Part 1 primary objectives: To determine the safety, tolerability and range of tolerated combination doses in subjects with BRAF-V600E mutation-positive CRC intwo dosing groups:* dabrafenib dosed orally in combination with panitumumab * trametinib…
ID
Source
Brief title
Condition
- Other condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Health condition
Colorectal Cancer
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1 primary objectives:
To determine the safety, tolerability and range of tolerated combination doses
in subjects with BRAF-V600E mutation-positive CRC in
two dosing groups:
* dabrafenib dosed orally in combination with panitumumab
* trametinib dosed orally in combination with dabrafenib and panitumumab
Part 2 primary objectives:
To determine the safety, tolerability and range of tolerated combination doses
in subjects with BRAF-V600E mutation-positive CRC in
two dosing groups:
* dabrafenib dosed orally in combination with panitumumab
* trametinib dosed orally in combination with dabrafenib and panitumumab
Secondary outcome
Part 1 secondary objectives:
To describe the pharmacokinetics of dabrafenib, trametinib and panitumumab
after combination therapy
To determine preliminary clinical activity of dabrafenib dosed orally in
combination with panitumumab
To determine clinical activity of trametinib dosed orally in combination with
dabrafenib and panitumumab
Part 2 secondary objectives:
To characterize the population PK parameters of dabrafenib and trametinib dosed
orally in combination with anti-EGFR antibody (panitumumab)
To characterize the durability of response with dabrafenib dosed orally in
combination with panitumumab
To characterize the durability of response with trametinib dosed orally in
combination with dabrafenib and panitumumab
Background summary
The study is designed to identify the recommended Phase 2 dose/regimen for the
doublet (dabrafenib/panitumumab) and the triplet
(dabrafenib/trametinib/panitumumab) in Part 1, identify an initial signal of
clinical activity in Part 2 and to perform a randomized
comparison of the experimental arms to a chemotherapy comparator arm (a regimen
of FOLFOX or FOLFIRI with or without panitumumab or bevacizumab) in Part 3.
Extrapolating from the experience in BRAF V600E -mutation positive melanoma, it
is expected that the triple combination is likely to provide the greatest
benefit to subjects, in which case the inclusion of the double combination
serves as a
control to assess the important *contribution of components* question. However,
another possible outcome is that the double combination is superior (e.g., due
to poor tolerability of the triple combination), an outcome that this study
design will also adequately evaluate.
Study objective
Part 1 primary objectives:
To determine the safety, tolerability and range of tolerated combination doses
in subjects with BRAF-V600E mutation-positive CRC in
two dosing groups:
* dabrafenib dosed orally in combination with panitumumab
* trametinib dosed orally in combination with dabrafenib and panitumumab
Part 2 primary objectives:
To determine the safety, tolerability and range of tolerated combination doses
in subjects with BRAF-V600E mutation-positive CRC in
two dosing groups:
* dabrafenib dosed orally in combination with panitumumab
* trametinib dosed orally in combination with dabrafenib and panitumumab
Study design
This study will evaluate the safety, tolerability and efficacy of the doublet
dabrafenib/panitumumab and triplet trametinib/dabrafenib/panitumumab
combinations in subjects with BRAF- mutation V600E positive CRC. Part 1
includes a 3+3
dose escalation that will identify tolerable combination doses for the two
combinations. The safety and tolerability of these combination doses will be
confirmed in expansion cohorts in Part 2, followed by a randomized evaluation
of the efficacy and safety of the combinations in Part 3.
Intervention
Patients will be enrolled in two dosing groups:
* dabrafenib in combination with panitumumab
* trametinib in combination with dabrafenib and panitumumab
Study burden and risks
See C4.
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Basel 4056
CH
Lichtstr. 35
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Listed location countries
Age
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-004802-81-NL |
| ClinicalTrials.gov | NCT#01750918 |
| CCMO | NL43976.031.13 |