A Phase I/II Study of MEDI4736 in Combination With Olaparib in Patients With Advanced Solid Tumors.

NCT ID: NCT02734004

Last Updated: 2025-11-25

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 264 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-03-17
• Study Completion Date: 2026-09-17

Brief Summary

The purpose of this study is to look at the effectiveness, safety, and antitumor activity of study drugs MEDI4736 in combination with olaparib (modules 1, 2, 3, 4, 5 and 7) and MEDI4736 in combination with olaparib and bevacizumab (module 6). It will also examine what happens to the study drugs in the body and investigate how well the combination between MEDI4736, olaparib and bevacizumab is tolerated.

Detailed Description

This is a phase I/II open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK) and antitumor activity of MEDI4736 in combination with olaparib in patients with advanced solid tumors, selected based on a rationale for response to olaparib.

Patients will be poly (adenosine diphosphate-ribose) polymerase (PARP)-inhibitor and immunotherapy (IMT)-naïve (defined as no prior exposure to PARP inhibitors or IMT, including, but not limited to, other anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], anti-programmed cell death 1 [PD-1], anti-programmed death-ligand 1 [PD-L1] monoclonal antibodies, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

The 4 initial stage cohorts (Modules 1 to 4) include patients with relapsed small cell lung cancer (SCLC), germline BRCA mutated (gBRCAm) metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer, gBRCAm platinum-sensitive relapsed ovarian cancer, and gastric cancer. The data cut-off occurred once all 4 Modules had reached last patient first visit (LPFV) + 2 years and all 4 cohorts had observed a median value for PFS.

Second stage cohorts (Modules 5 to 7) include patients with relapsed gBRCAm platinum-sensitive relapsed ovarian cancer and non gBRCAm platinum-sensitive relapsed ovarian cancer. The final data cut-off will be once Modules 6 and 7 have observed a median value for overall survival. At this timepoint, the clinical study database will close to new data.

Conditions

Ovarian; Breast; SCLC; Gastric Cancers

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1

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

Group Type: EXPERIMENTAL

Olaparib

Intervention Type: DRUG

Olaparib

MEDI4736

Intervention Type: DRUG

MEDI4736

Arm 2

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 Type: EXPERIMENTAL

Olaparib

Intervention Type: DRUG

Olaparib

MEDI4736

Intervention Type: DRUG

MEDI4736

Arm 3

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 Type: EXPERIMENTAL

Olaparib

Intervention Type: DRUG

Olaparib

MEDI4736

Intervention Type: DRUG

MEDI4736

Bevacizumab

Intervention Type: DRUG

Bevacizumab

Interventions

Olaparib

Olaparib

Intervention Type: DRUG

MEDI4736

MEDI4736

Intervention Type: DRUG

Bevacizumab

Bevacizumab

Intervention Type: DRUG

Other Intervention Names

Avastin

Eligibility Criteria

Inclusion Criteria

• Patients must have histologically or cytologically confirmed progressive advanced or metastatic solid tumor of one of the following:

• Platinum sensitive relapsed small cell lung cancer (module 1)
• gBRCAm HER2-negative metastatic breast cancer (module 2)
• gBRCAm ovarian cancer (modules 3 and 5)
• Metastatic or relapsed Gastric cancer (adenocarcinoma) (module 4)
• gBRCAm negative ovarian cancer (modules 6 and 7)
• 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. The baseline scan must be obtained within 28 days prior to the first dose of olaparib.
• Male or female patients, age ≥18 years (≥19 years for South Korea)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Life expectancy ≥12 weeks
• Adequate organ and marrow function
• Ability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses that would preclude the absorption of olaparib, which is an oral agent. For the gastric cancer cohort, patients with a full or partial gastrectomy will be permitted.
• Ability of patient to understand and the willingness to sign a written informed consent document prior to any protocol related procedures, including screening evaluations.
• Female patients must either:

• Be of non-reproductive potential OR
• Have a negative serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on Day 1, and agree to use contraception if they or their partner are of reproductive potential

