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
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Olaparib; Carboplatin; Anthracycline; Cyclophosphamide
Intervention description: tablets taken orally twice daily; intravenous injections on day one of each cycle; The choice of anthracycline and cyclophosphamide (AC) regimen in Part B will be up to local Investigator following international guidelines; The choice of anthracycline and cyclophosphamide (AC) regimen in Part B will be up to local Investigator following international guidelines
Intervention MeSH terms: Cyclophosphamide; Carboplatin; Olaparib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: breast cancer

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.
    

Eligibility criteria:

        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.