MEDI4736 + Olaparib for Advanced Cancers

(MEDIOLA Trial)

Not currently recruiting at 52 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Brain metastases, Immunocompromised, others

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

Compensation: Varies

Number of Visits: 13

Duration: 56 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the drugs MEDI4736 (an immunotherapy) and olaparib, alone or with bevacizumab, work together to treat advanced cancers. Researchers aim to determine if these drug combinations can effectively shrink tumors and are safe for patients. The trial seeks participants with certain types of advanced or metastatic solid tumors, such as specific breast, ovarian, or lung cancers, with tumors measurable by CT or MRI scan. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as strong or moderate CYP3A inhibitors and inducers, and any other anticancer therapy or chronic use of systemic corticosteroids. If you are on these medications, you may need to stop them before participating.

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

Research has shown that the combination of MEDI4736 (durvalumab) and olaparib is generally safe, as previous studies have indicated. Some trials reported an increase in immune cells among patients, which is a positive sign, along with clinical benefits. This combination has proven safe for treating certain cancers, such as leiomyosarcoma and muscle-invasive bladder cancer (MIBC).

Adding bevacizumab to MEDI4736 and olaparib has also been studied. Research on patients with advanced ovarian cancer indicates that this triple combination is safe without major concerns. However, individual experiences may vary, and side effects can occur. It is important to consult a healthcare professional to understand the implications of participating in a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of MEDI4736 and Olaparib for advanced cancers because it targets cancer cells differently than traditional treatments. Most current treatments rely on chemotherapy, which attacks rapidly dividing cells, but MEDI4736, an immunotherapy, works by enhancing the body's immune response against cancer cells. Olaparib, on the other hand, is a PARP inhibitor that prevents cancer cells from repairing their DNA, leading to cell death. This dual approach not only provides a novel mechanism of action but also offers the potential for increased effectiveness, especially in cancers that are resistant to standard therapies.

What evidence suggests that this trial's treatments could be effective for advanced cancers?

In this trial, participants will receive different combinations of treatments. Previous studies have shown that the combination of olaparib and durvalumab (known as MEDI4736, a drug that helps the immune system fight cancer) significantly benefits patients, more than doubling the average response time compared to chemotherapy in certain cancers. In one arm of this trial, participants will receive olaparib and MEDI4736. Another arm will test the addition of bevacizumab to olaparib and MEDI4736. This combination has been tested in patients with advanced ovarian cancer and showed promising results for overall survival. These findings suggest that the drug combinations being tested in this trial could effectively combat advanced cancers by enhancing the immune system and preventing cancer cells from repairing themselves. ^{6 7 8 9 10}

Who Is on the Research Team?

Susan Domchek, MD

Principal Investigator

Abramson Cancer Center, University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for adults with certain advanced solid tumors, including specific breast and ovarian cancers, stomach cancer, or small cell lung cancer. Participants must have a life expectancy of at least 12 weeks, measurable lesions for assessment, and be able to swallow pills without altering them. They should not have had recent chemotherapy or other treatments that might interfere with the study drugs.

Inclusion Criteria

Ability of patient to understand and the willingness to sign a written informed consent document prior to any protocol related procedures

At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) suitable for assessment as per RECIST 1.1

Life expectancy ≥12 weeks

Exclusion Criteria

I have not had chemotherapy or cancer drugs within the specified time.

Pregnant and breastfeeding women

Involvement in the planning and/or conduct of the study

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 MEDI4736 in combination with olaparib, with bevacizumab added in some cohorts

56 weeks

Visits every 4 weeks for MEDI4736, every 2 weeks for bevacizumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Every 8 weeks +/-7 days

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• MEDI4736
• Olaparib

Trial Overview The trial is testing the combination of MEDI4736 with olaparib (and in one module also bevacizumab) to evaluate their effectiveness and safety in treating these cancers. It will also assess how these drugs interact within the body and determine how well patients tolerate this drug regimen.

How Is the Trial Designed?

Group I: Arm 3 Experimental Treatment 3 Interventions

Includes 2nd stage cohort (module 6): Olaparib twice daily starting on week 1 day 1 / MEDI4736 every 4 weeks starting on week 1 day 1 / Bevacizumab every 2 weeks starting on week 1 day 1

Group II: Arm 2 Experimental Treatment 2 Interventions

Includes 2nd stage cohorts (modules 5 \& 7): Olaparib twice daily starting on week 1 day 1 and MEDI4736 every 4 weeks starting on week 1 day 1

Group III: Arm 1 Experimental Treatment 2 Interventions

Includes initial stage cohorts (modules 1 to 4): Olaparib twice daily starting on week 1 day 1 and MEDI4736 every 4 weeks starting on week 5 day 1

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

Iqvia Pty Ltd

Industry Sponsor

Trials

120

Recruited

177,000+

Ari Bousbib

Iqvia Pty Ltd

Chief Executive Officer since 2016

MBA from Columbia University, Master of Science in Mathematics and Mechanical Engineering from Ecole Superieure des Travaux Publics, Paris

Jeffrey Spaeder

Iqvia Pty Ltd

Chief Medical Officer

MD

Published Research Related to This Trial

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[2016]

In a Phase I study involving 28 Japanese patients with advanced solid tumors, olaparib tablets at doses of 200 and 300 mg twice daily were found to be tolerable, with no dose-limiting toxicities reported.

