MEDI4736 Alone and in Combination With Tremelimumab or AZD9150 in Adult Subjects With Relapsed/Refractory DLBCL (D4190C00023)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and efficacy of MEDI4736 (durvalumab) alone and in combination with either tremelimumab or AZD9150 in adult subjects with relapsed or refractory dIffuse large B-cell lymphoma.

Detailed Description
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This is a multicenter, open-label, dose-escalation and dose-expansion study of MEDI4736 (durvalumab) as monotherapy or in combination with either tremelimumab or AZD9150. The objectives are to describe any dose-limiting toxicities, determine the maximum tolerated dose, and evaluate the safety, tolerability, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics of MEDI4736 as monotherapy or in combination with either tremelimumab or AZD9150 in adult subjects with relapsed or refractory diffuse large B-cell lymphoma.

Official Title
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A Phase 1b Study to Evaluate the Safety and Efficacy of MEDI4736 as Monotherapy and in Combination With Tremelimumab or AZD9150 in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma.

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: MEDI4736
* Drug: tremelimumab
* Drug: AZD9150


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Subjects with histologically confirmed relapsed or refractory DLBCL who have received at least 1 prior rituximab containing chemotherapy regimen but no more than 5 prior lines of therapy Eastern Cooperative Group (ECOG) performance status of 0 or 1 Measurable disease by International Working Group (IWG) response criteria for lymphoma Adequate organ and marrow function Exclusion Criteria: Previous immune-mediated therapy Subjects with prior ASCT or allogenic HCT. Subjects ineligible for available curative options after failing ASCT and have met the hematologic criteria are eligible to participate in this study. Subjects with prior allogenic HCT will be excluded. Documented current central nervous system involvement 3. Active or prior documented autoimmune or inflammatory disease within 3 years, with some exceptions 4. Concurrent or prior conventional or investigational anticancer therapy, within 28 days prior to the first dose of study medication(s)

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI4736<br> | Drug: MEDI4736<br>* MEDI4736 is an anti-PD-L1 monoclonal antibody (MAb) administered via intravenous infusion<br>|
| Experimental: MEDI4736 and tremelimumab<br> | Drug: MEDI4736<br>* MEDI4736 is an anti-PD-L1 monoclonal antibody (MAb) administered via intravenous infusion<br>Drug: tremelimumab<br>* Tremelimumab is an anti-CTLA4 monoclonal antibody (MAb) administered via intravenous infusion<br>|
| Experimental: MEDI4736 and AZD9150<br> | Drug: MEDI4736<br>* MEDI4736 is an anti-PD-L1 monoclonal antibody (MAb) administered via intravenous infusion<br>Drug: AZD9150<br>* AZD9150 is an antisense oligonucleotide (ASO) administered via intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects reporting adverse events and number (percentage) of subjects reporting serious adverse events |  | Screening through 90 days after the last dose of study medication | 
| Number of subjects experiencing dose-limiting toxicities | Changes from baseline in laboratory parameters, vital signs, and ECGs | First dose of study medications through 28 days after the administration of MEDI4736 or MEDI4736 and tremelimumab, 35 days after administration of MEDI4736 and AZD9150 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects who develop anti-drug antibodies (ADA) |  | Screening through 90 days after last dose of study medication | 
| Time to Response |  | Screening though 3 years after the last subject receives the first dose of study medication | 
| Duration of Response |  | Screening though 3 years after the last subject receives the first dose of study medication | 
| Progression Free survival |  | Screening though 3 years after the last subject receives the first dose of study medication | 
| Time to progression |  | Screening though 3 years after the last subject receives the first dose of study medication | 
| Event free survival |  | Screening though 3 years after the last subject receives the first dose of study medication | 
| Overall survival |  | Screening though 3 years after the last subject receives the first dose of study medication | 
| MEDI4736 Maximum Plasma Concentration (Cmax) |  | Measured at defined study visits from time of first dose through end of treatment | 
| Tremelimumab Maximum Plasma Concentration (Cmax) |  | Measured at defined study visits from time of first dose through end of treatment | 
| AZD9150 Maximum Plasma Concentration (Cmax) |  | Measured at defined study visits from time of first dose through end of treatment | 
| MEDI4736 Minimum Plasma Concentration (Cmin) |  | Measured at defined study visits from time of first dose through end of treatment | 
| Tremelimumab Minimum Plasma Concentration (Cmin) |  | Measured at defined study visits from time of first dose through end of treatment | 
| AZD9150 Minimum Plasma Concentration (Cmin) |  | Measured at defined study visits from time of first dose through end of treatment | 
| Individual MEDI4736 Concentrations |  | Measured at defined study visits from time of first dose through 90 days after the end of treatment (approximately 15 months) | 
| Individual tremelimumab Concentrations |  | Measured at defined study visits from time of first dose through 90 days after the end of treatment (approximately 15 months) | 
| Individual AZD9150 Concentrations |  | Measured at defined study visits from time of first dose through 90 days after the end of treatment (approximately 15 months) | 
| Change from baseline of STAT3 RNA (signal transducer and activator of transcription) |  | Measured at defined study visits from time of first dose through 90 days after last dose (approximately 15 months) | 
| Baseline PD-L1 protein expression within the tumor |  | Measured on tumor samples provided at screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL, MEDI4736, durvalumab, tremelimumab, AZD9150, anti-PD-L1, anti-CTLA-4, immunotherapy, IMTC, STAT3