A Phase I/II Study of MCS110 with BRAF/MEK Inhibition in Patients with Melanoma after Progression on BRAF/MEK Inhibition

This research study is studying a combination of targeted therapies as a possible treatment
for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation.

The interventions involved in this study are:

- MCS110

- Dabrafenib

- Trametinib

Inclusion Criteria:

- For enrollment to the phase I portion: participants must have a histologically
confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen
sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is
metastatic or unresectable and for which standard curative measures do not exist or
are no longer effective.

- For enrollment to the phase II portion: participants must have a histologically
confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen
sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and have had
progression of disease on prior BRAF and MEK inhibitor therapy.

- Participants enrolling to the phase I portion of the trial must have evaluable or
measurable disease.

- Participants enrolling to the phase II portion of the trial must have measurable
disease, defined as at least one lesion that can be accurately measured in at least
one dimension (longest diameter to be recorded for non-nodal lesions and short axis
for nodal lesions) as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam.
See Section 11 for the evaluation of measurable disease.

- Age ≥ 18 years. As no dosing or adverse event data are currently available in
participants < 18 years of age, children are excluded from this study but will be
eligible for future pediatric trials.

- ECOG performance status 0 - 2 (see Appendix A).

- Life expectancy of greater than 8 weeks.

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1.5 K/uL

- Platelets ≥ 100 K/uL

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)

- AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN

- Serum creatinine ≤ 1.5 × institutional ULN

- PT-INR ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤
1.5 × their baseline value)

- aPTT ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤
1.5 × their baseline value)

- Participants must have a left ventricular ejection fraction (LVEF) ≥ 50%.

- Participants must have a QTc of ≤ 470 msec for females and ≤ 450 for males on the
screening EKG.

- The effects of MCS110, trametinib and dabrafenib on the developing human fetus are
unknown. For this reason and because anti-cancer agents are known to be teratogenic,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 4 months after the last dose of MCS110.
Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of study participation, and 4 months after
completion of MCS110 administration. Highly Effective contraception methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment

- Male sterilization (at least 6 months prior to screening). For female subjects on
the study, the vasectomized male partner should be the sole partner for that
subject

- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception. In case of use
of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.

- Double-barrier contraception: condom and occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/cream/suppository).

- Ability to understand and the willingness to sign a written informed consent document.

- Participants must have archival tumor tissue available. Participants without archival
tissue may be enrolled at the discretion of the principal investigator.

- All prior anti-cancer treatment-related toxicities (except alopecia and laboratory
values as listed on Table 1) must be ≤ Grade 1 according to the Common Terminology
Criteria for Adverse Events version 4 (CTCAE version 4.0; NCI, 2009) at the time of
randomization

Exclusion Criteria:

- Participants who have had chemotherapy, radiotherapy, biologic therapy, major surgery,
or another investigational agent within 3 weeks (6 weeks for nitrosoureas or mitomycin
C) prior to entering the study. Previous BRAF/MEK inhibitor use is allowed with no
washout period for the phase I and II portions.

- Participants who have not recovered to ≤ CTCAE grade 1 or baseline from toxicity as a
result of previous cancer treatment prior to entering the study (with the exception of
alopecia and peripheral neuropathy which can be ≤ grade 2).

- For enrollment to the phase II portion: participants who have not received prior BRAF
or MEK inhibitor therapy.

- Participants with known untreated brain metastases should be excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events. Participants with a history of brain metastases that have
been treated, are no longer taking corticosteroids, and have been stable on imaging
for ≥ 4 weeks following the last date of treatment are permitted.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MCS110, dabrafenib, or trametinib.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because MCS110, dabrafenib and trametinib
are anti-cancer agents with the potential for teratogenic or abortifacient effects.
Pregnancy status will be verified at various points in the trial and a serum pregnancy
test will be required. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with MCS110, dabrafenib
or trametinib, breastfeeding should be discontinued if the mother is treated with
MCS110, dabrafenib or trametinib.

- Participants with a known history of HIV are ineligible because of the potential for
pharmacokinetic interactions with MCS110, dabrafenib, and trametinib with
antiretroviral agents. In addition, these participants are at increased risk of lethal
infections when treated with marrow-suppressive therapy.

- Participants with a personal or family history of long QT syndrome.

- Participants with a history of a second primary malignancy. Exceptions include:
patients with a history of malignancies that were treated curatively and have not
recurred within 3 years prior to study entry; resected basal and squamous cell
carcinomas of the skin, and completely resected carcinoma in situ of any type.

- Participants with impairment of GI function or GI disease that may significantly alter
the absorption of dabrafenib and trametinib in the opinion of the treating
investigator (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome, small bowel resection).

- Participants who are unable to swallow or retain oral medication.

- Participants that require co-administration of strong or moderate CYP3A inhibitors, as
these medications may alter dabrafenib and trametinib concentrations.

- Participants who require treatment with medications that are strong or moderate CYP3A
inducers, as these medications may alter the concentration of trametinib.

- Participants with evidence of retinal pathology on ophthalmologic examination that is
considered a risk factor for neurosensory retinal detachment/central serous
chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular
degeneration.

- Participants with a history of or current evidence of retinal vein occlusion or
retinal pigment epithelial detachment.

- Participants taking corticosteroids (≥ 10 mg of prednisone or equivalent). Exceptions
may be discussed with the Overall PI on a case by case basis.