Exclusion Criteria

• Prior chemotherapy or other systemic anticancer therapy within 4 weeks prior to start of olaparib treatment, 6 weeks for nitrosoureas or mitomycin. Exceptions include: Anti-hormonal treatment for ER positive or PR positive breast cancer is allowed until 7 days prior to treatment with olaparib, exposure to an investigational agent within 30 days or 5 half-lives (whichever is the longer) prior to start of olaparib treatment is not allowed, prior receipt of biologics targeting T cell co-regulatory proteins and/or immune checkpoints is not allowed. Examples include MEDI4736 or other PD1 or PD-L1 or PD-L2 inhibitors or anti-CTLA4 therapy, previous treatment with a PARP inhibitor, is not allowed.
• Radiation therapy within 4 weeks prior to start of olaparib treatment (includes radiation targeting bone metastases) or radionuclide treatment within 6 weeks of treatment start.
• Current dependency on total parenteral nutrition or IV fluid hydration.
• Concomitant use of known strong cytochrome P450 (CYP) 3A (CYP3A) inhibitors or moderate CYP3A inhibitors. Concomitant use of known strong or moderate CYP3A inducers.
• Concomitant therapy with any other anticancer therapy or chronic use of systemic corticosteroids.
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation
• Whole blood transfusions in the last 120 days
• Patients with symptomatic or uncontrolled brain metastases.
• Patients being considered at poor medical risk due to a serious, uncontrolled medical disorder or non-malignant systemic disease.
• Any psychiatric disorder that prohibits obtaining informed consent
• Major surgery or significant traumatic injury within 2 weeks of run-in
• Immunocompromised patients
• QTc prolongation >470 msec or other significant ECG abnormality noted within 14 days of treatment
• Pregnant and breastfeeding women are excluded.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
• Previous enrolment in the present study
• Participation in a clinical study within 28 days or 5 half-lives of the drug, whichever is longer.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Iqvia Pty Ltd

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Susan Domchek, MD

Role: PRINCIPAL_INVESTIGATOR

Abramson Cancer Center, University of Pennsylvania

Locations

Research Site

Newnan, Georgia, United States

Research Site

Towson, Maryland, United States

Research Site

Boston, Massachusetts, United States

Research Site

Detroit, Michigan, United States

Research Site

St Louis, Missouri, United States

Research Site

Hilliard, Ohio, United States

Research Site

Philadelphia, Pennsylvania, United States

Research Site

Bordeaux, , France

Research Site

Caen, , France

Research Site

Clermont-Ferrand, , France

Research Site

Dijon, , France

Research Site

Marseille, , France

Research Site

Nantes, , France

Research Site

Paris, , France

Research Site

Pierre Benit Cedex, , France

Research Site

Toulouse, , France

Research Site

Villejuif, , France

Research Site

Haifa, , Israel

Research Site

Jerusalem, , Israel

Research Site

Petah Tikva, , Israel

Research Site

Ramat Gan, , Israel

Research Site

Tel Aviv, , Israel

Research Site

Amsterdam, , Netherlands

Research Site

Amsterdam, , Netherlands

Research Site

Maastricht, , Netherlands

Research Site

Nijmegen, , Netherlands

Research Site

Rotterdam, , Netherlands

Research Site

Utrecht, , Netherlands

Research Site

Goyang-si, , South Korea

Research Site

Seongnam-si, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Seoul, , South Korea

Research Site

Chur, , Switzerland

Research Site

Lausanne, , Switzerland

Research Site

Cambridge, , United Kingdom

Research Site

Dundee, , United Kingdom

Research Site

Glasgow, , United Kingdom

Research Site

Greater London, , United Kingdom

Research Site

London, , United Kingdom

Research Site

London, , United Kingdom

Research Site

Manchester, , United Kingdom

Research Site

Newcastle upon Tyne, , United Kingdom

Research Site

Sutton, , United Kingdom

Countries

United States; France; Israel; Netherlands; South Korea; Switzerland; United Kingdom

References

Drew Y, Kim JW, Penson RT, O'Malley DM, Parkinson C, Roxburgh P, Plummer R, Im SA, Imbimbo M, Ferguson M, Rosengarten O, Steeghs N, Kim MH, Gal-Yam E, Tsoref D, Kim JH, You B, De Jonge M, Lalisang R, Gort E, Bastian S, Meyer K, Feeney L, Baker N, Ah-See ML, Domchek SM, Banerjee S; MEDIOLA Investigators. Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naive Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study. Clin Cancer Res. 2024 Jan 5;30(1):50-62. doi: 10.1158/1078-0432.CCR-23-2249.

Reference Type: DERIVED

PMID: 37939124 (View on PubMed)

Staniszewska AD, Armenia J, King M, Michaloglou C, Reddy A, Singh M, San Martin M, Prickett L, Wilson Z, Proia T, Russell D, Thomas M, Delpuech O, O'Connor MJ, Leo E, Angell H, Valge-Archer V. PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors. Oncoimmunology. 2022 Jun 18;11(1):2083755. doi: 10.1080/2162402X.2022.2083755. eCollection 2022.

Reference Type: DERIVED

PMID: 35756843 (View on PubMed)

Domchek SM, Postel-Vinay S, Im SA, Park YH, Delord JP, Italiano A, Alexandre J, You B, Bastian S, Krebs MG, Wang D, Waqar SN, Lanasa M, Rhee J, Gao H, Rocher-Ros V, Jones EV, Gulati S, Coenen-Stass A, Kozarewa I, Lai Z, Angell HK, Opincar L, Herbolsheimer P, Kaufman B. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 2020 Sep;21(9):1155-1164. doi: 10.1016/S1470-2045(20)30324-7. Epub 2020 Aug 6.

Reference Type: DERIVED

PMID: 32771088 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

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Other Identifiers

2015-004005-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D081KC00001

Identifier Type: -

Identifier Source: org_study_id