A Study of the Effect of R1507 in Combination With Tarceva (Erlotinib) on Progression-Free Survival in Patients With Stage IIIb/IV Non-Small Cell Lung Cancer (NSCLC) Having Received Tarceva Monotherapy.

Study Overview
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Brief Summary
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This single arm study in patients with advanced Stage IIIb/IV NSCLC who have progressive disease after deriving clinical benefit (defined as response or stable disease after 12 weeks) from second or third line Tarceva monotherapy will determine the proportion of patients with progression-free survival at 12 weeks following combination therapy with R1507 and Tarceva. Patients will receive R1507 (9mg/kg iv) weekly in combination with Tarceva (150mg oral daily) for up to a maximum of 24 months. Other disease-related endpoints including overall survival, objective response rate, time to response, time to progressive disease and duration of response will also be evaluated. The anticipated time on study treatment is 1-2 years, and the target sample size is <100 individuals.

Official Title
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An Open-label Study to Determine the Effect of R1507 Plus Tarceva (Erlotinib) on Progression-free Survival in Patients With Stage IIIB/IV Non-small Cell Lung Cancer (NSCLC) With Progressive Disease After Clinical Benefit to Second or Third Line Tarceva Monotherapy.

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: RG1507
* Drug: erlotinib [Tarceva]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male or female patients >=18 years with histologically documented inoperable, locally advanced or metastatic (stage IIIB or IV) NSCLC; currently receiving Tarceva monotherapy and having failed at least one standard chemotherapy regimens; prior response or stable disease 12 weeks from start of Tarceva; documented progressive disease at enrollment; measurable disease according to the RECIST criteria; ECOG performance status 0-2; life expectancy >12 weeks. Exclusion Criteria: patients with active CNS lesions; prior treatment with agents acting via IGF-1R inhibition or EGFR targeting; administration with high doses of systemic corticosteroids; radiotherapy in the 4 weeks prior to study start; surgery or significant traumatic injury with in the last 2 weeks prior to study start.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: RG1507<br>* iv 9mg/kg weekly<br>Drug: erlotinib [Tarceva]<br>* 150mg oral daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Progression Free Survival (PFS) | The primary efficacy endpoint is progression-free survival at 12 weeks after start of therapy. A progression-free survival rate at 12 weeks will be calculated, with patients categorized in a dichotomous manner as alive and progression-free or in progression or dead at 12 weeks. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Overall Survival | The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. | From start of treatment to death; up to the time that all participants ended treatment | 
| Participants Achieving Objective Response | Objective response is defined as a complete response (CR) or partial response (PR) that has been confirmed by a second tumor assessment no earlier than 4 weeks after the initial documentation. Response is assessed using Response Evaluation Criteria in Solid Tumors (RECIST)criteria. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. | Patients were followed from start of therapy until date of first response | 
| Time to Best Response | This is defined as time from the start of therapy to the date of first CR or PR. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. | Patients were followed from start of therapy until date of first response | 
| Time to Progressive Disease (PD) | The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. | From start of therapy to the date of first documentation of PD. Pts who never progress prior to final analysis or are withdrawn from the study without documented progression will be censored at the date of the last valid tumor assessment. | 
| Duration of Objective Response | This is defined similarly for complete and partial responders. Complete response or partial response lasts from the date the complete response or partial response was first recorded to the date on which progressive disease is first noted or date of death. If a patient does not progress or die while being followed, the date of the last valid tumor assessment will be taken. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. | from the date the complete or partial response was first recorded to the date which progressive disease is first noted or date of death. If a patient does not progress or die while being followed, the date of the last valid tumor assessment will be taken | 
| Baseline Electrocardiogram (ECG) | Standard safety monitoring includes baseline Electrocardiogram (ECG). The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. The study was prematurely terminated due to discontinuation of R1507 development (not for safety reasons). As a result, data not provided for outcome measures listed. | baseline within 28 days of starting treatment (screening visit). | 
| Fasting Glucose, Highest Post-Baseline Value | A fasting glucose was required at baseline, and random non-fasting glucose testing was performed weekly for the first 6 weeks followed by day 1 of each 3 week treatment phase. The number of participants with the highest post-baseline fasting glucose level at any time point post baseline relative to the participant's baseline glucose level is reported. | Baseline, Highest Post-Baseline value within the timeframe of post-baseline collection up to when patient discontinued (up to 59 weeks) | 
| Hemoglobin A1c (HbA1c) | Standard safety monitoring includes baseline Electrocardiogram (ECG), Fasting glucose and HbA1c, monthly urine pregnancy test in female patients of childbearing potential and Human anti-human antibody (HAHA) testing. Data will be represented in the Serious Adverse Event (SAE) Adverse Event (AE) section of Protocol Registration System (PRS). | screening | 
| Monthly Urine Pregnancy Test in Female Patients of Childbearing Potential | Standard safety monitoring includes baseline Electrocardiogram (ECG), Fasting glucose and HbA1c, monthly urine pregnancy test in female patients of childbearing potential and Human anti-human antibody (HAHA) testing. Not posted; it will be represented in the Serious Adverse Event (SAE) Adverse Event (AE) section of Protocol Registration System (PRS). | Within 7 days of starting treatment (baseline visit) | 
| Number of Participants With Positive Results for Human Anti-human Antibody (HAHA) Testing | Number of participants who tested positive for Human anti-human antibody (HAHA) testing for immunogenicity. To determine HAHA specificity, screened positive samples were tested in a confirmatory assay in the presence of 10 ug/mL R1507. Samples with > 19.7% inhibition were considered true positives, whereas those with < 19.7% inhibition were considered to be false positives. | prior to dosing on week 1 (day 1), week 4 (day 22), week 10 (day 64), final visit, follow up visit and 12 weeks post last dose (up to 71 weeks) | 
| Electrocardiogram (ECG) | 12 lead ECG is required at baseline and will be measured during the trial as clinically indicated at the discretion of the investigators. For each reading, QTcF value will be calculated as the QT value (seconds) divided by the cube root of the RR interval in seconds (Fridericia correction). A listing will be generated showing, for each patient, the visits at which ECGs were taken and the results (normal or abnormal, as well as any comments provided). | baseline and thereafter as clinically indicated at the discretion of the investigator up to the time that the patient discontinued (up to 59 weeks) | 
| Population Pharmacokinetics of R1507 and Tarceva | Population PK of R1507 and erlotinib were planned but not analyzed due to the termination of the trial. | Throughout study | 
| Assessment of Potential Predictive and Prognostic Biomarkers. | Total IGF-I, free IGF I/II and other potential biomarkers present in serum. Further putative biomarker analyses in blood and tumor samples were planned in the protocol for exploratory assessment of correlation with clinical outcome. None of these were analyzed due to the termination of the trial. | Throughout study |