A Study in Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the hypothesis that cixutumumab given in combination with cisplatin and pemetrexed is superior to cisplatin and pemetrexed as first-line therapy for patients with advanced nonsquamous non-small cell lung carcinoma (NSCLC).

Official Title
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An Open-label, Multicenter, Randomized Phase 2 Study Evaluating the Safety and Efficacy of Cisplatin and Pemetrexed With or Without Cixutumumab as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small Cell Lung Carcinoma

Conditions
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Non-Small-Cell Lung Carcinoma

Intervention / Treatment
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* Drug: Pemetrexed
* Drug: Cisplatin
* Drug: Cixutumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has histologically or cytologically confirmed, nonsquamous (adenocarcinoma/large cell or other) NSCLC. The participant has Stage IV disease at the time of study entry. Participants with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 14 days prior to randomization, or after surgical resection performed at least 28 days prior to randomization. The participant may have no evidence of Grade 1 (or greater) Central Nervous System (CNS) hemorrhage based on pretreatment scans(performed within 21 days before randomization). The participant has measurable or nonmeasurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 guidelines. The participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. If prior adjuvant or neoadjuvant chemotherapy, the last dose of adjuvant or neoadjuvant treatment was administered at least 6 months prior to randomization. The participant has adequate bone marrow reserve, and renal and hepatic function The participant has fasting serum glucose less than or equal to 125 mg/dL, and hemoglobin A1C less than or equal to 6%. Females with reproductive potential: Must have a negative serum or urine pregnancy test within 7 days prior to the first dose of any study drug. Males and females with reproductive potential: Must agree to use medically approved contraceptive precautions during the study and for 6 months following the last dose of any study drug. The participant has the ability to understand and the willingness to sign a written informed consent form. Previous radiation therapy is allowed to less than 25% of the bone marrow, but should have been limited and must not have included whole pelvis radiation. The participant has archived tumor tissue available for analysis (can be either primary tumor or metastases). The participant has an estimated life expectancy of at least 12 weeks. Exclusion Criteria: Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Participants who have squamous histology. The participant's tumor fully or partially contains Small Cell Lung Cancer (SCLC). The participant has leptomeningeal disease. The participant is currently or has previously received chemotherapy for advanced (Stage IV) NSCLC. The participant has a history of treatment with other agents targeting the Insulin-like or Epidermal Growth factor receptors. Participants who have received prior Pemetrexed treatment. The patient has a known allergy/history of hypersensitivity reaction to any of the treatment components. The participant has diabetes mellitus as defined by being treated with glucose lowering medications in the past 3 months prior to enrollment. The participant has an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parenteral antibiotics, symptomatic congestive heart failure, uncontrolled hypertension, clinically significant cardiac arrhythmia,or psychiatric/social situations that would limit compliance with study requirements. The participant has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy. The participant has undergone major surgery within 28 days prior to randomization. The participant has received a prior autologous or allogeneic organ or tissue transplantation. The participant is pregnant or lactating. The participant has a history of another primary cancer, with the exception of the following: curatively resected nonmelanomatous skin cancer, curatively treated carcinoma in situ, or other primary solid tumor treated with curative intent and no known active disease present and no treatment administered during the last 5 years. The participant has superior vena cava syndrome contraindicating hydration. The participant has current clinically-relevant coronary artery disease (New York Heart Association III or IV) or uncontrolled congestive heart failure. The participant has any Grade 2 (or greater) peripheral neuropathy. The participant has clinically significant third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry. The participant is unable to interrupt aspirin or other nonsteroidal anti-inflammatory agents, other than an aspirin dose less than or equal to 1.3 grams per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam). The participant is unwilling or unable to take premedications (folic acid, vitamin B12, or corticosteroids) required by the pemetrexed label. The participant has received a recent (within 30 days of enrollment) or is receiving concurrent yellow fever vaccination.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pemetrexed + Cisplatin + Cixutumumab<br>Induction Treatment: Pemetrexed 500 mg/m^2 plus cisplatin 75 mg/m^2 plus cixutumumab 20 mg/kg given intravenously (IV) on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for patients with significant tumor size reduction, after sponsor approval. Maintenance Therapy: Pemetrexed 500 mg/m^2 plus cixutumumab 20 mg/kg given IV every 21 days until progression of disease, unacceptable toxicity, or another withdrawal criterion is met. | Drug: Pemetrexed<br>* Administered intravenously (IV)<br>* Other names: LY231514;Drug: Cisplatin<br>* Administered IV<br>Drug: Cixutumumab<br>* Administered IV<br>* Other names: LY3012217;|
