Ceralasertib + Olaparib/Durvalumab for Cancer

Overseen by Rahul Aggarwal, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Rahul Aggarwal

Must be taking: LHRH analogs

Must not be taking: Corticosteroids, CYP3A4 inhibitors

Disqualifiers: Secondary malignancy, CNS metastases, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called ceralasertib to see if it can stop the growth of advanced cancers. It targets patients with various types of advanced solid tumors. The treatment works by blocking enzymes that cancer cells need to grow.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you should avoid using strong CYP3A4 inhibitors, inducers, and certain other medications within 21 days before starting the trial. It's best to discuss your current medications with the trial team to ensure safety and compliance.

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

Research shows that Ceralasertib, when combined with Olaparib, has demonstrated antitumor activity, especially in cancers with specific genetic defects. Additionally, combining Ceralasertib with Durvalumab has shown clinical activity in advanced gastric cancer, suggesting potential effectiveness in other cancers as well. ^{1 2 3 4 5}

Is the combination of Ceralasertib and Durvalumab safe for humans?

Research shows that Ceralasertib, when combined with Durvalumab, has been studied for safety in patients with advanced gastric cancer and melanoma. These studies suggest that the combination is generally safe and tolerable in humans, although specific side effects were not detailed in the abstracts. ^{2 3 6 7 8}

What makes the drug combination of Ceralasertib, Olaparib, and Durvalumab unique for cancer treatment?

This drug combination is unique because it targets DNA damage repair pathways and enhances the immune response against cancer. Ceralasertib inhibits ATR kinase, which is crucial for DNA repair, while Olaparib inhibits PARP, another DNA repair enzyme, and Durvalumab boosts the immune system by blocking PD-L1, a protein that helps cancer cells evade immune detection. ^{2 3 5 9 10}

Research Team

Rahul Aggarwal, MD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for adults with advanced or metastatic solid tumors, including kidney, pancreatic, endometrial and prostate cancers. Participants must have progressed on prior therapy and have measurable disease. They need adequate organ function, available tumor tissue samples, and must agree to use effective contraception.

Inclusion Criteria

I meet specific health, treatment history, and contraception use criteria.

Patients must provide written informed consent prior to performance of study-specific procedures or assessments

My cancer has spread, worsened after treatment, and lacks ATM protein.

Exclusion Criteria

I don't have allergies to medications, chronic hepatitis B or C, or a weakened immune system.

I haven't been treated for another cancer within the last year.

I don't have a history of specific health issues like recent major surgeries or untreated brain metastases.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ceralasertib alone or in combination with olaparib or durvalumab based on their cancer type and genetic markers

Up to 3 years

Continuous treatment cycles every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• ATR Kinase Inhibitor AZD6738 (ATR Kinase Inhibitor)
• Durvalumab (PD-L1 Inhibitor)
• Olaparib (PARP Inhibitor)

Trial Overview The study tests the effectiveness of Ceralasertib alone or combined with Olaparib or Durvalumab in treating various solid tumors. It aims to see if blocking certain enzymes needed for cell growth can control tumor progression better than current treatments.

Participant Groups

Group I: Arm III (Ceralasertib, Durvalumab) Experimental Treatment 2 Interventions

In combination with durvalumab, ceralasertib will be given at a continuous daily dose of 240 mg BID days 1-7 of a 28-day dosing schedule. Durvalumab will be given at a flat dose of 1500 mg IV on day 8 of a 28-day cycle for participants with histologically confirmed endometrial cancers. Participants treated with the combination of ceralasertib plus durvalumab may continue treatment beyond first radiographic progression until the occurrence of either confirmed radiographic progression or clinical progression, whichever occurs first.

Group II: Arm II (Ceralasertib, Olaparib) Experimental Treatment 2 Interventions

In combination with olaparib, ceralasertib will be given at a continuous daily dose of 160 mg daily days 1-7 in each 28-day cycle. Olaparib will be given at a starting dose of 300 mg twice daily days 1-28 of a 28-day cycle for participants who are BAF250a positive. Treatment will continue until disease progression, unacceptable toxicity, or participant withdrawal from study, whichever occurs first.

Group III: Arm I (Ceralasertib Monotherapy) Experimental Treatment 1 Intervention

As monotherapy ceralasertib will be given at a starting dose of 160 mg two times per day (BID), on days 1-14 of a 28-day cycle for participants who are BAF250a negative or show an ATM-Mutation by CLIA assay. Treatment will continue until disease progression, unacceptable toxicity, or participant withdrawal from study, whichever occurs first.

Who Is Running the Clinical Trial?

Rahul Aggarwal

Lead Sponsor

Trials

13

Recruited

550+

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

ATR inhibitors are being developed as a promising anti-cancer strategy because cancer cells often rely on ATR for repairing DNA damage, especially under replication stress, making them vulnerable to these inhibitors.

