Study Of CP-751,871 In Combination With Cisplatin And Gemcitabine In Chemotherapy-Naïve Patients With Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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CP 751,871 is a fully human monoclonal antibody against the Insulin-Like Growth Factor 1 Receptor (IGF-1R). Preclinical and clinical data indicate that CP 751,871 augments the anti-tumor activity of chemotherapy. This study will identify the Maximal Tolerated Dose of CP 751,871 (or the Maximal Feasible Dose) in combination with standard gemcitabine-cisplatin chemotherapy for the treatment of advanced Non-Small Cell Lung cancer.

Official Title
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Phase 1, Dose Escalation Study Of CP-751,871 In Combination With Cisplatin And Gemcitabine In Previously Untreated Patients With Advanced Non-Small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: CP-751,871
* Drug: Cisplatin
* Drug: Gemcitabine
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven diagnosis of Stage IIIB (N3 and/or T4) or Stage IV Non-Small Cell Lung Cancer in patients 18-year-old or older, with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 not amenable to curative surgery or radiation therapy and an adequate organ function (bone marrow, hepatic, renal, and cardiac) within 14 days prior to enrollment. Exclusion Criteria: Any prior treatment for Non-Small Cell Lung Cancer including chemotherapy, biologic response modifiers or therapy with any investigational agents. Patients with known brain metastases, spinal cord compression, uncontrolled superior vein cava syndrome or carcinomatous meningitis. Patients with gastrointestinal abnormalities including active gastrointestinal bleeding, pre-diabetes (pre-fasting glycemia > 120 g/dL and/or glycosylate haemoglobin level > 7.5%), known HIV or AIDS-related illness, significant active cardiac disease or receiving chronic steroid therapy or concurrent use of growth hormones or growth hormone inhibitors or aminoglycoside antibiotics should be excluded from the study.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: CP-751,871<br>* CP-751,871 at doses ranging from 6 to 20 mg/Kg on Day 1 of each 21-day cycle. CP-751,871 may be administered even after active comparators discontinuation, for a total number of 17 cycles (1 year).<br>Drug: Cisplatin<br>* Cisplatin 75* mg/m2 or 80* mg/m2, IV on Day 1 of each 21-day cycle up to 6 cycles. * 75 mg/m2 when in combination with pemetrexed, 80 mg/m2 when in combination with gemcitabine<br>Drug: Gemcitabine<br>* Gemcitabine 1250 mg/m2, IV on Days 1 and 8 of each 21-day cycle up to 6 cycles<br>Drug: Pemetrexed<br>* Pemetrexed 500 mg/m2, IV on Day 1 of each 21-day cycle up to 6 cycle<br>|

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 (DLT) | Cycle 1 figitumumab attributed: Grade (Gr) 4 neutropenia (absolute neutrophil count <500 cells/cubic millimeter [mm^3]) >=7 days, febrile neutropenia (Gr 3, fever >=38.5 degrees Celsius), neutropenic infection (Gr 3 neutropenia, infection); Gr 4 thrombocytopenia (platelet <25,000 cells/mm^3), Gr 3 thrombocytopenia >=7 days/bleeding; other Gr 3 not blood/bone marrow Common Terminology Criteria for Adverse Events bar gastrointestinal toxicity, treatment-managed hyperglycemia/fatigue, hypersensitivity; Gr 3-4 hyperglycemia despite treatment; fail to adequately recover to continue study treatment | Start of treatment up to end of Cycle 1, Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration at the End of Infusion (Cinf) for Figitumumab | Figitumumab pharmacokinetic (PK) data was analyzed using noncompartmental methods | Cycle 1 for dose escalation and Cycle 4 for dose expansion | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Figitumumab | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Figitumumab PK data was analyzed using noncompartmental methods | 0 (pre-dose), 1, 24, 72, 168, 336, 504 hr in Cycle 1 for dose escation and 0 (pre-dose), 1, 24, 72, 168, 336, 504 hr in Cycle 4 for expansion | 
| Minimum Observed Plasma Trough Concentration (Cmin) for Figitumumab | Concentration at the end of Cycle 4 | 0 (pre-dose) in Cycle 5 Day 1 | 
