Durvalumab + Olaparib for Endometrial Cancer

(DUO-E Trial)

Not currently recruiting at 205 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: PARP inhibitors, Immune therapy

Disqualifiers: Leptomeningeal carcinomatosis, Brain metastases, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of durvalumab, a cancer-fighting drug, when combined with chemotherapy and possibly olaparib (a PARP inhibitor) for advanced or recurring endometrial cancer. The researchers aim to determine if this combination is more effective and safe than standard treatment. Participants will join one of three groups: standard treatment with placebo, durvalumab with placebo, or durvalumab with olaparib. Women diagnosed with advanced endometrial cancer or whose cancer has recurred, and who have not yet received systemic treatment, are suitable candidates for this trial. As a Phase 3 trial, this study is the final step before potential FDA approval, allowing participants to contribute to the development of a promising new treatment.

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, it does mention that you should not have had prior treatment with certain types of cancer therapies, like PARP inhibitors or immune-mediated therapies.

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

Research has shown that durvalumab is generally well-tolerated, meaning most people can handle it without serious issues. In patients with advanced or returning endometrial cancer, common side effects included constipation and tiredness, each affecting about 4.5% of patients. Most side effects were not serious. When combined with olaparib, durvalumab remains well-tolerated. The side effects align with what is already known about these drugs, indicating that while side effects can occur, they are usually manageable and expected. Overall, previous research supports the promising safety record of the durvalumab and olaparib combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about durvalumab and olaparib for endometrial cancer because these drugs offer a fresh approach compared to traditional chemotherapy. Unlike standard treatments that mainly focus on killing cancer cells directly, durvalumab is an immunotherapy that helps the body's immune system recognize and attack cancer cells. Olaparib, on the other hand, is a PARP inhibitor that interferes with cancer cells' ability to repair their DNA, making it harder for them to survive. By combining these two innovative mechanisms, there's potential for more effective control of the cancer with possibly fewer side effects than conventional therapies.

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

Research has shown that using durvalumab with chemotherapy can significantly reduce the risk of cancer progression or death in advanced endometrial cancer, cutting these risks by more than half. In this trial, participants in Arm B will receive durvalumab with chemotherapy. Additionally, combining durvalumab with olaparib has demonstrated even better results. Participants in Arm C will receive this combination, which more than doubled the response time compared to chemotherapy alone. For patients with mismatch repair-proficient endometrial cancer, their cancer remained controlled for an average of 15 months, compared to 9.7 months with chemotherapy alone. These findings suggest that durvalumab and the durvalumab-olaparib combination could be effective treatments for advanced or recurring endometrial cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Shannon Westin, MD

Principal Investigator

The University of Texas MD Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for women over 18 with advanced or recurrent endometrial cancer, including carcinosarcomas but not sarcomas. Participants can be newly diagnosed or have a recurrence after at least 12 months since last treatment if previously treated in the adjuvant setting. They must have an ECOG performance status of 0 or 1 and cannot have brain metastases, spinal cord compression, history of leptomeningeal carcinomatosis, prior PARP inhibitors use, or previous immune-mediated therapy.

Inclusion Criteria

I have a tumor sample available for a specific genetic test.

I have been recently diagnosed with Stage IV cancer.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I have cancer that has spread to my brain or spinal cord.

I have previously received immunotherapy, excluding cancer vaccines.

I have been treated with PARP inhibitors before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive platinum-based chemotherapy (paclitaxel + carboplatin) in combination with durvalumab

6-12 weeks

Maintenance

Participants receive maintenance therapy with durvalumab with or without olaparib

Up to 4 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 years

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Olaparib

Trial Overview The study tests durvalumab combined with chemotherapy (paclitaxel + carboplatin), followed by maintenance durvalumab alone or with olaparib versus placebo in patients with new or recurring endometrial cancer. The goal is to assess how well these treatments work and their safety as maintenance therapy.

How Is the Trial Designed?

Group I: Arm C (durvalumab+olaparib) Experimental Treatment 4 Interventions

Platinum-based chemotherapy and durvalumab followed by maintenance durvalumab and olaparib.

Group II: Arm B (durvalumab+placebo) Experimental Treatment 4 Interventions

Platinum-based chemotherapy and durvalumab followed by maintenance durvalumab and olaparib placebo

Group III: Arm A (control) Active Control 4 Interventions

Platinum-based chemotherapy and durvalumab placebo followed by maintenance durvalumab placebo and olaparib placebo (tablets).

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

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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

The Gynecologic Oncology Group (GOG) Foundation Inc

Collaborator

Trials

1

Recruited

810+

The European Network for Gynaecological Oncological Trial groups (ENGOT)

Collaborator

Trials

2

Recruited

870+

Published Research Related to This Trial

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

In a study of 71 women with advanced endometrial cancer, durvalumab showed a significant objective tumor response rate of 47% in patients with mismatch repair deficient (dMMR) tumors, compared to only 3% in those with proficient tumors (pMMR).

The median progression-free survival was notably longer in the dMMR cohort at 8.3 months versus 1.8 months in the pMMR cohort, indicating that durvalumab is more effective in treating dMMR endometrial cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial. Antill, Y., Kok, PS., Robledo, K., et al.[2021]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

In a study involving 34 patients with BRCA1 or BRCA2 mutated metastatic breast cancer, the combination of olaparib and durvalumab demonstrated promising antitumor activity, with 80% of patients showing disease control at 12 weeks.

The treatment was generally safe, with 32% of patients experiencing grade 3 or worse adverse events, but no treatment-related deaths were reported, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Domchek, SM., Postel-Vinay, S., Im, SA., et al.[2021]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

In the KEYNOTE-158 study, pembrolizumab showed a clinically meaningful objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, with 84 out of 90 patients completing health-related quality of life (HRQoL) assessments.

Patients receiving pembrolizumab experienced significant improvements in their quality of life, with mean scores on the QLQ-C30 and EQ-5D-3L questionnaires increasing notably, especially among those who achieved a complete or partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2022]

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]

Citations

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Clinical activity of durvalumab for patients with advanced ... In this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)

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NCT03015129 | A Study of Durvalumab With or Without ... This study will test the safety and efficacy of the experimental drug called durvalumab with or without another experimental drug called tremelimumab in ...

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dMMR Endometrial Cancer Clinical Trial Results Learn how IMFINZI® (durvalumab) with chemotherapy was studied in people diagnosed with dMMR endometrial cancer and view the clinical trial results.

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IMFINZI® (durvalumab) Efficacy for Advanced or Recurrent ... Learn more about how IMFINZI® (durvalumab) in combination with carboplatin and paclitaxel cut the risk of progression or death by more than half.

5. sciencedirect.com sciencedirect.com/science/article/pii/S1048891X24010211

A multicenter phase II randomized trial of durvalumab ... Patients with recurrent ovarian clear cell carcinoma treated with durvalumab will have improved progression-free survival compared with those treated with ...

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IMFINZI® (durvalumab) Safety in Advanced or Recurrent ... The most common Grade 3 or 4 adverse reactions (≥3%) were constipation (4.5%) and fatigue (4.5%). In patients with advanced or recurrent dMMR endometrial cancer ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2016.67.9761

Safety and Efficacy of Durvalumab (MEDI4736), an Anti– ... Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1–positive patients with UBC, many of whom were heavily ...