Conditions: Melanoma
Keywords: Melanoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 6
Healthy volunteers: no

Brief summary:
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

Detailed description:
This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved MSC110 as a treatment for any disease.

The FDA has approved dabrafenib and trametinib as treatment options for this disease.

Dabrafenib and trametinib attack different proteins that promote the growth of cancerous cells. These two treatments work in cancers with a mutation in the BRAF gene which alters a protein signaling pathway in cancer cells. The BRAF mutation status will be confirmed during this trial by review or procedure in order to make sure this clinical trial is right for the participant. Dabrafenib is a BRAF inhibitor that works by preventing altered BRAF proteins from stimulating the growth of the melanoma cancer cells. Trametinib works by blocking a protein related to BRAF called MEK that has been known to stimulate cells that also promote melanoma growth. In order to participate in the study, the participant disease needs to be tested positive for a mutation (a permanent change in the DNA sequence of a gene) of the BRAF gene that belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. Once the BRAF gene is mutated, the normal functioning of the BRAF protein may be changed. It is normal for patients with a BRAF mutation to receive these types of inhibitor therapies at some point in their treatment.

MCS110 is a colony-stimulating factor-1 (CSF-1) inhibitor. It is a human monoclonal antibody which binds CSF-1. A monoclonal antibody is a type of protein made in the laboratory that can locate and bind to substances in the body, including tumor cells. MCS110 is being developed as a treatment for patients with advanced cancer.

In this research study, the investigators are adding MCS110 to the treatment with dabrafenib and trametinib at the time when the participant's disease is growing despite these medications. The hope is that MCS110 will enhance how the cancer will respond to dabrafenib and trametinib and overcome any resistance to these medications that has developed. In previous laboratory studies performed by treating melanoma cancer cells with a CSF-1R (CSF-1 Receptor which interacts with the CSF-1 protien) inhibitor and a BRAF inhibitor, it was found that the CSF-1R inhibitor was successful in increasing efficacy.

Arms:
arm 1: * MCS110 2.5mg/kg will be administered intravenously every 3 weeks.
* Dabrafenib 150mg is given orally every 12 hours.
* Trametinib 2mg is given orally daily arm 2: * MCS110 will be administered intravenously every 3 weeks. The Dosage will be determined by the DLT of Phase 1
* Dabrafenib 150mg is given orally every 12 hours.
* Trametinib 2mg is given orally daily arm 3: * MCS110 1.25 mg/kg was administered intravenously every 3 weeks.
* Dabrafenib 150mg is given orally every 12 hours.
* Trametinib 2mg is given orally daily arm 4: * MCS110 5mg/kg was administered intravenously every 3 weeks.
* Dabrafenib 150mg is given orally every 12 hours.
* Trametinib 2mg is given orally daily arm 5: * MCS110 10mg/kg was administered intravenously every 3 weeks.
* Dabrafenib 150mg is given orally every 12 hours.
* Trametinib 2mg is given orally daily

Interventions: intervention 1: MCS110 intervention 2: Dabrafenib intervention 3: Trametinib
Intervention descriptions: intervention 1: MCS110 is a colony-stimulating factor-1 (CSF-1) inhibitor. It is a human monoclonal antibody which binds CSF-1. intervention 2: Dabrafenib attack different proteins that promote the growth of cancerous cells intervention 3: Trametinib attack different proteins that promote the growth of cancerous cells

Protocol document:
Prot_SAP_000.pdf: 
 
 
 1 
 
NCI Protocol #: 
Not Applicable 
 
DF/HCC Protocol #: 17-656 
 
TITLE:  A Phase I/II Study of MCS110 with BRAF/MEK Inhibition in Patients with Melanoma 
after Progression on BRAF/MEK Inhibition  
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
*Principal Investigator (PI): 
Elizabeth Buchbinder MD 
 
Melanoma Program 
 
Dana-Farber Cancer Institute 
Elizabeth_Buchbinder@dfci.harvard.edu 
 
 
 
 
 
Statistician: 
 
 
Project Manager:  
Anita Giobbie-Hurder 
Jennifer Maattala 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute  
Telephone: 617-632-2193 
Telephone: 617-632-3992 
Fax: 617-632-2444 
Fax: 617-582-8216 
agiohur@jimmy.harvard.edu 
jennifera_maattala@dfci.harvard.edu 
 
 
Agents:  
MCS110 – Novartis  
Dabrafenib – Commercial 
Trametinib – Commercial 
 
IND #: 135909 
 
IND Sponsor: Investigator-Initiated Study, Dr. Elizabeth Buchbinder MD 
 
 
Protocol Type / Version # / Version Date: Revised / Version #04 / March 11, 2019 
 
 


 
 
 2 
 
SCHEMA 
 
 
Phase I Portion : 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase II Portion: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enroll 
beginning 
with dose 
level 1 
Treat cohort 
(3 participants 
per cohort, with 1 
cycle = 21 days) 
No further escalation. 
Proceed with fallback 
dose if at dose level 1. 
Recruit 3 more 
participants 
Further 
DLTs? 
Escalate dose 
Yes 
No 
1 
Participant 
diagnosed with 
advanced melanoma 
that has been 
confirmed to harbor 
a BRAF V600E/K 
mutation
Informed consent 
and confirmation of 
trial eligibility 
Number of 
DLTs 
(After 28-day 
total DLT 
observation) 
No further escalation. 
Proceed with fallback 
dose if at dose level 1. 
2 or 3 
0 
Informed consent 
and confirmation 
of trial eligibility 
 
Participant 
receives 2 cycles 
of treatment 
(where 1 cycle = 
21  days)   
Discontinue protocol 
therapy and complete end 
of study assessments 
Stable disease, 
partial, or 
complete 
response 
Disease 
Progression 
Tumor 
Assessment 
Participant diagnosed with 
advanced melanoma that has 
been confirmed to harbor a 
BRAF V600E/K mutation with 
progression of disease on 
BRAF/MEK 
Continue for another 2 cycles 


 
 
3 
 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives...................................................................................................5 
1.3 
Secondary Objectives...............................................................................................5 
1.4 
Exploratory Objectives ............................................................................................5 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease ...........................................................................................................6 
2.2 
MCS110 ...................................................................................................................6 
2.3 
Dabrafenib..............................................................................................................13 
2.4 
Trametinib ..............................................................................................................15 
2.5 
Rationale ................................................................................................................17 
2.6 
Correlative Studies Background ............................................................................17 
3. 
PARTICIPANT SELECTION ...........................................................................................19 
3.1 
Eligibility Criteria ..................................................................................................19 
3.2 
Exclusion Criteria ..................................................................................................22 
3.3 
Inclusion of Women and Minorities ......................................................................23 
4. 
REGISTRATION PROCEDURES ...................................................................................24 
4.1 
General Guidelines for DF/HCC Institutions ........................................................24 
4.2 
Registration Process for DF/HCC Institutions .......................................................24 
4.3 
General Guidelines for Other Investigative Sites ..................................................24 
4.4 
Registration Process for Other Investigative Sites.................................................24 
5. 
TREATMENT PLAN ........................................................................................................24 
5.1 
Treatment Regimen ................................................................................................24 
5.2 
Pre-Treatment Criteria ...........................................................................................26 
5.3 
Agent Administration.............................................................................................27 
5.4 
Definition of Dose-Limiting Toxicity (DLT) ........................................................28 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................28 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................29 
5.7 
Duration of Follow Up ...........................................................................................30 
5.8 
Criteria for Taking a Participant Off Study ...........................................................30 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................31 
6.1 
Specific Toxicity Management ..............................................................................31 
6.2 
Treatment Delays ...................................................................................................40 
6.3 
Dose Modifications ................................................................................................40 
6.4 
Overdose management ...........................................................................................42 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................42 


