MEDI4736 (Anti PD-L1) Combined With Gefitinib in Subjects With Non-Small Cell Lung Cancer(NSCLC).

Study Overview
=================
Brief Summary
-----------------
This a Phase I, Open-Label, Multicentre Study to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumour activity of gefitinib in combination with MEDI4736 (anti PD-L1) in Subjects with Non-small cell lung cancer (NSCLC). The study consists of two phases: Escalation phase and an expansion phase to be conducted in locally advanced or metastatic NSCLC subjects

Detailed Description
-----------------
In Escalation phase: MEDI4736 and gefitinib in NSCLC subjects In Expansion phase: Subjects with EGFR mutation positive locally advanced or metastatic NSCLC will be enrolled in expansion arms. Initiation of expansion arms with the recommended dose of MEDI4736 in combination with gefitinib will be based on an adequate safety and tolerability profile of the combination from the escalation phase.

Official Title
-----------------
A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Gefitinib in Combination With MEDI4736 (Anti PD-L1) in Subjects With Non-Small Cell Lung Cancer(NSCLC)

Conditions
-----------------
Carcinoma, Non-Small-Cell Lung

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Provision of signed and dated, written informed consent Male or female aged 18 years and older. Subjects must have a. In the escalation phase, locally advanced or metastatic NSCLC subjects who have either failed to respond or relapsed following any line of standard treatment, were unable to tolerate, or were not eligible for standard treatment b. In the expansion phase, histologically or cytologically confirmed locally advanced or metastatic NSCLC that is EGFR mutation positive, naïve to EGFR TKI therapy, and sensitive to EGFR TKIs therapy a.For Escalation Phase: At least one lesion (measurable and/or non-measurable) b.For Expansion Phase: At least one measurable lesion. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. For Japan Escalation - the same as the global escalation I/E criteria except patients must be EGFR mutation positive Key Exclusion Criteria: Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Any investigational agent, chemotherapy, immunotherapy, biologic, hormonal within 28 days of the first dose of study treatment Inadequate bone marrow reserve or organ function

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Escalation<br>MEDI4736 will be combined with gefitinib to assess safety and tolerability | Drug: Gefitinib<br>* Gefitinib QD<br>Drug: MEDI4736<br>* MEDI4736 IV Q2W<br>|
| Experimental: Expansion Arm<br>MEDI4736 will be combined with gefitinib | Drug: Gefitinib<br>* Gefitinib QD<br>Drug: MEDI4736<br>* MEDI4736 IV Q2W<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Escalation Phase: safety and tolerability: AEs, laboratory data, vital signs, ECG changes and Echo. Expansion Phase: safety and tolerability of the recommended dose for MEDI4736; AEs, laboratory data, vital signs, ECG changes and Echo. | AEs: Type, incidence, severity, seriousness and relationship to study medications of adverse events (AE) (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]; Safety Labs: Blood and urine samples for determination of clinical chemistry, hematology, coagulation, thyroid function tests and urinalysis will be taken at the visits; any laboratory abnormalities, and including dose-limiting toxicities (DLTs), ECG measurements and Creatinine Clearance | From first dose of study treatment until 90 days after the last dose, assessed up to 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To obtain a preliminary assessment of the anti-tumour activity of gefitinib in combination with MEDI4736 by evaluation of tumour response | At each visit subjects will be programmatically assigned a RECIST visit response of CR, PR, SD or PD depending on the status of their disease compared to baseline and previous assessments; Objective response rate: the percentage of subjects who have at least one visit response of CR or PR prior to any evidence of progression . Disease control rate: the percentage of subjects who have at least one visit response of CR or PR or SD prior to any evidence of progression. Progression Free Survival (PFS) : the time from start of study treatment to the first documentation of objective disease progression (PD) or death from any cause. | From baseline assessment to disease progression, assessed up to 30 months | 
| To determine the immunogenicity of MEDI4736 in combination with gefitinib: anti-drug antibodies (ADAs) | Assessed by evaluating the number and percentage of subjects who develop detectable anti-drug antibodies (ADAs). The impact of ADAs on overall MEDI4736 PK will also be evaluated. | From first dose of study treatment until 90 days after the last dose, assessed up to 32 months | 
| To determine the pharmacokinetics of MEDI4736 | Individual MEDI4736 concentrations will be tabulated by dose cohort along with descriptive statistics. Noncompartmental PK data analysis will be performed | From first dose of study treatment until 90 days after the last dose, assessed up to 32 months | 
| To assess MEDI4736 pharmacodynamics in subjects receiving MEDI4736 in combination with gefitinib. | PD-L1 levels before and after treatment with MEDI4736 will be measured to evaluate its association with response to treatment with MEDI4736 and clinical outcome | From first dose of study treatment until 90 days after the last dose, assessed up to 32 months | 
| To determine overall survival (OS) in expansion Arm 1 and Arm 1a patients | Survival information may be obtained via telephone contact with the patient, patients family or by checking the patients notes, hospital records, contacting the patients general practitioner or public death registry, where it is possible to do so under applicable local laws. | From final safety follow-up visit after last dose until 1 year after the final patient discontinues investigational product (initial Medi4736). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NSCLC