Clinical Trials /

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

NCT02734004

Description:

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, 8 and 9) and MEDI4736 in combination with olaparib and bevacizumab (module 6 and 10). 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.

Related Conditions:
  • Breast Carcinoma
  • Ovarian Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: D081KC00001
  • SECONDARY ID: 2015-004005-16
  • NCT ID: NCT02734004

Conditions

  • Ovarian
  • Breast
  • SCLC
  • Gastric Cancers

Interventions

DrugSynonymsArms
OlaparibArm 1
MEDI4736Arm 1
BevacizumabAvastinArm 3

Purpose

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, 8 and 9) and MEDI4736 in combination with olaparib and bevacizumab (module 6 and 10). 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. Enrollment for these cohorts has been completed.

      Second stage cohorts (Modules 5 to 7) will include patients with relapsed BRCAm
      platinum-sensitive relapsed ovarian cancer and non BRCAm platinum-sensitive relapsed ovarian
      cancer.

      Third stage cohorts (Modules 8 to 10) will include patients with HER2-negative, BRCAm breast
      cancer (Module 8), HER2 negative, non BRCAm, Homologous Recombination Repair gene mutated
      (HRRm) breast cancer (Module 9) and non BRCAm, non HRRm triple negative breast cancer (TNBC)
      breast cancer (Module 10).
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalIncludes 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
  • Olaparib
  • MEDI4736
Arm 2ExperimentalIncludes 2nd stage cohorts (modules 5&7) and 3rd stage cohorts (modules 8&9): Olaparib twice daily starting on week 1 day 1 and MEDI4736 every 4 weeks starting on week 1 day 1
  • Olaparib
  • MEDI4736
Arm 3ExperimentalIncludes 2nd stage cohort (module 6) and 3rd stage cohort (module 10): 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
  • Olaparib
  • MEDI4736
  • Bevacizumab

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)

               -  BRCAm (including germline and tumor BRCA1/2 mutations) human epidermal growth
                  factor receptor 2 (HER2)-negative breast cancer patients with metastatic or
                  locally advanced disease, which is unresectable (or the patient is not a
                  candidate for resection) (Module 8 BRCAm)

               -  Human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients
                  with metastatic or locally advanced disease, which is unresectable (or the
                  patient is not a candidate for resection) Patients must have documented evidence
                  from Myriad central tumor testing that they do not have a mutation in BRCA1 or
                  BRCA2 that is predicted to be deleterious or suspected deleterious (known or
                  predicted to be detrimental/lead to loss of function) and do have a deleterious
                  or suspected deleterious mutation in at least 1 of the following 13 HRR genes:
                  ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C,
                  RAD51D, RAD54L. (Module 9 HRRm).

               -  Breast cancer patients with metastatic or locally advanced disease, which is
                  unresectable (or the patient is not a candidate for resection). Patients must
                  have documented evidence from Myriad central tumor testing that they do not have
                  any mutation in BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL,
                  PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L that is predicted to be
                  deleterious or suspected deleterious (known or predicted to be detrimental/lead
                  to loss of function) (Module 10 TNBC).

          -  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.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease control rate (DCR) [Complete response + Partial response + Stable disease (CR+PR+SD)] based on RECIST 1.1
Time Frame:At 12 weeks, compared to Baseline
Safety Issue:
Description:Assessments will be performed using CT/MRI assessments of the chest, abdomen, and pelvis (Modules 1, 2, 3 and 4)

