A Study Evaluating Dalotuzumab (MK-0646) in Combination With Erlotinib for Participants With Non-Small Cell Lung Cancer (MK-0646-007)

Study Overview
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Brief Summary
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This is a Phase I/IIa study to evaluate safety and efficacy of dalotuzumab (MK-0646) in combination with erlotinib in participants with recurrent Non-Small Cell Lung Cancer (NSCLC). The Phase I part of this study will determine the highest tolerated dose of dalotuzumab to be given in combination with erlotinib. The primary hypothesis for the Phase I part of the study is that administration of erlotinib in combination with dalotuzumab in participants with recurrent NSCLC is generally well-tolerated as evidenced by accumulated safety data from this trial. The Phase II part of this study will investigate how well dalotuzumab works in conjunction with erlotinib at treating recurrent NSCLC. The primary hypothesis for the Phase II part of this study is that administration of erlotinib in combination with dalotuzumab in participants with recurrent NSCLC results in improvement in Progression Free Survival (PFS) compared to participants treated with erlotinib alone. PFS is defined as the time from randomization until either the emergence of radiographic evidence of disease progression (as documented by an independent core laboratory) or death due to any cause, whichever occurs first.

Detailed Description
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Dalotuzumab is a humanized monoclonal antibody (mAb) that targets the Insulin-like Growth Factor Receptor (IGF-1R). Dalotuzumab may act through: Inhibition of IGF-1-mediated cell signaling to cause reductions in tumor growth and spread Antibody dependent cell-mediated cytotoxicity In preclinical studies, dalotuzumab improved the activity of an anti-Epidermal Growth Factor Receptor (EGFR) mAb and the activity of Erlotinib, a small molecule inhibitor of EGFR Trial Duration of Treatment: Participants will continue on the study for as long as their disease is not progressing and they do not have unmanageable side effects from the treatment.

Official Title
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An Open Label, Randomized Phase I/IIa Trial Evaluating MK-0646 in Combination With Erlotinib (TARCEVA™) for Patients With Recurrent Non-Small Cell Lung Cancer

Conditions
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Carcinoma, Non-small-cell Lung

Intervention / Treatment
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* Drug: Dalotuzumab
* Drug: Erlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has locally advanced or metastatic stage IIIB/IV NSCLC that has relapsed after hemotherapy/chemoratiotherapy Participant has had at least one chemotherapy regimen for recurrent or metastatic disease Participant is 18 years of age or older Participant has a performance status of 0-2 on Eastern Cooperative Group (ECOG) scale Women of childbearing potential have a negative pregnancy test Exclusion Criteria: Participant has had chemotherapy within 2 weeks or biological therapy (e.g. bevacizumab) within 4 weeks Participant has not recovered from adverse events from previous therapy within 4 weeks Participant has received EGFR-Tyrosine Kinase Inhibitor (TKI) inhibitor/anti-EGFR mAb therapy Participant has received IGF1R-TKI inhibitor/anti-IGF1R mAB therapy Participant has had more than 2 systemic chemotherapies for metastatic disease Participant has not completed radiotherapy with complete resolution of toxicities at least 2 weeks before starting in the study Participant is taking part in another clinical study Participant has a primary central nervous system tumor Participant abuses drugs or alcohol Participant is pregnant or breastfeeding Participant is Human Immunodeficiency Virus (HIV) positive Participant has a history of hepatitis B or C Participant is using growth hormone or growth hormone inhibitors

