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

• Progression Free Survival [ Time Frame: Approximately 18 months ] [ Designated as safety issue: No ]
• Duration of Response [ Time Frame: Approximately 18 months ] [ Designated as safety issue: No ]
• Safety profile as assessed through standard clinical and laboratory tests and through collection of AEs and SAEs [ Time Frame: Approximately 18 months ] [ Designated as safety issue: No ]
• Overall Response Rate [ Time Frame: Approximately 18 months ] [ Designated as safety issue: No ]

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.

• Drug: GSK1120212
  administered orally starting on day 1 followed by a continuous daily dosing of 2.0 mg
• Drug: Gemcitabine
  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.
• Drug: Placebo
  administered orally starting on day 1 followed by a continuous daily dosing of 2.0 mg

• Experimental: GSK1120212 plus Gemcitabine
  GSK1120212 administered orally plus gemcitabine IV
  Interventions:

  • Drug: GSK1120212
  • Drug: Gemcitabine
• Active Comparator: Placebo plus Gemcitabine
  Placebo administered orally plus gemcitabine IV
  Interventions:

  • Drug: Gemcitabine
  • Drug: Placebo

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