Sponsors & Collaborators

• Spanish Breast Cancer Research Group: lead
• AstraZeneca: collaborator

Study Sites (16)

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Hospital Universitario San Joan de Reus

Reus, Tarragona, 43204, Spain

Location

Hospital del Mar

Barcelona, 08003, Spain

Location

Hospital Universitario Vall d´Hebron

Barcelona, 08035, Spain

Location

Hospital Clinic i Provincial

Barcelona, 08036, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

Location

Hospital San Pedro de Alcántara

Cáceres, 10003, Spain

Location

Complejo Hospitalario Universitario Reina Sofía

Córdoba, 14005, Spain

Location

Hospital General Universitario Gregorio Marañón

Madrid, 28007, Spain

Location

Centro Oncológico MD Anderson International España

Madrid, 28033, Spain

Location

Hospital Universitario Puerta de Hierro Majadahonda

Madrid, 28222, Spain

Location

Hospital Universitario Virgen de la Macarena

Seville, 41009, Spain

Location

Instituto Valenciano de Oncología (IVO)

Valencia, 46009, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Hospital Clínico Universitario de Zaragoza "Lozano Blesa"

Zaragoza, 50006, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain

Location

Related Links

• Spanish Breast Cancer Research Group (GEICAM) is a Spanish Breast Cancer Research Group

MeSH Terms

Interventions

olaparib

Results Point of Contact

• Title: Scientific Director / Medical Lead / Project Manager
• Organization: Spanish Breast Cancer Research Group

geicam@geicam.org

+34916592870

Study Officials

• Study Director

  Complejo Hospitalario Universitario Reina Sofía

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 9, 2017
• First Posted: July 2, 2017
• Study Start: October 23, 2017
• Primary Completion: December 15, 2022
• Study Completion: December 15, 2022
• Last Updated: October 18, 2024
• Results First Posted: May 1, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

ES (16)