A Dose-Escalation to Rash Study of Tarceva (Erlotinib) Plus Gemcitabine in Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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This study will compare the efficacy and safety of escalating versus standard doses to rash of Tarceva, in combination with gemcitabine, in patients with metastatic pancreatic cancer. During a 4 week run-in period, all patients will receive Tarceva 100mg/day po plus gemcitabine 1000mg/m2 iv on days 1, 8,15 and 22. After 4 weeks, patients who have not developed rash, or only develop grade 1 rash, will be randomized to one of 2 groups. Group 1 will receive a starting dose of Tarceva 150mg po daily, increased in steps of 50mg every 2 weeks up to a maximum of 250mg/day po, until development of grade 2 rash or other dose-limiting toxicity. Group 2 will continue to receive Tarceva 100mg/day po. All patients will continue to receive gemcitabine 1000mg/m2 iv on days 1, 8 and 15 of each 4 week cycle. The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.

Official Title
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A Randomized, Open-label, Dose-escalation to Rash Study to Assess the Effect of Tarceva in Combination With Gemcitabine on Overall Survival in Patients With Metastatic Pancreatic Cancer.

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Erlotinib, escalating dose
* Drug: Erlotinib, standard dose
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >=18 years of age; histologically or cytologically confirmed pancreatic cancer with measurable or non-measurable metastatic disease; ECOG performance status of 0-1. Exclusion Criteria: local, or locally advanced, pancreatic cancer; prior systemic treatment for metastatic pancreatic cancer; <=6 months since last adjuvant chemotherapy; other malignancies within last 5 years, except for adequately treated cancer in situ of the cervix, or basal or squamous cell skin cancer.

