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BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01750918
First received: December 6, 2012
Last updated: August 28, 2014
Last verified: July 2014
  Purpose

This is an open-label, three-part Phase 1/2 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 or V600K positive colorectal cancer (CRC). Part 1 of the study will consist of dose-escalation cohorts Part 2 of the study will consist of expansion cohorts to investigate safety and clinical activity, and Part 3 of the study will be a randomized Phase II study comparing both the dabrafenib/panitumumab and dabrafenib/trametinib/panitumumab combinations to a chemotherapy comparator with respect to safety and clinical activity.


Condition Intervention Phase
Cancer
Drug: Part 1 Cohort 1: Dabrafenib plus Panitumumab
Drug: Part 1 Cohort 2: Dabrafenib plus Trametinib plus Panitumumab
Drug: Part 1 Cohort 3A: Dabrafenib plus Trametinib plus Panitumumab
Drug: Part 1 Cohort 3B: Dabrafenib plus Trametinib plus Panitumumab
Drug: Part 1 Cohort 4: Dabrafenib plus Trametinib plus Panitumumab
Drug: Part 2 Cohort 1: Dabrafenib plus Panitumumab
Drug: Part 2 Cohort 2: Dabrafenib plus Trametinib plus Panitumumab
Drug: Part 3 Cohort 1: Dabrafenib plus Panitumumab
Drug: Part 3 Cohort 2: Dabrafenib plus Trametinib plus Panitumumab
Drug: Part 3 Cohort 3: 5-fluorouracil-based chemotherapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Three-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 or V600K Positive Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Dose-limiting toxicities (DLTs) [ Time Frame: one year ] [ Designated as safety issue: Yes ]
    Patients will be monitored weekly for changes from baseline in vital signs, electrocardiograms (ECGs), laboratory blood tests and for any adverse effects over the first 28 days of dosing. In the continuation period, patients will be monitored every 4 weeks for changes from baseline in vital signs, ECGs, laboratory blood tests and for any adverse effects.


Secondary Outcome Measures:
  • Plasma pharmacokinetics of dabrafenib, trametinib and panitumumab in combination dosing. [ Time Frame: up to and including Week 20 ] [ Designated as safety issue: No ]
    Serial blood samples will be collected predose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Pharmacokinetic paramenters will include maximum observed concentration, time of occurrence of maximum observed concentration, and area under the concentration-time curve and trough concentrations.

  • Response rate (complete response + partial response) [ Time Frame: one year ] [ Designated as safety issue: No ]
    Tumors will be assessed using investigator read computed tomography (CT) or magnetic resonance imaging (MRI) at baseline, then every 6 weeks until Week 24 on study, then every 8 weeks, and again at follow-up for patients who discontinue study medication for any reason other than progression or death.

  • progression -free survival (PFS) [ Time Frame: one year ] [ Designated as safety issue: No ]
    Tumors will be assessed using investigator read computed tomography (CT) or magnetic resonance imaging (MRI) at baseline, then every 6 weeks until Week 24 on study, then every 8 weeks, and again at follow-up for patients who discontinue study medication for any reason other than progression or death.

  • duration of response [ Time Frame: one year ] [ Designated as safety issue: No ]
    Tumors will be assessed using investigator read computed tomography (CT) or magnetic resonance imaging (MRI) at baseline, then every 6 weeks until Week 24 on study, then every 8 weeks, and again at follow-up for patients who discontinue study medication for any reason other than progression or death.


