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

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ClinicalTrials.gov Identifier: NCT03462342
Recruitment Status : Recruiting
First Posted : March 12, 2018
Last Update Posted : January 27, 2021
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
High Grade Serous Carcinoma Drug: Olaparib Pill Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Each cycle is 28 days. Patient will take Olaparib daily for all 28 days of the cycle and patient will take the investigational AZD6738 from days 1-7 of the cycle. Patient will visit the care provider to assess the treatment effects.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination ATR and PARP Inhibitor (CAPRI) Trial With AZD 6738 and Olaparib in Recurrent Ovarian Cancer
Actual Study Start Date : March 9, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Experimental: 1- Olaparib Pill + AZD6738.

All 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.

Drug: Olaparib Pill

For Cohorts A, B, and C:

Olaparib is prescribed at 300 mg twice daily by mouth (taken as two 150 mg tablets 12 hours apart) which is taken continuously for 28 days, which is one cycle. The tablets should be taken at the same time each day, approximately 12 hours apart with one glass of water.

AZD6738 is prescribed at 160 mg orally once daily for first 7 days of every cycle (Days 1-7 of each 28-day cycle). You will take one 100 mg tablet and three 20mg tablets (for a total of 160mg) once daily after taking your olaparib tablets in the morning.

Cohort D: a lower dose of olaparib (100-200mg daily for a 28-day cycle) and a higher dose of AZD6738 (160-320 mg daily for about 14 days). Three to five dosing schedules will be evaluated.

Other Name: investigational AZD6738




Primary Outcome Measures :
  1. Incidence of treatment-emergent adverse events [ Time Frame: 2 years ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.03


Secondary Outcome Measures :
  1. Progression free survival [ Time Frame: 2 years ]
    Clinical anti-tumor effect by standard criteria (RECIST)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Gynecology Oncology trial for ovarian cancer patients.
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03462342


Contacts
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Contact: Diego Rodriguez 1-215-614-0234 diegorod@pennmedicine.upenn.edu

Locations
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United States, Maryland
Johns Hopkins University School of Medicine Recruiting
Baltimore, Maryland, United States, 21287
Contact: Mary Kate Jones       mjone242@jhmi.edu   
Principal Investigator: Stephanie L Wethington, MD         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Kim MacNeill       kimberley_Macneill@dfci.harvard.edu   
Principal Investigator: Jennifer Veneris, MD         
United States, Pennsylvania
Hospital of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Diego Rodriguez    215-614-0234    diegorod@pennmedicine.upenn.edu   
Contact: Fiona Simpkins, MD    215-662-7336    fiona.simpkins@pennmedicine.upenn.edu   
Principal Investigator: Fiona Simpkins, MD         
Sponsors and Collaborators
University of Pennsylvania
AstraZeneca
Investigators
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Principal Investigator: Fiona Simpkins, MD University of Pennsylvania
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03462342    
Other Study ID Numbers: ESR-16-12311
First Posted: March 12, 2018    Key Record Dates
Last Update Posted: January 27, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: It is not yet known if there will be a plan to make IPD available. Even if made available, it will only be the clinical information that will be shared; no patient identifiers will be disclosed to any outside party at any time point of the study (unless required by law).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cystadenocarcinoma, Serous
Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Cystadenocarcinoma
Adenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents