Clinical trial NCT02734004: A Phase I/II Study of MEDI4736 in Combination With Olaparib in Patients With Advanced Solid Tumors.
Official title: A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination With Olaparib (PARP Inhibitor) in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Ovarian
Breast
SCLC
Gastric Cancers
Keywords: MEDIOLA
Olaparib
MEDI4736
Bevacizumab
Ovarian cancer
Breast cancer
Small Cell Lung Cancer
Gastric Cancer
Phase I/II, Adults
PDL-1
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Iqvia Pty Ltd
First posted: 2016-04-12
Enrollment: 264
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12
timeFrame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019.
measure: Second Stage Cohort: Objective Response Rate (ORR)
timeFrame: RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021.
measure: Second Stage Cohorts: DCR at Week 24
timeFrame: RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021.
Secondary outcomes:
measure: Second Stage Expansion Cohort: DCR at Week 24
timeFrame: RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021.
measure: Initial Stage Cohorts: DCR at Week 28
timeFrame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019.
measure: Second Stage Cohorts: DCR at Week 56
timeFrame: RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021.
measure: Initial and Second Stage Cohorts: ORR
timeFrame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
measure: Initial and Second Stage Cohorts: Duration of Response (DoR)
timeFrame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
measure: Initial and Second Stage Cohorts: Progression-Free Survival (PFS)
timeFrame: RECIST performed at baseline, at 4 weeks after first dose of olaparib monotherapy (for initial stage cohort only) and every 8 weeks +/-7 days thereafter. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
measure: Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28
timeFrame: Baseline (Day 1) and Weeks 12 and 28. Assessed until DCO 14 Jun 2019
measure: Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56
timeFrame: Baseline (Day 1) and Weeks 24 and 56. Assessed until DCO 17 Sep 2021
measure: Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size
timeFrame: From baseline (Day 1) until confirmed PD/death. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
measure: Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT)
timeFrame: From baseline (Day 1) until treatment discontinuation/death. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
measure: Initial and Second Stage Cohorts: OS
timeFrame: From baseline (Day 1) until death from any cause. Assessed until DCO 14 Jun 2019 for initial stage cohorts except for ovarian cancer cohort and DCO 17 Sep 2021 for initial stage ovarian cancer cohort and second stage cohorts
measure: Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736
timeFrame: Pre-dose and within 10 minutes of end of infusion on Days 1, 85 and 113; Pre-dose on Days 29, 57 and 169; and 90 days post last dose of MEDI4736. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
measure: Initial and Second Stage Cohorts: Serum Concentrations of Olaparib
timeFrame: Pre-dose and 0.5-1 hour postdose on Days 1 and 22 of monotherapy; Pre-dose and 0.5-1, 1-3, 3-6 and 6-12 hours postdose on Day 15 of combination therapy. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
measure: Second Stage Cohort: Serum Concentrations of Bevacizumab
timeFrame: Pre-dose and within 10 minutes of end of infusion on Days 1 and 85; Pre-dose on Days 29 and 169; and 90 days post last dose of bevacizumab. Assessed until DCO 17 Sep 2021
measure: Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736
timeFrame: Pre-dose on Days 1, 15, 57, 85, 113 and 169; and 90 days post-last dose of MEDI4736. Assessed until DCO 14 Jun 2019 and 17 Sep 2021 for initial and second stage cohorts, respectively
Other outcomes:
Locations:
city: Newnan
country: United States
facility: Research Site
state: Georgia
city: Towson
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Hilliard
country: United States
facility: Research Site
state: Ohio
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Bordeaux Cedex
country: France
facility: Research Site
city: Caen Cedex 05
country: France
facility: Research Site
city: Clermont Ferrand cedex 01
country: France
facility: Research Site
city: Dijon cedex
country: France
facility: Research Site
city: Marseille CEDEX 5
country: France
facility: Research Site
city: Nantes
country: France
facility: Research Site
city: Paris cedex 14
country: France
facility: Research Site
city: Pierre Benit Cedex
country: France
facility: Research Site
city: Toulouse Cedex 9
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Petah Tikva
country: Israel
facility: Research Site
city: Ramat Gan
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Maastricht
country: Netherlands
facility: Research Site
city: Nijmegen
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Utrecht
country: Netherlands
facility: Research Site
city: Chur
country: Switzerland
facility: Research Site
city: Lausanne
country: Switzerland
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Dundee
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Greater London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle Upon Tyne
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Abramson Cancer Center, University of Pennsylvania
name: Susan Domchek, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.