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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 : December 25, 2018
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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
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, 2020
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

Women with Pt-sensitive or Pt-resistant high grade serous cancer are eligible to enroll.

Patients will be given Olaparib to be taken orally on all 28 days of the cycle and investigational AZD 6738 to be taken orally on days 1-7 of each cycle.

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)



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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:

  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

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
Contact: Katie Elkins, MEd 1-215-615-6740 Katie.Elkins@uphs.upenn.edu
Contact: Elaine Spangler, MA 1-215-614-0234 espangle@pennmedicine.upenn.edu

Locations
United States, Pennsylvania
Gynecology Oncology Division Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Katie Elkins, MEd    215-615-6740    katie.elkins@uphs.upenn.edu   
Contact: Fiona Simpkins, MD    215-662-7336    fionasimpkins@uphs.upenn.edu   
Sponsors and Collaborators
University of Pennsylvania
AstraZeneca
Investigators
Principal Investigator: Fiona Simpkins, MD University of Pennsylvania

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03462342     History of Changes
Other Study ID Numbers: ESR-16-12311
First Posted: March 12, 2018    Key Record Dates
Last Update Posted: December 25, 2018
Last Verified: March 2018
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).

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Ovarian Neoplasms
Cystadenocarcinoma, Serous
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Cystadenocarcinoma
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Cystic, Mucinous, and Serous
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents