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 Positive Colorectal Cancer.

Completed

Conditions: 10017991
colorectal cancer
Colorectal Cancer

Registration Number: NL-OMON47621

Lead Sponsor: ovartis

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 16

Inclusion Criteria

* BRAF V600E mutation positive colorectal cancer (CRC), as determined by local genetic testing.
* Provision of archival tissue; if archival tissue is not available or found to not contain tumor tissue, a fresh biopsy is required.
* Willingness to follow contraception requirements.
* ECOG 0 or 1.
* LVEF *LLN, or 50% if not defined by institution.
* Organ function as noted in Table 17:
* ANC *1.2 × 109/L
* Hemoglobin *9 g/dL or 5.6 mmol/L
* Platelets *75 × 109/L
* PT/INR and PTT *1.5 x ULN
* Mg++ * LLN
* Albumin *2.5 g/dL or 25 g/L
* Total bilirubin *1.5 x ULN
* Creatinine * 1.5 ULN or Calculated creatinine clearance * 50 mL/min

Exclusion Criteria

* Prior malignancy, other than colorectal cancer.
* Prior exposure to BRAF or MEK inhibitors.
* Part 2 ONLY* prior exposure to EGFR antibodies or inhibitors.
* KRAS mutation positive.
* 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).
* RVO, CSR or predisposing factors to RVO or CSR. Ophthalmic exam is required at screening, and intraocular pressure must not exceed 21mm Hg.
* Brain mets must be stable *90 days and treated with surgery or stereotactic radiosurgery.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Part 1 primary objectives:<br /><br>To determine the safety, tolerability and range of tolerated combination doses<br /><br>in subjects with BRAF-V600E mutation-positive CRC in<br /><br>two dosing groups:<br /><br>* dabrafenib dosed orally in combination with panitumumab<br /><br>* trametinib dosed orally in combination with dabrafenib and panitumumab<br /><br><br /><br><br /><br>Part 2 primary objectives:<br /><br>To determine the safety, tolerability and range of tolerated combination doses<br /><br>in subjects with BRAF-V600E mutation-positive CRC in<br /><br>two dosing groups:<br /><br>* dabrafenib dosed orally in combination with panitumumab<br /><br>* trametinib dosed orally in combination with dabrafenib and panitumumab</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Part 1 secondary objectives:<br /><br>To describe the pharmacokinetics of dabrafenib, trametinib and panitumumab<br /><br>after combination therapy<br /><br>To determine preliminary clinical activity of dabrafenib dosed orally in<br /><br>combination with panitumumab<br /><br>To determine clinical activity of trametinib dosed orally in combination with<br /><br>dabrafenib and panitumumab<br /><br><br /><br>Part 2 secondary objectives:<br /><br>To characterize the population PK parameters of dabrafenib and trametinib dosed<br /><br>orally in combination with anti-EGFR antibody (panitumumab)<br /><br>To characterize the durability of response with dabrafenib dosed orally in<br /><br>combination with panitumumab<br /><br>To characterize the durability of response with trametinib dosed orally in<br /><br>combination with dabrafenib and panitumumab</p><br>