Several ATR inhibitors (M6620, M4344, AZD6738, and BAY1895344) are currently in clinical trials, showing potential for use alone or in combination with other treatments like chemotherapy and PARP inhibitors, although challenges remain in patient selection and biomarker identification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations? Bradbury, A., Hall, S., Curtin, N., et al.[2020]

Ceralasertib, an oral ATR protein inhibitor, combined with paclitaxel, showed a 33.3% overall response rate in melanoma patients who had previously failed anti-PD1 therapy, indicating its potential efficacy in difficult-to-treat cases.

The treatment was generally well tolerated, with the most common side effects being neutropenia, anemia, and thrombocytopenia, suggesting a manageable safety profile for patients with advanced malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer. Kim, ST., Smith, SA., Mortimer, P., et al.[2023]

In a phase II trial involving 31 patients with advanced gastric cancer, the combination of ceralasertib and durvalumab showed an overall response rate of 22.6% and a disease control rate of 58.1%, indicating promising antitumor activity.

Patients with specific biomarkers, such as loss of ATM expression or high homologous repair deficiency, experienced significantly longer progression-free survival (5.60 months) compared to those without these markers, suggesting that biomarker-driven approaches could enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer. Kwon, M., Kim, G., Kim, R., et al.[2022]

AZD6738 (ceralasertib) is a selective ATR kinase inhibitor that shows promise in treating cancer by modulating DNA damage response pathways, particularly in cells with defects in the ATM pathway or those experiencing replication stress.

In preclinical models, AZD6738 demonstrated significant antitumor activity, especially when combined with chemotherapy agents like carboplatin and irinotecan, achieving complete tumor regression in certain breast cancer models, suggesting its potential for clinical evaluation as both a monotherapy and in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib. Wilson, Z., Odedra, R., Wallez, Y., et al.[2023]

The combination of olaparib and durvalumab (O+D) showed a progression-free survival rate of 35% at 6 months in patients with advanced solid tumors, including rare cancers with homologous recombination repair (HRR) defects, indicating its efficacy in this challenging patient population.

O+D was found to be safe, with only 6% of patients experiencing serious adverse events, and it produced durable objective tumor responses in several rare cancer types, suggesting it could be a promising treatment option without new toxicity concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations. Thavaneswaran, S., Kansara, M., Lin, F., et al.[2023]

The phase 1 study of the ATR inhibitor ceralasertib showed that intermittent dosing (160 mg twice daily) was better tolerated than continuous dosing, which caused dose-limiting hematological toxicity.

Ceralasertib demonstrated antitumor activity with 8% of patients achieving confirmed partial responses and 52% experiencing stable disease, particularly in tumors with specific genetic defects related to DNA damage response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. Dillon, MT., Guevara, J., Mohammed, K., et al.[2023]

In a phase II trial involving 30 patients with metastatic melanoma who had previously failed anti-PD-1 therapy, the combination of ceralasertib and durvalumab showed an overall response rate of 31% and a disease control rate of 63.3%.

The treatment resulted in a median overall survival of 14.2 months and a median progression-free survival of 7.1 months, indicating promising antitumor activity, especially in tumors with immune-enriched environments or DDR pathway alterations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy. Kim, R., Kwon, M., An, M., et al.[2022]

Berzosertib, an ATR inhibitor, combined with cisplatin was well tolerated in a study of 31 patients with advanced solid tumors, with the recommended dose established at 140 mg/m2 for berzosertib and 75 mg/m2 for cisplatin.

Despite prior treatment failures with platinum-based chemotherapy, 4 out of 31 patients showed a partial response to the combination therapy, indicating preliminary efficacy that supports further investigation in Phase 2 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours. Shapiro, GI., Wesolowski, R., Devoe, C., et al.[2023]

The combination of olaparib, cediranib, and durvalumab was found to be tolerable in a phase 1 study involving 9 patients with recurrent women's cancers, with no dose-limiting toxicities reported.

The treatment showed promising preliminary efficacy, with a 67% clinical benefit rate, including partial responses in 44% of patients, indicating potential for further investigation in a phase 2 study for recurrent ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses. Zimmer, AS., Nichols, E., Cimino-Mathews, A., et al.[2023]

In a study involving 34 patients with BRCA1 or BRCA2 mutated metastatic breast cancer, the combination of olaparib and durvalumab demonstrated promising antitumor activity, with 80% of patients showing disease control at 12 weeks.

The treatment was generally safe, with 32% of patients experiencing grade 3 or worse adverse events, but no treatment-related deaths were reported, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Domchek, SM., Postel-Vinay, S., Im, SA., et al.[2021]

References

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

Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations? [2020]

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

Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer. [2023]

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

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer. [2022]

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

ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib. [2023]

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

A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations. [2023]

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

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours. [2023]

9. England pubmed.ncbi.nlm.nih.gov

A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women's cancers with biomarker analyses. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. [2021]