Immune-Modulated Study of Selected Small Molecules (Gefitinib, AZD9291, or Selumetinib + Docetaxel) or a 1st Immune-Mediated Therapy (IMT; Tremelimumab) With a Sequential Switch to a 2nd IMT (MEDI4736) in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Study Overview
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Brief Summary
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Primary objective: To assess the efficacy of various sequences of either a small molecule or an IMT (IMT-A) followed by a IMT-B (MEDI4736) .

Detailed Description
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This is a multi-arm, multi-cohort, Phase IIa, open-label study of selected small molecules (gefitinib, AZD9291, or selumetinib + docetaxel) or 1st IMT (hereafter referred to as IMT-A; tremelimumab) followed by sequential switch to a 2nd IMT (hereafter referred to as IMT-B; MEDI4736) in locally advanced or metastatic NSCLC (Stage IIIB-IV). Patients will be enrolled concurrently into multiple cohorts.

Official Title
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A Phase IIa, Open-Label, Multi-Center, Multi-Cohort, Immune-Modulated Study of Selected Small Molecules (Gefitinib, AZD9291, or Selumetinib + Docetaxel) or a 1st Immune-Mediated Therapy (IMT; Tremelimumab) With a Sequential Switch to a 2nd IMT (MEDI4736) in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (Stage IIIB-IV)

Conditions
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Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (Stage IIIB-IV)

Intervention / Treatment
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* Drug: Gefitinib
* Drug: AZD9291
* Drug: Selumetinib+Docetaxel
* Drug: Tremelimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of archived tumor tissue sample and mandatory tissue biopsy Patients must have either histologically or cytologically documented NSCLC who present with locally advanced or metastatic stage IIIB-IV disease Life expectancy ≥12 weeks Patients must have measurable disease and at least 1 lesion not previously irradiated World Health Organization (WHO) performance status of 0 or 1 Exclusion Criteria: Mixed small cell and NSCLC histology Prior exposure to any anti-PD-1 or anti-PD-L1 antibody

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gefitinib with a Seq. Switch to a MEDI4736<br>Gefitinib once daily followed by MEDI4736 | Drug: Gefitinib<br>* Gefitinib once daily followed by MEDI4736<br>|
| Experimental: AZD9291 with a Seq. Switch to a MEDI4736<br>AZD9291 once daily followed by MEDI4736 | Drug: AZD9291<br>* AZD9291 once daily followed by MEDI4736<br>|
| Experimental: Selumetinib+Docetaxel with a Seq. Switch to a MEDI4736<br>Selumetinib twice daily + docetaxel, followed by MEDI4736 | Drug: Selumetinib+Docetaxel<br>* Selumetinib twice daily + docetaxel, followed by MEDI4736<br>|
| Experimental: Tremelimumab with a Seq. Switch to a MEDI4736<br>Tremelimumab every 4 weeks followed by MEDI4736 | Drug: Tremelimumab<br>* Tremelimumab every 4 weeks followed by MEDI4736<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Complete Response (CR) Rate | To assess the efficacy of various sequences. CR (per RECIST 1.1 as assessed by the local/site Investigator) is defined as the disappearance of all target and non-target lesions. Confirmed complete response rate (CR rate) is defined as the number (%) of patients with a confirmed overall response of CR and was based on the evaluable analysis set. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | To further assess the efficacy of various sequences. Objective response rate (ORR; per RECIST 1.1 as assessed by the site Investigator) is defined as the number (%) of patients with a confirmed overall response of CR or PR and was based on the evaluable analysis set. Per RECIST v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 2 years | 
| Progression-free Survival | Progression-free survival (per RECIST 1.1 as assessed by Investigator) is defined as the date of 1st dose of MEDI4736 until the date of objective disease progression or death. Progression of disease (PD) At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | Up to 2 years | 
| Duration of Response | Duration of response (DoR; per RECIST 1.1 as assessed by the site Investigator) will be defined as the time from the date of 1st documented response (which is subsequently confirmed) until the 1st date of documented progression or death in the absence of disease progression. | Within 12 months | 
| Overall Survival | To assess the efficacy of various sequences. In survival follow up at data cut off. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung cancer; NSCLC