A Study in Head and Neck Cancer

Study Overview
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Brief Summary
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This study will begin with a 30 participant lead-in part: these 30 participants will receive cetuximab manufactured by ImClone on a weekly basis in combination with other chemotherapy drugs [cisplatin or carboplatin plus 5-fluorouracil (5-FU)] administered every 3 weeks. After 18 weeks, participants who benefit from this treatment may continue to receive cetuximab once-weekly until progression of the disease, an unacceptable side effect occurs, participants withdraw consent, or the study is closed. In the second part of this study, 200 participants will be randomized in 2 arms: 100 participants will receive commercial cetuximab manufactured by ImClone (Group A) 100 participants will receive cetuximab manufactured by Boehringer Ingelheim (Group B). All these 200 participants will receive other chemotherapy drugs (cisplatin or carboplatin plus 5-FU) administered every 3 weeks. After 18 weeks, participants who benefit from this treatment may continue to receive cetuximab once-weekly until progression of the disease, an unacceptable side effect occurs, participants withdraw consent, or the study is closed.

Official Title
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A Randomized, Double-Blind, Phase 2 Safety Study of Cetuximab, Using ImClone Versus Boehringer Ingelheim Manufacturing Processes, in Combination With Cisplatin or Carboplatin and 5-Fluorouracil in the First-Line Treatment of Patients With Locoregionally Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: Cetuximab
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: 5-Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Head and neck cancer that was confirmed by tissue biopsy or cytology Disease not suitable for local therapy Measurable or evaluable disease Karnofsky performance status (KPS) score of at least 70 Organs are functioning well (bone marrow reserve, liver and kidney) Life expectancy of at least 12 weeks Signed informed consent document Exclusion Criteria: Receiving another investigational medication within the last 30 days Prior chemotherapy, except if given as part of a multimodal treatment for locally advanced head and neck cancer that was completed more than 4 months prior to study entry. Nasopharyngeal carcinoma Previous treatment with monoclonal antibody therapy or other signal transduction inhibitors or epidermal growth factor receptor (EGFR) targeting therapy except for prior cetuximab treatment given as part of a multimodal treatment for locally advanced head and neck cancer that was completed more than 4 months prior to study entry. Uncontrolled high blood pressure Heart disease or had a heart attack within the last year Currently have an infection that requires for you to take an IV antibiotic Currently receiving other therapies for your cancer, such as chemotherapy, radiation therapy, immunotherapy, and hormonal therapy Medical or psychological condition that would not permit the participant to complete the study or sign informed consent Known drug abuse (with the exception of alcohol abuse) Known allergic reaction against any of the components of the study treatment Second primary malignancy that is clinically detectable at the time of consideration for study enrollment Have had another type of cancer within the last 2 years You are currently pregnant or breastfeeding You are considering becoming pregnant or fathering a child

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead-In (cetuximab manufactured by ImClone)<br>Cycle 1: Week 1 - Cetuximab 400 milligrams per square meter (mg/m^2) on Day 1; Cisplatin 100 mg/m^2 on Day 1 or carboplatin area under the curve (AUC) 5 on Day 1; 5-FU 1000 mg/m^2 on Days 1-4 Week 2 - Cetuximab 250 mg/m^2 on Day 1 Week 3 - Cetuximab 250 mg/m^2 on Day 1 Cycle 2-6: Week 1 - Cetuximab 250 mg/m^2 on Day 1; Cisplatin 100 mg/m^2 on Day 1 or carboplatin AUC 5 on Day 1; 5-FU 1000 mg/m^2 on Days 1-4 Week 2 - Cetuximab 250 mg/m^2 on Day 1 Week 3 - Cetuximab 250 mg/m^2 on Day 1 After 6 cycles, participants may then receive weekly cetuximab monotherapy 250 mg/m^2 until progression of disease, unacceptable toxicity, or another withdrawal criteria is met. | Drug: Cetuximab<br>* Administered intravenously<br>* Other names: LY2939777;Drug: Cisplatin<br>* Administered intravenously<br>Drug: Carboplatin<br>* Administered intravenously<br>Drug: 5-Fluorouracil<br>* Administered intravenously<br>* Other names: 5-FU;|
