Optimal Sequencing of Pembrolizumab (MK-3475) and Standard Platinum-based Chemotherapy in First-Line NSCLC

Study Overview
=================
Brief Summary
-----------------
This is a multicenter randomized phase II to determine if the administration of standard platinum-based chemotherapy before MK-3475 in with Chemotherapy naive stage IV Non-small Cell Lung Cancer (NSCLC) will improve the overall response rate (ORR) compared to MK-3475 administered before chemotherapy. Patients will be given Pembrolizumab as maintenance up to 2 years: Carboplatin and paclitaxel or pemetrexed every 3 weeks x 4 cycles followed by pembrolizumab every 3 weeks for up to 2 years. Pembrolizumab every 3 weeks x 4 cycles followed by carboplatin and paclitaxel or pemetrexed every 3 weeks x 4 cycles followed by pembrolizumab every 3 weeks for up to 2 years.

Detailed Description
-----------------
While a genotype-directed strategy has been established as effective in treatment selection for patients with advanced NSCLC, only a minority of patients at this time will have a readily identifiable actionable molecular target. Furthermore, genotype-directed therapy has not been validated for patients with squamous cell carcinoma of the lung. Therefore, the majority of patients with advanced NSCLC will continue to rely on standard platinum-based doublet chemotherapy. Given the plateau in effectiveness of this approach, novel treatment strategies are clearly warranted.

Official Title
-----------------
Randomized Phase II Trial Evaluating the Optimal Sequencing of PD-1 Inhibition With Pembrolizumab (MK-3475) and Standard Platinum-based Chemotherapy in Patients With Chemotherapy Naive Stage IV Non-small Cell Lung Cancer

Conditions
-----------------
Non-Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: MK-3475
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Pemetrexed


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be ≥ 18 years of age on day of signing informed consent. Have a life expectancy of at least 3 months. Have a histologically or cytologically confirmed diagnosis of stage IV NSCLC. Have a performance status of 0 or 1 on the ECOG. Have a measurable disease based on RECIST 1.1. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of tumor lesion. In patients with non-squamous non-small cell lung cancer, investigators must be able to produce source documentation of the EGFR mutation status or ALK translocation status. Demonstrate adequate organ function. Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours. Female parents of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile. Male patients must agree to use an adequate method of contraception. Patients with sensitizing EGFR mutation or ALK rearrangement must have progressed on an appropriate tyrosine kinase inhibitor (TKI) Exclusion Criteria: Has received prior treatment with chemotherapy or biologic therapy for stage IV NSCLC. Is currently participating in or has participated in a study of an investigational agent or using an investigational device. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy. Has had a prior mAb within 4 weeks prior to study Day 1 or who has not recovered from adverse events due to agents administered more than 4 weeks earlier. Has had prior chemotherapy or radiation. Has a known additional malignancy that is progressing or requires active treatment. Has known active CNS metastases and/or carcinomatous meningitis. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. Has an active infection requiring systemic therapy. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial. Has known psychiatric or substance abuse disorders. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody. Has a known history of HIV. Has known active Hepatitis B or Hepatitis C. Has received a live vaccine within 30 days prior to the planned first dose of study therapy. Has a known history of active TB. Hypersensitivity to pembrolizumab or any of it's excipients.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A<br>For Squamous Carcinoma Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles Paclitaxel 200 mg/m2 IV day 1 every 21-days for up to 4 cycles OR For Non-squamous Carcinoma Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles Pemetrexed 500 mg/m2 IV day 1 every 21-days for up to 4 cycles | Drug: Carboplatin<br>* Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)<br>* Other names: Taxol;Drug: Pemetrexed<br>* Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)<br>* Other names: Alimta;|
| Active Comparator: Arm B<br>MK-3475 200 mg/m2 IV every 21-days for up to 4 cycles Patients with CR, PR, or SD by irRC will then be treated with: For Squamous Carcinoma: Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles Paclitaxel 200 mg/m2 IV day 1 every 21-days for up to 4 cycles OR For Non-squamous Carcinoma Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles Pemetrexed 500 mg/m2 IV day 1 every 21-days for up to 4 cycles | Drug: MK-3475<br>* Dose frequency of Q3W, Day 1 of each cycle<br>* Other names: Pembrolizumab;Drug: Carboplatin<br>* Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)<br>* Other names: Taxol;Drug: Pemetrexed<br>* Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)<br>* Other names: Alimta;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Per RECIST 1.1 | The primary objective of this randomized phase II trial to determine the overall response rate (ORR per RECIST 1.1) in Chemotherapy naive patients with stage IV NSCLC after the administration of standard platinum-based chemotherapy before MK-3475 (arm A) and administration of MK-3475 administered before standard platinum-based chemotherapy (arm B). Overall Response (OR) = CR + PR. | 18 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Progression-Free Survival (PFS) Per RECIST 1.1 | To compare the progression-free survival (PFS) per RECIST 1.1 in previously untreated patients with advanced NSCLC treated with first line carboplatin-based chemotherapy followed by MK-3475 to patients treated with MK-3475 prior to first-line carboplatin-based chemotherapy. | 24 Months | 
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | To characterize the adverse events related to MK-3475 by frequency, type and grade in patients with Chemotherapy naive advanced NSCLC based on the sequence of administration with first-line chemotherapy. A count of participants experiencing an adverse event is summarized here, the detailed summary is in the adverse events section of this report. | 24 Months |