Durvalumab + Olaparib + Cediranib for Ovarian Cancer

Not currently recruiting at 1 trial location

Overseen By Ann C McCoy, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must be taking: GnRH agonists/antagonists

Must not be taking: Antiretrovirals, Immunosuppressants

Disqualifiers: Cardiac history, Auto-immune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 12 cycles (48 weeks)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of three drugs to determine their effectiveness in treating ovarian cancer. Each drug works differently: Durvalumab boosts the immune system to fight cancer, Olaparib blocks cancer cells' ability to repair DNA, and Cediranib stops blood vessel growth that aids tumor growth. The trial seeks participants with advanced ovarian cancer who have no standard treatment options left. Participants will receive one drug through an IV and the others as pills, and they must monitor their symptoms and blood pressure at home. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on antiretroviral therapy for HIV, you may be ineligible due to potential drug interactions. It's best to discuss your current medications with the trial team to ensure there are no interactions with the study drugs.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive medication, you must stop it 28 days before starting the trial, except for certain low-dose corticosteroids.

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

Research has shown that the combination of Durvalumab and Olaparib is generally well-tolerated. One study found that this combo can lower the risk of disease progression or death compared to other treatments, indicating its safety. Another study supports these findings, showing that this combination seems safe and effective for patients with recurring ovarian cancer.

For the Durvalumab and Cediranib combination, early research has demonstrated its effectiveness and manageable side effects for women's cancers, including ovarian cancer. This suggests that patients handle the combination fairly well.

When using all three drugs together—Durvalumab, Olaparib, and Cediranib—research has shown that this combination is also tolerable for patients. Studies comparing it with standard treatments suggest that it does not cause unexpected side effects.

Overall, these treatments appear safe and manageable based on research findings. However, participants in any clinical trial should always discuss potential risks and benefits with their doctors. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for ovarian cancer focus on surgery and chemotherapy. But the combination of Durvalumab, Olaparib, and Cediranib offers something new by targeting the cancer in multiple ways. Durvalumab is an immunotherapy that helps the immune system attack cancer cells, while Olaparib is a PARP inhibitor that interferes with the cancer cells' ability to repair DNA. Cediranib, on the other hand, blocks the growth of blood vessels that tumors need to grow. Researchers are excited because this multi-pronged attack could potentially be more effective than existing options, offering hope for a more comprehensive treatment strategy.

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

Research has shown that using durvalumab with olaparib more than doubled the average response time compared to chemotherapy for certain cancers. In this trial, some participants will receive the combination of durvalumab and olaparib, which has shown promise in advanced ovarian cancer by reducing the risk of disease progression or death by 37%. Other participants will receive durvalumab and olaparib with the addition of cediranib, which has shown potential in delaying cancer progression. Previous studies reported a 44% response rate and an average of 5.6 months without disease progression with these drug combinations. These findings suggest that these drug combinations could be effective treatment options for ovarian cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Takeo Fujii, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults with certain advanced cancers (ovarian, triple negative breast, lung, prostate and colorectal) that have progressed despite previous treatments. Participants must be over 18 years old with controlled blood pressure and no history of autoimmune diseases requiring steroids or primary immunodeficiency. They should not have had prior treatment with the drugs being tested in this trial or other similar immune therapies.

Inclusion Criteria

My blood pressure is under control with up to three medications.

My prostate cancer has spread and is not responding to hormone therapy.

My ovarian, fallopian tube, or peritoneal cancer has come back or didn't respond to treatment, including at least two prior treatments or resistance to platinum-based therapy.

Exclusion Criteria

I have previously been treated with PARP inhibitors.

I have previously received treatments like MEDI4736 or other therapies targeting PD1, PD-L1, or CTLA4.

I have had a stroke or a mini-stroke in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Durvalumab through IV every 4 weeks and take Olaparib or Cediranib orally daily. Each cycle lasts 28 days.

12 cycles (48 weeks)

Cycle 1: 2 visits, subsequent cycles: 1 visit per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

1-3 months

1-2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cediranib
• Durvalumab
• Olaparib

Trial Overview The study is testing a combination of Durvalumab (an immune system booster), Olaparib (a DNA damage inhibitor), and Cediranib (a drug that halts blood vessel growth in cancer cells). The Phase I part checks for safety and tolerability while Phase II assesses effectiveness against ovarian cancer specifically.

How Is the Trial Designed?

Group I: P2 Durvalumab+O+C Experimental Treatment 3 Interventions

Ph II Durvalumab + olaparib + cediranib at RP2D

Group II: P2 Durvalumab+O Experimental Treatment 2 Interventions

Ph II Durvalumab + olaparib at RP2D

Group III: P2 Durvalumab+C Experimental Treatment 2 Interventions

Ph II Durvalumab + cediranib at RP2D

Group IV: P1 Durvalumab+O+C Experimental Treatment 3 Interventions

Ph I Durvalumab + olaparib + cediranib dose escalation

Group V: P1 Durvalumab+O Experimental Treatment 2 Interventions

Ph I Durvalumab + olaparib dose escalation

Group VI: P1 Durvalumab+C Experimental Treatment 2 Interventions

Ph I Durvalumab + cediranib dose escalation

Cediranib is already approved in United States, European Union for the following indications:

Approved in United States as Cediranib for:

• Alveolar soft part sarcoma

Approved in European Union as Cediranib for:

• Alveolar soft part sarcoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

In a study involving 30 patients with platinum-resistant ovarian cancer and HRR gene mutations, both olaparib-based combinations showed promising efficacy, with objective response rates of 50.0% for olaparib plus cediranib and 42.9% for olaparib plus durvalumab.