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Protocol Version Date: March 11, 2019 
 
4 
7.1 
Expected Toxicities ................................................................................................43 
7.2 
Adverse Event Characteristics ...............................................................................46 
7.3 
Serious Adverse Events .........................................................................................47 
7.4 
Expedited Adverse Event Reporting ......................................................................48 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ......................49 
7.6 
Expedited Reporting to Hospital Risk Management .............................................49 
7.7 
Routine Adverse Event Reporting .........................................................................50 
8. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................50 
8.1 
Collection of Archival Tissue ................................................................................50 
8.2 
Exploratory Fresh Tumor Biopsies ........................................................................50 
8.3 
Laboratory Correlative Studies ..............................................................................51 
9. 
STUDY CALENDAR .......................................................................................................51 
10. 
MEASUREMENT OF EFFECT........................................................................................61 
10.1 
Antitumor Effect – Solid Tumors ..........................................................................61 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................68 
11.1 
Data Reporting .......................................................................................................68 
11.2 
Data Safety Monitoring..........................................................................................68 
11.3 
Multicenter Guidelines...........................................................................................69 
11.4 
Collaborative Agreements Language .....................................................................69 
12. 
STATISTICAL CONSIDERATIONS...............................................................................69 
12.1 
Study Design/Endpoints.........................................................................................69 
12.2 
Sample Size, Accrual Rate and Study Duration ....................................................70 
12.3 
Analysis of Primary and Secondary Endpoints .....................................................71 
12.4 
Reporting and Exclusions ......................................................................................72 
13. 
Ethical considerations and administrative procedures .......................................................72 
14. 
PUBLICATION PLAN .....................................................................................................74 
REFERENCES ..............................................................................................................................75 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................78 
APPENDIX B          BRAF/MEK Ophthalmic Worksheet   .........................................................79 
 
 
 
 


DF/HCC Protocol #: 17-656 
Protocol Version Date: March 11, 2019 
 
5 
1. OBJECTIVES 
 
1.1 
Study Design 
 
This is an open-label, phase I/II study investigating the combination of colony-stimulating 
factor-1 (CSF-1) inhibition using MCS110 with BRAF/MEK inhibitor therapy using dabrafenib 
and trametinib in patients with advanced melanoma harboring a BRAF V600 E/K mutation . In 
phase I, the BRAF and MEK inhibition will be maintained at standard dosing with the addition 
of the MCS110 using the “3+3” trial design. Once the maximum tolerated dose (MTD) is 
reached and a recommended phase II dose (RP2D) is chosen, a single-arm phase II study in 
patients with BRAF mutant melanoma whose disease has progressed on BRAF/MEK inhibition 
will move forward.   
 
1.2 
Primary Objectives 
 
Phase I:   
• To determine the MTD and RP2D of the combination of MCS110 with dabrafenib 
and trametinib. 
 
Phase II:   
• To evaluate the overall response rate (ORR) to the combination of MCS110 with 
dabrafenib and trametinib in patients with BRAF V600E or V600K mutated 
melanoma who have had progression on BRAF/MEK 
 
1.3 
Secondary Objectives 
 
Phase I:  
• To evaluate the preliminary overall response rate (ORR) and PFS to the 
combination of MCS110 with dabrafenib and trametinib in patients with BRAF 
V600E or V600K mutated melanoma who have had progression on BRAF/MEK. 
 
Phase II: 
• To evaluate the progression free survival (PFS) to the combination of MCS110 
with dabrafenib and trametinib in patients with BRAF V600E or V600K mutated 
melanoma who have had progression on BRAF/MEK. 
• To evaluate the overall survival (OS) to the combination of MCS110 with 
dabrafenib and trametinib in patients with BRAF V600E or V600K mutated 
melanoma who have had progression on BRAF/MEK. 
• To continue to evaluate the safety and tolerability of the combination of MCS110 
with dabrafenib and trametinib in patients with BRAF V600E or V600K mutated 
melanoma who have had progression on BRAF/MEK. 
 
 
1.4 
Exploratory Objectives 
• To investigate the effect of the combination of MCS110 with dabrafenib and 
trametinib on mitogen-activated protein kinase (MAPK) pathway signaling and 


DF/HCC Protocol #: 17-656 
Protocol Version Date: March 11, 2019 
 
6 
the immune tumor microenvironment via collection of blood, archival tumor 
tissue, and optional pre and on-treatment tissue biopsies obtained during both 
phases of the trial.  
• To investigate the relationship between the levels of tumor DNA in serially 
collected plasma samples and the observed clinical outcomes during both phases 
of the trial. 
 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
Melanoma is the most deadly form of skin cancer, with over 10,000 deaths estimated in the US 
in 20161. About 40 - 60% of cutaneous melanomas carry mutations in BRAF that lead to 
constitutive activation of downstream signaling through the MAPK pathway. Approximately 
90% of these mutations result in the substitution of glutamic acid for valine at codon 600 (BRAF 
V600E), however other activating mutations are known to occur (e.g., BRAF V600K)2,3.  
 
BRAF inhibitor therapy with dabrafenib or vemurafenib has an improved overall survival in 
patients with BRAF mutations with an even larger effect observed when combined with MEK 
inhibition using trametinib or cobimetinib2,4,5. The response rate to the combination is 64 - 68%; 
however, these responses are of limited duration. The median PFS for combination BRAF/MEK 
inhibitor therapy is only 9.9 - 11.4 months.  Progression on therapy is thought to occur primarily 
due to the development of acquired resistance through reactivation of the MAPK pathway4,5. 
 
 
2.2 
MCS110 
 
CSF-1R is a receptor tyrosine kinase expressed on monocyte/macrophage and granulocyte cell 
lineages in normal as well as tumor cells6,7. When colony-stimulating factor-1 (CSF-1) or 
interleukin 34 (IL-34) binds to CSF-1R, the receptor is phosphorylated, initiating downstream 
signaling events which result in the regulation of proliferation, differentiation, survival and 
migration of monocytes/macrophages8-10.  
 
In cancer, increased infiltration of macrophages within and surrounding the tumor mass 
correlates with increased tumor invasiveness, growth, and poor prognosis. In breast, prostate, 
ovarian, and cervical cancer, there is a correlation between tumor-associated macrophages 
(TAMs) and poor prognosis11-13. Clinical evidence of TAM participation in tumor growth is 
corroborated in animal models where CSF-1R/CSF-1 signaling is inhibited or knocked out. Mice 
with null mutations in the CSF-1 gene have similar initiation rates of virally induced mammary 
tumors as normal mice, but the tumors do not progress to advanced carcinoma stages and the 
number of metastases are greatly reduced14. In addition to the effects of CSF-1R on 
macrophages, there are numerous reports of CSF-1R expression on cancer cells. For example 
breast, ovarian, endometrial, and leukemia cells of myeloid origin express CSF-1R and 
proliferate in response to CSF-16,15-18. Targeting CSF-1 or CSF-1R have the potential to limit 
cancer progression. 


