A Phase I, Open-Label, Multicentre Study to Evaluate the Safety, Tolerability and Pharmacokinetics of MEDI4736 in Patients With Advanced Solid Tumours

Study Overview
=================
Brief Summary
-----------------
This is a phase I, open-label, multicentre study of MEDI4736 administered intravenously with a standard 3+3 dose-escalation phase to evaluate safety, tolerability, and pharmacokinetics in patients with advanced solid tumor followed by an expansion phase in patients with advanced solid tumors.

Official Title
-----------------
A Phase I, Open-Label, Multicentre Study to Evaluate the Safety, Tolerability and Pharmacokinetics of MEDI4736 in Patients With Advanced Solid Tumours

Conditions
-----------------
Advanced Solid Tumors

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: In the dose-escalation phase: patients with advanced solid tumors refractory to standard treatment, intolerant of standard treatment, or for which no standard therapy exists. In the dose-expansion phase: histologically- or cytologically-confirmed advanced or metastatic biliary tract cancer (BTC), esophagus cancer(EC) (squamous cell carcinoma) or squamous cell carcinoma of the head and neck (SCCHN). - men or women. - Eastern Cooperative Oncology Group (ECOG) status of 0 or 1. - Adequate organ and marrow function. - Subjects must have at least 1 measurable lesion. - Available archived tumor tissue sample. - Willingness to provide consent for biopsy samples. Exclusion Criteria: Any prior Grade ≥ 3 irAE while receiving immunotherapy - Prior exposure to any anti-PD-1 or anti-PD-L1 antibody - Active or prior documented autoimmune disease within the past 2 years - History of primary immunodeficiency - Symptomatic or untreated central nervous system (CNS) metastases requiring concurrent treatment - Women who are pregnant or lactating - Uncontrolled intercurrent illness - Known history of tuberculosis - Known to be human immunodeficiency virus (HIV) positive - Hepatitis B or C infection - Other invasive malignancy within 5 years

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 Q2W<br>Evaluate MEDI4736 given every 2 weeks | Drug: MEDI4736<br>* MEDI4736 will be administered by IV infusion every 14, 21 or 28 days.<br>|
| Experimental: MEDI4736 Q3W<br>Evaluate MEDI4736 given every 3 weeks | Drug: MEDI4736<br>* MEDI4736 will be administered by IV infusion every 14, 21 or 28 days.<br>|
| Experimental: MEDI4736 Dose Expansion<br>evaluate MEDI4736 given every 2 weeks | Drug: MEDI4736<br>* MEDI4736 will be administered by IV infusion every 14, 21 or 28 days.<br>|
| Experimental: MEDI4736 Q4W<br>Evaluate MEDI4736 given every 4 weeks | Drug: MEDI4736<br>* MEDI4736 will be administered by IV infusion every 14, 21 or 28 days.<br>|
| Experimental: MEDI4736 combined with another drug<br>evaluate MEDI4736 in combination with another drug given every 4 weeks | Drug: tremelimumab<br>* tremelimumab is administered by IV infusion every 4 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants experiencing dose-limiting toxicities, adverse events (AEs), serious adverse events (SAEs) | Safety profile will be assessed through number of participants experiencing adverse events (AEs), serious adverse events (SAEs), laboratory evaluations, vital signs, and physical examinations. | 90 days after the last dose of MEDI4736 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration of MEDI4736 time curve | If data allow, noncompartmental PK parameter (AUC) will be estimated. | Up to 90 days after the last dose of MEDI4736 | 
| Percentage of participants who developed detectable anti-drug antibodies (ADAs). | The immunogenic potential of MEDI4736 or tremelimumab will be assessed by summarizing the number percentage of subjects who develop detectable anti-drug antibodies (ADAs). | Up to 6 months after the last dose of MEDI4736 or up to 1 month after the last dose of tremelimumab where applicable. | 
| Objective response rate (ORR) |  | From first dose of study drug until death or up to 2 years | 
| Maximum tolerated dose (MTD) or optimal biological dose (OBD) | maximum tolerated dose (MTD) or optimal biological dose (OBD) of MEDI4736, if possible | 90 days after the last dose of MEDI4736 | 
| Maximum concentration of MEDI4736 | If data allow, noncompartmental PK parameter (Cmax) will be estimated. | Up to 90 days after the last dose of MEDI4736 | 
| Clearance | If data allow, noncompartmental PK parameter (CL) will be estimated. | Up to 90 days after the last dose of MEDI4736 | 
| half-life after administration of MEDI4736 | If data allow, noncompartmental PK parameter (t½) will be estimated. | Up to 90 days after the last dose of MEDI4736 | 
| Disease control rate (DCR) |  | From first dose of study drug until death or up to 2 years | 
| Duration of response (DoR) |  | From first dose of study drug until death or up to 2 years | 
| Progression-free survival (PFS) | Alive and progression free at 6 months (APF6) and 12 months (APF12) will be obtained using the Kaplan-Meier plot of PFS. | From first dose of study drug until death or up to 2 years | 
| Overall survival (OS) | The proportion of patients alive at 12 months will be obtained from the Kaplan-Meier plot of OS. | From first dose of study drug until death or up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MEDI4736, Advanced solid tumors, squamous cell carcinoma of the head and Neck, biliary tract cancer, squamous cell carcinoma of esophagus cancer, B7-H1, PD-L1