Clinical Trials /

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

NCT03462342

Description:

Investigational agent, AZD6738 will be given in combination with Olaparib to women with recurrent ovarian cancer (platinum-sensitive or platinum-resistant). This study will determine if using Olaparib in combination with AZD6738 is safe and tolerable and also determine the objective response rate and progression free survival of combination of AZD 6738 and Olaparib in women with recurrent ovarian cancer in distinct Pt-sensitive and Pt-resistant cohorts.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination ATR and PARP Inhibitor (CAPRI) Trial With AZD6738 and Olaparib in Recurrent Ovarian Cancer
  • Official Title: Combination ATR and PARP Inhibitor (CAPRI) Trial With AZD 6738 and Olaparib in Recurrent Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: ESR-16-12311
  • NCT ID: NCT03462342

Conditions

  • High Grade Serous Carcinoma

Interventions

DrugSynonymsArms
Olaparib Pillinvestigational AZD67381- Olaparib Pill + AZD6738.

Purpose

Investigational agent, AZD6738 will be given in combination with Olaparib to women with recurrent ovarian cancer (platinum-sensitive or platinum-resistant). This study will determine if using Olaparib in combination with AZD6738 is safe and tolerable and also determine the objective response rate and progression free survival of combination of AZD 6738 and Olaparib in women with recurrent ovarian cancer in distinct Pt-sensitive and Pt-resistant cohorts.

Detailed Description

      Women 18 years or older, who have recurrent ovarian cancer will be enrolled in this study.
      After consenting to participate in this trial, they will undergo screening process which will
      involve medical exam and blood work. If found eligible to participate in the trial, they will
      be given olaparib to be taken on all 28 days of the cycle and investigational AZD 6738 from
      days 1-7. For the first cycle, the subject will need to come in every week for lab tests and
      physical exam - this will help the treating physician determine an adverse event as soon as
      it happens. After that, patients are expected to come in every month at the end of each cycle
      (each cycle is 28 days).

      Patients will undergo scans for tumor assessments every 2 cycles and if stable disease or
      response to therapy is documented after cycle 4, imaging will continue every 3 cycles
      thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
1- Olaparib Pill + AZD6738.ExperimentalAll patients will receive the combination of AZD6738 and olaparib. Patients will be administered olaparib orally twice daily at 300 mg BD. Patients will be administered AZD6738 orally once daily at 160 mg on days 1 to 7. For ease of administration, the AZD6738 should be administered at the same time as one of the olaparib doses and thus with one glass of water.
  • Olaparib Pill

Eligibility Criteria

        Inclusion Criteria:

          1. Patients ≥ 18 years of age and post-menopausal.

          2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life
             expectancy of at least 6 months.

          3. Patients must have high grade serous ovarian, primary peritoneal, and/or fallopian
             tube cancer histologically or cytologically confirmed at the University of
             Pennsylvania or JHH that is recurrent and for which standard curative measures do not
             exist or are no longer effective.

          4. All patients must have at least one lesion deemed safe to biopsy and be willing to
             undergo mandatory biopsies. Cohorts A & B: 75% will require all biopsies (Pre-Tumor,
             On-Treatment, PD). If safe, 25% will require a biopsy only at PD. Cohort C: 100% will
             require all biopsies (Pre-Tumor, On-Treatment, PD).

          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 patients per cohort.

        Cohort C: All patients must have either a germline or somatic BRCA mutation or other HRD
        germline mutation, or tumor is HRD positive.

        9. Adequate renal function, defined as measured creatinine clearance ≥ 51 ml/min.

        10. 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.

        11. 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).

        12. Patients must be at least 2 weeks from previous therapy (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.

        13. Platinum sensitive (recurrence >6 months by RECIST 1.1 imaging from last platinum)
        patients may not have had more than 3 prior therapies. Platinum resistant (recurrence <
        6months by RECIST 1.1 imaging from last platinum regimen) patients may not have had more
        than 3 prior therapies since the development of platinum resistance.

        14. Prior treatment with a PARPi is not permitted for Cohorts A and B. Patients enrolled in
        Cohort C have acquired resistance to PARPi monotherapy, i.e. initial response to a Parp
        inhibitor followed by disease progression while on a PARP inhibitor. Patients may have not
        received chemotherapy in the interval between PARPi monotherapy and enrollment. Cohort C
        patients must also be platinum sensitive.

        15. Patients who have had major surgery must be fully recovered and ≥4 weeks post-operative
        prior to enrolling on study.

        16. 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.

        17. Post menopausal 18. Able to understand and voluntarily sign consent 19. Patients with a
        history of brain metastases diagnosed greater than 1 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 1-year period.

        Exclusion Criteria:

          1. Patients with known brain metastases diagnosed within 1 year will be excluded from
             this clinical trial because of their poor prognosis and because they often develop
             progressive neurologic dysfunction that would confound the evaluation of neurologic
             and other adverse events.

          2. Patients who have had prior AZD6738 or other cell cycle checkpoint inhibitors such as
             other ATM or ATR inhibitor, WEE-1 inhibitor or CHK1 (or 1/2) inhibitors.

          3. Patients with a serious cardiac condition, such as congestive heart failure; New York
             Heart Association Class III/IV heart disease; unstable angina pectoris; myocardial
             infarction within the last 3 months; valvulopathy that is severe, moderate, or deemed
             clinically significant; or arrhythmias that are symptomatic or require treatment.
             Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or
             family history of long QT syndrome.

          4. Patients with a systolic blood pressure <90 mm Hg, or recurrent symptomatic
             orthostatic hypotension.

          5. Lack of recovery of prior adverse events due to prior cancer therapy to Grade ≤1 (NCI
             CTCAE v4.03; except alopecia). Stable persistent grade 2 peripheral neuropathy may be
             allowed as determined on a case-by-case basis at the discretion of the PI. Patients
             with platinum-related hypomagnesemia (on replacement) will be eligible.

          6. Uncontrolled intercurrent illness including, but not limited to, symptomatic
             congestive heart failure, unstable angina pectoris, cardiac arrhythmia, clinically
             significant GI bleeding or hemoptysis within 28 days prior to the start of the study,
             or psychiatric illness/social situations that would limit compliance with study
             requirements.

          7. Another previous, active or current invasive malignancy within the last 5 years, with
             the exception of curatively treated stage Ia cervical carcinoma, or resected stage IA,
             grade 1 endometrial cancer, noninvasive non-melanoma skin cancers, DCIS of the breast
             or other solid tumors including lymphomas (without bone marrow involvement) curatively
             treated with no evidence of disease > 5 yrs . Patients with localized triple negative
             breast cancer may be eligible who are disease free at least three years out from
             treatment.

          8. Immunocompromised patients or HIV-positive patients on HAART due to potential drug
             interaction

          9. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 2 weeks.

         10. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or
             moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
             period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents.

         11. Patients with myelodysplastic syndrome, Acute myeloid leukemia or with features
             suggestive of MDS/AML.

         12. Major surgery within 4 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery.

         13. Patients with a known hypersensitivity to AZD6738 or olaparib or any of the excipients
             of the product.

         14. Platinum refractory (progress in first line platinum therapy) are excluded

         15. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment

         16. Patients with known active hepatitis (ie Hepatitis B or C) due to risk of transmitting
             the infection through blood and other body fluids

         17. Previous allogneic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT)

         18. Whole blood transfusions in the last 120 days prior to entry to the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of treatment-emergent adverse events
Time Frame:2 years
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by CTCAE v4.03

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:2 years
Safety Issue:
Description:Clinical anti-tumor effect by standard criteria (RECIST)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Pennsylvania

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