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

The present 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 BRAF and MEK inhibition. Overall response rate and duration to this
combination will also be assessed.

Tissue will be collected at baseline and at 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. We anticipate that up to 50% of patients may
continue on therapy post-progression for 2-8 weeks.

BRF113220, the phase I/II trial of the BRAF inhibitor dabrafenib in combination with the MEK
inhibitor trametinib is ongoing in metastatic melanoma to establish the safety of this
combination, and to determine the recommended phase 2 doses (RP2D) for each agent. Expansion
cohorts at the RP2D for these drugs in combination were included in the phase I to
characterize the safety in more detail, and to explore the efficacy of this combination. The
combination was well tolerated as described in section 1.5, with decreased frequency of rash
compared to either agent alone and with just 1 report of cutaneous SCC.

This proposed study will utilize the RP2D determined in the Phase I/II study: trametinib 2mg
QD and dabrafenib 150 mg BID. Despite a very promising overall response rate of 81%, these
patients will also likely go on to develop resistance as a result of new resistance
mutations, and given the cooperative signaling network of kinases that sense inhibition of
key nodal kinases and induce compensatory responses that offset pharmacological intervention.
The study objectives are as follows: Objectives Primary Objective To identify kinases that
are differentially expressed pre- and post-treatment with BRAF (dabrafenib) and MEK
(trametinib) inhibitors, and to determine a kinome signature predictive of resistance to
BRAF/MEK inhibition in stage III/IV melanoma Secondary Objectives To explore whether
resistance to BRAF and MEK inhibition is associated with new functional mutations in the
approximately 150 oncogenes / tumor suppressor genes that are assessed in more than 10% of
the tumors (using NextGen DNA sequencing technology) in the subset of patients who co-enroll
in LCCC1108, with particular focus on one of five established resistance genes (BRAF, NRAS,
MEK1, MAP3K8 or COT, and PTEN) To determine the overall response rate (ORR: complete response
+ partial response) as measured via RECISTv1.1 To estimate the duration of ORR as measured
via RECISTv1.1 To estimate progression-free survival (PFS) as defined by RECISTv1.1 To
estimate the rate of overall survival (OS) at 1 year from day 1 of treatment

Primary Endpoint Kinome signature pathway will be based on comparison of kinome expression
from pre- and post-treatment biopsies using Multiplexed Inhibitor Beads (MIBs) coupled with
mass spectrometry.

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 <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

Main Study Exclusion Criteria:

Any subject meeting any of the following exclusion criteria at baseline will be ineligible
for study participation:

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

Brain metastases are excluded unless:

- All known lesions were previously treated with surgery or stereotactic surgery
(whole-brain radiation is not allowed unless given after definitive treatment with
surgery or stereotactic surgery), AND

- Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in
lesion size) for ≥ 12 weeks prior to D1 of study treatment (stability must be
confirmed with two consecutive magnetic resonance image (MRI) or computed tomography
(CT) scans with contrast, AND

- Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to D1 of study
treatment, AND

- Treatment with any CYP enzyme inducing anticonvulsants occurred < 4 weeks prior to D1
of study treatment

NOTE: if study subject has history of brain metastasis, but currently has no evidence of
disease in brain (NED), confirmation by two consecutive scans separated by ≥6 weeks prior
to D1 of treatment is required.

Pulmonary embolism on active therapy History of interstitial lung disease or pneumonitis
Known HIV, Hepatitis B or C infection (with the exception of chronic or cleared HBV and HCV
infection which will be allowed provided the following tests are done at screening: viral
hepatitis serology, Hepatitis B surface antigen and Hepatitis B core antibody (IgM) and/or
Hepatitis C RNA) Currently active GI disease, or prior surgery that may affect ability to
absorb oral medications

History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment
epithelial detachment (RPED):

- Predisposing factors to RVO or RPED (e.g. uncontrolled glaucoma or ocular
hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus,
or history of hyperviscosity or hypercoagulability syndromes)

- Visible retinal pathology as assessed by ophthalmic exam that is considered a risk
factor for RVO or CSR such as:

- Evidence of new optic disc cupping

- Evidence of new visual field defects

- Intraocular pressure > 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.