Triple Combination Immunotherapy for Ovarian Cancer

Not currently recruiting at 443 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Bevacizumab

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Platinum-refractory, Brain metastases, Cardiac history, 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: 1

Duration: Up to 11 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine whether combining three drugs—durvalumab (an immunotherapy drug), olaparib, and cediranib—can more effectively combat ovarian, primary peritoneal, or fallopian tube cancer compared to the usual treatment. These drugs enhance the immune system and inhibit cancer cells' ability to repair themselves. Participants must have cancer that recurred after responding to platinum-based treatment and should have tried at least two other therapies. Those who have previously used bevacizumab (a cancer treatment drug) and have a BRCA gene mutation might be suitable candidates. The trial will test various combinations of these drugs to identify which best slows cancer progression. As a Phase 2 trial, this research focuses on evaluating 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 need to stop taking your current medications. However, you cannot use any complementary or alternative medicines, and you should not be on strong inhibitors or inducers of CYP3A4. It's best to discuss your current medications with the study team.

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

Research shows that the combination of durvalumab, olaparib, and cediranib is generally safe and well-tolerated. Previous studies have examined these drugs in various combinations. For instance, research has found that using cediranib and olaparib together is safe for treating certain cancers, such as ovarian, fallopian tube, or primary peritoneal cancer.

Durvalumab, a monoclonal antibody, has been tested in various solid tumors and is considered safe to use, even with other medications. Studies on olaparib have also shown it to be well-tolerated, particularly in patients with specific genetic backgrounds.

Although some serious side effects have been reported in trials, they fall within the expected range for cancer treatments. Patients should discuss potential side effects with their doctors to determine if joining a trial is the right choice for them. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine innovative drugs to tackle ovarian cancer in new ways. Unlike the standard treatments like chemotherapy, which directly kill cancer cells, this trial uses a mix of immunotherapy and targeted therapies. Durvalumab is an immunotherapy that helps the immune system recognize and fight cancer cells. Cediranib maleate and olaparib are targeted therapies; cediranib disrupts blood vessel growth that tumors need, while olaparib inhibits a protein that cancer cells use to repair their DNA. By combining these mechanisms, the treatment offers a multi-faceted approach that could enhance effectiveness and reduce the chance of cancer cells developing resistance.

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

Research has shown that combining the drugs durvalumab, olaparib, and cediranib may help treat ovarian cancer that doesn't respond to standard treatments. In this trial, participants will be assigned to different treatment arms to evaluate these combinations. One arm will receive durvalumab, cediranib, and olaparib together. Another arm will receive durvalumab and cediranib, while a separate arm will receive cediranib and olaparib. Studies have found that these combinations can delay cancer growth longer than chemotherapy. Specifically, using durvalumab and olaparib together has doubled the time some patients' cancer remains under control. Additionally, when cediranib is used with olaparib, it has significantly extended the time patients live without the cancer worsening. This suggests that these drug combinations could be a promising option for those with recurring ovarian cancer. ^{2 3 4 5 6}

Who Is on the Research Team?

Jung-min Lee

Principal Investigator

NRG Oncology

Are You a Good Fit for This Trial?

This trial is for women with certain types of ovarian, fallopian tube, or peritoneal cancer that has returned after platinum therapy. Participants must have had at least two prior treatments and can have had bevacizumab, PARP inhibitors, or immune checkpoint blockade. They should not have primary platinum-refractory disease or a history of severe bowel issues within the last 3 months.

Inclusion Criteria

I have previously used a PARP inhibitor.

Side effects from my previous treatments are mild or gone, except for hair loss or skin color changes.

I have previously been treated with immune checkpoint inhibitors.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

You have a condition that causes problems with blood clotting or excessive bleeding.

I do not have an active infection like TB, hepatitis B, or C.

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 assigned treatment based on randomization into one of four arms, with cycles repeating every 21 or 28 days in the absence of disease progression or unacceptable toxicity

Up to 11 months

Multiple visits (in-person) for IV administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up continuing periodically for up to 5 years

Up to 5 years

Periodic visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cediranib Maleate
• Durvalumab
• Olaparib

Trial Overview The study compares combinations of durvalumab (an immunotherapy), olaparib (a PARP inhibitor), and cediranib (a drug blocking tumor growth) against standard treatments to see if they extend the time without cancer progression in patients with recurrent platinum-resistant ovarian-related cancers.

How Is the Trial Designed?

Group I: Arm IV (cediranib maleate, olaparib) Experimental Treatment 7 Interventions

Patients receive cediranib maleate PO QD on days 1-28 and olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

Group II: Arm III (durvalumab, cediranib maleate) Experimental Treatment 8 Interventions

Patients receive durvalumab IV over 60 minutes on day 1 and cediranib maleate PO QD Monday through Friday. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

Group III: Arm II (durvalumab, cediranib maleate, olaparib) Experimental Treatment 9 Interventions

Patients receive durvalumab IV over 60 minutes on day 1, cediranib maleate PO QD Monday through Friday, and olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

Group IV: Arm I (paclitaxel, doxorubicin, topotecan hydrochloride)) Active Control 9 Interventions

Patients receive paclitaxel IV over 60 minutes on days 1, 8, and 15, or pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1, or topotecan hydrochloride IV over 30 minutes on days 1, 8 and 15 or days 1-5 per the discretion of the treating physician. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Published Research Related to This Trial

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]

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 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]

Olaparib, approved by the FDA for patients with advanced ovarian cancer carrying BRCA mutations, showed a 34% objective response rate in a trial of 137 patients who had undergone three or more prior chemotherapy treatments, with a median response duration of 7.9 months.

Common side effects included anemia, nausea, and fatigue, with a small risk (2%) of developing myelodysplastic syndrome or acute myeloid leukemia, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy. Kim, G., Ison, G., McKee, AE., 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6503628/

Overall survival and updated progression-free ... In this updated analysis, combination cediranib/olaparib significantly improved progression-free survival over olaparib (16.5 versus 8.2 months) in relapsed ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02502266

NCT02502266 | Testing the Combination of Cediranib and ... Cediranib maleate and olaparib may stop the growth of tumor cells by blocking enzymes needed for cell growth. Chemotherapy drugs work in different ways to stop ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01116648

NCT01116648 | Cediranib Maleate and Olaparib in ... Cediranib maleate may help keep cancer cells from growing by affecting their blood supply. Olaparib may stop cancer cells from growing abnormally. The ...

4. astrazeneca.com astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-gy004-trial-for-cediranib-added-to-lynparza-in-platinum-sensitive-relapsed-ovarian-cancer.html

Update on Phase III GY004 trial for cediranib added to ... Cediranib has shown anti-tumour activity in many cancers, including ovarian, breast, colorectal, renal, lung, sarcoma and glioblastoma.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6489675/

Efficacy and safety of olaparib maintenance therapy in ... The meta-analysis results confirmed that olaparib maintenance therapy was generally effective and well tolerated in patients with BRCA-mutated advanced ovarian ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01116648

NCT01116648 | Cediranib Maleate and Olaparib in ... The combination of cediranib maleate and olaparib may be safe, tolerable and/or effective in treating patients with recurrent ovarian, fallopian tube, or ...