A Study of the Combination of Necitumumab (LY3012211) and Pembrolizumab (MK3475) in Participants With NSCLC

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and efficacy of the combination of necitumumab with pembrolizumab in participants with stage IV non-small cell lung cancer (NSCLC).

Official Title
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An Open-Label, Multicenter, Phase 1b Study With an Expansion Cohort to Evaluate Safety and Efficacy of the Combination of Necitumumab With Pembrolizumab in Patients With Stage IV Non-Small Cell Lung Cancer

Conditions
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Stage IV Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Necitumumab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has Stage IV NSCLC. Part A: NSCLC Stage IV (any type) Part B: NSCLC Stage IV (squamous and nonsquamous) Part C: NSCLC Stage IV in Japanese participants (squamous and nonsquamous) The participant must have progressed after 1 platinum-based chemotherapy regimen for Stage IV NSCLC. Prior therapy with VEGF/VEGFR targeting agents is permitted. Prior neoadjuvant/adjuvant therapy is permitted. Prior treatment with EGFR-TKI and ALK inhibitors is mandatory in participants with NSCLC whose tumor has EGFR-activating mutations or ALK translocations, respectively. Measurable disease at the time of study entry as defined by Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The participant has evaluable tumor tissue available for biomarker analyses. The participant has adequate organ function. Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1. Exclusion Criteria: The participant is currently enrolled in a clinical trial involving an investigational product or non-approved use of a drug or device. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 monoclonal antibody. Have a serious concomitant systemic disorder or significant cardiac disease. The participant has undergone major surgery or received anti-cancer monoclonal antibody therapy in the 30-days prior to study enrollment. The participant has undergone chest irradiation within 2 weeks prior to receiving study treatment. The participant has brain metastases that are symptomatic. The participant has a history of arterial thromboembolism event (ATE) or venous thromboembolism event (VTE) within 3 months prior to study enrollment. Participants with history of VTE beyond 3 months prior to study enrollment can be enrolled if they are appropriately treated with low molecular weight heparin. The participant has a known allergy / history of hypersensitivity reaction to any of the treatment components, including any ingredient used in the formulation of necitumumab or pembrolizumab, or any other contraindication to one of the administered treatments. The participant has a concurrent active malignancy. Previous history of malignancy is permitted, provided that the participant has been free of disease for ≥3 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin, preinvasive carcinoma of the cervix, or any cancers that in the judgment of the investigator and sponsor may not affect the interpretation of results (for example, prostate, bladder). History of interstitial lung disease, pneumonitis, autoimmune disease or syndrome that requires steroids or immunosuppressive agents. The participant has active infection requiring systemic therapy, including active tuberculosis or known history of infection with the human immunodeficiency virus (HIV 1/2 antibodies), or hepatitis B (e.g., HBsAg reactive) and/or C virus (e.g., HCV RNA [qualitative] is detected). The participant has an active autoimmune disease or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. The participant has received a live vaccine within 30 days prior to the first dose of trial treatment.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Necitumumab + Pembrolizumab<br>Part A Cohort 1: 600 mg Necitumumab + 200 mg Pembrolizumab: Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 600 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in participants with Stage IV NSCLC (all histologies). Part A Cohort 2, Part B and Part C: 800mg Necitumumab + 200mg Pembrolizumab: Participants received 200 mg pembrolizumab absolute dose by intravenous (IV) infusion on Day 1 of 21 days cycles followed by 800 mg necitumumab absolute dose by IV infusion on Days 1 and 8 of 21 days cycles in Part A cohort 2 participants with any histology, Part B and C participants with Stage IV NSCLC of squamous and nonsquamous histology. Part C were Japan participants. Part C were Japan participants. | Drug: Necitumumab<br>* Administered IV<br>* Other names: LY3012211;Drug: Pembrolizumab<br>* Administered IV<br>* Other names: MK3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) in Part A and Part C | A dose limiting toxicity (DLT) was defined as an adverse event (AE) during the first 21 days that was possibly related to the study drug and fulfilled any of the following criteria using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0: Grade 3 or 4 nonhematologic toxicity, Grade 4 nausea, vomiting, or diarrhea that persists more than 3 days despite maximal supportive intervention, Grade 3 thrombocytopenia with bleeding requiring transfusion, Grade 4 thrombocytopenia with or without bleeding, Grade 4 neutropenia that persists more than 5 days, Grade 3 or 4 neutropenia with fever, Grade ≥3 skin toxicity despite best supportive care with some exceptions, if a total at least 75% of the planned dose for both agents cannot be administered in the first cycle due to toxicity, prolonged delay (>2 weeks) in initiating cycle 2 due to treatment-related toxicity and Grade 5 toxicity. | Baseline through Cycle 1 (21 day cycles) | 
| Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Response Rates [ORR]) in Part A and Part B | ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. Progressive disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 16 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Response Rates [ORR]) in Part A Cohort 2, Part B and Part C | ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 40 Months) | 
| Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab in Part A, Part B and Part C | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab. | Predose sample (within 1 hour before infusion) and postdose sample (within 10 min after infusion) on Day 1 at Cycles 1, 2, 4, 6, 8; 30 days post treatment discontinuation | 
| Number of Participants With Anti-Necitumumab Antibodies in Part A, Part B and Part C | Result is considered as treatment emergent anti-necitumumab antibody positive if postbaseline titer = 4*baseline titer for baseline titer > 0 or if postbaseline titer >= 20 for samples with antibody not detected. | Predose Cycle 1 Day 1 through Predose Cycle 8 Day 1 (21 Day Cycles) | 
| Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate [DCR]) in Part A Cohort 2 and Part B | Disease control rate (DCR) is the percentage of participants with a best overall response of CR, PR or SD as defined by RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Up To 16 Months) | 
| Duration of Response (DoR) in Part A Cohort 2 and Part B | DOR was defined only for responders (participants with confirmed CR or PR). It was measured from the date of first evidence of a confirmed CR or PR to the date of objective progression or the date of death due to any cause, whichever was earlier. | Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 16 Months) | 
| Progression Free Survival (PFS) in Part A Cohort 2 and Part B | PFS was defined as the time from the date of first dose of study drug until first observation of objective (radiographically documented) PD as defined by RECIST v1.1 or death from any cause, whichever comes first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Baseline to Measured Progressive Disease or Death Due to Any Cause (Up To 16 Months) | 
| Overall Survival (OS) in Part A Cohort 2, Part B | OS duration was measured from the date of first dose of study drug (necitumumab and/or pembrolizumab) to the date of death from any cause. | Baseline to Death from Any Cause (Up To 16 Months) |