Durvalumab + Olaparib + Cediranib for Ovarian Cancer

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)

268 Participants Needed

Trial Summary

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.

What data supports the idea that Durvalumab + Olaparib + Cediranib for Ovarian Cancer is an effective treatment?

The available research shows that combining cediranib and olaparib can be more effective than using olaparib alone for treating certain types of ovarian cancer. For example, in one study, the combination of cediranib and olaparib improved outcomes for women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone. Another study found that the combination of olaparib and cediranib had a higher response rate in patients with specific genetic mutations. While the specific combination of Durvalumab + Olaparib + Cediranib wasn't directly compared to other treatments in the provided studies, the data suggests that using these drugs together could potentially offer benefits for certain patients with ovarian cancer. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination Durvalumab, Olaparib, and Cediranib for ovarian cancer?

Research shows that combining Cediranib and Olaparib can improve progression-free survival (the time during and after treatment that a patient lives with the disease without it getting worse) in women with recurrent platinum-sensitive ovarian cancer compared to Olaparib alone. Additionally, a study found that Olaparib combined with either Cediranib or Durvalumab showed promising response rates in patients with platinum-resistant ovarian cancer. ^{1 2 3 4 5}

What safety data is available for the combination of Durvalumab, Olaparib, and Cediranib in treating ovarian cancer?

The combination of Durvalumab, Olaparib, and Cediranib has been studied for safety and tolerability. A phase I study tested Durvalumab with either Olaparib or Cediranib. The recommended phase II dose (RP2D) was Durvalumab 1,500 mg every 4 weeks with Olaparib 300 mg twice a day, or Cediranib 20 mg on an intermittent schedule (5 days on/2 days off). No dose-limiting toxicity was recorded with Durvalumab plus Olaparib. However, the daily Cediranib schedule showed recurrent grade 2 and non-dose-limiting grade 3 and 4 adverse events, including hypertension, diarrhea, pulmonary embolism, pulmonary hypertension, and lymphopenia. The intermittent Cediranib schedule had fewer severe adverse events, with grade 3 and 4 events including hypertension and fatigue. The combination therapies were found to be tolerable and active, with ongoing phase II studies for further evaluation. ^{1 2 3 5 6}

What safety data exists for the combination of Durvalumab, Olaparib, and Cediranib in humans?

The combination of Durvalumab, Olaparib, and Cediranib has been studied for safety in women with recurrent cancers. In a study, no severe dose-limiting side effects were found with Durvalumab and Olaparib, but some side effects like high blood pressure and fatigue were noted with Durvalumab and Cediranib. These combinations were generally considered tolerable. ^{1 2 3 5 6}

Is the drug combination of Cediranib, Durvalumab, and Olaparib promising for ovarian cancer?

Yes, the combination of Cediranib, Durvalumab, and Olaparib shows promise for treating ovarian cancer. Studies indicate that these drugs together can control the disease effectively, with high response rates and disease control in patients. This suggests that the combination could be a valuable option for ovarian cancer treatment. ^{1 2 4 5 6}

What makes the drug combination of Durvalumab, Olaparib, and Cediranib unique for treating ovarian cancer?

This drug combination is unique because it combines a PARP inhibitor (Olaparib), a VEGF receptor inhibitor (Cediranib), and an immune checkpoint inhibitor (Durvalumab), which together may enhance antitumor activity by targeting cancer cells through different mechanisms. This approach is novel as it leverages the potential synergy between these drugs to improve outcomes in ovarian cancer, especially in cases resistant to standard platinum-based therapies. ^{1 2 4 5 6}

What is the purpose of this trial?

Background: - Durvalumab is a drug that may help people s immune systems respond to and kill cancer cells. Olaparib is a drug that may inhibit repairing DNA damage of cancer cells. Cediranib is a drug that may stop the blood vessel growth of cancer cells. This study has two components. In the phase 1 component of the study, researchers want to investigate how well participants tolerate the combination of these drugs in treating advanced solid tumors, and in the phase 2 part of this study, researchers want to study if the combination treatments are effective in ovarian cancer. Objectives: - Phase 2 part of the study: To determine how effective this combination is in treating ovarian cancer. Eligibility: - Phase 2 part of the study: Adults age 18 or older with advanced or recurrent ovarian cancer that has no standard treatment. Design: * Participants will be screened with medical history, physical exam, and blood and urine tests. They will have CT or MRI scans. For these, they will lie in a machine that takes pictures of their bodies. * Phase 2 part of the study requests the participants to have tumor samples removed. * Participants will get Durvalumab through an IV. A small plastic tube will be inserted into a vein. The drug will be given every 4 weeks until disease progression. * Participants will take olaparib or cediranib by mouth every day. * Every 28 days will be 1 cycle. For cycle 1, participants will have 2 study visits. All other cycles, they will have 1 visit. At these visits, they will repeat the screening procedures. * Patients will keep a drug and diarrhea diary. * Patients on cediranib will monitor their blood pressure and keep a blood pressure diary. * Participants who can become pregnant, or have a partner who can become pregnant, must practice an effective form of birth control. * After 12 cycles, participants will have 1-3 months of follow-up.

Research Team

Jung-Min Lee, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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]

References

1. 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]

2. 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]

3. England 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. [2021]

4. United States 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. [2023]

5. Switzerland 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. [2020]

6. United States 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. [2022]