Olaparib + Ceralasertib for Cancer

Recruiting at 14 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Other malignancy, Cardiac diseases, 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: 2

Duration: 28 days per cycle, repeated

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing olaparib and ceralasertib in patients with specific genetic mutations in their cancer. The drugs work by stopping cancer cells from repairing themselves and growing. The goal is to see if this combination can be more effective for these hard-to-treat cancers. Olaparib has been approved for use in various cancers, including ovarian and breast cancer.

Will I have to stop taking my current medications?

The trial requires a washout period for certain medications. If you are taking strong or moderate CYP3A inhibitors or inducers, you will need to stop them 2 to 5 weeks before starting the study treatment. Please discuss your current medications with the study team to determine if any adjustments are needed.

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

Olaparib has shown effectiveness in treating certain types of breast and ovarian cancers, particularly in patients with specific genetic mutations (BRCA mutations). It has been used successfully in combination with other drugs to improve outcomes in ovarian cancer, suggesting potential benefits when combined with Ceralasertib. ^{1 2 3 4 5}

Is the combination of Olaparib and Ceralasertib safe for humans?

Olaparib, also known as Lynparza, has been studied for safety in various cancers. Common side effects include nausea, fatigue, and anemia (low red blood cell count). Serious conditions like myelodysplastic syndrome (a bone marrow disorder) and acute myeloid leukemia (a type of blood cancer) occurred in a small percentage of patients. ^{5 6 7 8 9}

How is the drug Olaparib + Ceralasertib unique for cancer treatment?

The combination of Olaparib and Ceralasertib is unique because it targets cancers with DNA repair issues by combining a PARP inhibitor (Olaparib) with an ATR inhibitor (Ceralasertib), potentially overcoming resistance seen with PARP inhibitors alone. ^{1 2 5 10 11}

Research Team

Patricia M Lorusso

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

This trial is for adults (18+) with IDH1 or IDH2 mutant cholangiocarcinoma or solid tumors that have progressed despite standard therapy, or no effective therapy exists. Participants must be willing to provide tissue samples and undergo extra blood sampling. They should not have severe chronic health issues, uncontrolled infections, or a history of certain heart conditions. Women must use contraception, and men agree to prevent partner pregnancy.

Inclusion Criteria

Subjects must have progressive cancer at the time of study entry

Subjects must be diagnosed with a solid malignant tumor (other than cholangiocarcinoma primary central nervous system [CNS]) that has progressed despite standard therapy, or for which no effective standard therapy exists

All patients must be willing to provide 5 unstained archival slides, if available, for pre-treatment 2-HG analysis and correlation with 2-HG levels in pre-treatment frozen specimens

Exclusion Criteria

Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication

Pregnant women

Persistent toxicities caused by previous cancer therapy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive olaparib orally twice daily on days 1-28 and ceralasertib once daily on days 1-7 of each 28-day cycle

28 days per cycle, repeated

Regular visits for tumor biopsies, blood samples, and imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days

1 visit (in-person)

Treatment Details

Interventions

• Ceralasertib
• Olaparib

Trial Overview The phase II trial tests the effectiveness of olaparib and ceralasertib in treating patients with specific gene mutations in their tumors. These drugs may block enzymes needed for tumor cell growth. The study involves computed tomography, biopsies, bone marrow aspirations, and MRI scans to monitor treatment effects.

Participant Groups

Group I: Treatment (olaparib, ceralasertib) Experimental Treatment 8 Interventions

Patients receive olaparib PO BID on days 1-28 of each cycle and ceralasertib PO QD on days 1-7 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo tumor biopsies during screening and on study, collection of blood samples throughout the trial, and undergo CT and/or MRI scans throughout the trial. Patients may also undergo bone marrow aspiration and biopsy as clinically indicated on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., et al.[2022]

Olaparib is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

Olaparib is an effective oral treatment for patients with BRCA mutation-positive ovarian cancer, approved for maintenance therapy after platinum-based chemotherapy, showing good tolerability with common side effects like nausea, fatigue, and anemia being mild to moderate.

Long-term monitoring is recommended due to a low risk of serious hematological complications, such as anemia and myelodysplastic syndrome, ensuring patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. Lheureux, S., Bowering, V., Karakasis, K., et al.[2015]

In the BAROCCO trial involving 123 patients with recurrent platinum-sensitive ovarian cancer, the combination of cediranib and olaparib did not show superior progression-free survival (PFS) compared to paclitaxel chemotherapy, with median PFS of 5.6 months for the continuous cediranib-olaparib group and 3.1 months for the control group.

Despite not outperforming chemotherapy, the cediranib-olaparib combination was associated with a lower rate of treatment discontinuation due to adverse events (5% in the intermittent arm) and offers a potential non-chemotherapy treatment option for heavily pretreated patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. Colombo, N., Tomao, F., Benedetti Panici, P., et al.[2022]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

In a Phase I study involving 28 Japanese patients with advanced solid tumors, olaparib tablets at doses of 200 and 300 mg twice daily were found to be tolerable, with no dose-limiting toxicities reported.

The most common side effects included nausea, decreased appetite, anemia, and constipation, but no confirmed antitumor responses were observed, leading to the selection of 300 mg bid as the recommended dose for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Yonemori, K., Tamura, K., Kodaira, M., et al.[2022]

Olaparib, approved by the FDA for patients with advanced ovarian cancer carrying BRCA mutations, showed a 34% objective response rate in a trial of 137 patients who had undergone three or more prior chemotherapy treatments, with a median response duration of 7.9 months.

Common side effects included anemia, nausea, and fatigue, with a small risk (2%) of developing myelodysplastic syndrome or acute myeloid leukemia, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. Kim, G., Ison, G., McKee, AE., et al.[2022]

In a phase IIb trial involving 60 women with platinum-resistant recurrent ovarian cancer, the combination of cediranib and olaparib showed a modest objective response rate (ORR) of 15.3%, indicating some clinical activity in this heavily pretreated population.

The treatment was associated with significant safety concerns, as 73.3% of patients experienced grade ≥3 adverse events, highlighting the need for careful monitoring and further research into biomarkers that could predict treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. Lee, JM., Moore, RG., Ghamande, S., et al.[2023]

Olaparib significantly improves overall survival in patients with recurrent platinum-sensitive ovarian cancer, with a hazard ratio of 1.24 based on a meta-analysis of 7 randomized controlled trials involving 2406 patients.

However, the treatment is associated with a higher incidence of adverse events, particularly for grades 3 or higher, indicating that while olaparib is effective, it also carries a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. Chen, Q., Li, X., Zhang, Z., et al.[2022]

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]

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

References

1. England pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. [2015]

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

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. [2022]

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

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. [2022]

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

FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. [2022]

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

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. [2022]

10. 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]

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

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. [2016]