DF/HCC Protocol #: 17-656 
Protocol Version Date: March 11, 2019 
 
7 
 
While CSF-1R levels are infrequently increased on tumor cells compared to analogous normal 
cells, increased CSF-1 ligand in sera of cancer patients is frequently observed and is associated 
with poor prognosis and severity of disease in multiple cancers19,20. This suggests that circulating 
CSF-1 modulates the stroma (i.e., macrophages) that contribute to tumor progression. For 
example, in breast cancer, CSF-1 expression correlated with increased leukocytic infiltration, 
high tumor grade, and poor clinical outcome21. It is hypothesized that the CSF-1 produced by 
tumor cells suppresses dendritic cell maturation and recruits TAMs that are immunosuppressive, 
thus promoting angiogenesis and tumor growth22. The association of high levels of CSF-1 with 
poor prognosis in cancer patients may be a consequence of elevated CSF-1 production by tumor 
cells. Moreover, elevated CSF-1 levels in sera of cancer patients may be an indicator of 
individuals more likely to benefit from anti-CSF-1 treatment. 
 
MCS110 is a high-affinity, humanized monoclonal antibody directed against human macrophage 
colony stimulating factor (M-CSF; also known as colony-stimulating factor-1 [CSF-1]). CSF-1 
and IL-34 bind to the receptor tyrosine kinase CSF-1R (CSF-1 Receptor) to drive the 
differentiation, migration and survival of tissue macrophages. MCS110 neutralizes multiple 
forms of human CSF-1, inhibiting its effect on monocytes and macrophages.  
 
 
Non-Clinical Studies 
 
In vitro pharmacology 
In vitro, the ability of MCS110 to neutralize the activity of CSF-1 was established using two 
different assays. The first assay involved CSF-1-dependent proliferation of the mouse 
myelogenous leukemia cell line M-NFS-60. This cell line responds to various recombinant forms 
of CSF-1, as well as CSF-1 forms present in serum, in medium conditioned by tumor cell lines, 
and on the cell surface. MCS110 potently inhibited the proliferation of M-NFS-60 cells in 
response to all human forms of CSF-1 tested. Cell proliferation in response to 10 ng/mL 
recombinant human CSF-1 could be completely blocked by MCS110. MCS110 blocks the 
activity of cynomolgus CSF-1 but has no ability to neutralize recombinant mouse CSF-1. The 
second assay, in vitro osteoclastogenesis, was set up to reflect the principal in vivo function of 
CSF-1: regulation of the survival, proliferation and differentiation of cells of the mononuclear 
phagocyte lineage. MCS110 induced potent inhibition of the osteoclastogenesis process as well 
as the morphological changes associated with the differentiation into osteoclasts. 
In vivo pharmacology 
Given (a) the lack of activity against mouse CSF-1, and (b) the likely immune response that 
would develop with long-term dosing of mice with a humanized monoclonal Antibody (mAb), in 
vivo efficacy studies in human tumor cell xenograft models were conducted using two surrogate 
mAbs rather than MCS110 itself. These two surrogate mAbs were 5A1, a rat monoclonal 
IgG1antibody which neutralizes mouse (host) CSF-1, and 5H4, a mouse monoclonal IgG1 
antibody which neutralizes human (tumor-derived) CSF-1. Using a combination of these two 
mAbs, inhibition of tumor-induced osteolysis was demonstrated in mice injected intratibially 
with a human breast cancer cell line (MDA-MB-231Luc). Treatment with a combination of 
neutralizing antibodies directed against both the host mouse source of CSF-1 and human tumor-
derived CSF-1 had the lowest mean osteolytic score and a reduced number of individual animals 
with clearly evident bone lesions. 


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8 
 
To evaluate the competence of TAMs for signaling via the CSF1/CSF1R pathway, macrophages 
from spontaneous tumors arising in MMTV-PyMT mice were analyzed for CSF1R expression by 
flow cytometry. CD45+CD11b+F4/80+ positive TAMs stained positively for CSF1R while 
CD45− tumor cells showed no expression of the receptor. The functional dependence of TAMs 
on signaling mediated by the CSF1/CSF1R pathway was assessed after 6 days of treatment with 
the 5A1 Anti MCSF antibody to show a significant reduction in macrophages 
(CD45+CD11b+F4/80+ cells) suggesting a functional interdependency between CSF1 and 
CSF1R in regulating TAMs in this breast cancer model (Strachan 2013). 
 
2.2.1.1 
Pharmacokinetics 
 
The preclinical pharmacokinetics (PK) and pharmacodynamics (PD) of MCS110 were evaluated 
in cynomolgus monkeys following single intravenous (i.v) bolus injection of 0.2, 2 or 20 mg/kg, 
or multiple weekly iv bolus injections of 10 mg/kg for 3 weeks and 2, 20 or 100 mg/kg for up to 
13 weeks. Free MCS110 (unbound to target CSF-1) exhibited dose-dependent PK, with 
decreasing clearance (CL) and increasing mean residence time (MRT) or effective t1/2 when 
dose increased. The PK profiles of free MCS110 were notably nonlinear at concentrations below 
approximately 20 μg/mL, presumably due to target-mediate disposition. 
 
In the 13-week study, 2 out of 22 animals tested had anti-drug antibodies detected in serum, 
which correlated with lower MCS110 exposure at the corresponding time points. For PD, time 
and dose dependent increase in total CSF-1 was observed in the 13-week study following 
MCS110 administration, presumably due to slower clearance of the CSF-1 after it formed 
immune complexes with MCS110, indicating target engagement. Decreases in other downstream 
biomarkers such as circulating monocytes and serum NTx were also observed following 
MCS110 administration. 
 
2.2.1.2 
Safety Pharmacology and Toxicology 
 
The cynomolgus monkey was selected as the relevant species for toxicology studies because 
MCS110 showed similar functional activity against cynomolgus monkey and human CSF-1 in in 
vitro bioassays. In cynomolgus monkey studies there were no severe toxicological effects in any 
animal given MCS110 intravenously as a single dose or as multiple doses once weekly up to 13 
weeks and up to doses of 100 mg/kg, showing good tolerability of MCS110 given systemically. 
Mild increases in liver enzymes were seen in all studies without histopathological correlates, 
which resolved with clearance of the drug. This included consistent mild/moderate, dose-
dependent increases in lactate dehydrogenase (LD), mild increases in AST, and minimal 
increases in gamma-glutamyl transpeptidase (GGT) and ALT. All parameters returned to 
baseline levels with the clearance of MCS110 from the serum. The most likely cause of these 
increases is reduced clearance rate of the serum enzymes due to the diminished numbers of 
Kupffer cells in the liver. This was demonstrated in cynomolgus monkey study with a single 
intravenous dose of MCS110, which showed a decreased clearance of histidine-tagged creatine 
kinase injected in parallel to MCS110. After 13 weekly doses, minimal or mild interstitial edema 
was seen in multiple organs histopathologically in all dose groups, including the low-dose group. 
Although periorbital swelling was observed to occur sporadically in all groups (including 
controls), the increased incidence and severity of periorbital swelling observed at 100 mg/kg 


DF/HCC Protocol #: 17-656 
Protocol Version Date: March 11, 2019 
 
9 
suggested a relationship of this effect to MCS110 administration. No interstitial or periorbital 
edema was present at the end of the recovery period showing the reversal of this effect. All other 
effects seen, such as bone morphology changes and monocyte depletion were due to the expected 
pharmacological effects of MCS110. The data support the intravenous use of MCS110 in clinical 
trials at the doses selected. 
 
