ATR Inhibitor + PARP Inhibitor for Ovarian Cancer

(CAPRI Trial)

No longer recruiting at 2 trial locations

Overseen By Diego Rodriguez

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must be taking: PARPi

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Brain metastases, Cardiac conditions, Others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for women with recurring ovarian cancer. Researchers aim to determine if combining AZD6738 (an ATR inhibitor) with Olaparib (a PARP inhibitor) is safe and effective in slowing or stopping cancer growth. The trial includes women whose ovarian cancer has returned and either responds to or resists platinum-based treatments. Participants should have previously responded to treatments like Olaparib or possess specific genetic characteristics, such as BRCA mutations, that influence cancer response. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for some drugs. If you are taking strong or moderate CYP3A inhibitors, you need to stop them two weeks before starting the trial. If you are on strong or moderate CYP3A inducers, the washout period is three to five weeks, depending on the specific drug.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining Olaparib and AZD6738 may help treat ovarian cancer. The FDA has already approved Olaparib for some cancers, and it is usually well-tolerated. In studies with patients who have high-grade serous ovarian cancer, this combination has demonstrated positive effects, such as stabilizing the disease or partially reducing it in several cases.

Early results suggest that the combination can be safe, although some patients might experience side effects. Common side effects for similar treatments include nausea, tiredness, and changes in blood cell counts. However, the trial is still studying the safety of this treatment.

As this study is in an early phase, researchers are still collecting safety information. Participants might help discover more about the treatment's safety and tolerability. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of olaparib and AZD6738 for ovarian cancer because it targets cancer cells in a unique way. Unlike standard treatments that primarily focus on platinum-based chemotherapy, this combination uses a PARP inhibitor (olaparib) and an ATR inhibitor (AZD6738) to attack cancer cells that have specific genetic mutations, like BRCA or HRD mutations. This approach is especially promising for patients who have become resistant to other PARP inhibitors, offering a potential new option for those who have limited treatment choices. Additionally, the study explores different dosing schedules, which could personalize treatment for better effectiveness and fewer side effects.

What evidence suggests that this trial's treatments could be effective for ovarian cancer?

Research has shown that combining the drugs Olaparib and AZD6738 may help treat ovarian cancer. In this trial, all participants will receive this combination, but dosing and patient criteria will vary across different cohorts. Studies have found that this combination can reduce cancer cell survival and lead to more tumor shrinkage in patients who did not respond to previous treatments. Patients with BRCA mutations or DNA repair issues seem to benefit the most from this treatment. This suggests that using both drugs together might be effective for those with recurring ovarian cancer, regardless of their response to platinum-based treatments. Although this combination is still under study, early results are promising for those with certain genetic mutations. ^{1 3 5 6 7}

Who Is on the Research Team?

Fiona Simpkins, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

Women over 18 with recurrent ovarian cancer, either platinum-sensitive or resistant, can join. They must have good kidney and liver function, a certain level of fitness (ECOG 0 or 1), and a life expectancy over six months. Participants need measurable disease by RECIST v1.1 standards and may require specific BRCA mutation statuses depending on the cohort they're in.

Inclusion Criteria

My ovarian cancer is not mucinous and has been reviewed by specific universities.

I am willing to have a biopsy of my tumor.

All patients must have a measurable disease by RECIST v1.1

Exclusion Criteria

I have not received a whole blood transfusion in the last 120 days.

I have previously taken AZD6738 or similar medications.

I don't have serious heart issues, my blood pressure is above 90 mm Hg, and any side effects from previous cancer treatments are mild.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the combination of AZD6738 and olaparib. Dosing schedules vary by cohort, with olaparib administered orally twice daily and AZD6738 once daily.

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of treatment-emergent adverse events and progression-free survival.

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib and AZD6738

Trial Overview The trial tests AZD6738 combined with Olaparib pills in women with recurrent ovarian cancer to check safety, tolerability, response rate to treatment, and time without disease progression. It includes different cohorts based on sensitivity to platinum-based chemotherapy.

How Is the Trial Designed?

Group I: D-2 Olaparib Pill + AZD6738. Experimental Treatment 2 Interventions

Cohort D Part II: Patients with ovarian cancer who are PARP inhibitor (PARPi) resistant (patients who have progressed on a PARPi). Patients must be platinum-sensitive and have a germline or somatic BRCA mutation or an HRD mutation. Approximately 12 patients will be treated. All patients will receive the combination of AZD6738 and olaparib. Cohort D will take a lower dose of olaparib (100-200 mg 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.

