Official Title
Phase I/II Study of Dabrafenib, Trametinib, and Navitoclax in BRAF Mutant Melanoma (Phase I and II) and Other Solid Tumours (Phase I Only)
Summary:
This partially randomized phase I/II trial studies the side effects and best dose of
dabrafenib, trametinib, and navitoclax and to see how well they work in treating patients
with v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant melanoma or solid tumours
that have spread to other parts of the body or cannot be removed by surgery. Dabrafenib,
trametinib, and navitoclax may stop the growth of tumour cells by blocking some of the enzymes
needed for cell growth.
Trial Description
Primary Outcome:
- Maximal degree of tumour regression (Phase II)
- Proportion of patients with a complete response (CR), per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, in the cohort of patients treated with dabrafenib, trametinib, and navitoclax (DTN) (Phase II)
- Recommended phase II dose of the combination of dabrafenib, trametinib, and navitoclax determined by dose-limiting toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (Phase I)
Secondary Outcome:
- Objective response rate (ORR) (Phase II)
- Overall survival (OS) (Phase II)
- Progression free survival (PFS) (Phase II)
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD), toxicity, and safety profile of navitoclax
when given in combination with dabrafenib and trametinib in patients with BRAF-mutant solid
tumours. (Phase I) II. To estimate the complete response (CR) rate in patients with
BRAF-mutant melanoma treated with dabrafenib, trametinib, and navitoclax as compared to the
historical control dabrafenib and trametinib combination (DT). (Phase II) III. To compare the
maximal tumour regression in patients with BRAF-mutant melanoma treated with dabrafenib,
trametinib versus dabrafenib, trametinib, and navitoclax. (Phase II)
SECONDARY OBJECTIVES:
I. To describe pharmacodynamics effects of treatment with dabrafenib, trametinib, and
navitoclax on both serial tumour biopsies and serial blood draws in a small subset of patients
treated with BRAF-mutant melanoma. (Phase I) II. To describe the pharmacokinetics of
treatment with dabrafenib, trametinib, and navitoclax. (Phase I) III. To compare the
progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) in
patients with BRAF-mutant melanoma treated with dabrafenib, trametinib, versus dabrafenib,
trametinib, and navitoclax. (Phase II) IV. To compare the degree of apoptosis induced in
on-treatment biopsies of patients with BRAF-mutant melanoma treated with dabrafenib,
trametinib versus dabrafenib, trametinib, and navitoclax. (Phase II) V. To explore other
pharmacodynamic effects in on-treatment biopsies of patients with BRAF-mutant melanoma
treated with either dabrafenib, trametinib versus dabrafenib, trametinib, and navitoclax
including cell proliferation (Ki-67), proteomics (reverse-phase protein microarrays [RPPA]),
and B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (BCL-2) family gene expression
analysis. (Phase II)
OUTLINE:
This is a phase I, dose-escalation study of dabrafenib, trametinib, and navitoclax
followed by a randomized phase II study.
PHASE I: Patients receive navitoclax orally (PO) once daily (QD) on days -7 to -1 of course 1
only. Patients also receive dabrafenib PO twice daily (BID), trametinib PO QD, and navitoclax
PO QD days 1-28. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive navitoclax PO QD days -7 to -1 of course 1 only. Patients also
receive dabrafenib PO BID, trametinib PO QD, and navitoclax PO QD on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After the completion of study treatment, patients are followed up for 28 days.
View this trial on ClinicalTrials.gov