Biomarker profiling revealed that specific markers, such as high vascular endothelial growth factor for cediranib and immune markers for durvalumab, could guide treatment decisions, potentially enhancing outcomes for patients based on their individual biomarker status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, two-arm, noncomparative phase 2 study of olaparib plus cediranib or durvalumab in HRR-mutated, platinum-resistant ovarian cancer: A substudy of KGOG 3045. Kim, YN., Joung, JG., Park, E., et al.[2023]

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 a phase II study involving 13 women with recurrent platinum-sensitive ovarian cancer, the combination of olaparib and cediranib showed greater biological activity than olaparib alone, indicated by significant decreases in IL-8 levels and increases in circulating endothelial cells (CEC).

Changes in CEC and IL-8 levels on treatment day 3 were associated with longer progression-free survival, suggesting these biomarkers could help predict patient response to the combination therapy, although further validation is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CECs and IL-8 Have Prognostic and Predictive Utility in Patients with Recurrent Platinum-Sensitive Ovarian Cancer: Biomarker Correlates from the Randomized Phase-2 Trial of Olaparib and Cediranib Compared with Olaparib in Recurrent Platinum-Sensitive Ovarian Cancer. Lee, JM., Trepel, JB., Choyke, P., et al.[2020]

In a phase I study involving 26 women with recurrent cancers, the combination of the PD-L1 inhibitor durvalumab with olaparib or cediranib was found to be tolerable and showed promising anti-tumor activity, with an 83% disease control rate for the durvalumab plus olaparib group.

The recommended phase II doses were established as durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice daily, or cediranib 20 mg on an intermittent schedule, indicating that these combinations could be viable options for further investigation in treating recurrent women's cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. Lee, JM., Cimino-Mathews, A., Peer, CJ., et al.[2022]

Cediranib, when used in combination with chemotherapy and as maintenance therapy, significantly improved progression-free survival (PFS) in women with platinum-sensitive ovarian cancer, showing a hazard ratio of 0.56, indicating a 44% reduction in the risk of disease progression.

While the overall survival (OS) analysis was underpowered due to a reduced number of participants, there was a 14% relative reduction in the risk of death, suggesting that cediranib may still provide meaningful benefits in extending survival time for patients with recurrent ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cediranib in addition to chemotherapy for women with relapsed platinum-sensitive ovarian cancer (ICON6): overall survival results of a phase III randomised trial. Ledermann, JA., Embleton-Thirsk, AC., Perren, TJ., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40192715/

The Phase II NRG-GY023 Trial - PubMed - NIH We assessed the efficacy of anti-PD-L1 durvalumab in combination with olaparib and cediranib (DOC), compared with the standard-of-care chemotherapy (SOC)

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04739800

Study Details | NCT04739800 | Comparison of Standard ... Giving different combinations of durvalumab, olaparib and cediranib may work better in increasing the duration of time that the cancer does not progress ...

3. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2016.72.1340?journal=

A Dose-Escalation, Phase I Study Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab ...

4. international-journal-of-gynecological-cancer.com international-journal-of-gynecological-cancer.com/article/S1048-891X(24)02357-0/fulltext

Chemotherapy-free treatment of recurrent advanced ... Study results showed an objective response rate of 44% and a median duration of response of 7.6 months. The median progression-free survival was 5.6 months (95% ...

5. aacrjournals.org aacrjournals.org/clincancerres/article/30/1/50/732074/Olaparib-plus-Durvalumab-with-or-without

Olaparib plus Durvalumab, with or without Bevacizumab, as ... Bevacizumab, an anti-VEGF monoclonal antibody with antiangiogenic effects, is a standard treatment option for first-line and recurrent advanced ovarian cancer ( ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5493052/

A Dose-Escalation, Phase I Study - PMC Our phase I study findings demonstrated an interesting activity with durvalumab plus cediranib combination ... ovarian cancer. Expert Opin ...

7. astrazeneca.com astrazeneca.com/media-centre/press-releases/2023/lynparza-and-imfinzi-combination-reduced-risk-of-disease-progression-or-death-vs-chemotherapy-and-bevacizumab-in-patients-with-advanced-ovarian-cancer-without-tumour-brca-mutations-in-the-duo-o-phase-iii-trial.html

Lynparza and Imfinzi combination reduced risk of disease ... The combination of Lynparza, Imfinzi, chemotherapy and bevacizumab reduced the relative risk of disease progression or death by 37% versus chemotherapy and ...