Phase 1 Study to Evaluate MEDI4736 in Subjects With Myelodysplastic Syndrome

Study Overview
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Brief Summary
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This is a multicenter, open-label, Phase 1 study to assess the safety and antitumor activity of MEDI4736 as Monotherapy or in Combination with Tremelimumab with or without Azacitidine in Subjects with myelodysplastic syndrome after treatment with hypomethylating agents

Detailed Description
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A dose-escalation and dose-expansion study of MEDI4736 (a monoclonal antibody that targets programmed cell death-1 ligand 1 [PD-L1]) to evaluate the safety, tolerability, PK, IM, and antitumor activity of MEDI4736 as monotherapy or in combination with Tremelimumab with or without Azacitidine in adult patients with myelodysplastic syndrome.

Official Title
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A Phase 1 Study to Evaluate the Safety and Tolerability of MEDI4736 as Monotherapy or in Combination With Tremelimumab With or Without Azacitidine in Subjects With Myelodysplastic Syndrome After Treatment With Hypomethylating Agents

Conditions
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Myelodysplastic Syndrome

Intervention / Treatment
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* Biological: MEDI4736 Evaluate MEDI4736 in MDS
* Drug: VIDAZA
* Biological: tremelimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female subjects with pathologically confirmed MDS who failed to respond, relapsed after an initial response, or were unable to tolerate hypomethylating agents, ECOG performance status of 0 - 2, and adequate organ and marrow function. Exclusion Criteria: Concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment, prior MAb against CTLA-4, PD-1, or PD-L1, alllogenic or haploidentical transplant, current immunosuppressive medication or autoimmune or inflammatory disease.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI4736 Evaluate MEDI4736 in MDS<br>Evaluate MEDI4736 monotherapy and MEDI4736 in combination with azacitidine after monotherapy progression in MDS | Biological: MEDI4736 Evaluate MEDI4736 in MDS<br>* MEDI4736 will be administered by IV infusion<br>* Other names: durvalumab;Drug: VIDAZA<br>* VIDAZA will be administered subcutaneously as described on the package insert VIDAZA will be administered in combination with MEDI4736 upon progression from MEDI4736 monotherapy<br>* Other names: azacitidine;|
| Experimental: MEDI4736 + tremelimumab<br>Evaluate MEDI4736 in combination with tremelimumab | Biological: tremelimumab<br>* tremelimumab will be administered by IV infusion<br>|
| Experimental: MEDI4736 + tremelimumab + azacitidine<br>Evaluate MEDI4736 in combination with tremelimumab and azacitidine | Drug: VIDAZA<br>* VIDAZA will be administered subcutaneously as described on the package insert VIDAZA will be administered in combination with MEDI4736 upon progression from MEDI4736 monotherapy<br>* Other names: azacitidine;Biological: tremelimumab<br>* tremelimumab will be administered by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subject's safety where no more than one out of six subjects experience DLTs at a given dose | DLT (MEDI4736 monotherapy only) assessment will be done by reviewing adverse events (AEs), serious adverse events (SAEs), laboratory evaluations, vital signs, physical examinations, and electrocardiogram (ECG) results. For monotherapy or combo w/aza AEs, SAEs, lab evaluations, vital signs, physical exams, ECGs will be done. | 180 days | 
| Subject's safety overall (monotherapy and combination therapies) | Overall safety assessments will be done by reviewing adverse events (AEs, serious adverse events (SAEs), laboratory evaluations, vital signs, physical examinations and electrocardiogram (ECG) results. | 730 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical outcome in terms of response: duration of response | As defined by IWG 2006 MDS response criteria | 2 years | 
| Clinical outcome in terms of response: transfusion requirements | As defined by IWG 2006 MDS response criteria and incidence of transfusions. | 2 years | 
| Clinical outcome in terms of response: progression-free survival (PFS) | As defined by IWG 2006 MDS response criteria | 2 years | 
| Clinical outcome in terms of response: survival (OS) | As defined by IWG 2006 MDS response criteria and collection of survival data | 2 years | 
| Pharmacokinetics: MEDI4736 and tremelimumab concentrations in serum: peak concentration | Peak concentration of MEDI4736 and tremelimumab in serum | 1 year | 
| Pharmacokinetics: MEDI4736 and tremelimumab concentrations in serum: area under the concentration-time curve | Analysis of area under the concentration-time curve | 1 year | 
| Pharmacokinetics: MEDI4736 and tremelimumab concentration in serum: clearance | Rate of MEDI4736 and tremelimumab clearance | 1 year | 
| Pharmacokinetics: MEDI4736 and tremelimumab concentration in serum: terminal half-life | MEDI4736 and tremelimumab concentration terminal half-life | 1 year | 
| Immunogenicity | Determine by number of subjects who develop ADA (anti-drug antibody). | 1 year | 
| Health-related quality of life (QOL): disease- and treatment-related symptoms (Part 1 only) | Analysis of reporting of disease- and treatment-related symptoms (Part 1 only) | 2 years | 
| Health-related quality of life (QOL): pain (Part 1 only) | Analysis of incidence of pain reporting (Part 1 only) | 2 years | 
| Health-related quality of life (QOL): health status (Part 1 only) | Analysis of reporting of health status. (Part 1 only) | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic syndrome, MDS