ATR Inhibitor + PARP Inhibitor for Ovarian Cancer

(CAPRI Trial)

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

123 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination of Olaparib and AZD6738 for ovarian cancer?

Research shows that combining Olaparib, a drug used for ovarian cancer, with ATR inhibitors like AZD6738 can potentially overcome resistance in cancer cells that no longer respond to Olaparib alone. This combination has shown promise in enhancing the effectiveness of treatment in patients with certain genetic mutations. ^{1 2 3 4 5}

Is the combination of ATR and PARP inhibitors safe for humans?

Olaparib, a PARP inhibitor, has been shown to be generally well-tolerated in patients with ovarian cancer, including those with BRCA mutations. While specific safety data for the combination of ATR and PARP inhibitors is not detailed, olaparib alone has been used safely in various studies. ^{1 2 4 6 7}

What makes the ATR Inhibitor + PARP Inhibitor treatment for ovarian cancer unique?

This treatment combines olaparib, a PARP inhibitor, with AZD6738 (ceralasertib), an ATR inhibitor, to target ovarian cancer cells that have developed resistance to PARP inhibitors alone. By inhibiting both PARP and ATR pathways, it aims to overcome resistance and enhance the effectiveness of the treatment in patients with BRCA mutations and other DNA repair deficiencies. ^{1 3 4 6 8}

What is the purpose of this trial?

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 AZD6738 and Olaparib in women with recurrent ovarian cancer in distinct platinum-sensitive and platinum-resistant cohorts.

Research Team

Fiona Simpkins, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Olaparib-Resistant BRCA2MUT Ovarian Cancer Cells with Restored BRCA2 Abrogate Olaparib-Induced DNA Damage and G2/M Arrest Controlled by the ATR/CHK1 Pathway for Survival. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). [2022]

4. England pubmed.ncbi.nlm.nih.gov

Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Spotlight on olaparib in the treatment of BRCA-mutated ovarian cancer: design, development and place in therapy. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

The current status of PARP inhibitors in ovarian cancer. [2017]