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 |
| --- | --- |
| Active Comparator: Gemcitabine, Erlotinib Standard Dose<br>Participants received erlotinib, 100 milligrams (mg), orally (PO), once daily until disease progression or unacceptable toxicity. Participants also received gemcitabine, 1000 mg per (/) square meter (m^2), intravenously (IV), on Days 1, 8, and 15 of consecutive 4 week cycles until disease progression or unacceptable toxicity. | Drug: Erlotinib, standard dose<br>* 100mg, PO, once daily<br>* Other names: Tarceva;Drug: Gemcitabine<br>* 1000 mg/m2, IV, on days 1,8 and 15 of each 4 week cycle<br>|
| Experimental: Gemcitabine, Erlotinib Escalating Dose<br>Participants received erlotinib, beginning at 150 mg/day, PO, once daily, and increasing in increments of 50 mg every 2 weeks up to a maximum of 250 mg/day, until development of a grade 2 rash, or occurrence of other, non-rash, dose-limiting toxicity; treatment was continued until disease progression, unacceptable toxicity, death or withdrawal. Participants also received gemcitabine, 1000 mg/m^2, IV, on Days 1, 8, and 15 of consecutive 4 week cycles until disease progression or unacceptable toxicity. | Drug: Erlotinib, escalating dose<br>* 100mg, PO, once daily, escalating to a maximum of 250mg, PO, once daily<br>* Other names: Tarceva;Drug: Gemcitabine<br>* 1000 mg/m2, IV, on days 1,8 and 15 of each 4 week cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Died Assessed From Point of Randomization | Overall survival (OS) assessed from the point of randomization was defined as the time from randomization to the date of death due to any cause. Participants still alive at the time of analysis were censored at the date they were last known to be alive. | Randomization [Day 1 of Cycle 2 (4-week cycles)] and weekly thereafter for up to 46 months. | 
| OS Assessed From Point of Randomization | OS assessed from the point of randomization was defined as the median time, in months, from randomization to the date of death due to any cause. Participants still alive at the time of analysis were censored at the date they were last known to be alive. The 95 percent (%) confidence interval (CI) was determined using Kaplan-Meier methodology. | Randomization [Day 1 of Cycle 2 (4-week cycles)] and weekly thereafter for up to 46 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Disease Progression or Death as Assessed From Point of Randomization | Progression-free survival (PFS) as assessed from the point of randomization was defined as the time from randomization to the first occurrence of progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause. For target lesions (TLs), PD was defined as at least a 20% increase in the sum of longest diameter (SLD) of TLs, taking as reference the smallest SLD recorded since the treatment started. For non-target lesions (NTLs), PD was defined as unequivocal progression of existing NTLs. Participants who had neither progressed nor died at time of analysis were censored at the date of last tumor assessment. | Randomization [Day 1 of Cycle 2 (4-week cycles)] and weekly thereafter for up to 46 months. | 
| PFS Assessed From Point of Randomization | PFS assessed from the point of randomization was defined as the median time, in weeks, from randomization to disease progression or death due to any cause. Participants who had neither progressed nor died at time of analysis were censored at the date of last tumor assessment. The 95% CI was determined using Kaplan-Meier methodology. | Randomization [Day 1 of Cycle 2 (4-week cycles)] and weekly thereafter for up to 46 months. | 
| Percentage of Participants With a Best Overall Response (BOR) of Confirmed Complete Response (CR) or Partial Response (PR) According to RECIST | BOR was defined as a confirmed CR or PR for at least 4 weeks. CR was defined as the disappearance of all TLs. PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline (BL) SLD. The 95% CI for one sample binomial was determined using Pearson-Clopper method. | BL, Weeks 8, 16, 24, 32, 40, every 12 weeks thereafter until disease progression for up to 46 months. | 
| Percentage of Participants With a CR, PR, Stable Disease (SD), or PD According to RECIST | CR was defined as the disappearance of all TLs. PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the BL SLD SD was defined as neither sufficient decrease in SLD to qualify for PR nor sufficient increase in SLD to qualify for PD. PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. The 95% CI for one sample binomial was determined using the Pearson-Clopper method. | BL, Weeks 8, 16, 24, 32, 40, every 12 weeks thereafter until disease progression for up to 46 months. | 
| Percentage of Participants With SD (Maintained for at Least 8 Weeks) or CR or PR (Maintained for at Least 4 Weeks) According to RECIST | Disease control was defined as a participant with a response of CR or PR for at least 4 weeks at any time during treatment, or SD that was maintained for at least 8 weeks after the start of treatment. The 95% CI for one sample binomial was determined using the Pearson-Clopper method. | BL, Weeks 8, 16, 24, 32, 40, every 12 weeks thereafter until disease progression for up to 46 months. | 
| Percentage of Participants Who Died as Assessed From Start of 4-Week Run-In | OS assessed from the start of the 4-week run in period was defined as the time from BL to the date of death due to any cause. Participants still alive at the time of analysis were censored at the date they were last known to be alive. | BL and weekly thereafter for up to 46 months. | 
| OS Assessed From Start of 4-Week Run-In | OS assessed from the start of the 4-week run in period was defined as the median time, in months, from BL to the date of death, due to any cause. Participants who were still alive at the time of analysis were censored at the date they were last known to be alive. The 95% CI was determined using Kaplan-Meier methodology. | BL and weekly thereafter for up to 46 months. | 
| Percentage of Participants With Disease Progression or Death as Assessed From the Start of 4-Week Run-In | PFS as assessed from the start of 4-week run-in was defined as the time from BL to the first occurrence of PD according to RECIST or death due to any cause. For TLs, PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. For NTLs, PD was defined as unequivocal progression of existing NTLs. Participants who had neither progressed nor died at time of analysis were censored at the date of last tumor assessment. | BL, Weeks 8, 16, 24, 32, 40, every 12 weeks thereafter until disease progression or death for up to 46 months. | 
| PFS Assessed From the Start of 4-Week Run-In | PFS assessed from the start of 4-week run-in was defined as the median time, in weeks, from BL to disease progression or death due to any cause. Participants who had neither progressed nor died at time of analysis were censored at the date of last tumor assessment. The 95% CI was determined using Kaplan-Meier methodology. | BL, Weeks 8, 16, 24, 32, 40, every 12 weeks thereafter until disease progression or death for up to 46 months. |