Cancer
Conditions
Brief summary
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.
Interventions
DRUGGSK1120212
administered orally starting on day 1 followed by a continuous daily dosing of 2.0 mg
DRUGGemcitabine
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.
DRUGPlacebo
administered orally starting on day 1 followed by a continuous daily dosing of 2.0 mg
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization until death due to any cause or until the data cutoff of 15-March-2013 (up to 24 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Investigator-assessed Best Response, With or Without Confirmation, of Complete Response (CR) or Partial Response (PR) | From randomization until disease progression or death due to any cause or until the data cutoff of 17-April-2012 (up to 15 months) | 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. |
| Investigator-Assessed Duration of Response | 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) | 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). |
| Progression-free Survival (PFS) as Assessed by the Investigator | 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) | 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. |
| Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | 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) | 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. |
| Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | 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) | 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. |
| Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) | 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) | 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. |
Countries
South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Trametinib + Gemcitabine Participants received 2 milligrams (mg) trametinib orally once daily in combination with 1000 mg/m\^2 of gemcitabine given as intravenous (IV) infusion over 30 minutes (min). In the first cycle, gemcitabine was infused weekly for 7 weeks followed by a week of rest from treatment and then subsequent cycles on Day 1, 8, and 15 followed by 1 week of rest from treatment for each 28-day treatment cycle until progressive disease (PD), unacceptable toxicity, or permanent discontinuation from study treatment for any reason. | 80 |
| Placebo + Gemcitabine Participants received placebo orally once daily in combination with 1000 mg/m\^2 of gemcitabine given as IV infusion over 30 min. In the first cycle, gemcitabine was infused weekly for 7 weeks followed by a week of rest from treatment and then subsequent cycles on Day 1, 8, and 15 followed by 1 week of rest from treatment for each 28-day treatment cycle until PD, unacceptable toxicity, or permanent discontinuation from study treatment for any reason. | 80 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 65 | 64 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Ongoing | 1 | 0 |
| Overall Study | Study Closed/Terminated | 6 | 5 |
| Overall Study | Withdrawal by Subject | 6 | 9 |
Baseline characteristics
| Characteristic | Trametinib + Gemcitabine | Placebo + Gemcitabine | Total |
|---|---|---|---|
| Age Continuous | 62.3 Years STANDARD_DEVIATION 10.35 | 62.2 Years STANDARD_DEVIATION 9.56 | 62.3 Years STANDARD_DEVIATION 9.93 |
| Race/Ethnicity, Customized African American Africa | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 24 Participants | 13 Participants | 37 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 50 Participants | 59 Participants | 109 Participants |
| Sex: Female, Male Female | 41 Participants | 34 Participants | 75 Participants |
| Sex: Female, Male Male | 39 Participants | 46 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 80 / 80 | 80 / 80 |
| serious Total, serious adverse events | 42 / 80 | 37 / 80 |
Outcome results
Primary
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.
Time frame: From randomization until death due to any cause or until the data cutoff of 15-March-2013 (up to 24 months)
Population: Intent-to-Treat (ITT) Population: all randomized participants regardless of whether or not treatment was administered
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib + Gemcitabine | Overall Survival | 8.4 months |
| Placebo + Gemcitabine | Overall Survival | 6.7 months |
p-value: 0.35295% CI: [0.66, 1.32]Log Rank
Secondary
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).
Time frame: 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)
Population: MD Population. Duration of response was assessed for only those participants with a CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib + Gemcitabine | Investigator-Assessed Duration of Response | 23.9 Weeks |
| Placebo + Gemcitabine | Investigator-Assessed Duration of Response | 16.1 Weeks |
Secondary
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.