| Maximum Observed Plasma Concentration (Cmax) for Cisplatin | Cisplatin PK data was analyzed using noncompartmental methods. Plasma exposure parameters for cisplatin were analyzed in the absence (Cycle 1) and presence of (Cycle 2) figitumumab | 0 (pre-dose), 1.917, 2.5, 3, 4, 5, 24 hr on Cycle 1, Day 1 and Cycle 2, Day 1 for cisplatin 75 mg/m^2 and 0 (pre-dose), 0.917, 1.5, 2, 3, 4, 23 hr on Cycle 1, Day 1 and Cycle 2, Day 1 for cisplatin 80 mg/m^2 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Cisplatin | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Cisplatin PK data was analyzed using noncompartmental methods. Plasma exposure parameters for cisplatin were analyzed in the absence (Cycle 1) and presence (Cycle 2) of figitumumab | 0 (pre-dose), 1.917, 2.5, 3, 4, 5, 24 hr on Cycle 1, Day 1 and Cycle 2, Day 1 for cisplatin 75 mg/m^2 and 0 (pre-dose), 0.917, 1.5, 2, 3, 4, 23 hr on Cycle 1, Day 1 and Cycle 2, Day 1 for cisplatin 80 mg/m^2 | 
| Maximum Observed Plasma Concentration (Cmax) for Gemcitabine | Gemcitabine PK data was analyzed using noncompartmental methods. Plasma exposure parameters for gemcitabine were analyzed in the absence (Cycle) 1 and presence (Cycle 2) of figitumumab | 0 (pre-dose), 0.417, 1, 1.5, 2.5, 3.5 hr on Cycle 1, Day 1 and Cycle 2, Day 8 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Gemcitabine | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Gemcitabine PK data was analyzed using noncompartmental methods. Plasma exposure parameters for gemcitabine were analyzed in the absence (Cycle 1) and presence (Cycle 2) of figitumumab | 0 (pre-dose), 0.417, 1, 1.5, 2.5, 3.5 hr on Cycle 1, Day 1 and Cycle 2, Day 8 | 
| Maximum Observed Plasma Concentration (Cmax) for Pemetrexed | Pemetrexed PK data was analyzed using noncompartmental methods. Plasma exposure parameters for pemetrexed were analyzed in the absence (Cycle 1) and presence (Cycle 2) of figitumumab | 0, 0.167, 1.167, 2.167, 4.167, 6.167, 24.167 hr on Cycle 1, Day 1 and Cycle 2, Day 1 for pemetrexed 500 mg/m^2 | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Pemetrexed | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Pemetrexed PK data was analyzed using noncompartmental methods. Plasma exposure parameters for pemetrexed were analyzed in the absence (Cycle 1) and presence (Cycle 2) of figitumumab | 0, 0.167, 1.167, 2.167, 4.167, 6.167, 24.167 hr on Cycle 1, Day 1 and Cycle 2, Day 1 for pemetrexed 500 mg/m^2 | 
| Percentage of Participants With Objective Response or Prolonged Stabilization | Percentage of participants with a confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD) for at least 12 weeks on study according to Response Evaluation Criteria in Solid Tumors (RECIST). Participants with non measurable disease were considered having a clinical benefit response only in the case of achievement of CR. Participants who developed early progressive disease post dosing and prior to response evaluation were considered to have progressed on study. Confirmed responses were those that persisted on repeat imaging >= 4 weeks after initial response | Screening, from Cycle 2 onwards computerized tomography (CT) scan done within 7-10 days prior to next cycle (approximately Day 15 of each cycle), follow-up (30 days after last study treatment dose) | 
| Progression-Free Survival (PFS) | Time from the date of enrollment to date of documented disease progression, or death due to any cause | Screening, from Cycle 2 onwards CT scan done within 7-10 days prior to next cycle (approximately Day 15 of each cycle), follow-up (30 days after last study treatment dose) | 
| Duration of Response (DR) | For responding patients (CR and PR): Time from the date that CR or PR was first recorded to the date of the first documentation of progression | Screening, from Cycle 2 onwards CT scan done within 7-10 days prior to next cycle (approximately Day 15 of each cycle), follow-up (30 days after last study treatment dose) | 
| Percentage of Participants With Blood Anti-drug Antibody (ADA) Specific for Figitumumab | Percentage of participants with positive total or neutralizing anti-drug antibody (ADA) for figitumumab | 30 min prior to figitumumab infusion in Cycle 1 and Cycle 4, end of study, fourth follow up visit (approximately 150 days after last dose) | 
| Serum Total Circulating Insulin-like Growth Factor (IGF-1) Levels | To monitor serum total IGF-1 levels as a potential pharmacodynamic response to figitumumab treatment | Baseline, Day 8, end of study |