A Study of Paclitaxel/Carboplatin With or Without Olaratumab (IMC-3G3) in Previously Untreated Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The purpose of this study is to determine if participants with untreated locally advanced or metastatic non-small cell lung cancer have a better outcome when treated with olaratumab in combination with paclitaxel/carboplatin then when treated with paclitaxel/carboplatin alone.

Detailed Description
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The primary objective of this study is to evaluate the progression-free survival (PFS) in previously untreated participants with Stage IIIB/IV non-small cell lung cancer (NSCLC) treated with olaratumab plus paclitaxel and carboplatin versus paclitaxel and carboplatin in the first-line metastatic setting.

Official Title
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A Randomized Phase 2 Study of Human Anti-PDGFRα Monoclonal Antibody (IMC-3G3) With Paclitaxel/Carboplatin or Paclitaxel/Carboplatin Alone in Previously Untreated Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Biological: Olaratumab
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participants has histologically or cytologically confirmed Non-Small Cell Lung Cancer (NSCLC)Stage IIIB with effusion. Mixed Non-Small Cell Lung Cancer (NSCLC) tumors will be categorized by the predominant cell type. Primary or metastatic site may be used for histology For squamous cell histology or for centrally located mediastinal masses (< 3 cm from the carina) identified by computed tomography scan (CT) or chest x-ray, the participant must undergo a magnetic resonance imaging (MRI) of the chest or I.V. contrast CT scan within 3 weeks of randomization, to exclude major airway or blood vessel invasion (in the investigator's opinion) by cancer The participant has measurable disease (Tumors within a previously irradiated field will be designated as nontarget lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy The participant's Eastern Cooperative Oncology Group (ECOG) performance status is 0-1 The participant's age at the time of study entry is ≥ 18 years The participant has adequate hematologic function as defined by an absolute neutrophil count (ANC) ≥ 1500/μL, hemoglobin ≥ 9.5 g/dL, and a platelet count ≥ 100,000/μL obtained within 2 weeks prior to randomization The participant has adequate hepatic function as defined by a total bilirubin ≤ 1.5 mg/dL, and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 × the upper limit of normal (ULN), or ≤ 5 × the ULN in the presence of known liver metastases) The participant has adequate renal function as defined by serum creatinine ≤ 1.5 × the institutional ULN. If creatinine is above the ULN, the patient's creatinine clearance (CrCl) is ≥ 60 mL/min The participant has urinary protein ≤ 1+ on dipstick or routine urinalysis; if urine dipstick or routine analysis is ≥ 2+, a 24-hour urine for protein must demonstrate < 1 g of protein in 24 hours to allow participation The participant has adequate coagulation function, as defined by international normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 5 seconds above ULN if not receiving anticoagulation therapy. Participants on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin, have therapeutic INR, no active bleeding (defined as within 14 days randomization) and no pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels or known varices) Because the teratogenicity of Olaratumab is not known, women of childbearing potential (WOCBP) and sexually active males must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to randomization and for the duration of study participation The participant has resolution to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4 (NCI-CTCAE v 4.02) of all clinically significant toxic effects of prior locoregional therapy, surgery, chemoembolization, or other anticancer therapy. The exceptions for such effects are events that pertain to the lab values found elsewhere in these inclusion criteria. (For example, criterion # 6 states that a patient with hemoglobin ≥ 9.5 g/dL is considered eligible, even though NCI-CTCAE v 4.02 defines this value as Grade 2 anemia.) The participant has a life expectancy of ≥ 3 months The participant has provided signed informed consent Exclusion Criteria: The participant has untreated central nervous system (CNS) metastases. Participants are eligible if they are clinically stable, off all steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, stereotactic radiosurgery)ending at least 2 weeks prior to randomization, or after surgical resection performed at least 4 weeks prior to randomization The participant has radiologically documented evidence of major blood vessel invasion or encasement by cancer, or of intratumor cavitation The participant received prior systemic chemotherapy or biologic therapy (eg erlotinib) for Stage IIIB/IV NSCLC outside of the adjuvant setting. Participants who received prior cytotoxic chemotherapy or biologic therapy in the adjuvant setting will not be excluded based on such therapy The participant has a history of another primary cancer, with the exception of a) curatively resected nonmelanomatous skin cancer b) curatively treated cervical carcinoma in situ c)other primary solid tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years prior to randomization The participant is receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, chemo-embolization, targeted therapy, or an investigational agent The participant has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements The participant has an uncontrolled thrombotic or hemorrhagic disorder The participant has a history of gross hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months of randomization The participant has a serious non-healing wound, ulcer, or bone fracture within 28 days prior to randomization The participant has undergone major surgery within 28 days prior to randomization The participant has received adjuvant chemotherapy 21 days prior to randomization or has participated in clinical trials of experimental agents within 28 days prior to randomization The participant has an elective or a planned major surgery to be performed during the course of the trial The participant has peripheral neuropathy ≥ Grade 2 NCI-CTCAE v 4.02 The participant has known human immunodeficiency virus (HIV) positivity The participant, if female, is pregnant or lactating The participant has received previous therapy with any agent that targets platelet derived growth factor (PDGF) or platelet derived growth factor receptor (PDGFR) The participant has a known allergy to any of the treatment components The participant has a history of allergic reactions attributed to compounds of chemical or biologic composition similar to that of Olaratumab