Time frame: 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)
Population: Safety Population. Only those par. with laboratory values for worst-case on therapy were analyzed. The same par. were not necessarily analyzed for each laboratory parameter; thus, the number of par. analyzed reflects all par. in the Safety Population. The number of par. analyzed for a particular parameter is included in the parameter title.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Glucose (hypoglycemia), Grade 3, n=74, 72 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Calcium (hypocalcemia), Grade 3, n=73, 73 | 1 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Alkaline Phosphatase, Grade 4, n=74, 73 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Calcium (hypocalcemia), Grade 4, n=73, 73 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Aspartate Aminotransferase, Grade 4, n=73, 72 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Creatinine, Grade 3, n=74, 75 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Alanine Amino Transferase, Grade 3, n=74, 73 | 7 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Creatinine, Grade 4, n=74, 75 | 1 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Potassium (hypokalemia), Grade 3, n=74, 72 | 4 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Glucose (hyperglycemia), Grade 3, n=74, 72 | 9 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Aspartate Aminotransferase, Grade 3, n=73, 72 | 6 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Glucose (hyperglycemia), Grade 4, n=74, 72 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Albumin, Grade 3, n=73, 73 | 7 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Total Bilirubin, Grade 3, n=74, 73 | 1 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Glucose (hypoglycemia), Grade 4, n=74, 72 | 1 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Total Bilirubin, Grade 4, n=74, 73 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Potassium (hyperkalemia), Grade 3, n=74, 72 | 2 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Alanine Amino Transferase, Grade 4, n=74, 73 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Potassium (hyperkalemia), Grade 4, n=74, 72 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Calcium (hypercalcemia), Grade 3, n=73, 73 | 1 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Potassium (hypokalemia), Grade 4, n=74, 72 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Alkaline Phosphatase, Grade 3, n=74, 73 | 7 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Sodium (hyponatremia), Grade 3, n=74, 74 | 5 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Calcium (hypercalcemia), Grade 4, n=73, 73 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Sodium (hyponatremia), Grade 4, n=74, 74 | 2 participants |
| Trametinib + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Albumin, Grade 4, n=73, 73 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Sodium (hyponatremia), Grade 4, n=74, 74 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Albumin, Grade 4, n=73, 73 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Alanine Amino Transferase, Grade 3, n=74, 73 | 7 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Aspartate Aminotransferase, Grade 3, n=73, 72 | 7 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Total Bilirubin, Grade 3, n=74, 73 | 7 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Potassium (hyperkalemia), Grade 4, n=74, 72 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Albumin, Grade 3, n=73, 73 | 4 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Alkaline Phosphatase, Grade 3, n=74, 73 | 4 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Alkaline Phosphatase, Grade 4, n=74, 73 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Alanine Amino Transferase, Grade 4, n=74, 73 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Aspartate Aminotransferase, Grade 4, n=73, 72 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Total Bilirubin, Grade 4, n=74, 73 | 1 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Calcium (hypercalcemia), Grade 3, n=73, 73 | 1 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Calcium (hypercalcemia), Grade 4, n=73, 73 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Calcium (hypocalcemia), Grade 3, n=73, 73 | 2 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Calcium (hypocalcemia), Grade 4, n=73, 73 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Creatinine, Grade 3, n=74, 75 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Creatinine, Grade 4, n=74, 75 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Glucose (hyperglycemia), Grade 3, n=74, 72 | 10 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Glucose (hyperglycemia), Grade 4, n=74, 72 | 1 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Glucose (hypoglycemia), Grade 3, n=74, 72 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Glucose (hypoglycemia), Grade 4, n=74, 72 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Potassium (hyperkalemia), Grade 3, n=74, 72 | 1 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Potassium (hypokalemia), Grade 3, n=74, 72 | 1 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Potassium (hypokalemia), Grade 4, n=74, 72 | 0 participants |
| Placebo + Gemcitabine | Number of Participants (Par.) With a Worst-case Change to Grade 3 or Grade 4 From Baseline Grade in Chemistry Parameters | Sodium (hyponatremia), Grade 3, n=74, 74 | 3 participants |
Secondary
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.