 
 
Clinical Studies 
 
Five clinical trials with MCS110 have been initiated. Brief information on clinical experience of 
relevant MCS110 studies is provided below. For additional information, please refer to MCS110 
Investigator Brochure. 
 
Table 1    Clinical trials with MCS110 
Trial 
Study Type 
Study Objectives 
Patients 
MCS110 dose range 
and schedule 
[MCS110A2101] 
Closed 
First in 
human, dose 
escalation 
MTD, safety, PK/PD, 
preliminary efficacy 
Prostate cancer with 
bone metastases, 
n=3 
0.01mg/kg every 14 
days 
[MCS110X2101] 
Completed 
Healthy 
volunteers, 
dose 
escalation 
MTD, safety, PK/PD 
Healthy, n= 52 
0.01-20 mg/kg, 1-2 iv 
infusions every 21-56 
days 
[MCS110X2201] 
Ongoing 
Efficacy 
study 
Safety, tolerability, 
PK/PD, efficacy 
Pigmented 
Villonodular 
Synovitis (PVNS), 
n=37 
3mg/kg - 10 mg/kg, 
1-4 iv infusions every 
28 days 
[MCS110Z2201] 
Ongoing 
Efficacy 
study 
Safety, tolerability, 
PK/PD, efficacy 
Triple Negative 
Breast 
Cancer (TNBC), 
n=100 
10 mg/kg iv infusions 
every 21 days  
[MCS110Z2102] 
Ongoing 
Dose 
escalation 
efficacy 
Safety tolerability, 
establish dose for 
phase 2 and efficacy 
TNBC, pancreatic, 
endometrial, 
melanoma 
N=95 
MCS110: 3mg/kg 
starting dose to 
10mg/kg every 21 
days. 
PDR001: 100 mg flat 
dose to 300 mg flat 
dose every 21 days 
 
 
Brief information on clinical experience of MCS110 will be provided below. For additional 
information, please refer to the Investigator’s Brochure (IB). 
 
2.2.2.1 
MCS110A2101, a first in human clinical trial 
 
CMCS110A2101 was a first in human study in prostate cancer with bone metastases, designed to 
evaluate safety, tolerability and MTD of MCS110. MCS110 was administered at doses 0.01 
mg/kg repeated every 2 weeks in a 28 day cycle for a total of 3 cycles. The study was closed 
after 3 patients due to prioritization within Novartis. No MTD was established. 
 


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10 
Clinical safety and tolerability 
MCS110 was well-tolerated and all patients completed the 3-cycle treatment. The only adverse 
event suspected to be related to MCS110 was an infusion reaction with chills (Grade 1), 
dizziness (Grade 2) and hypotension (Grade 2).  No DLTs were reported. One patient 
experienced an infusion reaction starting 1 hour after completing the first MCS110 infusion, 
which resolved 1 hour after occurrence. 
 
Clinical pharmacokinetics 
Formal PK analysis was not conducted due to small number of serum samples with measurable 
concentrations.  
 
Clinical pharmacodynamics 
No consistent changes in monocyte count were observed in the 3 patients treated. All patients’ 
peripheral monocytes were within 70% of baseline levels throughout the study.  
 
Clinical efficacy 
Biologic activity of MCS110 was not observed. No consistent direction of change was seen in 
bone markers. 
 
2.2.2.2 
MCS110X2101, a clinical trial in healthy volunteers 
 
CMCS110X2101 was a phase I study designed to evaluate safety, tolerability and MTD of 
MCS110 in 52 healthy volunteers (HV). MCS110 was delivered to 27 HV at increasing single 
doses from 0.01-20 mg/kg. Additionally, 6 HV received 2 doses (5 mg/kg) given 21 days apart, 
and another 6 received 2 doses (10 mg/kg) given 56 days apart. 
 
Clinical safety and tolerability 
Asymptomatic and reversible creatine kinase (CK) elevations were seen in 15 of 52 HV. The CK 
elevation did not appear to reflect muscle damage since neither troponin T (marker for cardiac 
muscle damage) nor aldolase (marker for skeletal muscle tissue damage) was elevated. The CK 
elevations are thought to be caused by the pharmacological effect of MCS110. 
 
Mild periorbital edema was observed in 4 of 52 HV and was transient, lasting between 2 and 158 
days. None of the subjects who presented with periorbital edema had developed anti-drug 
antibodies. The dose limiting toxicity was identified at 20 mg/kg, based on CK elevations 
exceeding more than 5 times the upper limit of normal. The recommended dose for future studies 
was set at 10mg/kg. 
 
Clinical pharmacokinetics 
Following intravenous administration of MCS110 in healthy volunteers, serum free MCS110 
exhibited concentration/dose-dependent PK, with decreasing CL (clearance) and increasing MRT 
(mean residence time) or effective t1/2 when doses increased from 0.01 to 20 mg/kg  across 8 
dose levels. The shape of the serum free MCS110 PK profiles indicated target mediated 
disposition, where the MCS110 concentration declined more rapidly at concentrations lower than 
approximately 10 μg/mL. This was presumably due to binding of MCS110 to the target, 
suggesting that serum free MCS110 concentrations above approximately 10 μg/mL is required to 


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11 
saturate circulating CSF-1. At the 10 mg/kg single dose level, MCS110 concentrations were 
maintained above 10 μg/mL for up to 42 days post dose. As expected, total CSF-1 exhibited 
dose-dependent increase in plasma following MCS110 treatment, presumably due to slower 
clearance of CSF-1 after it formed immune complexes with MCS110, indicating successful 
target engagement. The total CSF-1 concentration reached plateau at the single-dose level at or 
above 10 mg/kg, and it maintained at the plateau for at least 42 days at the 10 mg/kg dose. 
 
Clinical pharmacodynamics 
Expected pharmacological responses were observed in downstream biomarkers including dose-
dependent decreases in circulating CD14+ or CD14+CD16+ monocytes and C-terminal 
telopeptide of type I collagen (CTX-1), a bone resorption marker. In addition, dose-dependent 
increases in CK were observed. Simulation of steady-state dose-response relationships for 
biomarkers showed that with the once-every-4 week (Q4W) iv administration of MCS110, the 
response of PD biomarkers (CD14+ and CD14+CD16+ monocytes, and CTX-1) was expected to 
be close to maximal at the doses at or above 5 mg/kg and minimal at doses at or below 1 mg/kg. 
 