Estimated Enrollment: 200
Study Start Date: December 2012
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Doublet: Dabrafenib plus Panitumumab
dabrafenib plus panitumumab
Drug: Part 1 Cohort 1: Dabrafenib plus Panitumumab
Doublet
Drug: Part 2 Cohort 1: Dabrafenib plus Panitumumab
Doublet
Drug: Part 3 Cohort 1: Dabrafenib plus Panitumumab
Doublet
Experimental: Triplet: Dabrafenib plus Trametinib plus Panitumumab
dabrafenib plus trametinib plus panitumumab
Drug: Part 1 Cohort 2: Dabrafenib plus Trametinib plus Panitumumab
Triplet
Drug: Part 1 Cohort 3A: Dabrafenib plus Trametinib plus Panitumumab
Triplet
Drug: Part 1 Cohort 3B: Dabrafenib plus Trametinib plus Panitumumab
Triplet
Drug: Part 1 Cohort 4: Dabrafenib plus Trametinib plus Panitumumab
Triplet
Drug: Part 2 Cohort 2: Dabrafenib plus Trametinib plus Panitumumab
Triplet
Drug: Part 3 Cohort 2: Dabrafenib plus Trametinib plus Panitumumab
Triplet
Active Comparator: 5-fluorouracil-based chemotherapy comparator
5-fluorouracil-based chemotherapy
Drug: Part 3 Cohort 3: 5-fluorouracil-based chemotherapy
chemotherapy comparator

Detailed Description:

This is an open-label, three-part Phase 1/2 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 or V600K positive colorectal cancer (CRC). Part 1 of the study will consist of dose-escalation cohorts, following a 3 + 3 enrollment scheme. The maximum tolerated dose (MTD)/Recommended Phase 2 Regimen (RP2R) of dabrafenib plus panitumumab will be defined first in Part 1. Upon definition of a tolerable dose of dabrafenib plus panitumumab, trametinib will be added to the combination and subsequent cohorts will dose with all three drugs in combination. Part 2 of the study will consist of expansion cohorts to enroll subjects with BRAF-mutation V600E or V600K positive CRC, and investigate safety and clinical activity of dabrafenib in combination with panitumumab and trametinib plus dabrafenib in combination with panitumumab. For each combination (dabrafenib/panitumumab and dabrafenib/trametinib/panitumumab), the optimal safe and tolerable dose combinations defined in Part 1 will be brought forward into Part 2. Based on the safety and tolerability of these combinations, these doses may be modified during Part 2 of the study. 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 a chemotherapy comparator. Subjects will be assigned to one of three treatment groups in a randomized fashion to compare safety and clinical activity: 1) dabrafenib plus panitumumab, 2) dabrafenib plus trametinib plus panitumumab, or 3) chemotherapy comparator. Dose levels for dabrafenib, trametinib, and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2. In the event that the benefit/risk ratio for either of the two experimental combinations is not sufficiently positive (either due to excessive toxicity or clearly inferior efficacy), one of the arms may be excluded from Part 3 of the study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

  • Written informed consent provided.
  • At least 18 years of age or older.
  • Able to swallow and retain oral medication.
  • No clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
  • Confirmed diagnosis of advanced or metastatic BRAF V600E or V600K mutation positive colorectal cancer (CRC).
  • 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.
  • Performance Status Score of 0 or 1 according to the Eastern Cooperative Oncology Group scale.
  • Men must have either:

had a prior vasectomy, or agree to use one of the contraception methods listed in the protocol from the time of the first dose of study drug(s) and until 6 months after the last dose of panitumumab, or 16 weeks following the last dose of dabrafenib or trametinib, based on the life cycle of sperm.

  • 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 >40MIU/mL and estradiol level <40pg/mL.

Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in the protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

Child-bearing potential and agrees to use one of the contraceptive methods listed in the protocol for an appropriate period of time as determined by the product label and applicable IBs) prior to the start of dosing to sufficiently minimize risk of pregnancy at that point.

  • Female subjects must agree to use contraception from the time of the first dose of study drug(s) until 60 days after the last dose of any study drug. Note: oral contraceptives are not reliable due to potential drug-drug interactions.
  • 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 functions, including:

absolute neutrophil count greater than or equal to 1.2X10^9/L, hemoglobin greater than or equal to 9 g/dL or 5.6 mmol/L, platelets greater than or equal to75 × 10^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and Partial Thromboplastin Time (PTT) less than or equal to 1.5Xupper 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 g/L, total bilirubin less than or equal to 1.5XULN, and AST and ALT less than or equal to 2.5XULN 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).

