Ceralasertib + Olaparib/Durvalumab for Gynecological Cancers

(ATARI Trial)

Recruiting at 8 trial locations

Overseen By Trial Manager

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Institute of Cancer Research, United Kingdom

Must not be taking: CYP3A4 inhibitors, CYP1A2 inducers

Disqualifiers: Active infection, Cardiac disease, Autoimmune disease, 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: 16 weeks minimum

174 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for women with certain types of relapsed gynecological cancers, such as ovarian or endometrial cancer. Researchers are examining the effectiveness of the drug ceralasertib (AZD6738) both alone and in combination with other drugs like olaparib (Lynparza) or durvalumab. The goal is to evaluate how different treatments perform based on specific cancer characteristics, such as the presence of a gene abnormality (ARID1A). This trial may suit women whose cancer has returned after treatment and who can provide a cancer tissue sample for testing. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but there are restrictions. You cannot take certain medications that affect CYP3A4 and CYP1A2 enzymes, and there are washout periods for some treatments, like 21 days for cytotoxic treatments and 42 days for immunotherapy. It's best to discuss your current medications with the trial team to see if they are allowed.

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

A previous study found that ceralasertib was generally well-tolerated by patients with advanced cancers, showing promising results both alone and with other treatments. Side effects were manageable, and most patients handled the treatment well.

When combined with olaparib, ceralasertib was also well-tolerated. Patients with certain genetic mutations responded positively, highlighting its potential benefits. Side effects, such as nausea and tiredness, were similar to those seen with many cancer treatments but were not severe for most patients.

Research indicates that combining ceralasertib with durvalumab resulted in manageable side effects, which were present but usually not serious. This combination also demonstrated promising anti-tumor activity, suggesting potential effectiveness.

Overall, these treatments have been tested in people before and are considered safe enough for further study. However, as with all treatments, side effects may occur, and individual experiences can vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer new hope for women with relapsed gynecological cancers, particularly those with specific genetic markers. Unlike standard treatments like chemotherapy or radiation, ceralasertib (AZD6738) targets the DNA damage response, making cancer cells more vulnerable to treatment. When combined with olaparib, a PARP inhibitor, or durvalumab, an immune checkpoint inhibitor, these combinations aim to enhance the body's ability to fight cancer by either exploiting DNA repair weaknesses or boosting the immune system. This dual approach could potentially offer more effective and personalized treatment options for patients with these hard-to-treat cancers.

What evidence suggests that this trial's treatments could be effective for relapsed gynecological cancers?

Research has shown that ceralasertib, when combined with olaparib, yields promising results for treating certain gynecological cancers. In this trial, participants in different groups will receive either ceralasertib alone or in combination with olaparib. One study found that this combination helped nearly half of the patients with recurring ovarian cancer by shrinking their tumors or halting their growth. Additionally, some participants will receive ceralasertib combined with durvalumab. This combination controlled the disease in over half of the patients, preventing their cancer from worsening. These treatments are under study in this trial for their potential to effectively manage relapsed gynecological cancers. ^{4 5 6 7 8}

Who Is on the Research Team?

Susana Banerjee

Principal Investigator

Royal Marsden NHS Foundation Trust

Are You a Good Fit for This Trial?

This trial is for women with certain types of gynecological cancers (like ovarian, endometrial clear cell, and others) that have worsened after treatment. They must have a specific gene abnormality (ARID1A), measurable disease by scans, and be in good physical condition with a life expectancy over 16 weeks.

Inclusion Criteria

My cancer is mostly clear cell type without serous features.

My cancer is endometrioid type.

My cervical cancer is either adenocarcinoma or squamous.

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 subtype and ARID1A status

16 weeks minimum

Follow-up

Participants are monitored for safety and effectiveness after treatment

16 weeks

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• AZD6738
• Olaparib

Trial Overview

The ATARI trial is testing the effectiveness of ceralasertib alone or combined with olaparib or durvalumab on patients whose cancer cells show ARID1A loss. It aims to see how well these drugs work based on the patient's cancer subtype.

How Is the Trial Designed?

Group I: 5: ceralasertib (AZD6738) + durvalumab Experimental Treatment 2 Interventions

Women with endometrial cancers (serous, clear cell, endometroid, carcinosarcoma) with NO loss of ARID1A.

