A Study of Necitumumab and Abemaciclib in Participants With Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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This is medical research evaluating the safety and efficacy of two new medicines (necitumumab and abemaciclib), administered in combination in participants affected by a defined type of advanced lung cancer (stage IV non-small-cell lung cancer).

Official Title
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A Single-Arm, Multicenter, Phase 1b Study With an Expansion Cohort to Evaluate Safety and Efficacy of Necitumumab in Combination With Abemaciclib in Treatment of Patients With Stage IV Non-Small Cell Lung Cancer (NSCLC)

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

Intervention / Treatment
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* Drug: Necitumumab
* Drug: Abemaciclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed NSCLC Stage IV: Part A: NSCLC Stage IV (any type). Part B: NSCLC Stage IV (squamous and nonsquamous). 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 must have progressed after platinum-based chemotherapy AND have received a maximum of 1 other prior chemotherapy for advanced and/or metastatic disease OR must be judged by the physician as ineligible for further standard second-line chemotherapy. Prior treatment with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and anaplastic lymphoma kinase (ALK) inhibitors is mandatory in participants whose tumor has EGFR-activating mutations or ALK translocations. Prior targeting agents and neoadjuvant/adjuvant therapies are permitted with the exception of cyclin-dependent kinase (CDK)4/6-targeting agents or necitumumab. The participant has tumor tissue available for biomarker analyses. The participant has an Eastern Cooperative Oncology Group performance status score of 0-1. Have adequate organ functions. 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 cyclin-dependent kinase 4 and 6 (CDK4/6) - targeting agents or necitumumab is not permitted. Have a serious concomitant systemic disorder or significant cardiac disease. The participant has undergone major surgery or received any investigational therapy in the 30-days prior to study enrollment. The participant has undergone chest irradiation within 4 weeks prior to receiving study treatment. The participant has brain metastases that are symptomatic. History of arterial or venous thromboembolism within 3 months prior to study enrollment. Participants with a history of venous thromboembolism beyond 3 months prior to study enrollment can be enrolled if they are appropriately treated with low molecular weight heparin. The participant has active infection requiring systemic therapy. 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 abemaciclib, or any other contraindication to one of the administered treatments. The participant is pregnant or breastfeeding. 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 or an active non-infectious pneumonitis.

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 + Abemaciclib<br>Cohort 1 Part A: Necitumumab 800 mg administered intravenously (IV) on Days 1 and 8, followed by abemaciclib 100 mg given orally every 12 hours on Days 1 to 21. (21 day cycles.) Treatment may continue until discontinuation criterion is met. Cohort 2 Part A: Necitumumab 800 mg administered IV on Days 1 and 8, followed by abemaciclib 150 mg given orally every 12 hours on Days 1 to 21. Treatment may continue until discontinuation criterion is met. Cohort 3 Part A: Necitumumab 800 mg administered IV on Days 1 and 8, followed by abemaciclib 200 mg given orally every 12 hours on Days 1 to 21. Treatment may continue until discontinuation criterion is met. Part B (expansion cohort): Necitumumab 800 mg administered IV on Days 1 and 8, followed by abemaciclib 150 mg given orally every 12 hours on Days 1 to 21. Treatment may continue until discontinuation criterion is met. | Drug: Necitumumab<br>* Administered IV.<br>* Other names: LY3012211;Drug: Abemaciclib<br>* Administered orally.<br>* Other names: LY2835219;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Abemaciclib Dose Limiting Toxicities (DLTs) | A DLT was defined as one of the following adverse events (AEs), occurring in Cycle 1 if considered to be definitely, probably, or possibly related to necitumumab and abemaciclib: Grade 3 or 4 nonhematologic toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0), except for nausea, vomiting, diarrhea, or electrolyte disturbance. Grade 3 or 4 nausea, vomiting, or diarrhea that persists more than 2 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. | Baseline through Cycle 1 (Up to 21 Days) | 
| Progression Free Survival (PFS) Rate at 3 Months (Percentage of Participants With PFS at 3 Months) | PFS is defined as the time from baseline until first observation of progressive disease(PD) defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause.PD was at least 20% increase in sum of diameters of target lesions with reference being smallest sum on study and an absolute increase of at least 5 millimeter (mm) or unequivocal progression of non-target lesions,or 1 or more new lesions.If participant does not have complete baseline disease assessment,PFS time censored at date of randomization, regardless of whether or not objectively determined disease progression or death observed for participant.If participant was not known to have died or have objective progression as of data inclusion cutoff date for analysis, the PFS time censored at last adequate tumor assessment date.The use of new anticancer therapy prior to occurrence of PD resulted in censoring at the date of last radiographic assessment prior to initiation of new therapy. | Baseline to measured progressive disease or death due to any cause (3 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve Best Overall Tumor Response of Complete or Partial Response (Objective Response Rate [ORR]) | ORR was the percentage of participants achieving a best overall response 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 nontarget lesions, and no appearance of new lesions. PD was 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. Confidence intervals are based on Clopper-Pearson method. | Baseline to measured progressive disease or start of new anti-cancer therapy (up to 21 months) | 
| Pharmacokinetics (PK): Predose Concentration (Cmin) of Necitumumab | Predose necitumumab concentration data following doses of 800 mg administered Day 1 and 8 of a 3-week cycle as an intravenous (IV) infusion over 60 minutes. | Cycle 1, Day 8 (C1D8) and C2,3,5,7 D1: Predose | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Necitumumab | Maximum necitumumab concentration data following doses of 800 mg administered Day 1 and 8 of a 3-week cycle as an intravenous (IV) infusion over 60 minutes. | Cycle 1, Day 1 (C1D1): 0.25, 2,4,10 hours(h) post dose, C1D8: 0.25h post dose, Cycle 2, Day 1 (C2D1): 0.25, 2,4,10h post dose; C3,5,7 D1: 0.25h post dose | 
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib summary of LSN3106729 noncompartmental PK parameters after twice daily oral dose of Abemaciclib. | Cycle 1, Day 1 (C1D1): 0.25, 2,4,6,8,10 hours(h) post dose, C1D8: 0.25h post dose, C2D1: 0.25, 2,4,6,8,10h post dose; C3,5,7 D1: 0.25h post dose | 
| Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) From Zero to the Last Time Point (AUC[0-tlast]) Abemaciclib | Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) From Zero to the Last Time Point (AUC[0-tlast]) summary of LSN3106729 noncompartmental PK parameters after twice daily oral dose of Abemaciclib. (tlast = 10 hours) | Cycle 1, Day 1 (C1D1): 0.25, 2,4,6,8,10 hours(h) post dose | 
| Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) (Disease Control Rate [DCR]) | Disease Control Rate (DCR) is defined as the percentage of participants achieving a best overall response of stable disease (SD), PR, or CR. DCR used the same denominator as defined in ORR. Among participants counted in the denominator, the numerator counted those with a confirmed best tumor response of SD, PR, or CR per RECIST v1.1. Confidence intervals are based on Clopper-Pearson method. | Baseline to measured progressive disease or start of new anti-cancer therapy (up to 21 months) | 
| Overall Survival | Overall survival (OS) is defined as the time from the date of study enrollment to the date of death from any cause. For each participant who is not known to have died as of the data -inclusion cutoff date for a particular analysis, OS was censored for that analysis at the last known alive date. | Baseline to date of death from any cause (24 Months) |