Last updated: 11/03/2018 19:40:06
This product has been transferred to Novartis. GSK Clinical Study Register is no longer maintained for this study. The most up to date information is available on clinicaltrials.gov.
An Open-Label, Four-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the anti-EGFR Antibody Panitumumab in Combination in Subjects with BRAF-mutation V600E Positive Colorectal Cancer and in Subjects with CRC With Secondary Resistance to Prior Anti-EGFR Therapy
GSK study ID
116833
Clinicaltrials.gov ID
EudraCT ID
EU CT Number
Not applicable
Trial status
No longer a GSK study
No longer a GSK study
Trial overview
Official title: An Open-Label, Four-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the anti-EGFR Antibody Panitumumab in Combination in Subjects with BRAF-mutation V600E Positive Colorectal Cancer and in Subjects with CRC With Secondary Resistance to Prior Anti-EGFR Therapy
Trial description: This is an open-label, four-part Phase I/II study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of trametinib (GSK1120212) and dabrafenib (GSK2118436) when administered in combination with the anti-EGFR antibody panitumumab in subjects with BRAF-mutation V600E positive colorectal cancer (CRC) and in subjects with CRC with secondary resistance to prior anti-EGFR therapy. Part 1 of the study will consist of dose-escalation cohorts, following a 3 + 3 enrollment scheme. Part 2 of the study will consist of expansion cohorts to investigate safety and clinical activity of dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination with panitumumab. Part 3 of the study will be a randomized Phase II study comparing dosing with dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination with panitumumab as compared to the chemotherapy comparator (a regimen of leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX), leucovorin calcium, fluorouracil, irinotecan hydrochloride (FOLFIRI) or irinotecan with or without panitumumab or bevacizumab). Subjects will be assigned to treatment groups in a randomized fashion to compare safety and clinical activity. Part 4 of the study will investigate the trametinib/panitumumab combination, including dose escalation and subsequent cohort expansion in two patient populations: 1) BRAF-mutation V600E positive CRC and 2) subjects with CRC who developed secondary resistance to prior anti-EGFR therapy. The objective of Part 4 is to identify the recommended Phase 2 dose/regimen for trametinib dosed in combination with panitumumab in dose escalation and to identify an initial signal of clinical activity in expansion cohorts.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
None (Open Label)
Allocation:
Randomized
Primary outcomes:
Part 1, Part 2, Part 4A and Part 4B: Composite safety parameters including adverse events and changes in laboratory values, vital signs and dose interruptions, modifications and discontinuations
Timeframe: one year
Part 2 and Part 4B: Response rate (Complete Response [CR] + Partial Response [PR]) in subjects in the dosing groups
Timeframe: one year
Part 3: Progression -free survival (PFS)
Timeframe: one year
Secondary outcomes:
Part 1: Plasma pharmacokinetics (PK) profile of dabrafenib, trametinib and panitumumab in combination dosing
Timeframe: up to and including Week 20
Part 1: Response rate (CR +PR) of dabrafenib dosed orally in combination with panitumumab
Timeframe: one year
Part 1 and Part 2: Progression free survival of subjects treated with dabrafenib dosed orally in combination with panitumumab
Timeframe: one year
Part 1 and Part 2: Duration of response of dabrafenib dosed orally in combination with panitumumab
Timeframe: one year
Part 1: Response rate (CR +PR) of trametinib dosed orally in combination with dabrafenib and panitumumab
Timeframe: one year
Part 1 and Part 2: Progression free survival subjects treated with trametinib dosed orally in combination with dabrafenib and panitumumab
Timeframe: one year
Part 1 and Part 2: Duration of response of trametinib dosed orally in combination with dabrafenib and panitumumab
Timeframe: one year
Part 1, Part 2, Part 4A and Part 4B: Change in levels of proteins/ Ribonucleic acid (RNA) in pre- and post-dose tumor tissue
Timeframe: One year (At the time of disease progression)
Part 2: Plasma pharmacokinetics profile of of dabrafenib and trametinib dosed orally in combination with anti-EGFR antibody (panitumumab)
Timeframe: up to and including Week 20
Part 2: Overall survival (OS) of subjects treated with dabrafenib dosed orally in combination with panitumumab
Timeframe: one year