| Experimental: Cetuximab manufactured by ImClone<br>Cycle 1: Week 1 - Cetuximab 400 mg/m^2 on Day 1; Cisplatin 100 mg/m^2 on Day 1 or carboplatin AUC 5 on Day 1; 5-FU 1000 mg/m^2 on Days 1-4 Week 2 - Cetuximab 250 mg/m^2 on Day 1 Week 3 - Cetuximab 250 mg/m^2 on Day 1 Cycle 2-6: Week 1 - Cetuximab 250 mg/m^2 on Day 1; Cisplatin 100 mg/m^2 on Day 1 or carboplatin AUC 5 on Day 1; 5-FU 1000 mg/m^2 on Days 1-4 Week 2 - Cetuximab 250 mg/m^2 on Day 1 Week 3 - Cetuximab 250 mg/m^2 on Day 1 After 6 cycles, participants may then receive weekly cetuximab monotherapy 250 mg/m^2 until progression of disease, unacceptable toxicity, or another withdrawal criteria is met. | Drug: Cetuximab<br>* Administered intravenously<br>* Other names: LY2939777;Drug: Cisplatin<br>* Administered intravenously<br>Drug: Carboplatin<br>* Administered intravenously<br>Drug: 5-Fluorouracil<br>* Administered intravenously<br>* Other names: 5-FU;|
| Experimental: Cetuximab manufactured by Boehringer Ingelheim<br>Cycle 1: Week 1 - Cetuximab 400 mg/m^2 on Day 1; Cisplatin 100 mg/m^2 on Day 1 or carboplatin AUC 5 on Day 1; 5-FU 1000 mg/m^2 on Days 1-4 Week 2 - Cetuximab 250 mg/m^2 on Day 1 Week 3 - Cetuximab 250 mg/m^2 on Day 1 Cycle 2-6: Week 1 - Cetuximab 250 mg/m^2 on Day 1; Cisplatin 100 mg/m^2 on Day 1 or carboplatin AUC 5 on Day 1; 5-FU 1000 mg/m^2 on Days 1-4 Week 2 - Cetuximab 250 mg/m^2 on Day 1 Week 3 - Cetuximab 250 mg/m^2 on Day 1 After 6 cycles, participants may then receive weekly cetuximab monotherapy 250 mg/m^2 until progression of disease, unacceptable toxicity, or another withdrawal criteria is met. | Drug: Cetuximab<br>* Administered intravenously<br>* Other names: LY2939777;Drug: Cisplatin<br>* Administered intravenously<br>Drug: Carboplatin<br>* Administered intravenously<br>Drug: 5-Fluorouracil<br>* Administered intravenously<br>* Other names: 5-FU;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Had Treatment-Emergent Adverse Events (TEAEs); Data Analysis Cut-Off: September 27, 2013 | September 27, 2013 is the date when data was last collected for the primary endpoint. Prior to this date, the manufacturing process for the BI-manufactured cetuximab was changed necessitating the need to switch participants to US commercial cetuximab. All other components of their treatment regimen remained unchanged and participants stayed in their original reporting group. Therefore, the number of participants in the BI-manufactured cetuximab treatment arm who had TEAEs includes TEAEs while participants received BI-manufactured and US-commercial cetuximab. Using September 27 cut-off, the analysis of TEAEs is confounded by the switch from BI-manufactured to US commercial cetuximab. TEAEs were defined as serious and other non-serious AEs that occurred or worsened after study treatment (regardless of causality). TEAE information for Safety Lead-In group available in Reported Adverse Events module which is summary of serious and other non-serious AEs regardless of causality. | Part 2: Baseline to end of combination therapy (up to 18 weeks) | 
| Number of Participants Who Had TEAEs; Data Analysis Cut-Off: January 23, 2013 | January 23, 2013 is the date when the first participant in the BI-manufactured cetuximab treatment arm switched to US commercial cetuximab due to changes in the manufacturing process for the BI-manufactured cetuximab necessitating the need to switch participants to US commercial cetuximab. Each participant who switched treatments received at least 2 cycles of BI-manufactured cetuximab before switching. All other components of their treatment regimen remained unchanged. The number of participants who had TEAEs during combination therapy is reported. Using January 23 cut-off, data is un-confounded by lack of BI-manufactured cetuximab. TEAEs were defined as serious and other non-serious adverse events (AEs) that occurred or worsened after study treatment (regardless