A Two-stage Simon Design Phase II Study for Non-BRCA MBC Patients With HRD Treated With Olaparib Single Agent

NCT03367689 | Terminated Phase 2

• 2 other identifiers: MedOPP1002016-002892-80
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 5

Brief Summary

This is an international, multi-centre, non-controlled, open-label, single arm, two-stage Simon Design phase II study for non-BRCA metastatic breast cancer (MBC) patients with homologous recombination deficiency treated with Olaparib single agent. The main objective is to assess the efficacy of olaparib single agent as determined by Clinical Benefit Rate (CBR) using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). In the first stage Triple negative (TN) non-BRCA, metastatic breast cancer (MBC) patients whose tumours exhibited any characteristic related to homologous recombination deficiency (HRD). In the second stage, luminal patients (RH positive HER2 negative) will be allowed in the same conditions that TN. Patients whose tumours are identified as Homologous Recombination Deficient by deleterious HRR gene mutations (according to Foundation Medicine's Foundation One assay) will receive olaparib 300 mg (two tablets of 150mg) orally twice daily (bid) on days 1-28 each 28 days. Study commitment is 39 patients: 17 patients will be enrolled at first stage and 22 at the second stage. The total duration of the study period is 34 months.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (1)

• To assess the efficacy of olaparib single agent in non-BRCA MBC patients whose tumours exhibit an homologous recombination deficiency (HRD) signature, as determined by Clinical Benefit Rate (CBR) using RECIST 1.1 criteria

  The CBR as best response, defined as the percentage of patients who experience a complete response, partial response or stable disease for at least 24 weeks and assessed by modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) criteria

  Baseline up to 24 weeks

Secondary Outcomes (6)

• To assess the accuracy of Foundation One's HRR assay in predicting the proportion of patients with response to olaparib.

  Baseline up to 34 months

• To assess incidence of Treatment-Emergent Adverse Events (Safety profile) of olaparib in this population

  Baseline up to 34 months

• To investigate the prevalence of HRD signature within triple negative and luminal non-BRCA patients' cohorts

  Baseline up to 34 months

• To explore the efficacy of olaparib in terms of Progression-free survival (PFS)

  Baseline up to 34 months

• To explore the efficacy of olaparib in terms of objective response rate (ORR)

  Baseline up to 34 months

Study Arms (1)

Olaparib 300 mg

EXPERIMENTAL

Patients whose tumours are identified as Homologous Recombination Deficient, will receive olaparib 300 mg (two tablets of 150mg) orally twice daily (bid) on days 1-28 each 28 days.

Drug: Olaparib

Interventions

Olaparib DRUG

Olaparib 300 mg twice a day (orally) beginning on Day 1 and continuing through Day 28 of every 28-day cycle.

Also known as: Lynparza, AZD2281

Olaparib 300 mg

Eligibility Criteria

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

You may qualify if:

• Female patients ≥ 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) score lower or equal to 1.
• Life expectancy greater or equal to 16 weeks.
• Confirmed TN locally advanced or metastatic breast cancer in the first stage. For the second stage, luminal-like patients (RH-positive HER2-negative) will be allowed.
• Wild type BRCA1 and BRCA2 (germline). Variants with unknown significance are eligible.
• Tumors must exhibit a HRD signature according to Foundation Medicine's Foundation One assay. Formalin fixed, paraffin embedded (FFPE) tumor sample from the metastatic cancer must be available for central testing. If there is not written confirmation of the availability of an archived tumor sample prior to enrolment the patient is not eligible for the study.
• No more than three (and at least one) previous lines for the metastatic disease. Previous treatment must include taxanes (neo/adjuvant scenario is also possible) if not formally contraindicated.
• Patient must have measurable disease according to RECIST 1.1 criteria. At least one lesion, 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 \> or equal 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
• Patients must have normal organ and bone marrow function measured within 35 days prior to administration of study treatment as defined below:
• Hematological: White blood cell (WBC) count \>3.0 x 109/L, absolute neutrophil count (ANC) \> or equal 1.5 x 109/L, platelet count ≥100.0 x109/L, and hemoglobin \>10.0 g/dL (\>6.2 mmol/L) with no blood transfusion in the past 35 days.
• Hepatic: bilirubin ≤ 1.5 times the upper limit of normal (x ULN); alkaline phosphatase (ALP), Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) \< or equal 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be \< or equal 5x ULN.
• Renal: creatinine clearance estimated using the Cockcroft-Gault equation of \> or equal 51 mL/min
• Patient has been informed about the nature of study, and has agreed to participate, and signed the Informed Consent form (ICF) prior to participation in any study-related activities
• No other malignancies within the past five years except adequate treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCICTCAE version 4.03 Grade \< or equal 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).

You may not qualify if:

• Patients will be excluded from the study if they meet ANY of the following criteria:
• RH-positive (based on local laboratory results) or unknown for the first stage. In the second stage, luminal-like HER2-negative patients will be allowed.
• HER2-positive (based on local laboratory results \[performed by immunohistochemistry/fluorescence in situ hybridization (FISH)\] or unknown.
• Locally advanced breast cancer candidate for a radical treatment.
• Has deleterious germline BRCA1 or BRCA2 mutation as determined by local test.
• Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. 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 35 days.
• Patients with symptomatic visceral disease are not eligible.
• Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumors including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years.
• Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML
• Have had a major surgery (defined as requiring general anesthesia) or significant traumatic injury within 2 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery or patients that may require major surgery during the course of the study.
• Resting ECG with QTc \> 470 msec on 2 or more time points within a 24-hour period or family history of long QT syndrome.
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
• Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors. The required washout period prior to starting olaparib is 2 weeks.
• Concomitant use of known strong or moderate CYP3A inducers. The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.

Sponsors & Collaborators

• MedSIR: lead

Study Sites (5)

Hospital del Mar

Barcelona, Spain

Location

Onkologikoa

Donostia / San Sebastian, Spain

Location

Institut Català d' Oncologia L'Hospitalet (ICO)

L'Hospitalet de Llobregat, Spain

Location

Hospital Ramón y Cajal

Madrid, Spain

Location

Hospital Arnau de Vilanova de Valencia

Valencia, Spain

Location

Related Publications (1)

• Cortes A, Lopez-Miranda E, Fernandez-Ortega A, Caranana V, Servitja S, Urruticoechea A, Lema-Roso L, Marquez A, Lazaris A, Alcala-Lopez D, Mina L, Gener P, Rodriguez-Morato J, Antonarelli G, Llombart-Cussac A, Perez-Garcia J, Cortes J. Olaparib monotherapy in advanced triple-negative breast cancer patients with homologous recombination deficiency and without germline mutations in BRCA1/2: The NOBROLA phase 2 study. Breast. 2024 Dec;78:103834. doi: 10.1016/j.breast.2024.103834. Epub 2024 Nov 3.

  PMID: 39520738 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

olaparib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Javier Cortes

  Hospital Universitario Ramon y Cajal

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: This is an international, multi-centre, non-controlled, open-label, single arm, two-stage Simon Design phase II study.

Study Record Dates

• First Submitted: November 24, 2017
• First Posted: December 11, 2017
• Study Start: April 17, 2018
• Primary Completion: July 31, 2021
• Study Completion: December 31, 2021
• Last Updated: February 22, 2023

Record last verified: 2022-06

Locations

ES (5)