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: Ph I: Dalotuzumab 5 mg/kg + Erlotinib<br>During the Phase I part of the study, participants receive dalotuzumab intravenously (IV) at 5 mg/kg weekly plus open-label erlotinib at 150 mg daily for 4 weeks. After 4 weeks of therapy, participants in Phase I who do not have disease progression and are satisfactorily tolerating study drug can continue to receive study drug. | Drug: Dalotuzumab<br>* Dalotuzumab 20 mg/mL in sterile solution. Intravenous (IV) infusion over 60 minutes at 5 mg/kg, administered weekly at dosage according to treatment group.<br>* Other names: MK-0646;|
| Experimental: Ph I: Dalotuzumab 10 mg/kg + Erlotinib<br>During the Phase I part of the study, participants receive dalotuzumab intravenously (IV) at 10 mg/kg weekly plus open-label erlotinib at 150 mg daily for 4 weeks. After 4 weeks of therapy, participants in Phase I who do not have disease progression and are satisfactorily tolerating study drug can continue to receive study drug. | Drug: Dalotuzumab<br>* Dalotuzumab 20 mg/mL in sterile solution. Intravenous (IV) infusion over 60 minutes at 5 mg/kg, administered weekly at dosage according to treatment group.<br>* Other names: MK-0646;|
| Experimental: Ph II: Dalotuzumab 10 mg/kg + Erlotinib<br>During the Phase II part of the study, participants are randomized to receive dalotuzumab intravenously (IV) at 10 mg/kg weekly plus open-label erlotinib at 150 mg daily until disease progression or occurrence of unacceptable toxic effects. | Drug: Dalotuzumab<br>* Dalotuzumab 20 mg/mL in sterile solution. Intravenous (IV) infusion over 60 minutes at 5 mg/kg, administered weekly at dosage according to treatment group.<br>* Other names: MK-0646;|
| Active Comparator: Ph II: Erlotinib<br>During the Phase II part of the study, participants are randomized to receive open-label erlotinib at 150 mg daily until disease progression or occurrence of unacceptable toxic effects. | Drug: Erlotinib<br>* Open-label erlotinib administrated orally (tablets) by mouth (PO) at 150 mg daily.<br>* Other names: Erlotinib hydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Number of Participants Experiencing at Least One Dose-Limiting Toxicity (DLT) Adverse Event (AE) During the First Four Weeks of Dalotuzumab Plus Erlotinib Treatment | A DLT was an AE related (definitely, probably, or possibly) to study therapy and occurring within first 4 weeks of therapy. Hematologic DLTs included Grade (Gr)4 neutropenia lasting for ≥7 days, Gr 3/Gr 4 neutropenia with fever >38.5 °C and/or infection requiring antibiotic or anti-fungal treatment, and Gr 4 thrombocytopenia (25.0 x 10^9/L). Non-hematologic DLT defined as any ≥Gr 3 nonhematologic toxicity, except Gr 3 reversible rash; Gr 3 nausea, vomiting, diarrhea, dehydration, or hyperglycemia occurring in setting of inadequate compliance with supportive care; alopecia; anorexia; asthenia; inadequately-treated hypersensitivity reactions; Gr 3 elevated transaminases (≤1 week duration); or infusion reactions to dalotuzumab. Any drug-related AEs that led to dose modification of dalotuzumab/erlotinib or any unresolved drug-related toxicity that caused a ≥3 week delay of next scheduled dose of study drug, regardless of Common Terminology Criteria grade, were DLTs. | Up to 4 weeks after initiation of treatment | 
| Phase II: Median Progression Free Survival (PFS) in Participants Receiving Dalotuzumab Plus Erlotinib Treatment | PFS was defined as the time from randomization until either the emergence of radiographic evidence of disease progression or death due to any cause, whichever occurs first. Disease progression was classified as a radiographic assessment of progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) using computed tomography (CT) or magnetic resonance imaging (MRI). As pre-specified by the protocol, final analysis of PFS was to take place after approximately 49 PFS events or deaths had occurred in the Phase II part of the trial. A non-parametric Kaplan-Meier method was used to estimate the median PFS time for each treatment group. Participants who discontinued from the study for reasons other than progression of disease were treated as right-censored observations at the time of the last response evaluation. Participants who withdrew from the study due to PD were considered to have a disease progression between the last visit and the time of withdrawal. | Duration of time required to collect approximately 49 deaths or PFS events (assessed up to  20 months total on this study from randomization to cut-off date) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Median Overall Survival (OS) in Participants Receiving Dalotuzumab Plus Erlotinib Treatment | OS was defined as the time from randomization to death in months due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The nonparametric Kaplan-Meier method was used to estimate the survival time distribution and the median survival of each treatment group. | Duration of time required to collect approximately 49 deaths or PFS events (assessed up to  20 months total on this study from randomization to cut-off date) | 
| Phase II: Percentage of Participants With Complete Response (CR) or Partial Response (PR) After Dalotuzumab Plus Erlotinib Treatment (Objective Response Rate [ORR]) | ORR was defined as the percentage of participants in the Phase II analysis population having complete response (CR) or partial response (PR) during the course of the study. RECIST criteria were used to quantify response rate. For evaluation of target lesions, CR was defined as disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of the LD. For evaluation of non-target lesions, CR was defined as disappearance of all non-target lesions and normalization of tumor marker level. Confirmation of response required a second assessment performed 4 weeks or more after the initial assessment. If the confirmation assessment contradicted the initial assessment, it was considered that a response had not been observed. If the confirmation assessment of a participant was not available, that participant was not considered as a responder in the response rate analyses. | Duration of time required to collect approximately 49 deaths or PFS events (assessed up to  20 months total on this study from randomization to cut-off date) |