Olaparib Tablets as a Treatment for Ovarian Cancer Subjects With Different HRD Tumor Status

Non-Randomized, Open-Label Phase II Study to Assess Olaparib Tablets as a Treatment for Subjects With Different HRD Tumor Status and With Platinum-Sensitive, Relapsed, High-Grade Serous or High-Grade Endometrioid Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That Have Received at Least 1 Prior Line of Chemotherapy

This is a non-randomized, open-label study to assess olaparib tablets as a treatment for subjects with different homologous recombination deficiency (HRD) tumor status and with platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid ovarian cancer. Subjects should have received at least 1 prior line of platinum-based chemotherapy.

This is a Phase II, open-label, non-randomized, multi-center study assessing the efficacy and safety of olaparib tablets 300 mg (two 150 mg tablets) given orally twice daily (bid) in subjects with platinum-sensitive or partially platinum-sensitive, relapsed, high-grade serous or high-grade endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received at least 1 prior line of platinum-based chemotherapy.

The study will assess the effectiveness of olaparib tablets as measured by the objective response rate (ORR) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, in subjects with germline BRCA mutations (gBRCAm), somatic BRCA mutations (sBRCAm), or potential aberrations in homologous recombination deficiency (HRD) as determined by myChoice® HRD, as well as in subjects without identifiable HRD. This study will utilize Myriad BRACAnalysis CDx® for germline BRCA analysis and a tumor test (myChoice® HRD) for tumor BRCA analysis and HRD status. Four cohorts will be identified based upon the genetic testing described above:

• Cohort 1: gBRCAm,
• Cohort 2: sBRCAm and germline BRCA wild type,
• Cohort 3: myChoice® HRD positive (genomic instability positive) and BRCA wild type (BRCAwt) (no BRCA mutation),
• Cohort 4: myChoice® HRD negative (genomic instability negative) and BRCAwt (no BRCA mutation).

Inclusion Criteria:

• Provision of written signed informed consent prior to any study specific procedures;
• Female subjects with histologically diagnosed relapsed high-grade serous or high-grade endometrioid ovarian cancer;
• At least 1 lesion (measurable by RECIST v1.1) that can be accurately assessed at baseline by computed tomography (CT)/magnetic resonance imaging (MRI) and is suitable for repeated assessment;
• Subjects must have received at least 1 prior platinum-based line of chemotherapy for ovarian cancer. Note: There is no limit on the number of lines of chemotherapy;
• Subjects must be partially-platinum-sensitive (defined as progression 6 to 12 months after the end of the last platinum-based chemotherapy) or platinum sensitive (defined as progression > 12 months after the end of the last platinum-based chemotherapy);
• Subjects must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment;
• ECOG performance status 0 to 1;
• Subjects must have a life expectancy greater than or equal to 16 weeks;
• Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on Day 1;
• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations; and
• Formalin fixed, paraffin embedded tumor sample (either archival or fresh sample) from the primary or recurrent cancer must be available for central testing. If there is not written confirmation of the availability of an archived or fresh tumor sample prior to enrollment, the subject is not eligible for the study.

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca Representative staff and/or staff at the study site);
• Previous enrollment in the present study;
• Exposure to any investigational product (IP) within 30 days or 5 half-lives (whichever is longer) prior to start of study treatment;
• Any previous treatment with a PARP inhibitor, including olaparib;
• Subjects who have platinum-resistant or refractory disease defined as progression during or within 6 months of the last platinum-based chemotherapy;
• Other malignancy within the last 5 years (few exceptions apply);
• Resting ECG with clinically significant abnormal findings;
• Subjects 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;
• Concomitant use of known strong or moderate CYP3A inducers;
• Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade 2) caused by previous cancer therapy, excluding alopecia;
• Subjects with MDS/AML or with features suggestive of MDS/AML;
• Subjects with pneumonitis or at risk of pneumonitis;
• Subjects with symptomatic uncontrolled brain metastases;
• Major surgery within 2 weeks of starting study treatment, and subjects must have recovered from any effects of any major surgery;
• Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection;
• Breast feeding women;
• Immunocompromised subjects, e.g., subjects who are known to be serologically positive for human immunodeficiency virus;
• Subjects with known active hepatitis (i.e., Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids