Cediranib + Olaparib for Recurrent Ovarian Cancer

Recruiting at 421 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: PARP-inhibitors, VEGF/VEGFR inhibitors

Disqualifiers: Brain metastases, Stroke, Heart failure, 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: 9

Duration: Up to 42 months

582 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing two oral drugs, cediranib maleate and olaparib, alone or together, against standard chemotherapy for patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer that did not respond to previous treatments. The drugs aim to block enzymes needed for cancer cell growth. The goal is to see if these drugs are more effective than standard chemotherapy.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking medications that are strong inhibitors or inducers of CYP3A4, or if you are using complementary or alternative medicines like herbal products. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Cediranib + Olaparib for recurrent ovarian cancer?

Research shows that the combination of Cediranib and Olaparib improved progression-free survival (PFS) in women with recurrent platinum-sensitive ovarian cancer compared to Olaparib alone, indicating that this drug combination may be more effective in delaying the progression of the disease. ^{1 2 3 4 5}

Is the combination of Cediranib and Olaparib safe for humans?

The combination of Cediranib and Olaparib has been studied in several trials for ovarian cancer, showing manageable side effects and toxicities. These studies suggest that the treatment is generally safe for humans, with side effects that can be managed. ^{1 3 4 5 6}

How is the drug combination of Cediranib and Olaparib unique for treating recurrent ovarian cancer?

The combination of Cediranib and Olaparib is unique because it combines two oral drugs with different actions: Olaparib, which helps repair damaged DNA in cancer cells, and Cediranib, which blocks blood vessel growth that tumors need to grow. This combination has shown to improve progression-free survival in women with recurrent ovarian cancer compared to using Olaparib alone. ^{1 2 4 5 7}

Research Team

Jung-min Lee

Principal Investigator

NRG Oncology

Eligibility Criteria

This trial is for adults with recurrent ovarian, fallopian tube, or primary peritoneal cancer that's resistant to platinum-based chemotherapy. Participants must not have used anti-angiogenic agents or PARP-inhibitors before and should be able to take oral medications. They need a good performance status (ECOG 0-2), controlled blood pressure and thyroid function, no severe cardiac history or untreated brain metastases, and can't be HIV-positive or pregnant.

Inclusion Criteria

My cancer can be measured and I can provide a recent or new biopsy sample if needed.

Patient must have provided study specific informed consent prior to study entry

Your blood test results need to be within certain limits.

Exclusion Criteria

I rely on IV fluids or nutrition through a vein.

You have taken any new, experimental medications in the last 4 weeks.

I have a history of heart problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive either a combination of cediranib and olaparib, cediranib alone, olaparib alone, or standard chemotherapy. Treatment cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 42 months

CT and MRI assessments every 9 weeks for the first year, then every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up includes assessments every 3 months for 2 years, then every 6 months for up to 3 years.

Up to 5 years

Treatment Details

Interventions

• Cediranib
• Olaparib

Trial Overview The study tests if cediranib maleate combined with olaparib is more effective than each drug alone or standard chemotherapy in treating certain cancers. It examines how these drugs block enzymes needed for tumor growth versus how chemo stops cell division/spread. The trial includes imaging tests like CT and MRI to monitor the disease.

Participant Groups

Group I: Phase III Arm III (single-agent cediranib maleate) Experimental Treatment 5 Interventions

Patients receive cediranib maleate PO as determined by the Phase II study. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI throughout the study.

Group II: Phase III Arm II (cediranib maleate, olaparib) Experimental Treatment 6 Interventions

Patients receive cediranib maleate PO and olaparib PO as in Phase II Arm II. Patients also undergo CT and MRI throughout the study.

Group III: Phase II Arm IV (olaparib) Experimental Treatment 4 Interventions

Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI throughout the study. (In July 2018, the Data Monitoring Committee voted to exclude the olaparib alone regimen).

Group IV: Phase II Arm III (cediranib maleate) Experimental Treatment 5 Interventions

Patients receive cediranib maleate PO daily continuously. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI throughout the study.

Group V: Phase II Arm II (cediranib maleate, olaparib) Experimental Treatment 6 Interventions

Patients receive cediranib maleate PO QD and olaparib PO BID. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and MRI throughout the study.

Group VI: Phase III Arm I (reference regimen) Active Control 7 Interventions

Patients undergo physician's choice standard of care chemotherapy as in Phase II Arm I. No modification of the assigned regimens, such as additional drugs (gemcitabine or bevacizumab) is allowed. Patients also undergo CT and MRI throughout the study. (12/05/2016)

Group VII: Phase II Arm I (reference regimen) Active Control 7 Interventions

Patients undergo physician's choice of standard of care chemotherapy, comprising either paclitaxel IV over 60 minutes on days 1, 8, 15, and 22 every 28 days (Regimen I); pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1 every 28 days (Regimen II); or topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15 every 28 days or days 1-5 every 21 days (Regimen III). Treatment continues in the absence of disease progression or unacceptable toxicity. No modification of the assigned regimens, such as additional drugs (gemcitabine, or bevacizumab) is allowed. Patients also undergo CT and MRI throughout the study. (12/05/2016)

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+

NRG Oncology

Collaborator

Trials

242

Recruited

105,000+

Canadian Cancer Trials Group

Collaborator

Trials

135

Recruited

70,300+

Findings from Research

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 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 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]

The combination of cediranib and olaparib was found to have significant hematologic toxicities, with 75% of patients experiencing grade 3 or higher side effects, including severe neutropenia and thrombocytopenia at the highest dose.

In terms of efficacy, the treatment showed a promising overall response rate of 44% in patients with recurrent ovarian cancer, while no clinical responses were observed in breast cancer patients, indicating that this combination may be more effective for ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Liu, JF., Tolaney, SM., Birrer, M., et al.[2021]

References

1. 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]

2. 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]

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 phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. [2023]