of causality). TEAE information for Safety Lead-in group available in Reported Adverse Event module which is summary of serious and other non-serious AEs regardless of causality. | Part 2: Baseline to end of combination therapy or date first participant switched to US commercial cetuximab (up to 18 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as duration from the date of randomization to the date of death from any cause. For each participant not known to have died as of the 23 October 2014 data cutoff date for the analysis, OS was censored at the date last known to be alive. In addition, any participants on Arm B who was switched from BI-manufactured cetuximab to ImClone-manufactured cetuximab was censored at the time of the switch. | Parts 1 and 2: Randomization to Date of Death from any Cause (Up to 36.3 Months) | 
| Progression-Free Survival (PFS) | PFS was defined as duration from the date of randomization to the first date of objective progressive disease (PD) or death from any cause. For each participant who was not known to have died or to have had objective PD as of the 23 October 2014 data cutoff date for the analysis, PFS was censored at the date of the participant's last complete tumor assessment prior to that cutoff date. In addition, any participant in Arm B who was switched from BI-manufactured cetuximab to ImClone-manufactured cetuximab was censored at the time of the switch. | Parts 1 and 2: Randomization to Progression of Disease or Death from any Cause (Up to 32.7 Months) | 
| Percentage of Participants Having a Confirmed Best Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) | Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version [v]1.0) criteria. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. Percentage of participants with a confirmed CR or PR=(number of participants whose best overall response was CR or PR)/(number of participants treated)*100. | Parts 1 and 2: Randomization to Progression of Disease (Up to 32.7 Months) | 
| Number of Participants With Anti-Cetuximab Antibodies |  | Day 1, Week 1 of Cycles 3 and 5 (postbaseline samples were collected prior to infusion). | 
| Percentage of Participants Having a Best Response of CR, PR, or Stable Disease (SD) - Disease Control Rate (DCR) | Response was defined using RECIST, v1.0 criteria. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. Progressive Disease (PD) was defined as having at least a 20% increase in the sum of the longest diameter of target lesions. Stable Disease (SD) was defined as small changes that did not meet the above criteria. | Parts 1 and 2: Randomization to Progression of Disease (Up to 32.7 Months) | 
| Maximum Serum Concentration (Cmax) of Cetuximab Following 400 mg/m² Cetuximab Dosing | The Cmax of cetuximab following 400 mg/m² cetuximab dosing during Part 2 of the study is reported. As specified in the protocol, pharmacokinetics (PK) samples were not collected during Part 1 of the study, Safety Lead-In or during Part 2 monotherapy. | Part 2: Cycle 1, Day 1: 0 hours [(h); immediately postdose], 1 h, 2 h, and 24 h postdose | 
| Cmax of Cetuximab at Steady State | A total of 4 samples were collected at various times during combination therapy, from the third dose of 250 mg/m^2 cetuximab in Cycle 1 (Week 3) through the final dose in Cycle 3 (Week 3) and used to report Cmax of cetuximab at steady state during Part 2 of the study. As specified in the protocol, PK samples were not collected during Part 1 of the study, Safety Lead-In, or during Part 2 monotherapy. | Part 2: Weekly from Cycle 1, Week 3 through Cycle 3, Week 3: 0 h (immediately postdose), 24 h, 96 h, and 168 h postdose | 
| Area Under the Concentration Curve (AUC) of Cetuximab at Steady State | A total of 4 samples were collected during combination therapy, from the first dose of 250 mg/m^2 cetuximab in Cycle 1 (Day 1) through the final dose in Cycle 3 (Week 3) and used to report AUC of cetuximab at steady state during Part 2 of the study. As specified in the protocol, PK samples were not collected during Part 1 of the study, Safety Lead-In, or during Part 2 monotherapy. | Part 2: Weekly from Cycle 1, Day 1 through Cycle 3, Week 3: 0 h (immediately postdose), 24 h, 96 h, and 168 h postdose |