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
  • High Grade Ovarian Serous Adenocarcinoma
  • 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:

        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 histology's 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 Part II, must be willing
             to undergo mandatory tumor biopsies (non-target lesion). Patients should have at least
             one lesion (non-target) for biopsy. However, for 50% of patients in Cohorts A, B, C,
             and D Part II, 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 for consideration for Cohort D Part I (dose escalation) are not required to
             undergo a biopsy for enrollment. 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 SRC or University
                  of Pennsylvania PI.

               -  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 (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.

         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. Clinical benefit for maintenance is
             defined as: a) prior maintenance with PARPi after 1st line chemotherapy of at least 12
             months or b) prior maintenance with PARPi after >1 line of chemotherapy for minimum of
             6 months.

             If the prior PARP inhibitor used was olaparib, then patients must have received
             treatment without significant toxicity or the need for a permanent dose reduction. 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.

        Exclusion criteria:

          1. Patients with known brain metastases diagnosed within one 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 two 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 at two consecutive visits or
             recurrent symptomatic orthostatic hypotension.

          5. Lack of recovery of prior adverse events due to prior cancer therapy to Grade ≤1 (NCI
             CTCAE v5.0; 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 five 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 (e.g. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is two weeks.

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

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

         12. Major surgery within four weeks of starting study.

         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 for Cohorts
             A, B, C, D PART II.

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

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

         17. Previous allogeneic 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

Last Updated

June 22, 2020