Time frame: From randomization until disease progression or death due to any cause or until the data cutoff of 17-April-2012 (up to 15 months)
Population: Measurable Disease (MD) Population: all randomized participants regardless of whether or not treatment was administered who had measurable disease at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib + Gemcitabine | Number of Participants With an Investigator-assessed Best Response, With or Without Confirmation, of Complete Response (CR) or Partial Response (PR) | CR | 1 participants |
| Trametinib + Gemcitabine | Number of Participants With an Investigator-assessed Best Response, With or Without Confirmation, of Complete Response (CR) or Partial Response (PR) | PR | 16 participants |
| Placebo + Gemcitabine | Number of Participants With an Investigator-assessed Best Response, With or Without Confirmation, of Complete Response (CR) or Partial Response (PR) | PR | 14 participants |
| Placebo + Gemcitabine | Number of Participants With an Investigator-assessed Best Response, With or Without Confirmation, of Complete Response (CR) or Partial Response (PR) | CR | 0 participants |
Secondary
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.
Time frame: 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)
Population: Safety Population: all participants who were randomized and took at least one dose of study medication. This population was based on the actual treatment received, if it differed from that to which the participant was randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib + Gemcitabine | Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) | Any AE | 80 participants |
| Trametinib + Gemcitabine | Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) | SAE | 42 participants |
| Placebo + Gemcitabine | Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) | SAE | 37 participants |
| Placebo + Gemcitabine | Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) | Any AE | 80 participants |
Secondary
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.
Time frame: 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)
Population: Safety Population. Only those par. with laboratory values for worst-case on therapy were analyzed. The same par. were not necessarily analyzed for each laboratory parameter; thus, the number of par. analyzed reflects all par. in the Safety Population. The number of par. analyzed for a particular parameter is included in the parameter title.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Hemoglobin (Increased), Grade 4, n=80, 79 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Platelet count, Grade 4, n=80, 79 | 1 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Lymphocytes (Decreased), Grade 3, n=80, 79 | 9 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Hemoglobin (Anemia), Grade 3, n=80, 79 | 24 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Lymphocytes (Decreased), Grade 4, n=80, 79 | 3 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Hemoglobin (Increased), Grade 3, n=80, 79 | 3 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Absolute Neutrophil Count, Grade 3, n=80, 79 | 23 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Hemoglobin (Anemia), Grade 4, n=80, 79 | 0 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Absolute Neutrophil Count, Grade 4, n=80, 79 | 7 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | White Blood Cell count, Grade 4, n=80, 79 | 1 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Platelet count, Grade 3, n=80, 79 | 11 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Lymphocytes (Increased), Grade 3, n=80, 79 | 1 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | White Blood Cell count, Grade 3, n=80, 79 | 15 participants |
| Trametinib + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Lymphocytes (Increased), Grade 4, n=80, 79 | 0 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | White Blood Cell count, Grade 3, n=80, 79 | 14 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Platelet count, Grade 3, n=80, 79 | 10 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | White Blood Cell count, Grade 4, n=80, 79 | 4 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Hemoglobin (Increased), Grade 3, n=80, 79 | 0 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Hemoglobin (Increased), Grade 4, n=80, 79 | 0 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Hemoglobin (Anemia), Grade 3, n=80, 79 | 13 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Hemoglobin (Anemia), Grade 4, n=80, 79 | 0 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Lymphocytes (Increased), Grade 3, n=80, 79 | 0 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Lymphocytes (Increased), Grade 4, n=80, 79 | 0 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Lymphocytes (Decreased), Grade 3, n=80, 79 | 12 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Lymphocytes (Decreased), Grade 4, n=80, 79 | 6 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Absolute Neutrophil Count, Grade 3, n=80, 79 | 20 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Absolute Neutrophil Count, Grade 4, n=80, 79 | 10 participants |
| Placebo + Gemcitabine | Number of Participants With Change From Baseline Increase to Grade 3/Grade 4 in Lab Hematology Test Measurements | Platelet count, Grade 4, n=80, 79 | 4 participants |
Secondary
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.
Time frame: 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)
Population: ITT Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trametinib + Gemcitabine | Progression-free Survival (PFS) as Assessed by the Investigator | 16.1 weeks |
| Placebo + Gemcitabine | Progression-free Survival (PFS) as Assessed by the Investigator | 15.1 weeks |