Study of GSK1120212 Plus Gemcitabine vs Placebo Plus Gemcitabine in Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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GSK1120212 is a potent and highly selective inhibitor of MEK phosphorylation and kinase activity and has demonstrated potent anti-proliferative activity against human pancreatic cancer cell lines. This study is a Phase II, randomized placebo-controlled trial of the MEK inhibitor GSK1120212 plus gemcitabine vs. placebo plus gemcitabine in subjects with metastatic pancreatic cancer. Eligible subjects will receive intravenous gemcitabine with oral GSK1120212 or placebo. Therapy will continue until treatment discontinuation criteria are met. The primary objective will be to compare the overall survival of subjects in the GSK1120212 plus gemcitabine arm vs. subjects in the placebo plus gemcitabine arm. Secondary objectives include comparison of progression free survival, overall response rate, and duration of response between the two arms. Exploratory research objectives include the evaluation of population pharmacokinetics as well as blood and tissue based biomarkers. Safety will also be monitored throughout dosing. Once the determined number of survival events has occurred, if subjects are eligible, they will have the option to enter MEK114375, an open-label, Phase Ib rollover study of GSK1120212 monotherapy or GSK1120212 in combination with other anti-cancer treatments.

Official Title
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A Randomized, Double-Blind Placebo-Controlled Phase II Study of the MEK Inhibitor GSK1120212 Plus Gemcitabine vs Placebo Plus Gemcitabine in Subjects With Metastatic Pancreatic Cancer

Conditions
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Cancer

Intervention / Treatment
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* Drug: GSK1120212
* Drug: Gemcitabine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years old or older Histologically or cytologically confirmed diagnosis of metastatic (Stage IV) adenocarcinoma of the pancreas with measurable or non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale All prior treatment related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) ≤ Grade 1 (except alopecia) at the time of randomization Adequate baseline organ function Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Exclusion Criteria: Prior systemic therapy (i.e., chemotherapy, immunotherapy, hormone therapy, , targeted therapy or any investigational anti-cancer drug) for metastatic pancreatic adenocarcinoma. (Prior treatment with 5-FU based or gemcitabine administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed. Prior systemic chemotherapy in the adjuvant setting is allowed ; however, prior therapy with gemcitabine is allowed only if tumor recurrence occurred at least 6 months after completing the last dose of gemcitabine) History of another malignancy. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled. Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above Any serious and/or unstable pre-existing medical (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator or GSK Medical Monitor History of interstitial lung disease or pneumonitis History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 6 months

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: GSK1120212 plus Gemcitabine<br>GSK1120212 administered orally plus gemcitabine IV | Drug: GSK1120212<br>* administered orally starting on day 1 followed by a continuous daily dosing of 2.0 mg<br>Drug: Gemcitabine<br>* Intravenous gemcitabine infused over 30 minutes weekly for 7 weeks followed by one week of rest from treatment. Subsequent cycles will consist of 1000 mg/m2 intravenous infusion over 30 minutes on days 1, 8, and 15 followed by 1 week of rest from treatment for each 28-day treatment period.<br>|
| Active Comparator: Placebo plus Gemcitabine<br>Placebo administered orally plus gemcitabine IV | Drug: Gemcitabine<br>* Intravenous gemcitabine infused over 30 minutes weekly for 7 weeks followed by one week of rest from treatment. Subsequent cycles will consist of 1000 mg/m2 intravenous infusion over 30 minutes on days 1, 8, and 15 followed by 1 week of rest from treatment for each 28-day treatment period.<br>Drug: Placebo<br>* administered orally starting on day 1 followed by a continuous daily dosing of 2.0 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from randomization until death due to any cause. For the analysis of overall survival, the last date of known contact was used for those participants who were not dead at the time of analysis; such participants were considered censored. | From randomization until death due to any cause or until the data cutoff of 15-March-2013 (up to 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) as Assessed by the Investigator | PFS is defined as the time from randomization until the earliest date of radiological PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). PD was also based on unequivocal progression of existing non-target lesions. If the participant received subsequent anti-cancer therapy prior to the date of documented progression or death, or did not have a documented date of progression or death, PFS was censored at the last adequate assessment. | From randomization until disease progression (PD) or death due to any cause or until the data cutoff of 17-April-2012 (up to 15 months) | 
| Number of Participants With an Investigator-assessed Best Response, With or Without Confirmation, of Complete Response (CR) or Partial Response (PR) | CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must be <10 mm in the short axis. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). CR and PR were evaluated by the Investigator using standard criteria (RECIST version 1.1). Confirmation of response was not required. | From randomization until disease progression or death due to any cause or until the data cutoff of 17-April-2012 (up to 15 months) | 
| Investigator-Assessed Duration of Response | Duration of response is defined, for the subset of participants with a CR or PR, as the time from the first documented evidence of CR or PR until the first documented disease progression or death due to any cause. CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must be <10 mm in the short axis. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline). PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). | From the first documented CR or PR until disease progression or death due to any cause or until the data cutoff of 17-April-2012 (up to 13 months) | 
| Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Per protocol other events were considered SAEs like symptomatic left ventricular ejection fraction (LVEF) decreases or cases of central serous retinopathy (CSR) or retinal vein occlusion (RVO). AE and SAE data were collected from the start of the first dose of study treatment and continued until 28 days following discontinuation of the study treatment or death. Refer to the general AE/SAE module for a complete list of AEs and SAEs. | From the start of the first dose of study treatment until 28 days following discontinuation of the study treatment or until the data cutoff of 15-March-2013 (up to 21 months) | 
| Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | A grading (severity) scale is provided for each laboratory toxicity. Grade refers to the severity of the toxicity. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 displays Grades 1 through 5 based on the general guideline: Grade 1, mild toxicity; Grade 2, moderate toxicity; Grade 3, severe toxicity; Grade 4, life-threatening or disabling toxicity; Grade 5, death related to toxicity. | From the start of the first dose of study treatment until 28 days following discontinuation of the study treatment or until the data cutoff of 17-April-2012 (up to 17 months) | 
| Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | A grading (severity) scale is provided for each laboratory toxicity. Grade refers to the severity of the toxicity. The CTCAE version 3.0 displays Grades 1 through 5, with unique clinical descriptions of the severity for each toxicity based on the general guideline: Grade 1, mild toxicity; Grade 2, moderate toxicity; Grade 3, severe toxicity; Grade 4, life-threatening or disabling toxicity; Grade 5, death related to toxicity. | From the start of the first dose of study treatment until 28 days following discontinuation of the study treatment or until the data cutoff of 17-April-2012 (up to 17 months) |