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

A Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety, Tolerability and Efficacy of Olaparib in Combination With Carboplatin: Part A: Dose Escalation of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer; Followed by Part B: an Expansion Phase of Olaparib in Combination With Carboplatin in the Neoadjuvant Treatment of HER-2 Negative Breast Cancer Patients With Germline BRCA1/2 Mutations

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.

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.

Inclusion criteria

• Male or female aged ≥18 years
• Normal organ and bone marrow function, measured within 28 days prior to administration of study treatment
• Eastern Cooperative Oncology Group performance status of 0-1
• Postmenopausal or evidence of non-childbearing status for women of childbearing potential.

Additional for patients participating in Part A only

• Advanced or metastatic breast cancer that is HER-2 negative (HR positive or HR negative)
• Between 0 and 2 lines of prior cytotoxic chemotherapy. Additional for patients participating in Part B only
• Patients with operable breast adenocarcinoma and no evidence of metastatic disease are allowed.
• Patient must meet at least one of the following criteria: Clinical primary tumour size defined as T2 or above, clinical or patho-histological evidence of regional lymph nodes involvement (N+), grade 2-3 disease
• Availability of formalin fixed, paraffin embedded tumour sample from diagnostic biopsies (Not Applicable for patients at sites in Israel)
• Histological confirmation of HER-2 negative breast cancer
• Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious
• Eligible for neo-adjuvant chemotherapy, but have not yet received neoadjuvant chemotherapy for breast cancer (chemo-naive) Exclusion criteria
• Exposure to an investigational product within 30 days or 5 half-lives (whichever is the longer) prior to enrolment
• Prior use of Poly ADP Ribose Polymerase (PARP) inhibitors
• Patients with a known hypersensitivity to olaparib or carboplatin
• Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator. Patient must have discontinued use of such agents 3 weeks prior to beginning study treatment. Luteinising hormone-Releasing hormone (LHRH) analogues are allowed for all patients in Part A.
• Concomitant use of known potent Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers
• Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) grade ≥2 and neuropathy CTCAE > grade 1) caused by previous cancer therapy, excluding alopecia - Patient with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
• Patient must have recovered from any effects of any major surgery
• Patient considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled seizures or active uncontrolled infection
• Patient with known active Hepatitis B or C, or Human immunodeficiency virus (HIV)
• Other malignancy within the last 5 years (few exceptions apply). Additional for patients participating in Part A only
• Prior chemotherapy within 3 weeks of study entry
• Other anti-cancer therapy (eg, targeted biotherapy of hormonal agents) within 3 weeks of study entry
• Radiation therapy within 4 weeks or radionuclide treatment within 6 weeks of treatment start
• Prior use of platinum compound in the advanced or metastatic setting. Previous exposure to platinum compounds is allowed only if they were used in early adjuvant or neoadjuvant setting with relapse occurring >6 months after the last platinum administration and if there is no residual toxicity
• Patient with a history of treated Central Nervous System (CNS) metastases are eligible, provided they meet certain protocol-specified criteria.

Additional for patients participating in Part B only

• Prior treatment (local or systemic) of their breast tumour. Sentinel lymph node biopsy is considered as diagnostic procedure and therefore is authorized before neoadjuvant treatment in part B
• Patients with inflammatory breast cancer or patients with inoperable locally advanced breast cancer (including T4 lesions) at the time of enrolment.