2.2.2.3 
MCS110X2201, a phase II study in pigmented villonodular synovitis 
 
CMCS110X2201 is an ongoing phase II study designed to evaluate safety, tolerability and 
efficacy with MCS110 in pigmented villonodular synovitis (PVNS). PVNS is a benign tumor 
consisting of macrophages and multinucleated giant cells, most commonly located to joints. As 
of 04-Feb-2016, 18 PVNS patients have been dosed. Seven patients received a single dose of 10 
mg/kg MCS110 - (5) or placebo (2).  Eleven patients received multiple doses of 10 mg/kg 
MCS110; nine patients received up to 4 i.v. doses and two patients received 6 doses of 10 mg/kg 
MCS110.  
 
Clinical safety and tolerability 
 
Four SAEs were reported, but were not considered related to MCS110. They include 
hospitalization for anterior and posterior synovetomy, acute cholecystitis, nausea and vomiting 
with fever and dehydration, and hospitalization for chest pain, dizziness and head congestion 
(this SAE was reported 7 months after the patient received the last dose). 
Common adverse events reported include asymptomatic and reversible CK elevation; mild and 
reversible periorbital edema; skin adverse reactions (e.g. rash); mild or moderate nausea and 
vomiting; fever; and headaches. Only one patient was discontinued due to an adverse event 
(periorbital edema).  
Clinical pharmacokinetics 
PK analysis is ongoing. Preliminary data show serum concentration of free MCS110 was similar 
to that observed in the HV study. Serum PK profiles after repeated doses were consistent with 
anticipated PK profiles on single dose PK. 
Clinical pharmacodynamics 
Data from the ongoing study in PVNS patients showed an expected decrease in monocytes and 
CTX-1, and an increase in CK in patients treated with MCS110. Maximum CK values were 
generally observed at Day 28 or Day 43 and then returned back to baseline. 


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Clinical efficacy 
After receiving a single dose of 10 mg/kg of MCS110, all 18 patients showed mean reduction in 
tumor volume of 32.8%. In contrast, the 5 patients who received a single dose of placebo, 
showed tumor volume changes of < 20%, with a mean reduction of -7.7%. 
Data from a third interim analysis demonstrated the same reduction in tumor volume when 
multiple doses of MCS110 were administered. Nine patients given multiple doses of MCS110 
who completed the primary endpoint of 8-weeks, showed a clear reduction of tumor volume 
ranging from 25% to 75%. Two of these patients showed a moderate response of 25% tumor 
volume decrease; but all other patients show reduction of > 50%.  
In parallel with the reduction in tumor size, there were also meaningful clinical improvements of 
symptoms related to PVNS.  
 
2.2.2.4 
MCS110Z2201, a phase II study of MCS110 combined with carboplatin and gemcitabine in 
Triple Negative Breast Cancer 
 
MCS110Z2201 is a randomized, open label, phase II study of MCS110 combined with 
carboplatin and gemcitabine in patients with advanced triple negative breast cancer. The study 
targets TNBC patients with TAM high tumors, who have not previously been treated with 
chemotherapy for advanced breast cancer. The aim of the study is to investigate whether the 
addition of MCS110 improves the efficacy of carboplatin and gemcitabine by activating the 
immune system. 
 
All patients will be given carboplatin (AUC 2) and gemcitabine (1000 mg/m2) on Days 1 and 8 
in 21-day cycles. Additionally, patients randomized to Arm 1 (experimental arm) will receive 
MCS110 10 mg/kg Day 1 in 21-day cycles with an additional dose of MCS110 10 mg/kg on 
Cycle 1 Day 8. As of 3 May 2016, 10 patients were enrolled; 7 to arm 1 and 3 to arm 2. 
 
Clinical safety and tolerability 
 
As required by the protocol, an early safety review was performed on May 25, 2016. The data 
cutoff was May 3, 2016 and data was collected from seven patients treated with 
carboplatin/gemcitabine/MCS110 and two patients treated with carboplatin/gemcitabine for 2 
full cycles or until discontinuation earlier. After reviewing the safety data, the sponsor and 
investigators jointly proposed to remove the additional dose of MCS110 on cycle 1/day 8 
(C1D8) and to continue optional prophylaxis to prevent infusion reactions. 
 
The Steering Committee reviewed the patient data on May 31, 2016 and found no immediate 
safety concern with the current dosing. Limited data showed some instances of recurrent increase 
of liver transaminases after the C1D8. This increase was not seen in all patients, however, and 
additional data would be necessary to establish any potential relationship. Review of the PK 
parameters indicate a slightly increased Cmax compared to historical data, which implies that 
desired exposures can be achieved without the C1D8 administration. Given this information, the 
Steering Committee agreed with the recommendation to remove C1D8 additional dose. 
 
Grade 1-2 infusion reactions related to MCS110 were observed in 3 patients. Additional is 


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13 
needed, however, to establish the rate and severity of these events.  As all patients have been able 
to continue on MCS110 dosing with appropriate prophylaxis and without dose reductions, the 
Steering Committee deemed no further actions were necessary.  
 
Clinical pharmacokinetics 
A preliminary review of the PK parameters indicates a slightly increased Cmax compared to 
historical data. 
 
Clinical pharmacodynamics 
No data is available as May 2016 
 
2.2.2.5 
Drug Interactions 
 
Specific studies to investigate drug-drug interactions (DDI) have not been conducted with 
MCS110. Antibodies that modulate cytokines, which may regulate cytochrome P450 (CYP) 
enzymes, may cause DDI with small molecule drugs because of the potential to alter CYP-
mediated metabolism (lee et al 2010; Huang et al 2010). However, MCS110 specifically 
neutralizes CSF-1 and hence it is not expected to modulate cytokines. In addition, as an antibody, 
MCS110 is eliminated through protein catabolism and target-mediated disposition.  
 
2.3 
Dabrafenib 
 
Dabrafenib mesylate (GSK2118436B, Tafinlar®; referred to as dabrafenib hereafter), a 4- 
(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is an ATP-competitive, selective 
inhibitor of RAF kinase currently in clinical development. On May 29, 2013, the U.S. 
FDA approved dabrafenib for the treatment of patients with unresectable or metastatic 
melanoma with BRAFV600E mutation as detected by an FDA-approved test (FDA, 2013). 
On January 10, 2014, the FDA granted accelerated approval to dabrafenib and MEK 
inhibitor trametinib for use in combination to treat patients with unresectable or 
metastatic melanoma with either BRAFV600E or BRAFV600K mutation as detected by an 
FDA-approved test (FDA, 2014). 
 
Dabrafenib has been FDA approved for patients with unresectable or metastatic melanoma with 
a BRAF V600E mutation and is commercially available.  
 
 
Pharmacokinetics 
 
Following single-dose oral administration of dabrafenib HPMC capsules, plasma 
concentrations peaked approximately 2.0 hours post-dose. Oral bioavailability is near 
complete (94.5%) relative to an intravenous (IV) microdose. 
 
Dabrafenib is highly bound to plasma proteins (99.6%). Its volume of distribution after 
IV dosing is 45.5 L. Intravenous plasma clearance (12.0 L/hr) is low relative to liver 
blood flow, suggesting a low hepatic extraction ratio drug. Median terminal half-life is 
approximately 8 hours after a single oral dose. 