| Active Comparator: Pemetrexed + Cisplatin<br>Induction Treatment: Pemetrexed 500 mg/m^2 plus cisplatin 75 mg/m^2 given intravenously (IV) on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for patients with significant tumor size reduction, after sponsor approval. Maintenance Therapy: Pemetrexed 500 mg/m^2 given IV every 21 days until progression of disease, unacceptable toxicity, or another withdrawal criterion is met. | Drug: Pemetrexed<br>* Administered intravenously (IV)<br>* Other names: LY231514;Drug: Cisplatin<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from date of randomization until the date of disease progression, or death from any cause, whichever was first. Disease progression was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. Participants without documentation for disease progression or death were censored at the date of last tumor assessment. The PFS was estimated following the Kaplan-Meier method. | Randomization Date to Disease Progression or Death From Any Cause Up to 18.3 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving an Objective Response Rate (ORR) | The ORR is the percentage of all participants with Partial Response (PR) or Complete Response (CR) according to RECIST v1.1. Disease progression was defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. ORR is confirmed best overall tumor response of CR and PR. CR was defined as the disappearance of all target and non-target lesions; PR defined as a >30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD. | Randomization to Disease Progression Up to 18.3 Months | 
| Overall Survival (OS) | Overall survival is defined as the time from the 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 will be censored on the last date the participant is known to be alive. OS was estimated using the Kaplan-Meier method. | Randomization Date to Death From Any Cause Up to 20 Months | 
| Duration of Response (DOR) | Duration of response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the criteria for PD is met, or death, is objectively documented. DOR was estimated using the Kaplan-Meier method. Disease progression was assessed via RECIST version 1.1, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing non-target lesions | Time from Response to Disease Progression or Death from Any Cause Up to 20 Months | 
| Time to Progressive Disease (TTPS) | TTPS was defined as the time from the date of randomization until the date of disease progression. Disease progression was assessed via RECIST version 1.1, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing non-target lesions.TTPS was estimated using the Kaplan-Meier method. | Randomization Date to Disease Progression Up to 18.3 Months | 
| Time to Worsening of Symptoms as Measured by Lung Cancer Symptom Scale (LCSS) Score | TTPS was defined as the time from the date of randomization until the date of worsening of symptoms as measured by Lung Cancer Symptom Scale (LCSS) score. Symptomatic progression was defined as an increase (worsening) of the Average Symptomatic Burden Index (ASBI) that is, the mean of the six major lung cancer specific symptom scores of the LCSS patient scale - ranging from 0 to 100 where higher score indicates worst outcome). For each participant, the maximum improvement over baseline score was calculated for each of the 9 LCSS items, ASBI and LCSS total score. Participants without event are censored at the date of the last LCSS assessment. TTPS was estimated using the Kaplan-Meier method. | Time to worsening of symptoms as measured by LCSS score Up to 18.3 Months | 
| Change in Tumor Size (CTS) | CTS was measured by percentage change of tumor size at the end of Cycle 2 comparing to baseline tumor size. | Change from baseline measurement to the end of Cycle 2, average of 42 days | 
| Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Cixutumumab, Cycle 1 (First Infusion) and Cycle 4 (Fourth Infusion) |  | First Infusion: [Prior to Infusion (of Cycle1): 1, 72, 168, 336 hours(hrs) and 504 hrs (i.e. Prior to Infusion of Cycle 2)] and Fourth Infusion; [Prior to Infusion (of Cycle 4),1,24,72,120,168,240,336 hrs and 504 hrs (i.e. Prior to Infusion of Cycle 5)] | 
| PK: Area Under the Concentration Time Curve (AUC[0-inf]) of Cixutumumab, Cycle 1 (i.e. First Infusion) |  | Prior to Infusion (of Cycle 1), 1, 72, 168, 336 hrs and 504 hrs (i.e. Prior to Infusion of Cycle 2) | 
| PK: Area Under the Concentration Time Curve During 1 Dosing Interval (i.e. 504 hr, AUC(0-tau) of Cixutumumab, Cycle 4 (i.e. Fourth Infusion) |  | Prior to Infusion (of Cycle 4), 1, 24, 72, 120, 168, 240, 336 hrs and 504 hrs (i.e. Prior to Infusion of Cycle 5) | 
| Pharmacodynamics (PD) Markers: Free Insulin-like Growth Factor-I (IGF-I, Total IGF-I, and IGF Binding Proteins (IGFBP-3) | Blood samples for the determination of PD marker concentrations were collected at the specified time points for all participants. Analysis of the following markers include free IGF-I, total IGF-I, and IGFBP-3. | Preinfusion, Cycle 2, Cycle 4, Cycle 8, Postinfusion, 30-Day Follow-Up | 
| Immunogenicity of Cixutumumab |  | Preinfusion, Cycle1(C1): 1, 72, 168, 240, 336 hours(hrs); C2 and C3: 1, 168, 336 hrs; C4: 1, 24,72,120,168, 240, 336, 504 hrs, Postinfusion; 30 Day Follow Up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung cancer, advanced, non-small cell