Phase 2 N=17 Treatment

LCCC 1128: Open Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF Mutant Melanoma; Correlation of Resistance With the Kinome and Functional Mutations

Stage III Melanoma · Stage IV Melanoma · Unresectable Melanoma · BRAF Mutant Melanoma

Bottom Line

View on ClinicalTrials.gov: NCT01726738 ↗

Enrolled (actual)

Serious AEs

64.7%

Results posted

Sep 2020

Primary outcome: Primary: Change in Kinase Expression — -20.87259; -19.64376; -16.41738; -12.5401 Sum Log 2 Fold Change Kinase Expression

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: BRAF inhibitor dabrafenib and MEK inhibitor trametinib (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: UNC Lineberger Comprehensive Cancer Center
Primary completion: Nov 2017

Outcome Measures

Outcome	Result	p-value
PRIMARY Change in Kinase Expression	-20.87259; -19.64376; -16.41738; -12.5401; -12.31239; -12.38811	—
PRIMARY Kinome Signature Predictive of Resistance	—	—
SECONDARY BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes	—	—
SECONDARY Overall Response Rate (ORR)	76	—
SECONDARY Duration of Overall Response	13	—
SECONDARY Progression Free Survival (PFS)	17	—
SECONDARY Rate of Overall Survival (OS) at 12 Months	70	—

Summary

This phase II study in 20 patients with BRAFV600E mutant, unresectable stage III/IV melanoma is designed to explore the mechanisms by which tumors acquire resistance to the combination of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib). Tissue will be collected at baseline and at progression.If a subject is removed from the study for one of a variety of reasons including, but not limited to, an inability to tolerate the combination of dabrafenib and trametinib, a need to receive other therapy or completion of 3-years of study treatment without progression, and the subject later receives, as part of his/her standard of care, the combination of dabrafenib and trametinib and progresses on the standard of care regimen, then the subject may be contacted by the treating physician to be put back on to the LCCC 1128 protocol and have a progression biopsy at this progression time point. Markers of resistance will be explored by performing near kinome-wide profiling on tumor samples, and in patients who co-enroll in institutional protocol LCCC1108, by sequencing tumors using NextGen DNA sequencing technology. Overall response rate and duration to this combination will also be assessed.

Eligibility Criteria

Main Study Inclusion Criteria:

Subject must meet all of the inclusion criteria to participate in this study:

Age ≥18 years Signed written informed consent Histologically confirmed V600E or V600K BRAF mutant melanoma Unresectable Stage III/IV melanoma ECOG PS 0-2

Normal organ function as defined by the following:

Absolute neutrophil count >1.2 × 109/L
Hemoglobin >9 g/dL, platelets >75 × 109/L
PT/INR and PTT ≤1.5 x ULN (Note: subjects receiving anticoagulation treatment may enroll with INR established within the therapeutic range prior to D1 of treatment)
Albumin >2.5 g/dL
Total bilirubin 45 years in the absence of hormone replacement therapy (HRT). In questionable cases, the subject must have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value 30 days prior to D1 of study treatment are eligible.
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to study entry;
Patients with history of hypertension should have hypertension adequately controlled (BP 21 mm Hg Currently receiving cancer therapy (chemotherapy, radiotherapy, immunotherapy, or biologic therapy) NOTE: palliative radiation therapy is permitted for non-target lesions that are either new or present at baseline provided total dose does not exceed 30 Gy. However, radiation skin injury has been reported with concurrent use of dabrafenib and radiation. To reduce this risk, it is recommended that dabrafenib be held for seven days before and two days after radiation in subjects receiving dabrafenib in combination with trametinib when palliative radiation is prescribed.

Use of other prohibited medications within 5 half-lives or 14 days prior to the first dose of study drugs or requires any of these medications while receiving medication on this study Pregnant or lactating female

Inclusion Criteria for Off-Study Subjects to Receive Progression Biopsy

Currently progressing on Trametinib/Deabrafenib Combination Therapy

Willing to undergo biopsy for research purposes only.

Tumor amenable to research biopsy.

Signed written informed consent to have a progression biopsy performed on the LCCC 1128 protocol.

Previously enrolled on the LCCC 1128 study and did not have a progression biopsy previously performed while on study.

View full record on ClinicalTrials.gov →

Data sourced from ClinicalTrials.gov (NCT01726738). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.