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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination With Olaparib (PARP Inhibitor) in Patients With Advanced Solid Tumors

Conditions
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Ovarian, Breast, SCLC, Gastric Cancers

Intervention / Treatment
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* Drug: Olaparib
* Drug: MEDI4736
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>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 | Drug: Olaparib<br>* Olaparib<br>Drug: MEDI4736<br>* MEDI4736<br>|
| Experimental: Arm 2<br>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 | Drug: Olaparib<br>* Olaparib<br>Drug: MEDI4736<br>* MEDI4736<br>|
| Experimental: Arm 3<br>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 | Drug: Olaparib<br>* Olaparib<br>Drug: MEDI4736<br>* MEDI4736<br>Drug: Bevacizumab<br>* Bevacizumab<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial Stage Cohorts: Disease Control Rate (DCR) at Week 12 | The DCR at 12 weeks was defined as the percentage of participants who had complete response (CR) + partial response (PR) + stable disease (SD) at 12 weeks. Participants demonstrated SD for a minimum interval of 11 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 77 days) following the start of treatment. The DCR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). | 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. | 
| Second Stage Cohort: Objective Response Rate (ORR) | The ORR (based on RECIST 1.1 as assessed by the Investigator) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD or last evaluable assessment in the absence of progression. The 95% confidence interval (CI) were calculated using Exact Clopper-Pearson confidence limits for the binomial proportion. | RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021. | 
| Second Stage Cohorts: DCR at Week 24 | The DCR at 24 weeks was defined as the percentage of participants who had CR + PR + SD at 24 weeks. Participants demonstrated SD for a minimum interval of 23 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1. | RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Second Stage Expansion Cohort: DCR at Week 24 | The DCR at 24 weeks was defined as the percentage of participants who had CR + PR + SD at 24 weeks. Participants demonstrated SD for a minimum interval of 23 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1. | RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021. | 
| Initial Stage Cohorts: DCR at Week 28 | The DCR at 28 weeks was defined as the percentage of participants who had CR + PR + SD at 28 weeks. Participants demonstrated SD for a minimum interval of 27 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 189 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1. | 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. | 
| Second Stage Cohorts: DCR at Week 56 | The DCR at 56 weeks was defined as the percentage of participants who had CR + PR + SD at 56 weeks. Participants demonstrated SD for a minimum interval of 55 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 385 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1. | RECIST performed at baseline, and every 8 weeks +/-7 days thereafter. Assessed until 17 Sep 2021. | 
| Initial and Second Stage Cohorts: ORR | The ORR (based on RECIST 1.1 as assessed by the Investigator) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD or last evaluable assessment in the absence of progression. The 95% CI were calculated using Exact Clopper-Pearson confidence limits for the binomial proportion. | 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 | 
| Initial and Second Stage Cohorts: Duration of Response (DoR) | The DoR (based on RECIST 1.1 as assessed by the Investigator) was defined as the time from the date of first documented response until date of documented progression or death in the absence of PD. The DoR was calculated using Kaplan-Meier technique. | 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 | 
| Initial and Second Stage Cohorts: Progression-Free Survival (PFS) | The PFS (based on RECIST 1.1 as assessed by the Investigator) was defined as the time from start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) until the date of objective PD or death (by any cause in the absence of disease progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to disease progression. The PFS was calculated using Kaplan-Meier technique. | 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 | 
| Initial Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 12 and 28 | The percentage change in target tumor size at each timepoint (based on RECIST 1.1 target lesion measurements) was obtained for each participant taking the difference between the sum of the target lesions at each timepoint and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline times 100. Baseline was defined as the last evaluable assessment prior to starting olaparib treatment. | Baseline (Day 1) and Weeks 12 and 28. Assessed until DCO 14 Jun 2019 | 
| Second Stage Cohorts: Percentage Change From Baseline in Target Tumor Size at Weeks 24 and 56 | The percentage change in target tumor size at each timepoint (based on RECIST 1.1 target lesion measurements) was obtained for each participant taking the difference between the sum of the target lesions at each timepoint and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline times 100. Baseline was defined as the last assessment prior to Cycle 1 Day 1. | Baseline (Day 1) and Weeks 24 and 56. Assessed until DCO 17 Sep 2021 | 
| Initial and Second Stage Cohorts: Best Percentage Change From Baseline in Target Tumor Size | The best percentage change from baseline in target tumor size was based on RECIST 1.1 target lesion measurements taken at each RECIST 1.1 assessment. All measurements until PD or the last evaluable assessment in the absence of PD was included in the calculation. Baseline was defined as the last evaluable assessment prior to starting olaparib treatment for initial stage cohorts. Baseline was defined as the last assessment prior to Cycle 1 Day 1 for second stage cohorts. | 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 | 
| Initial and Second Stage Cohorts: Time to Study Treatment Discontinuation or Death (TDT) | The TDT was defined as the time from start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) to the earlier of the date of study treatment discontinuation or death. The TDT was calculated using the Kaplan-Meier technique. | 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 | 
| Initial and Second Stage Cohorts: OS | The OS was defined as the time from the start of study treatment (Day 1; start of olaparib monotherapy for initial stage cohorts) until death due to any cause. The OS was calculated using the Kaplan-Meier technique. | 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 | 
| Initial and Second Stage Cohorts: Serum Concentrations of MEDI4736 | Blood samples were collected to determine the serum concentration of MEDI4736. | 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 | 
| Initial and Second Stage Cohorts: Serum Concentrations of Olaparib | Blood samples were collected to determine the serum concentration of olaparib. | 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 | 
| Second Stage Cohort: Serum Concentrations of Bevacizumab | Blood samples were collected to determine the serum concentration of bevacizumab. | 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 | 
| Initial and Second Stage Cohorts: Number of Participants With Anti-Drug Antibody (ADA) Response to MEDI4736 | Blood samples were measured for the presence of ADAs and ADA-neutralizing antibodies (nAb) for MEDI4736 using validated assays. ADA prevalence was defined as the percentage of participants with positive ADA result at any time, baseline or post-baseline. ADA incidence (treatment-emergent ADA) was defined as the sum of both treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA. Treatment-boosted ADA was defined as baseline ADA titer that was boosted to 4-fold or higher following drug administration. Persistently positive was defined as positive at >=2 post-baseline assessments (with >=16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as having at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEDIOLA, Olaparib, MEDI4736, Bevacizumab, Ovarian cancer, Breast cancer, Small Cell Lung Cancer, Gastric Cancer, Phase I/II, Adults, PDL-1