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Paclitaxel + Carboplatin<br>(Initial 4-6 cycles) Paclitaxel 200 milligram/square meter (mg/m2) over 3 hrs (Day 1) Carboplatin Area Under Concentration (AUC)=6 (Day 1) of each 21-day cycle (Initial 4-6 cycles) Paclitaxel 200 mg/m2 over 3 hrs (Day 1) Carboplatin AUC=6 (Day 1) of each 21-day cycle Participants who experience progressive disease may cross over to olaratumab monotherapy. | Drug: Paclitaxel<br>* 200 mg/m2 is then administered IV over 3 hours<br>Drug: Carboplatin<br>* AUC=6 administered IV over 30 minutes on Day 1 of each 3-week cycle for a maximum of six cycles. Once the maximum of 6 cycles of carboplatin are reached the participant may continue on olaratumab maintenance for up to 12 months.<br>|
| Experimental: Olaratumab + Paclitaxel + Carboplatin<br>(Initial 4-6 cycles) Olaratumab 15 milligrams/kilogram (mg/kg) over 30 mins (Days 1 and 8) plus Paclitaxel 200 mg/m2 over 3 hrs (Day 1) Carboplatin AUC=6 (Day 1) of each 21-day cycle Participants can remain on study after completing chemotherapy and receive olaratumab monotherapy on Days 1 and 8, provided there is ongoing evidence of clinical benefit. | Biological: Olaratumab<br>* 15 mg/kg of olaratumab on Days 1 and 8 of each 21-day cycle, administered intravenously (IV) at 25 milligram/minute (mg/min), with a minimum infusion time of 30 minutes.<br>* Other names: IMC-3G3;Drug: Paclitaxel<br>* 200 mg/m2 is then administered IV over 3 hours<br>Drug: Carboplatin<br>* AUC=6 administered IV over 30 minutes on Day 1 of each 3-week cycle for a maximum of six cycles. Once the maximum of 6 cycles of carboplatin are reached the participant may continue on olaratumab maintenance for up to 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from the day of randomization to the first evidence of progression by RECIST version 1.1, or death from any cause. Participants who died without a reported prior progression were considered to have progressed on the day of their death. Participants who did not progress and were subsequently lost to follow-up had their data censored at the day of their last tumor assessment. If there was no radiologic assessment at baseline or post baseline, participants were censored at the date of randomization. If death or progressive disease (PD) occurred after 2 or more consecutive missing radiographic visits, censoring occurred at the date of the last radiographic visit prior to the missed visits. | Baseline to Measured PD or Death From Any Cause (Up to 31 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. | Baseline to Study Completion (Up to 43 Months) | 
| Safety and Tolerability of Olaratumab Administered at a More Rapid Rate (25mg/Min With Minimum Infusion Time of 30 Minutes), Determined by Number of Participants With Treatment Related Adverse Events |  | Up to 43 Months | 
| Overall Survival (OS) | Overall survival is defined as the time from date of randomization to the date of death from any cause. If the participant is alive at the end of the follow-up period or is lost to follow-up, OS was censored on the last date the participants is known to be alive. | Baseline to Death From Any Cause (Up to 31 Months) | 
| Percentage of Participants Who Achieve Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) Objective Tumor Response Rate (ORR) | The ORR is equal to the percentage of participants achieving a best overall response of partial response or complete response (PR + CR), according to RECIST version 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes must have reduction in short axis to <10 millimeter (mm) and normalization of tumor marker level of non-target lesions; PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions; PD was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir; Stable Disease (SD) was defined as small changes that did not meet above criteria. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR/total number of participants)*100. | Baseline to Measured PD or Study Discontinuation (Up to 31 Months) | 
| Median Duration of Response | The duration of overall response is measured from the time measurement criteria are first met for Complete Response (CR)/Partial Response (PR) (whichever is first recorded) until the first date that the criteria for PD are met (taking as a reference for PD the smallest measurement recorded since the treatment started), initiation of other/additional antitumor therapy is first reported, or death, is objectively documented. | First Criteria Met for CR or PR to Measured PD Start of Other Antitumor Therapy or Death From Any Cause (Up to 31 Months) | 
| Pharmacodynamics of Olaratumab | Pharmacodynamics of Olaratumab was determined by analysis of pharmacodynamic markers vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). | Cycle 1: Days 1, 8, and 15 pre- and post-infusion of Olaratumab; Cycles 2-6: day 1 only, pre- and post-infusion of Olaratumab | 
| Percentage of Participants With Anti-Olaratumab Antibodies | Participants with Treatment Emergent (TE) anti-olaratumab antibodies were participants with a 4-fold increase (2 dilutions) increase over a positive baseline antibody titer or for a negative baseline titer, a participant with an increase from the baseline to a level of 1:20. | Baseline to Study Completion (Up to 8 Months) | 
| Pharmacokinetics (PK) - Area Under the Curve (AUC) 0-168 of Olaratumab | AUC(0-168) = area under the concentration versus time curve from time zero to 168 hours post dose. | Cycle 3, Day 1: Predose, 30 minutes (min), 1.5 hours (hrs), 24,48,96,168 Hrs Post Dose | 
| PK - Maximum Concentration (Cmax) of Olaratumab |  | Cycle 3, Day 1: Predose, 30 min, 1.5 hrs, 24,48,96,168 Hrs Post Dose | 
| PK - Half-Life (t1/2) of Olaratumab |  | Cycle 3, Day 1: Predose, 30 min, 1.5 hrs, 24,48,96,168 Hrs Post Dose | 
| PK - Clearance (Cl) of Olaratumab |  | Cycle 3, Day 1: Predose, 30 min, 1.5 hr, 24,48,96,168 Hrs Post Dose | 
| PK - Steady State Volume of Distribution (Vss) of Olaratumab |  | Cycle 3, Day 1: Predose, 30 min, 1.5 hrs, 24,48,96,168 Hrs Post Dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung neoplasms, IMC-3G3, carboplatin, paclitaxel, PDGFr