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14 
 
Three metabolites of dabrafenib were characterized and may contribute to activity. 
GSK2285403 (hydroxy-metabolite [M7]) PK paralleled that of dabrafenib, while the 
carboxy- (GSK2298683 [M4]) and desmethyl- (GSK2167542 [M8]) metabolites 
exhibited a longer t1/2 (21-22 hours) and accumulated following repeat dosing. M7 is the 
most abundant, accounting for 54% of the three metabolites. Similar to dabrafenib 
concentrations, exposure for all metabolites showed a less than dose proportional increase 
with repeat dosing. 
 
Fecal excretion was a major route of dabrafenib elimination in humans, accounting for 
71.1% of the dose administered, and renal excretion accounted for about 20% of drug 
elimination. 
 
Administration of dabrafenib with a high-fat, high-calorie meal reduced the oral 
bioavailability of dabrafenib when compared to the fasted state with a decrease in Cmax 
and AUC of 51% and 31%, respectively, and delayed its absorption. Therefore, the 
current recommendation is to administer dabrafenib under fasting conditions, either 1 h 
before or 2 h after a meal. 
 
 
Drug Interactions 
 
Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of 
midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and Rwarfarin (a 
CYP3A4/CYP1A2 substrate). Co-administration of dabrafenib 150 mg twice daily for 15 days 
and a single dose of midazolam 3 mg (a CYP3A4 substrate) decreased midazolam AUC by 74%. 
Co-administration of dabrafenib 150 mg twice daily for 15 days and a single dose of warfarin 15 
mg decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and the AUC of R-warfarin 
(a CYP3A4/CYP1A2 substrate) by 33%. 
 
In vitro studies show that dabrafenib is a substrate of CYP3A4 and CYP2C8 while hydroxy-
dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Co-administration of dabrafenib 
75 mg twice daily and ketoconazole 400 mg once daily (a strong CYP3A4 inhibitor) for 4 days 
increased dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-
dabrafenib AUC by 68%. Co-administration of dabrafenib 75 mg twice daily and gemfibrozil 
600 mg twice daily (a strong CYP2C8 inhibitor) for 4 days increased dabrafenib AUC by 47%, 
with no change in the AUC of dabrafenib metabolites. Dabrafenib is a substrate of human P-
glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro. 
 
 
Clinical activity 
 
The single-agent MTD for dabrafenib was not reached. A dose of 150 mg BID was selected for 
further single-agent development, based on the following PK/pharmacodynamics, safety, and 
activity: a) dose increases beyond 150 mg BID yielded no increase in Cmax and <50% increase in 
AUC; b) incidence and severity of AEs was similar at 100-300 mg BID; c) pERK target 
suppression was >80%; and d) the tumor response rate (RR) was 50% at 150 mg BID. 
 
Activity in patients with BRAF V600E or V600K melanoma in the FTIH monotherapy study 


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15 
(BRF112680). The study enrolled 114 patients with BRAFV600 mutant melanoma in the dose 
escalation phase (Part 1), and 70 patients at the RP2D (150 mg BID) in Part 2. Within this study, 
a cohort of 10 patients with previously untreated asymptomatic brain metastasis was evaluated 
for intracranial response to dabrafenib (Long et al., 2011). All patients had decreases in the size 
of the brain metastasis; three patients achieved complete radiographic resolution of brain lesions 
as well as reduction in extracranial disease. The response rates in patients treated at 150 mg BID 
were 50% in 77 patients treated with V600E mutation, 20% in 14 patients treated with V600K 
mutation.   When dabrafenib was used at 50 mg BID (Part 2, Cohort C) in patients with 
BRAFV600E mutant melanoma, the response rate was only 17%. 
 
Correlative studies in the phase 1 monotherapy trial: 
Preliminary genomic analysis was performed on 37 patients with melanoma, using a Sequenom 
mutation analysis for 11 genes (AKT, BRAF, CDK4, CDKN2A, GNAQ, GNA11, Kit, MEK1, 
MEK2, and NRAS), and PTEN analysis by sequencing, comparative genomic hybridization 
(CGH), and multiplex ligation-dependent probe amplification (MPLA) (Nathanson et al., 2011). 
Nine patients (24%) had PTEN genetic alterations including mutation, hemi-/homozygous 
deletion. PTEN deficiency was associated with lower responses (ORR of 11% and 54% in 
patients with and without PTEN alteration, respectively). 
 
Phase III trial of dabrafenib versus chemotherapy in patients with advanced BRAFV600 mutant 
melanoma (BREAK3 Trial): Patients with previously untreated, unresectable stage III or IV 
BRAFV600E-mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib 
(150 mg PO BID) or dacarbazine (DTIC) (1000 mg/m2, IV, every 3 weeks [Q3W]). Of 250 
patients, 187 received dabrafenib and 63 received DTIC from February to September 2011. The 
hazard ratio for PFS was 0.30 (95% CI: 0.18-0.53; P<0.0001), with median PFS of 5.1 months 
for dabrafenib and 2.7 for DTIC. OS data were immature, with 30 deaths reported. Confirmed 
RR was 53% for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all 
subgroups evaluated. 
 
2.4 
Trametinib 
 
Trametinib (Mekinist) is a dimethyl sulfoxide (DMSO) solvate compound (ratio 1:1) with potent, 
allosteric and ATP non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM against 
MEK1 and MEK2, respectively) (Gilmartin et al., 2011). Trametinib inhibited MEK1/2 kinase 
activity  and prevented RAF-dependent MEK phosphorylation (S217 for MEK1), producing 
prolonged pERK1/2 inhibition. Trametinib showed better potency against unphosphorylated 
MEK1/2 (u-MEK1/2) when compared with preactivated diphosphorylated MEK (pp-MEK), 
suggesting that u-MEK affords a higher affinity binding site for trametinib than does pp-MEK. 
 
The specificity of trametinib was confirmed against a panel of 183 kinases, including MEK5 (the 
closet kinase homolog to MEK1/2), CRAF, BRAF, ERK1, and ERK2 (Yamaguchi et al., 2011). 
Trametinib demonstrated equal potency against activated MEK1- and MEK2-mediated 
phosphorylation of ERK (sequence identity of 85% across the whole protein and 100% in the 
active site for humans). Trametinib demonstrated preferential inhibition of RAF-mediated MEK1 
activation (IC50 = 0.60 nM) over pMEK1 kinase activity (IC50 = 13 nM) (Investigator’s 
Brochure, 2012a).  


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16 
 
Pharmacodynamic studies were performed in mice treated with trametinib for 14 days (Gilmartin 
et al., 2011). In the A375P F11s xenograft model, the first dose of trametinib (3 mg/kg) 
significantly reduced pERK for more than 8 hours on Day 1. pERK inhibition was more 
sustained (over 24 hours) after the Day 7 dose, probably due to an increase in the steady-state 
levels of trametinib after repeated doses. The average Cmax in blood was 1,410 nM on Day 7, 
with an estimated half-life (t1/2) of 33 hours. In addition, immunohistochemistry (IHC) also 
confirmed inhibition of cell proliferation (reduced Ki67) and G1 cell cycle arrest (elevated 
p27Kip1/CDKN1B) following 4 days of treatment. 
 
Trametinib has been FDA approved for patients with unresectable or metastatic melanoma with a 
BRAF V600E or V600K mutation and is commercially available.  
 