Group II: 4: ceralasertib (AZD6738) + durvalumab Experimental Treatment 2 Interventions

Women with endometrial cancers (serous, clear cell, endometroid, carcinosarcoma) with ARID1A loss.

Group III: 3: ceralasertib (AZD6738) + olaparib Experimental Treatment 2 Interventions

Women with other rare relapsed gynaecological cancers (endometrioid ovarian carcinoma, endometrioid endometrial carcinoma, cervical adenocarcinoma, cervical squamous, ovarian carcinosarcoma and endometrial carcinosarcoma) irrespective of ARID1A status, treated with AZD6738 in combination with olaparib.

Group IV: 2: ceralasertib (AZD6738) + olaparib Experimental Treatment 2 Interventions

Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with NO loss of ARID1A expression treated with AZD6738 in combination with olaparib.

Group V: 1B: ceralasertib (AZD6738) + olaparib Experimental Treatment 2 Interventions

In second stage of trial, opening of this cohort depends on response rate in cohort 1A during first stage of trial. Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with AZD6738 in combination with olaparib.

Group VI: 1A: ceralasertib (AZD6738) Experimental Treatment 1 Intervention

Women with relapsed ovarian (fallopian tube / primary peritoneal) and endometrial (uterus) clear cell carcinomas with loss of ARID1A expression treated with single agent AZD6738.

Who Is Running the Clinical Trial?

Institute of Cancer Research, United Kingdom

Lead Sponsor

Trials

167

Recruited

136,000+

Cancer Research UK

Collaborator

Trials

262

Recruited

4,435,000+

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

Olaparib (OLA) monotherapy showed a similar overall objective response rate (ORR) compared to chemotherapy (CT) in patients with relapsed ovarian cancer, with ORR of 24.3% for OLA and 28.3% for CT, indicating comparable efficacy.

In patients with platinum-resistant ovarian cancer (PROC) who had received more than four prior lines of treatment, OLA demonstrated a higher ORR of 22.9% compared to 0% for CT, suggesting that OLA may be more effective in heavily pretreated cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized CLIO/BGOG-ov10 trial of olaparib monotherapy versus physician's choice chemotherapy in relapsed ovarian cancer. Vanderstichele, A., Loverix, L., Busschaert, P., et al.[2022]

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]

In a study of 115 relapsing epithelial ovarian cancer patients with BRCA mutations receiving olaparib, the median progression-free survival (PFS) was 12.7 months and overall survival (OS) was 35.4 months after a median follow-up of 21 months.

Key factors associated with longer PFS and OS included a platinum-free interval of 12 months or more, achieving a complete or partial response to treatment, and normalization of CA-125 levels after the last platinum-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers. Labidi-Galy, SI., de La Motte Rouge, T., Derbel, O., et al.[2022]

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]

In the phase III SOLO1 trial, maintenance treatment with olaparib significantly improved progression-free survival in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, with 260 patients receiving olaparib compared to 131 on placebo.

The most common adverse events associated with olaparib, such as anemia and nausea, occurred early (within 3 months) but were manageable, with only a small number of patients needing to discontinue treatment, indicating a predictable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial. Colombo, N., Moore, K., Scambia, G., et al.[2022]

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]

Olaparib is an effective oral treatment for advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations, working by blocking DNA repair mechanisms in tumor cells, leading to selective cell death.

In clinical trials, olaparib significantly improved progression-free survival in patients with various types of ovarian cancer, and it is generally well tolerated, with mild side effects like nausea and fatigue being the most common.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of BRCA-mutated advanced ovarian cancer. Munroe, M., Kolesar, J.[2019]

The combination of olaparib and carboplatin was found to be safe and effective in treating breast and ovarian cancer in patients with germline BRCA1 or BRCA2 mutations, with 50% of patients showing a partial response and one patient achieving a complete response.

Proteomic analysis indicated that high levels of FOXO3a expression before treatment may predict a better response to the therapy, suggesting a potential biomarker for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. Lee, JM., Hays, JL., Annunziata, CM., et al.[2022]

Olaparib is established as a standard maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer who have BRCA mutations.

In the phase III SOLO 2 trial, Olaparib significantly extended overall survival by more than a year compared to a placebo, demonstrating its efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib Makes OS Gains in Ovarian Cancer. [2021]

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]

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