Ceralasertib + Olaparib/Durvalumab for Cancer

Recruiting at 2 trial locations

Overseen By Early Phase Clinical Trials Recruitment

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Rahul Aggarwal

Must be taking: LHRH analogs

Must not be taking: Corticosteroids, CYP3A4 inhibitors

Disqualifiers: Secondary malignancy, CNS metastases, 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: 28

Duration: Up to 3 years

89 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of ceralasertib, a treatment targeting specific enzymes in cancer cells, either alone or with other medications, in stopping or slowing the growth of advanced cancers such as kidney, bladder, pancreatic, and endometrial cancer. Researchers are testing ceralasertib by itself and in combination with either olaparib (a PARP inhibitor) or durvalumab (an immunotherapy drug) to determine the most effective approach. The trial seeks participants with certain types of cancer that have progressed despite previous treatments. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Previous studies have tested ceralasertib alone and with other drugs, showing promising results. When used by itself, ceralasertib has been studied in various cancer types, but its safety remains under evaluation as it is not yet approved for any condition. The main goal is to understand its tolerability and potential side effects.

Research indicates that the combination of ceralasertib and durvalumab is generally safe, though patients have experienced some side effects common to many cancer treatments. This combination has been studied in advanced non-small cell lung cancer, focusing on safety and tolerability.

Studies have shown positive effects when ceralasertib is combined with olaparib, particularly in certain ovarian cancer types. While safety information is still being collected, this combination has demonstrated activity in specific cancer types, suggesting some level of tolerability.

Overall, each study involving ceralasertib shows promise, but safety details continue to be closely monitored and developed through ongoing research. Participants considering joining the trial should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer new ways to target cancer. Ceralasertib is an ATR kinase inhibitor, which is different from many current treatments that focus on DNA damage repair. By inhibiting ATR kinase, Ceralasertib helps prevent cancer cells from repairing themselves, making them more vulnerable to destruction. Additionally, the combination arms with Olaparib and Durvalumab bring together different mechanisms: Olaparib is a PARP inhibitor that further hampers DNA repair, and Durvalumab is an immune checkpoint inhibitor that boosts the immune system’s ability to fight cancer. These innovative approaches could potentially enhance effectiveness, especially for patients with specific genetic mutations in their tumors.

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

Research shows that ceralasertib, one of the treatments in this trial, has produced promising results when used alone, with some patients experiencing partial or complete tumor shrinkage. In this trial, one group of participants will receive ceralasertib monotherapy.

Another group will test the combination of ceralasertib with durvalumab. Previous studies found that 50.6% of patients had their disease under control at 12 weeks, and 35.4% at 24 weeks, indicating a significant effect on slowing tumor growth.

The trial also includes a group testing the combination of ceralasertib with olaparib. While earlier results of this combination are less clear, as one study did not meet certain expectations, researchers continue to explore how well ceralasertib might work with olaparib or durvalumab. The aim is to determine if these combinations can stop tumor growth more effectively. ^{1 2 4 6 7}

Who Is on the Research Team?

Rahul Aggarwal, MD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• ATR Kinase Inhibitor AZD6738
• Durvalumab
• Olaparib

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8974415/

Phase I Study of Ceralasertib (AZD6738), a Novel DNA ... An additive effect of weekly paclitaxel and ceralasertib has been shown in an in vitro synergy panel, including in a subset of gastric cancer cell lines (4 of ...

2. nature.com nature.com/articles/s41467-024-45996-4

The ATR inhibitor ceralasertib potentiates cancer ... Here we show that ceralasertib in combination with anti-PD-L1 demonstrates strong antitumor effects in immunocompetent mouse tumor models.

3. jitc.bmj.com jitc.bmj.com/content/10/7/e005041

Phase II study of ceralasertib (AZD6738) in combination ... Results Among 31 patients, the ORR, disease control rate, median progression-free survival (PFS), and overall survival were 22.6% (95% CI 9.6% ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.3503

Results from a phase I, open-label study of ceralasertib ... 51 pts are evaluable for efficacy; we observed 1 complete response (1.9 %, melanoma), 12 confirmed partial responses (23.5%; 2 gastric, 10 ...

5. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1833/529604/Clinical-Activity-and-Safety-of-the-Oral-ATR

Clinical Activity and Safety of the Oral ATR Inhibitor ... Conclusion: Ceralasertib is an oral ATR inhibitor with clinical activity in patients with post-HMA MDS and CMML. The schedule of 160mg BID 7on/ ...

6. axonmedchem.com axonmedchem.com/3134-azd6738

AZD6738 | Ceralasertib | ATR inhibitor | Axon 3134 AZD6738 is a potent, selective, orally active and bioavailable ATR kinase inhibitor with an IC50 value of 0.001 µM against the isolated enzyme and 0.074 µM ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03682289

NCT03682289 | Ceralasertib (AZD6738) Alone and in ... To further characterize the safety and tolerability profile of ceralasertib alone and in combination with olaparib and durvalumab, respectively. V. To determine ...