 Pharmacokinetics 
 
PK measurements were conducted under fasting conditions. After a single dose (Day 1), AUC0-
24 and Cmax values were dose-proportional up to 6 mg, lower than dose proportional following 
8 mg, and greater than dose proportional following the 10 mg dose. Median Tmax was 1.5 hours. 
 
After repeat doses (Day 15), trametinib accumulated with a mean accumulation ratio of 6.6 at the 
RP2D of 2 mg QD. Between-subject variability in exposure ranged from 27- 50% for Cmax and 
20-41% for AUC0-24 across all dosing regimens. The effective t1/2 was approximately 4.5 days, 
and steady state was reached by approximately Day 15. Trametinib had a small peak:trough ratio 
of ~2 (Infante et al., 2010). At 2 mg QD on Day 15, mean AUC0-24 was 376 ng•h/mL and 
Cmax 23 ng/mL, and the mean trough concentrations ranged from 10.0 to18.9 ng/mL. The long 
half-life and small peak:trough ratio of trametinib allowed constant target inhibition within a 
narrow range of exposure.  
 
 Drug Interactions 
 
Trametinib is metabolized predominantly via deacetylation (non-cytochrome P450 [CYP450]-
mediated) with secondary oxidation or in combination with glucuronidation biotransformation 
pathways (Investigator’s Brochure, 2012a). The deacetylation is likely mediated by hydrolytic 
esterases, such as carboxylesterases, or amidases. Based on in vitro studies, trametinib is not an 
inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4. Although trametinib was 
found to be an in vitro inhibitor of CYP2C8, CYP2C9, and 2C19; inducer of CYP3A4; and 
inhibitor of transporters (OATP1B1, OATP1B3, P-glycoprotein [P-gp], and breast cancer 
resistance protein [BCRP]), its low efficacious dose, and low clinical systemic concentration 
(22.2 ng/mL or 0.04 mcM at 2 mg) relative to the in vitro inhibition/induction potency suggests 
an overall low potential for drug-drug interactions. 
 
 Clinical Activity 
 
In the FTIH phase 1 trial, 14 patients with BRAF-mutant melanoma received trametinib at 2 mg 
QD (2 mg/day continuously, or 2 mg for 21 days followed by a 1 week break).  The overall 
objective response rate (ORR) was 43% (6/14), including 2 complete responses (CRs) 


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17 
(Investigator's Brochure, 2012a). In 9 patients with BRAF wt melanoma, 2 patients achieved a 
partial response (PR), and 3 stable disease (SD) (Infante et al., 2010). In 26 evaluable pancreatic 
cancer patients, there were 2 PRs (1 PR was KRAS mutation-positive) and 11 SD (2 achieved 
≥20% tumor reduction) (Messersmith et al., 2011). Among the 27 CRC patients (without 
selection of RAS or RAF mutations), 8 SD were observed. 
 
In a phase 3 trial, patients with unresectable stage IIIC or IV cutaneous melanoma with a BRAF 
V600E or V600K mutation were randomized (2:1) to trametinib (2 mg, PO, QD) or 
chemotherapy (dacarbazine or paclitaxel) (Flaherty et al., 2012). There were 322 patients in the 
intention-to-treat (ITT) population, of whom 273 (85%) were in the primary efficacy population 
(patients with BRAFV600E-positive cancer who did not have brain metastases at baseline). In 
the ITT analyses, the ORR was 22% in the trametinib group and 8% in the chemotherapy group; 
the median duration of PFS was 4.8 months in the trametinib group as compared with 1.5 months 
in the chemotherapy group; and the 6- month OS rate was 81% in the trametinib group and 67% 
in the chemotherapy group.  
 
2.5 
Rationale 
 
The tumor microenvironment is known to play a role in innate or acquired resistance to BRAF 
inhibition29,30. Tumor cells can control the surrounding milieu by producing cytokines that 
suppress cytolytic T-cells and recruit immunosuppressive cells, and CSF-1 is one such cytokine 
that is secreted by melanoma. CSF-1 induces the proliferation and differentiation of 
immunosuppressive myeloid cells, such as M2 polarized macrophages and myeloid-derived 
suppressor cells (MDSCs), by binding to CSF-1R on the surface of the cell. This results in the 
ability of the tumor cell to evade the immune response and allows for subsequent metastasis31.  
 
Pre-clinical data by Mok et al. showed a dramatic reduction in tumor infiltrating myeloid cells 
when treated with CSF-1R inhibition.  When this was combined with BRAF inhibition superior 
antitumor responses and increased tumor-infiltrating lymphocytes were observed31. Inhibitors to 
CSF-1R have been shown to deplete certain populations of TAMs and in established tumors, the 
combination of CSF-1R inhibitors with chemotherapy has been shown to dramatically enhance 
responses32.  
 
Additional pre-clinical data from Wang et al. demonstrated that macrophages play a role in 
resistance to BRAF inhibitor therapy through paradoxical activation of the MAPK pathway 
leading to increased production of vascular endothelial growth factor (VEGF).  Targeting 
macrophages in a pre-clinical model led to increased tumor activity of BRAF inhibition in mouse 
and human tumor models33. These data together suggest that targeting macrophages in 
combination with BRAF inhibition in patients with melanoma may reduce baseline resistance 
and increase efficacy. Prior BRAF inhibition has also been shown to lead to increased TAMs, 
suggesting a potential role of combination therapy in patients with acquired resistance34. 
 
2.6 
Correlative Studies Background 
 
Use of immune and targeted therapies in patients with genomically complicated tumors presents 
a variety of confounding variables that could contribute to success or failure of the therapy.  


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Correlative studies are designed to both enable better understanding of the possible reasons that 
MCS110 in combination with dabrafenib and trametinib may prove to be effective or ineffective 
in individual patients, and to enable the development of more effective targeting strategies in the 
future.   
 
Collection of Tumor Tissue 
 
In order to retrospectively explore the determinants of response and resistance to MCS110 
combination therapy, archival tumor tissue will be collected at baseline from all patients 
enrolling to the trial. In addition, optional fresh tumor biopsies will be obtained from patients 
enrolled to either the phase I or phase II portion of the trial. These biopsies will be obtained on-
treatment and again at the time of disease progression. The genetic and immune characteristics 
identified in the tumor tissue will be correlated to clinical outcome. 
 
Analysis of tumor tissue samples taken at distinct points enables addressing of key questions 
including: (1) the genomic lesions and immune cell presence at baseline in samples studied and 
their potential impact upon response, (2) the identification of immediate pathways/gene 
expression programs activated by tumors following MCS110 combination therapy, and (3) 
mechanisms of acquired resistance to therapy. 
 
The first correlative question relates to the genetic and immune diversity of the patients enrolled 
in this study. It is the anticipation that most patients on this study will have had their tumor 
genomically characterized by either the OncoPanel test at DFCI/BWH (a custom hybrid capture 
panel which via next-generation sequencing will identify mutations and copy-number alterations 
in cancer associated genes) or via another CLIA-certified method at the time of enrollment. The 
archival tissue collected will be analyzed to look at the TAMs present at baseline. Macrophages 
are among the most abundant normal cells in the tumor micoenvironment. Substantial evidence 
has indicated that macrophages adopt a pro-tumoral phenotype, suppressing T cell response and 
promoting tumor progression via angiogenesis, tumor cell invasion, motility, intravasation, and 
promotion of persistent growth32. The levels of certain TAMs present at baseline can be 
correlated to the clinical response observed with the combination therapy, and this data may 
enable us to identify immune characteristics that may also impact clinical response. 
 
