Combination ATR and PARP Inhibitor (CAPRI) Trial With AZD6738 and Olaparib in Recurrent Ovarian Cancer

Inclusion Criteria

• •For inclusion in the study, patients must fulfill the following criteria:
• •1. Patients ≥ 18 years of age
• •2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life expectancy of at least 6 months.
• •3. For Cohorts A-C, and Cohort D, Part II, patients must have high grade serous ovarian, primary peritoneal, and/or fallopian tube cancer histologically or cytologically confirmed that is recurrent and for which standard curative measures do not exist or are no longer effective. For Cohort D, Part I, patients may have any non-mucinous epithelial ovarian cancer (including histologies such as clear cell, or endometrioid). Pathology must be reviewed internally at the University of Pennsylvania, Johns Hopkins University, or Harvard University prior to initiation of treatment.
• •4. All patients under consideration for Cohorts A, B, C, and D, must be willing to undergo mandatory tumor biopsies (non-target lesion). Patients should have at least one lesion (non-target) for biopsy. However, for patients in Cohorts A, B, C, and D, if patients are found to not have a safe lesion to biopsy by the radiology team, they may still be enrolled in the study and forego the biopsy. Patients who undergo attempted biopsies that are unsuccessful may still enroll and receive study drug.
• •5. All patients must have a measurable disease by RECIST v1.1.
• •6. Germline BRCA mutation status:
• •* Cohorts A and B: Patients with unknown BRCA status or negative BRCA germline mutation status will be permitted to enroll in the study. Patients with known BRCA germline mutations will be permitted to enroll up to a maximum of 10 subjects per cohort.
• •* Cohort C and Cohort D Part II: All subjects must have either a germline or somatic BRCA mutation, or other HRD mutation, or tumor is HRD positive. Other HRD mutations will be reviewed for consideration for enrollment by study review committee or University of Pennsylvania principal investigator.
• •* Cohort D Part I: Patients will be enrolled irrespective of BRCA status.
• •7. Adequate renal function, defined as measured creatinine clearance ≥ 51 ml/min.
• •8. Adequate hepatic function, defined as AST and ALT levels ≤ 2.5 X ULN (for subjects with liver metastases, AST or ALT ≤ 5 × ULN) and total bilirubin \< 1.5 X ULN, absent Gilbert's disease.
• •9. Adequate bone marrow function, defined as absolute neutrophil count (ANC ≥ 1.5 X 109/L), platelet count ≥ 100 x 109/L, and hemoglobin ≥ 10 g/dL (in the absence of transfusion within 28 days prior to dosing).
• •10. Patients must be at least 2 weeks from previous therapy for their ovarian cancer (chemotherapy, hormonal therapy, and radiation therapy, or investigational agents; 6 weeks for mitomycin C) to initiate screening and 3 weeks from previous therapy to initiate treatment. Hormones for breast cancer management may be continued at the discretion of the provider.
• •11. Platinum-sensitive is defined as recurrence \>6 months by RECIST 1.1 imaging from last platinum. Platinum-resistant is defined as recurrence ≤ 6 months by RECIST 1.1 imaging from last platinum regimen).
• •* For Cohort A, there is no limit to number of prior regimens.
• •* For Cohort B, patients may not have had more than 3 prior cytotoxic therapies since the development of platinum-resistance.
• •* Patients for Cohort D, Part I (dose escalation), patients may be either platinum-sensitive with no limit on prior regimens. Platinum-resistant patients are eligible but they may not have received more than 3 prior cytotoxic therapies since development of platinum resistance.
• •* Cohort C and Cohort D, Part II, patients must be platinum-sensitive BUT with no limit to number of prior cytotoxic therapies. These patients must demonstrate adequate bone marrow function as determined by the treating physician.
• •12. Prior treatment with a PARPi is permitted but not mandatory for Cohorts A and B and Cohort D Part I. Prior treatment with PARPi is mandatory for Cohort C and D Part II. If a patient has received a prior PARPi, then the patient must have demonstrated a clinical benefit of PARPi treatment by an initial response (by CA-125 or imaging) to PARPi treatment or clinical benefit from PARPi treatment as maintenance therapy followed by disease progression for enrollment onto Cohort C and D Part II. Clinical benefit for maintenance is defined as:
• •1. prior maintenance with PARPi after 1st line chemotherapy of at least 12 months or
• •2. prior maintenance with PARPi after \>1 line of chemotherapy for minimum of 6 months. Subjects on Cohort A may have received treatment with PARPi, clinically benefitted, but not have progressed on a PARPi. This arm is to evaluate participants who have received prior PARPi (PARPi after PARPi).
• •If the prior PARP inhibitor used was olaparib, it must have been tolerated without dose reduction for hematological toxicities. Olaparib must have been tolerated at a dose of 300mg twice daily for Arms A, B, \& C. Olaparib must have been tolerated at a dose of 200 mg twice daily or higher for Arm D.
• •For Cohort C and D Part II, patients may not have received cytotoxic chemotherapy in the interval between PARPi monotherapy and enrollment.
• •13. Patients who have had major surgery (as defined by the Site PI) must be fully recovered and ≥4 weeks post-operative prior to enrolling on study.
• •14. Patients must be able to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening, or otherwise altering the product formulation. They should not have gastrointestinal illnesses that would preclude the absorption of AZD6738 or olaparib, which are oral agents.
• •15. Postmenopausal defined as:
• •* Amenorrhea for 1 year or more following cessation of exogenous hormonal treatments;
• •* LH and FSH levels in post-menopausal range for women under 50;
• •* Radiation induced oophorectomy with last menses \>1 year ago;
• •* Chemotherapy-induced menopause with \>1 yr interval since last menses;
• •* Surgical sterilization (bilateral oophorectomy or hysterectomy).
• •16. Able to understand and voluntarily sign a written informed consent, and are willing and able to adhere to the protocol requirements.
• •17. Patients with a history of brain metastases diagnosed greater than one year prior to study entry may be considered if they received sterilizing therapy to the CNS (resection or radiation) and have been CNS recurrence-free for the one-year period.