A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety and Efficacy of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer

Phase 1

Terminated

Conditions: Breast Cancer

Interventions: Drug: Olaparib
Drug: Carboplatin
Drug: Anthracycline
Drug: Cyclophosphamide

Registration Number: NCT02561832

Lead Sponsor: AstraZeneca

Brief Summary: This is an open-label study to assess the safety, tolerability and efficacy of olaparib in combination with carboplatin. There are two parts in this study: Part A, a dose escalation in patients with advanced Human Epidermal Growth Factor 2 (HER-2) negative breast cancer and Part B, a dose expansion in the neoadjuvant treatment of HER-2 negative breast cancer patients with germline Breast Cancer Susceptibility Gene (BRCA)1/2 mutations.

Detailed Description: In Part A up to 36 evaluable patients with advanced breast cancer will be enrolled across 6 cohorts. The total number of patients will depend on the number of dose escalations necessary to enable a decision to be made on the recommended dose to take forward into Part B of the study.

The planned dose escalation will start with cohort 1, where patients will receive carboplatin (AUC5) on day 1 of cycle 1, and will start dosing with olaparib tablets at the dose of 50 mg twice daily (bd) on day 4 until day 19 of cycle 1 inclusive (a total of 16 days per cycle). Patients will receive carboplatin on day 1 of each 3 weeks cycle in combination with olaparib for a total of 4 cycles. Provided that there are no safety concerns after assessment of 6 evaluable patients in the first cohort, patients in subsequent cohorts may be dosed following Safety Review Committee (SRC) approval. Dose escalation scheme may be adjusted during the study on the basis of emerging safety, efficacy and pharmacokinetic data. Those patients in Part A who tolerate the combination up to and including cycle 4 may remain on treatment, either continuing with the combination, with carboplatin alone at the same AUC or with olaparib alone at the dose of 300 mg bd, if in the opinion of the treating Investigator, a patient is deemed to be deriving clinical benefit from treatment. In these cases, a patient may remain on treatment until progression, unacceptable toxicity or until other discontinuation criteria are met. Beyond cycle 4, patients will undergo assessments in line with the clinical protocol. Once the maximum tolerated dose (MTD) and/or recommended dose (RD) has been defined in Part A, a dose expansion phase, Part B will begin and this will include up to 21 patients with HER2 negative breast cancer, with a deleterious or suspected deleterious germlineBRCA1/2 (gBRCA1/2) mutation, who are deemed eligible for neoadjuvant therapy.

Part B will explore the safety, tolerability and efficacy of the combination of olaparib and carboplatin in terms of pathological complete response (pCR) rate. Neoadjuvant systemic therapy will consist of the following anti-cancer drugs for a total of 8 cycles of treatment:

* The first 4 cycles (cycle 1 to cycle 4: 12 weeks) will be based on combination of olaparib, at the defined RD and schedule from Part A, with carboplatin. It is expected that a cycle of treatment would be 3 weeks.

* Another 4 cycles (cycle 5 to cycle 8) will be based on a combination of an anthracycline and cyclophosphamide (AC). The choice of the AC regimen will be up to local Investigator following international guidelines (National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), and St Gallen).

The tumour response will be assessed through careful clinical examination and also with radiological examinations between cycle 4 and 5 and at the end of neoadjuvant part, before surgery. Additionally, tumour biopsy will be performed within 7 days before cycle 5 day 1, after completion of carboplatin and olaparib combination therapy and early pathological response assessed by local pathologist. Curative-intent surgery should be performed following completion of neoadjuvant treatment in all patients, 3 to 5 weeks after day 1 of the last cycle of neoadjuvant treatment.

A decision has been made to stop recruitment after Part A cohort 2, and to not start Part B of the study. The protocol has been amended to define that the collection of clinical data will stop once the final patient from cohort 2 of Part A has completed 4 cycles or all patients from cohort 2 of Part A discontinue prior to end of cycle 4 to enable data analysis and reporting. The database would close at this time point, however AstraZeneca commits to providing study treatment to ongoing patients that continue to receive clinical benefit, in Investigator's judgment. Patients who remain on study treatment after this time point will be monitored according to routine clinical practice as defined by the Investigator and no clinical data will be collected, other than SAEs and drug dispensing/accountability.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1	Anthracycline	Part A: ascending doses of olaparib in combination with carboplatin will be administered to investigate safety and tolerability and to define the MTD and/or RD for part B. Patients will be treated with this combination up to cycle 4, after cycle 4 they can continue with combination or monotherapy (carboplatin or olaparib). Cohorts will be started sequentially, based on SRC recommendation. Part B will start after MTD/RD identification in part A. Patients will receive olaparib and carboplatin combination for first 4 cycles (21 days per cycle), at the dose, frequency and schedule recommended from Part A. This will be followed by another 4 cycles of standard cancer therapy consisting of anthracycline and cyclophosphamide regimen. Total of 8 treatment cycles will be given before final surgery
Arm 1	Olaparib	Part A: ascending doses of olaparib in combination with carboplatin will be administered to investigate safety and tolerability and to define the MTD and/or RD for part B. Patients will be treated with this combination up to cycle 4, after cycle 4 they can continue with combination or monotherapy (carboplatin or olaparib). Cohorts will be started sequentially, based on SRC recommendation. Part B will start after MTD/RD identification in part A. Patients will receive olaparib and carboplatin combination for first 4 cycles (21 days per cycle), at the dose, frequency and schedule recommended from Part A. This will be followed by another 4 cycles of standard cancer therapy consisting of anthracycline and cyclophosphamide regimen. Total of 8 treatment cycles will be given before final surgery
Arm 1	Carboplatin	Part A: ascending doses of olaparib in combination with carboplatin will be administered to investigate safety and tolerability and to define the MTD and/or RD for part B. Patients will be treated with this combination up to cycle 4, after cycle 4 they can continue with combination or monotherapy (carboplatin or olaparib). Cohorts will be started sequentially, based on SRC recommendation. Part B will start after MTD/RD identification in part A. Patients will receive olaparib and carboplatin combination for first 4 cycles (21 days per cycle), at the dose, frequency and schedule recommended from Part A. This will be followed by another 4 cycles of standard cancer therapy consisting of anthracycline and cyclophosphamide regimen. Total of 8 treatment cycles will be given before final surgery
Arm 1	Cyclophosphamide	Part A: ascending doses of olaparib in combination with carboplatin will be administered to investigate safety and tolerability and to define the MTD and/or RD for part B. Patients will be treated with this combination up to cycle 4, after cycle 4 they can continue with combination or monotherapy (carboplatin or olaparib). Cohorts will be started sequentially, based on SRC recommendation. Part B will start after MTD/RD identification in part A. Patients will receive olaparib and carboplatin combination for first 4 cycles (21 days per cycle), at the dose, frequency and schedule recommended from Part A. This will be followed by another 4 cycles of standard cancer therapy consisting of anthracycline and cyclophosphamide regimen. Total of 8 treatment cycles will be given before final surgery

Primary Outcome Measures

Name	Time	Method
Part A: Number of Subjects Reporting Adverse Events (AEs)	From day 1 cycle 1, up to and including 30 days after last dose	Treatment-emergent AEs (TEAEs) defined as events occurring on or after cycle 1, day 1 up to and including 30 days after last dose (approximately 114 days).

Secondary Outcome Measures