Group II: D-1. Olaparib Pill + AZD6738. Experimental Treatment 2 Interventions

Cohort D Part I: Patients will be platinum sensitive/platinum resistant ovarian cancer. Patient may or may not have received prior PARPi and will be enrolled irrespective of their BRCA status. The number of subjects treated will depend on the number of dose levels explored with a minimum of 12 subjects up to 30 subjects. All patients will receive the combination of AZD6738 and olaparib. Cohort D will take a lower dose of olaparib (100-200 mg 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.

Group III: C. Olaparib Pill + AZD6738. Experimental Treatment 2 Interventions

Cohort C: PARP inhibitor (PARPi) resistant (subjects who have progressed on a PARPi), patients must be platinum-sensitive, and have a germline or somatic BRCA mutation or an HRD mutation. Approximately 12 subjects could be treated. 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.

Group IV: B. Olaparib Pill + AZD6738. Experimental Treatment 2 Interventions

Cohort B: Recurrent platinum-resistant ovarian cancer (progression less than or equal to 6 months of the last receipt), approximately 37 patients could be treated with an interim analysis after 12 subjects. 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.

Group V: A. Olaparib Pill + AZD6738. Experimental Treatment 2 Interventions

Cohort A: Recurrent platinum-sensitive ovarian cancer (progression greater than 6 months from last receipt of platinum-based chemotherapy), approximately 37 patients could be treated with an interim analysis after 17 subjects. 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.

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Myriad Genetics, Inc.

Industry Sponsor

Trials

18

Recruited

5,700+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

The combination of olaparib and ceralasertib showed preliminary effectiveness in treating patients with ATM-mutated tumors and those with BRCA1/2-mutated high-grade serous ovarian cancer (HGSOC) that were resistant to PARP inhibitors, with a clinical benefit rate of 62.5%.

Among the seven patients with PARP inhibitor-resistant HGSOC, one patient achieved a significant partial response and five maintained stable disease for 16 to 72 weeks, indicating that this combination therapy may provide a new treatment option for difficult-to-treat cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). Mahdi, H., Hafez, N., Doroshow, D., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03462342?term=AREA%5BBasicSearch%5D(azd6738)&rank=7

Combination ATR and PARP Inhibitor (CAPRI) Trial With ... This study will determine if using Olaparib in combination with AZD6738 is safe and tolerable and also determine the objective response rate and progression ...

2. dana-farber.org dana-farber.org/clinical-trials/20-320

Combination ATR and PARP Inhibitor (CAPRI) trial with ... Investigational agent, AZD6738 will be given in combination with Olaparib to women with recurrent ovarian cancer (platinum-sensitive or platinum-resistant).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9614917/

Combination ATR and PARP Inhibitor (CAPRI): A phase 2 ... Further, we have shown that combination PARP and ATR inhibition decreased survival and increased cancer regressions in PARPi and platinum-resistant BRCA½ mutant ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.3089

A phase 2 study of the olaparib and AZD6738, an ATM ... This study aims to evaluate the efficacy of Olaparib and AZD6738 in treating advanced IDH1/2 mutated solid.

5. clinicaltrial.be clinicaltrial.be/en/details/69197?per_page=20&only_recruiting=0&only_eligible=0&only_active=0

Combination ATR and PARP Inhibitor (CAPRI) Trial With ... This study will determine if using Olaparib in combination with AZD6738 is safe and tolerable and also determine the objective response rate and ...

6. onclive.com onclive.com/view/ceralasertib-olaparib-is-active-in-recurrent-platinum-sensitive-recurrent-ovarian-cancer-irrespective-of-hrd-status

Ceralasertib/Olaparib is Active in Recurrent, Platinum- ... Ceralasertib plus olaparib demonstrated clinical activity in platinum-sensitive, recurrent, high-grade serous ovarian cancer, regardless of HRD status.

7. aacrjournals.org aacrjournals.org/mct/article/18/12_Supplement/A080/240253/Abstract-A080-Olaparib-and-the-ATR-inhibitor

Abstract A080: Olaparib and the ATR inhibitor AZD6738 in ... Of 7 patients with HGSOC resistant to platinum and PARP inhibitors (1-3 prior agents), 1 achieved a PR ( -90%), 3 had a best response of SD with ...