Secondary Outcome Measures

Measure:PD-L1 expression in serum samples
Time Frame:Each cycle = 28 days in combination of treatment. Day 1 of cycle 1; Day 15 of cycle 1; Day 1 of cycle 3; Day 1 of cycle 5; Day 1 of cycle 7; 3 month Follow-up visit
Safety Issue:
Description:Samples will be measured for the presence of sPD-L1 (Modules 1, 2, 3 and 4)
Measure:Disease control rate (DCR) [Complete response + Partial response + Stable disease (CR+PR+SD)] based on RECIST 1.1
Time Frame:At 28 weeks, compared to Baseline
Safety Issue:
Description:Assessments will be performed using CT/MRI assessments of the chest, abdomen, and pelvis (Modules 1, 2, 3 and 4) and BICR (Modules 2 and 3)
Measure:Time to study treatment discontinuation (TDT)
Time Frame:From Cycle 1, Day 1 until treatment discontinuation from any cause or until death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Time of study treatment discontinuation or death (All modules)
Measure:Overall Survival (OS)
Time Frame:From Cycle 1, Day 1 until death from any cause, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Time from start of Olaparib treatment until death due to any cause (All modules)
Measure:Percentage change from baseline in tumor size
Time Frame:At 12 weeks and 28 weeks compared to Baseline
Safety Issue:
Description:Assessments will be performed using CT/MRI assessments of the chest, abdomen, and pelvis (Modules 1, 2, 3 and 4)
Measure:Best percentage change from baseline in tumor size
Time Frame:From Baseline, at 4 weeks (Modules 1, 2, 3 and 4) and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessments will be performed using CT/MRI assessments of the chest, abdomen, and pelvis (All modules)
Measure:Serum concentrations of anti-drug antibody (ADA)
Time Frame:Each cycle = 28 days in combination of treatment. Day 1 of cycle 1; Day 15 of cycle 1; Day 1 of cycle 3; Day 1 of cycle 5; Day 1 of cycle 7; 3 month Follow-up visit
Safety Issue:
Description:Samples will be measured for the presence of MEDI4736 ADAs (All modules)
Measure:Olaparib pharamacokinetic sample
Time Frame:Olaparib Run-In treatment week 1 day 1; Olaparib Run-In treatment week 4 day 1; Day 15 of Cycle 1
Safety Issue:
Description:Samples will be collected for determination of Olaparib levels in plasma (All modules)
Measure:MEDI4736 pharmacokinetic sample
Time Frame:Each cycle = 28 days in combination of treatment. Day 1 of cycle 1; Day 15 of cycle 1; Day 1 of cycle 3; Day 1 of cycle 5; Day 1 of cycle 7; 3 month Follow-up visit
Safety Issue:
Description:Samples will be collected for determination of MEDI4736 levels in plasma (All modules)
Measure:Objective response rate (Complete response+Partial response) based on RECIST 1.1
Time Frame:From Baseline, at 8 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by BICR (Modules 5 and 8)
Measure:Duration of response based on RECIST 1.1
Time Frame:From Baseline, at 8 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by the investigator and assessed by BICR (Modules 5 and 8)
Measure:PFS based on RECIST 1.1
Time Frame:From Baseline, at 8 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by the investigator and assessed by BICR (Modules 5 and 8)
Measure:Percentage change from baseline in tumor size
Time Frame:At 24 weeks and 56 weeks compared to Baseline
Safety Issue:
Description:Assessments will be performed using CT/MRI assessments of the chest, abdomen, and pelvis (Modules 5, 6, 7, 8, 9 and 10)
Measure:Objective response rate (Complete response+Partial response) based on RECIST 1.1
Time Frame:From Baseline, at 8 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by the investigator (Modules 6, 7, 9 and 10)
Measure:Duration of response based on RECIST 1.1
Time Frame:From Baseline, at 8 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by the investigator (Modules 5, 6, 7, 8, 9 and 10)
Measure:PFS based on RECIST 1.1
Time Frame:From Baseline, at 8 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by the investigator (Modules 5, 6, 7, 8, 9 and 10)
Measure:Disease control rate (DCR) [Complete response + Partial response + Stable disease (CR+PR+SD)] based on RECIST 1.1
Time Frame:At 24 weeks and 56 weeks, compared to Baseline
Safety Issue:
Description:Assessed by the investigator and assessed by BICR (Module 5)
Measure:Disease control rate (DCR) [Complete response + Partial response + Stable disease (CR+PR+SD)] based on RECIST 1.1
Time Frame:At 56 weeks, compared to Baseline
Safety Issue:
Description:Assessed by the investigator (Modules 6 and 7)
Measure:Bevacizumab pharmacokinetic sample
Time Frame:Each cycle = 28 days in combination of treatment. Day 1 of cycle 1; Day 1 of cycle 2; Day 1 of cycle 4; Day 1 of cycle 7
Safety Issue:
Description:Samples will be collected for determination of bevacizumab levels in plasma (Module 6)
Measure:Objective response rate (Complete response+Partial response) based on RECIST 1.1
Time Frame:From Baseline, at 4 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by the investigator (Modules 1, 2, 3 and 4) and by BICR (Modules 2 and 3)
Measure:Duration of response based on RECIST 1.1
Time Frame:From Baseline, at 4 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by the investigator (Modules 1, 2, 3 and 4) and by BICR (Modules 2 and 3).
Measure:PFS based on RECIST 1.1
Time Frame:From Baseline, at 4 weeks and every 8 weeks up to objective radiological progression, or death from any cause, whichever comes earlier, assessed until all patients receiving IP have completed 104 weeks of treatment.
Safety Issue:
Description:Assessed by the investigator (Modules 1, 2, 3 and 4) and by BICR (Modules 2 and 3).
Measure:Disease control rate (DCR) [Complete response + Partial response + Stable disease (CR+PR+SD)]
Time Frame:16 weeks and 24 weeks
Safety Issue:
Description:Assessments done with CT/MRI scans (Module 8) assessed by investigator and by BICR.
Measure:Disease control rate (DCR) [Complete response + Partial response + Stable disease (CR+PR+SD)]
Time Frame:24 weeks
Safety Issue:
Description:Assessments done with CT/MRI scans (Modules 9 and 10)
Measure:Olaparib plasma concentrations
Time Frame:Each cycle - 28 days; Day 15 of Cycle 1
Safety Issue:
Description:PK (plasms) samples collected (Modules 8, 9 and 10)
Measure:MEDI4736 serum concentrations
Time Frame:Each cycle = 28 days; Day 1 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 4, Day of Cycle 7 (Modules 8, 9 and 10)
Safety Issue:
Description:PK (plasms) samples collected (Modules 8, 9 and 10).
Measure:Bevacizumab serum concentrations
Time Frame:Each cycle = 28 days; Day 1 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 4, Day of Cycle 7 (Module 10)
Safety Issue:
Description:PK (plasms) samples collected (Modules 8, 9 and 10).
Measure:MEDI4736 ADA (Anti-drug Antigen) serum concentrations
Time Frame:Each cycle = 28 days; Day 1 of Cycle 1, Day 1 of Cycle 4, Day of Cycle 7 (Modules 8, 9 and 10)
Safety Issue:
Description:PK (plasms) samples collected (Modules 8, 9 and 10).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • MEDIOLA
  • Olaparib
  • MEDI4736
  • Bevacizumab
  • Ovarian cancer
  • Breast cancer
  • Small Cell Lung Cancer
  • Gastric Cancer
  • Phase I/II, Adults
  • PDL-1

Last Updated

January 24, 2020