EXCLUSION CRITERIA

  • 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), as described in the protocol.
  • Prior exposure to BRAF or MEK inhibitors.
  • Prior exposure to EGFR inhibitors, including anti-EGFR antibodies or EGFR (for patients enrolling in Part 2 ONLY)
  • Known presence of KRAS-mutation based on previous KRAS-testing.
  • 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).
  • Current use of a prohibited medication or requirement to dose with any of these medications during treatment with study drug(s).
  • Known human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection. Subjects who have evidence of clearance of Hepatitis B or Hepatitis C infection can be enrolled with approval of the GSK Medical Monitor.
  • Current use of therapeutic warfarin. Therapeutic dosing of warfarin is defined as resulting in an INR greater than 1.3. Low molecular weight heparin (LMWH) is permitted provided that the subject's PT and PTT meet entry criteria. Subjects requiring therapeutic levels of LMWH must receive approval from GSK Medical Monitor and must be monitored appropriately as clinically indicated.
  • 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) or central serous retinopathy (CSR), predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes).
  • Visible retinal pathology as assessed by ophthalmic examination that is considered a risk for RVO or CSR, such as:

Evidence of new optic disc cupping. Evidence of new visual field defects. Intraocular pressure greater than 21mm Hg as measured by tonography.

  • 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 radiosurgery, and Brain lesion(s), if present, must be confirmed stable (i.e., no increase in lesion size) for greater than or equal to 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 greater than or equal to 30 days prior to first dose of study drug(s), and No enzyme-inducing anticonvulsants for greater than or equal to 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 greater than or equal to 12 weeks is required and must be confirmed by two consecutive MRI or CT scans (using contrast) separated by greater than or equal to 6 weeks, prior to randomization. Enrollment of a subject with brain metastases who meet the above criteria requires approval of a 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 less than LLN A QT interval corrected for heart rate using the Bazett's formula (QTcB) greater than or equal to 480 msec; History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for greater than 30 days prior to randomization are eligible.

History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization.

History or evidence of current greater than or equal to Class II congestive heart failure as defined by New York Heart Association (NYHA).

Treatment refractory hypertension defined as a blood pressure of systolic greater than 140 mmHg and/or diastolic greater than 90 mm Hg which cannot be controlled by anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases;

  • Unstable pulmonary embolism, deep vein thrombosis, or other significant arterial/venous thromboembolic event less than or equal to 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01750918

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United States, Arizona
GSK Investigational Site Recruiting
Scottsdale, Arizona, United States, 85259
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, California
GSK Investigational Site Recruiting
San Francisco, California, United States, 94115
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Massachusetts
GSK Investigational Site Recruiting
Boston, Massachusetts, United States, 02114
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Recruiting
Boston, Massachusetts, United States, 02215
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, North Carolina
GSK Investigational Site Recruiting
Chapel Hill, North Carolina, United States, 27599-7305
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Pennsylvania
GSK Investigational Site Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Tennessee
GSK Investigational Site Recruiting
Nashville, Tennessee, United States, 37203
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Belgium
GSK Investigational Site Not yet recruiting
Bruxelles, Belgium, 1200
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Recruiting
Leuven, Belgium, 3000
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
France
GSK Investigational Site Recruiting
Paris cedex 12, France, 75571
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Recruiting
Villejuif Cedex, France, 94805
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Japan
GSK Investigational Site Recruiting
Aichi, Japan, 464-8681
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Recruiting
Chiba, Japan, 277-8577
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Netherlands
GSK Investigational Site Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Recruiting
Utrecht, Netherlands, 3584 CX
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Spain
GSK Investigational Site Recruiting
Barcelona, Spain, 08035
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United Kingdom
GSK Investigational Site Not yet recruiting
Birmingham, United Kingdom, B15 2TH
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01750918     History of Changes
Other Study ID Numbers: 116833
Study First Received: December 6, 2012
Last Updated: August 28, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
BRAF mutation
expansion cohorts
safety
Advanced Colorectal Cancer
KRAS wild-type
Dose escalation
combination dosing

Additional relevant MeSH terms:
Colorectal Neoplasms
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Rectal Diseases
Antibodies, Monoclonal
Dabrafenib
Fluorouracil
Trametinib
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014