The most common side effects included nausea, decreased appetite, anemia, and constipation, but no confirmed antitumor responses were observed, leading to the selection of 300 mg bid as the recommended dose for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Yonemori, K., Tamura, K., Kodaira, M., et al.[2022]

Olaparib is an oral medication that inhibits poly (ADP-ribose) polymerase and is primarily developed for treating BRCA mutation-positive ovarian cancer, with its capsule formulation already approved in the EU and USA.

The drug is currently undergoing extensive clinical trials for various cancers, including breast, gastric, and pancreatic cancers, indicating its potential broad application in oncology beyond ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: first global approval. Deeks, ED.[2020]

The pharmacokinetic (PK) profile of olaparib in Chinese patients with advanced solid tumors is similar to that observed in Western and Japanese populations, confirming that the recommended dose of 300 mg twice daily is appropriate for this group.

When olaparib was combined with paclitaxel, there was a significant decrease in olaparib exposure, and while adverse events were rare, hematological side effects were more common in patients receiving the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: results of a Phase I study in Chinese patients with advanced solid tumours. Yuan, P., Shentu, J., Xu, J., et al.[2020]

Olaparib is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

In a phase I study involving 12 patients with advanced solid tumors, the combination of olaparib and bevacizumab was found to be generally well tolerated, with no dose-limiting toxicities reported.

The most common side effects were mild nausea and fatigue, indicating that the treatment has an acceptable safety profile, making it a candidate for further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours. Dean, E., Middleton, MR., Pwint, T., et al.[2023]

Olaparib is an effective oral treatment for patients with BRCA mutation-positive ovarian cancer, approved for maintenance therapy after platinum-based chemotherapy, showing good tolerability with common side effects like nausea, fatigue, and anemia being mild to moderate.

Long-term monitoring is recommended due to a low risk of serious hematological complications, such as anemia and myelodysplastic syndrome, ensuring patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. Lheureux, S., Bowering, V., Karakasis, K., et al.[2015]

Olaparib significantly improves overall survival in patients with recurrent platinum-sensitive ovarian cancer, with a hazard ratio of 1.24 based on a meta-analysis of 7 randomized controlled trials involving 2406 patients.

However, the treatment is associated with a higher incidence of adverse events, particularly for grades 3 or higher, indicating that while olaparib is effective, it also carries a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. Chen, Q., Li, X., Zhang, Z., et al.[2022]

The OPINION study is evaluating the safety and efficacy of olaparib as a maintenance therapy for women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer who do not have BRCA mutations, involving patients who have undergone at least two prior lines of platinum-based chemotherapy.

The primary goal of the study is to assess progression-free survival, which will help determine how effective olaparib is in delaying cancer progression in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Poveda, AM., Davidson, R., Blakeley, C., et al.[2020]

Citations

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LYNPARZA® (olaparib) and IMFINZI® (durvalumab) ... LYNPARZA (olaparib) and IMFINZI (durvalumab) demonstrated strong clinical benefit and more than doubled median duration of response vs. chemotherapy.

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Efficacy and safety of durvalumab with olaparib in ... Conclusion: The combination of durvalumab and olaparib was well tolerated, but did not meet the prespecified 50% 6-month progression-free survival in this ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02484404

NCT02484404 | Phase I/II Study of the Anti-Programmed ... - 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 ...

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Bevacizumab, olaparib, and durvalumab in patients with ... Median overall survival (OS) was 18.8 months (95% CI 9.6-not reached) and 18.5 months (95% CI 15.6-not reached), respectively. Table 3 Efficacy ...

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6. clinicaltrials.gov clinicaltrials.gov/study/NCT05411094

NCT05411094 | Testing the Safety of the Anti-Cancer ... This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in patients with pancreatic cancer ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37566240/

Results of the DAPPER Clinical Trial Conclusions: Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some patients with leiomyosarcoma.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.6_suppl.542

Impact of the combination of durvalumab (MEDI4736) plus ... Preliminary clinical data suggest that Durvalumab in combination with Olaparib could be active and well-tolerated neoadjuvant treatment of MIBC.

9. nature.com nature.com/articles/s41416-023-02311-0

A signal-seeking Phase 2 study of olaparib and ... Here we conducted a Phase II study to evaluate the safety and efficacy of olaparib and durvalumab (O + D) in patients with advanced solid and ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S0090825822001457

Efficacy and safety of durvalumab with olaparib in ... The combination of durvalumab and olaparib was well tolerated, but did not meet the prespecified 50% 6-month progression-free survival in this heterogeneous ...