Part 2: OS of subjects treated with trametinib dosed orally in combination with dabrafenib and panitumumab
Timeframe: one year
Part 3: Response rate (CR +PR) of dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy
Timeframe: one year
Part 3: Duration of response to dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy
Timeframe: one year
Part 3: OS of subjects treated with dabrafenib/ panitumumab or trametinib/ dabrafenib/panitumumab combinations as compared to standard of care therapy
Timeframe: one year
Part 3: To evaluate and compare the PFS of the trametinib/dabrafenib/panitumumab combination as compared to the dabrafenib/panitumumab combination
Timeframe: one year
Part 3: Composite safety parameters including adverse events and changes in laboratory values, vital signs and dose interruptions, modifications and discontinuations
Timeframe: one year
Part 4A: Plasma pharmacokinetics profile of trametinib and panitumumab after combination therapy
Timeframe: up to and including Week 20
Part 4A: Response rate (CR +PR) of panitumumab/trametinib combination therapy in patient populations
Timeframe: one year
Part 4A and Part 4B: Progression free survival of panitumumab/trametinib combination therapy in patient populations
Timeframe: one year
Part 4A and Part 4B: Duration of response of panitumumab/trametinib combination therapy in patient populations
Timeframe: one year
Part 4B Plasma pharmacokinetics profile of trametinib dosed orally in combination with anti-EGFR antibody (panitumumab)
Timeframe: up to and including Week 20
Part 4B Overall survival of response with trametinib dosed in combination with panitumumab
Timeframe: one year
Interventions:
Drug: Panitumumab
Drug: Dabrafenib
Drug: Trametinib
Drug: 5-fluorouracil
Enrollment:
170
Observational study model:
Not applicable
Primary completion date:
2016-15-04
Time perspective:
Not applicable
Clinical publications:
Not applicable
Medical condition
Cancer, Neoplasms
Product
dabrafenib, dabrafenib/trametinib, panitumumab, trametinib
Collaborators
Not applicable
Study date(s)
December 2012 to March 2018
Type
Interventional
Phase
1/2
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
none
- Subjects eligible for enrolment in this study must meet all of the following criteria
- Provided written informed consent,
- Subjects meeting any of the following criteria must not be enrolled in the study
- History of prior malignancy, other than colorectal cancer.
Inclusion and exclusion criteria
Inclusion criteria:
- Subjects eligible for enrolment in this study must meet all of the following criteria
- Provided written informed consent,
- Male or female >=18 years of age and able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
- Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF V600E mutation positive CRC
- Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic CRC that either harbours the BRAF V600E –mutation, as determined by relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy, defined as patients that derived benefit (disease control based on investigator assessment for >6 months OR partial response [confirmed or unconfirmed] based on RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then subsequently progressed on therapy. The anti-EGFR therapy must have been the most recent therapy and the patient must have progressed based on investigator assessment within 3 months of screening. Acceptable prior anti-EGFR-containing therapies include: a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b. irinotecan/anti-EGFR combo after previously having disease progression (based on investigator assessment) on an irinotecan-containing regimen
- Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation positive advanced or metastatic colorectal cancer (CRC who are eligible to receive fluoropyrimidine-containing chemotherapy regimen that have experienced documented radiographic progression on one prior line of fluoropyrimidine-containing chemotherapy (previous anti-EGFR therapy is excluded), Second-line for advanced/metastatic disease, having failed or been intolerant to at least one regimen of fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in the advanced/metastatic setting. Enrollment in Part 3 may only occur following confirmation of KRAS wild-type cancer.
- Archival tissue is required; if archival tissue is not available or found to not contain tumor tissue, a fresh biopsy is required.
- Measurable disease per RECIST version 1.1.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use one of the contraception methods listed in protocol.
- Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal female defined as 12 months of spontaneous amenorrhea to be verified with a follicle-stimulating hormone (FSH) level >40 Milli-international units per milliliter (MIU/mL) and estradiol level <40 picogram per milliliter (pg/mL). Child-bearing potential and agrees to use one of the contraceptive methods listed in protocol.
- Female subjects must agree to use contraception from 7 days prior to the first dose of study drug(s) until 6 months after the last dose of panitumumab, until 4 months after the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever is longer. Additionally, women of childbearing potential must have had a negative serum pregnancy test within 7 days prior to the first dose of study drug(s).
- Adequate organ system function as defined in absolute neutrophil count greater than or equal to 1.2X10^9/Liter (L), hemoglobin greater than or equal to 9 grams per deciliter (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or equal to 75 × 10^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and Partial Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal (ULN); serum magnesium greater than or equal to the lower limit of normal (LLN); albumin greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total bilirubin less than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than or equal to 1.5XULN or calculated creatinine clearance greater than or equal to 50mL/min; left ventricular ejection fraction (LVEF) greater than or equal to the LLN by echocardiography (ECHO) or multigated acquisition scan (MUGA).
- Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
Exclusion criteria:
- Subjects meeting any of the following criteria must not be enrolled in the study
- History of prior malignancy, other than colorectal cancer.
- Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures.
- Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator’s assessment).
- History of sensitivity to heparin or heparin-induced thrombocytopenia.
- Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or biologic therapy).
- Prior exposure to a MEK inhibitor.
- Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF inhibitor.
- Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of KRAS-mutation based on previous KRAS-testing. Note: Propsective KRAS testing is not required. However, if the results of previous KRAS testing are known, they must be used in assessing eligibility. KRAS testing will be performed retrospectively for all patients.
- Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody
- Received an investigational or approved anti-cancer drug within 4 weeks, or within 5 half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug(s).
- Part 3: Received more than one prior anti-cancer therapy in the metastatic setting, exclusive of previous adjuvant regimens. Previous investigational anti-cancer therapy in the metastatic setting is prohibited.
- Current use of a prohibited medication or requirement to dose with any of these medications during treatment with study drug(s).
- Known Hepatitis B, or Hepatitis C infection.
- Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of study drug(s).
- Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of study drug(s). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within 2 weeks prior to first dose of study drug(s).
- Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer therapy, with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory values that are allowed per inclusion criteria.
- History of retinal vein occlusion (RVO).
- Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of drugs. Previous colectomy is acceptable.
- Subjects with brain metastases are excluded, unless: All known lesions must be previously treated with surgery or stereotactic radio-surgery, and Brain lesion(s), if present, must be confirmed stable (i.e., no increase in lesion size) for >=90 days prior to first dose of study drug(s). This must be documented with two consecutive MRI or CT scans using contrast, and Asymptomatic with no corticosteroids requirement for >=30 days prior to first dose of study drug(s), and No enzyme-inducing anticonvulsants for >=14 days prior to first dose of study drug(s). In addition, for subjects that had brain metastases but currently have no evidence of disease (NED), NED for >=12 weeks is required and must be confirmed by two consecutive MRI or CT scans (using contrast) separated by >=6 weeks, prior to randomization. Enrollment of a subject with brain metastases who meet the above criteria requires approval of a GlaxoSmithKline (GSK) Medical Monitor.
- Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol.
– History or evidence of cardiovascular risk including any of the following: LVEF
- Unstable pulmonary embolism, deep vein thrombosis, or other significant arterial/venous thromboembolic event <=30 days before randomization. If on anticoagulation, subject must be on stable therapeutic dose prior to randomization.
- Subjects with a history of pneumonitis or interstitial lung disease (ILD).
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug(s) or their excipients.
- Pregnant or lactating female.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Uncontrolled diabetes or other medical condition that may interfere with assessment of toxicity.
Trial location(s)
No location data available.
Study documents
No study documents available.
Results overview
Study Results yet to be posted
Recruitment status
No longer a GSK study
Actual primary completion date
Not applicable
Actual study completion date
Not applicable
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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