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

NCT01726738 | Completed Phase 2 Results DMC

• 1 other identifier: LCCC 1128
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Stage III Melanoma; Stage IV Melanoma; Unresectable Melanoma; BRAF Mutant Melanoma

Keywords

Melanoma; Stage III; Stage IV; Unresectable; BRAF Mutant; Dabrafenib; Trametinib; Kinome; Resistance; Sequencing; Mutations; Kinases; Mechanism

Outcome Measures

Primary Outcomes (2)

• Change in Kinase Expression

  The primary outcome of this study is to identify kinases that are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK (trametinib) inhibitors. The kinases will be profiled using Multiplexed Inhibitor Beads (MIBs) coupled with mass spectrometry (MS) and reported as a sum of the Log 2 Fold Change between baseline and one year post treatment across all patients

  Baseline and One year post treatment

• Kinome Signature Predictive of Resistance

  Prediction analysis of microarrays (PAM) based on nearest shrunken centroid will also be carried out to identify a subset of kinases that predicts resistance to BRAF+MEK inhibition.

  One year post treatment

Secondary Outcomes (5)

• BRAF and MEK Inhibition Associated With New Functional Mutations in the Approximately 150 Oncogenes

  One year

• Overall Response Rate (ORR)

  One year post treatment

• Duration of Overall Response

  One year post treatment

• Progression Free Survival (PFS)

  One year post treatment

• Rate of Overall Survival (OS) at 12 Months

  One year post treatment

Study Arms (1)

BRAF (dabrafenib) and MEK (trametinib) inhibitors

EXPERIMENTAL

Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

Drug: BRAF inhibitor dabrafenib and MEK inhibitor trametinib

Interventions

BRAF inhibitor dabrafenib and MEK inhibitor trametinib DRUG

Patients will receive the BRAF inhibitor dabrafenib and MEK inhibitor trametinib orally at the RP2D determined in the Phase I/II study (BRF113220): trametinib 2mg QD and dabrafenib 150 mg BID on a continuous basis. A cycle will be defined as 3 weeks in duration. Cycles will be repeated until disease progression (clinical or radiological). Patients may remain on treatment after progression (at the discretion of the investigator) as long as they are still experiencing clinical benefit.

Also known as: BRAF Inhibitor Dabrafenib GSK2118436, MEK Inhibitor Trametinib GSK1120212

BRAF (dabrafenib) and MEK (trametinib) inhibitors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 \<1.5 x ULN (patients with elevated bilirubin due to Gilbert's disease will not be excluded)
• AST and ALT \< 2.5× ULN
• CrCl ≥50mL/min per Cockcroft-Gault Prior anti-cancer treatment related toxicities except alopecia and lab values as outlined in the criterion above must be less than or equal to Grade 1 as per CTCAEv4 Willing to undergo biopsy for research purposes only Females of child-bearing potential: willing to use two forms of effective contraception, and to continue use for 16 weeks post last dose of study medication. Effective contraception is defined as any medically recommended method (or combination of methods) as per standard of care, including abstinence. Females of non-childbearing potential are those who are postmenopausal (defined as greater than 1 year without menses with appropriate clinical profile, e.g., age appropriate: \>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 \<40pg/mL (\<140 pmol/L); or who have had a bilateral tubal ligation or tubal occlusion, bilateral oophorectomy, or hysterectomy. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described from D1 of treatment, throughout the treatment period, and for 16 weeks after the last dose of study treatment. If a subject becomes pregnant during the treatment period of the study, the study treatments should be stopped immediately.
• In women of child-bearing potential, negative serum pregnancy test within 48 hours prior to day 1 of study treatment and agree to use effective contraception. Effective contraception is defined as: (a) an intrauterine device with a documented failure rate of less than 1% per year. (b) male partner sterilization prior to the female subject's entry, and this male is the sole sexual partner for that female. (c) complete abstinence from sexual intercourse for 14 days prior to enrollment throughout study treatment, and for at least 4 months after the last dose of study treatment. Abstinence is only acceptable when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar ovulation, symptothermal, post-ovulation methods, etc) and withdrawal are not acceptable methods of contraception. (d) double- barrier contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository). Note: hormonal based methods (e.g. oral contraceptives) are not permitted.
• Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for 4 months following the last dose of study treatment Measurable disease as defined by RECIST v1.1 Able to swallow and retain oral medication Left ventricular ejection fraction by ECHO ≥ institutional lower limit of normal

You may not qualify if:

• Patients with a history of a prior malignancy are excluded unless they have been disease free for 3 or more years or unless they have a completely resected non-melanoma skin cancer, and/or subjects with indolent second malignancies.
• History of malignancy with confirmed activating RAS mutation at any time. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility.
• Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib (GSK2118436), vemurafenib, and LX281/BMS-908662) or a MEK inhibitor (including but not limited to trametinib (GSK1120212), AZD6244, and RDEA119); NOTE: There is no limit to the number of other prior therapies, and patients may be previously untreated.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).
• Active GI or intracranial hemorrhage
• History or evidence of cardiovascular risk including any of the following:
• QTc ≥ 480 msec;
• History or evidence of current clinically significant uncontrolled arrhythmias;
• o Exception: Subjects with controlled atrial fibrillation for \>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\<140/90) with appropriate anti-hypertensive therapy or diet prior to study entry;
• Patients with intra-cardiac defibrillators or permanent pacemakers;
• Known cardiac metastases;
• Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram (subjects with grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
• History of known glucose-6-phosphate dehydrogenase (G6PD) deficiency

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

Lineberger Comprehensive Cancer Center, University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Related Links

• Lineberger Comprehensive Cancer Center, UNC Chapel Hill, NC

MeSH Terms

Conditions

Melanoma

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Robin Johnson
• Organization: University of North Carolina Lineberger Comprehensive Cancer Center

robin_v_johnson@med.unc.edu

919-966-1125

Study Officials

• Carrie Lee, MD

  UNC Lineberger Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 8, 2012
• First Posted: November 15, 2012
• Study Start: April 4, 2013
• Primary Completion: November 3, 2017
• Study Completion: September 17, 2020
• Last Updated: November 23, 2020
• Results First Posted: September 7, 2020

Record last verified: 2020-09

Locations

US (1)