Another key rationale for performance of biopsies in patients after initiating drug therapy is to 
address mechanisms of resistance to MCS110 combination therapy.  The emergence of 
resistance to therapy is a profound problem in oncology.  Such resistance can follow not only 
acquisition of secondary mutations but also from the ability of cancer cells to activate immediate 
compensatory signaling tracts following targeted inhibition of a key pathway39. Identification of 
these compensatory reactions is a necessary step in order to design subsequent rational therapies 
that may lead to even more durable and long-lasting clinical benefit. The optional on-treatment 
tissue samples will be examined for changes in MAPK activation as well as levels of TAMs and 
tumor immune infiltrates. 
 
Optional biopsies obtained at the time of disease progression will be used to characterize the 
change in the tumor at the time of resistance.  Such changes could stem from the acquisition of 
novel genomic alterations, from activation of other signaling pathways, or the production of anti-


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19 
inflammatory and immunosuppressive mediators. Biopsies obtained at progression will be 
analyzed for MAPK reactivation, other mechanisms of resistance (e.g., alternate kinase domain 
mutations), and tumor immune infiltrates. The information collected from these biopsies will be 
vital to understanding the methods of resistance to the combination therapy and planning 
subsequent treatment strategies in this population. 
 
Collection of Blood 
 
Cell-free DNA (cfDNA) will be collected and analyzed for BRAF V600E or V600K mutations. 
Levels of tumor DNA will decline longitudinally over time if there is a response to the treatment 
administered. To further assess this concept, plasma will be collected from participants to 
evaluate whether circulating free plasma DNA declines with the administration of MCS110, 
dabrafenib, and trametinib and this information will be compared to clinical outcome. 
 
Blood samples will also be collected to look at circulating immune cells including MDSCs. 
MDSCs are a heterogeneous group of myeloid-derived cells which are greatly expanded in 
experimental models of cancer. Studies in humans carried out thus far have reported an increased 
frequency as well as immune-suppressive activity in some of the myeloid-derived subsets of 
MDSCs present in the peripheral blood of patients with cancer. In the case of metastatic 
melanoma, both monocytic as well as granulocytic blood MDSCs with immune-suppressive 
function have been studied independently and proposed to exert an immune-regulatory role40. To 
further explore the relationship of circulating immune cells including MDSCs and their potential 
correlation to clinical outcomes, peripheral blood levels will be serially collected from patients 
enrolled to the trial. 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with 
the exception of the informed consent, echocardiogram, ophthalmologic exam, and baseline 
tumor imaging which may be obtained up to 28 days prior to the start of protocol therapy. 
 
 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. 
 


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 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 ≤ 480 msec for both females and males on the 
screening EKG. 
 


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


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22 
 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. 
 
 
 
3.2 
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. 
 


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 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.  This includes 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. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 


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4. REGISTRATION PROCEDURES 
  
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
Not Applicable. 
 
4.4 
Registration Process for Other Investigative Sites 
 
Not Applicable. 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
MCS110 will be administered intravenously every 3 weeks.  The doses of MCS110 will be 
calculated for each cohort and will be based on the subject’s weight.  Standard institutional 
policy can be used for weight based dosing.  MCS110 should be administered in a 1 hour (± 5 
min) infusion. 
 
Table 2 
 
Treatment and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
regimen 
MCS110 
Liquid concentrate in a vial, 
Intravenous infusion 
10 mg/kg, 5 mg/kg or 
2.5 mg/kg 
Every 3 weeks 
 


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25 
 
 
Table 3: Phase I Dose Escalation Schedule 
Dose Level 
Dose 
MCS110 
Dabrafenib 
Trametinib 
-1 
1.25 mg/kg IV every 
3 weeks 
150 mg BID 
2 mg daily  
1 (Starting Dose Level) 2.5 mg/kg IV every 3 
weeks 
150 mg BID 
2 mg daily  
2 
5 mg/kg IV every 3 
weeks 
150 mg BID 
2 mg daily  
3 
10 mg/kg IV every 3 
weeks 
150 mg BID 
2 mg daily  
 
 
Three patients will be enrolled to dose level 1. Enrollment to the dose level can occur in parallel 
with no observation period or delay between the start of therapy for each enrolled patient. The 
patients will be observed during the first cycle of therapy for toxicity consistent with a dose-
limiting toxicity (DLT) definition, located in Section 5.4.  There will be an added 7 days for DLT 
observation (28 days total) before each new dose escalation cohort begins.  This will not pause 
the 21 day dosing cycle of the current cohort under DLT observation.      
 
Dose escalation will proceed in a standard 3+3 fashion according to the scheme in Table 1. 
 
Table 4: Phase I Dose Escalation Decision Criteria 
Number of Participants with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose level. 
≥ 2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional participants will be 
entered at the next lowest dose level if only 3 
participants were treated previously at that dose. 
1 out of 3 
Enter at least 3 more participants at this dose level. 
• If 0 of these 3 participants experience DLT, proceed 
to the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
participants will be entered at the next lowest dose 
level if only 3 participants were treated previously at 


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Number of Participants with DLT 
at a Given Dose Level 
Escalation Decision Rule 
that dose. 
≤ 1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the RP2D. At least 6 participants must 
be entered at the RP2D. 
 
The maximally administered dose (MAD) of the study medications will be defined as the dose 
level where at least two participants develop toxicities consistent with a DLT definition. In this 
situation, the dose level immediately below the MAD will be defined as the MTD. In the event 
that dose level 1 is found to be intolerable (with either 2/3 or ≥ 2/6 patients experiencing a DLT), 
the fallback dose level -1 will be explored. If the fallback dose level is also found to be 
intolerable, the trial will be discontinued. In the situation where none of the dose levels have ≥ 2 
DLTs, the MTD will be the highest dose administered (i.e. dose level 3). The MTD will be 
defined in a minimum of six patients. 
 
Upon declaring the MTD, the Overall Principal Investigator will review safety data generated 
during the phase 1 portion of the trial to decide the RP2D. This review will include a review of 
the DLTs that occurred among the dose levels in conjunction with toxicities experienced among 
participants beyond the DLT time frame. Once the RP2D has been defined, the phase II portion 
of the trial will begin with enrollment of 25 patients with either BRAF V600E or V600K mutant 
melanoma who have progressed on prior BRAF/MEK inhibition. Patients enrolling into the 
phase II portion of the trial will be treated at the RP2D identified during the phase I portion of 
the study. 
 
Patients enrolled to the phase I dose escalation portion of the trial will be required to have 
received at least 75 percent of their doses of dabrafenib and trametinib, and must complete the 
MCS110 infusion during the first cycle to be considered evaluable for DLT purposes. Patients 
who do not meet these parameters during cycle 1 for reasons other than toxicity (for example, 
withdrawal of consent for participation on the trial, or rapid disease progression and subsequent 
removal from the trial) will be replaced. 
 
Participants will be requested to maintain a study medication diary that will indicate each dose of 
oral medication taken to illustrate treatment compliance. The medication diary should be 
returned to appropriate research staff for review at the end of each treatment cycle. 
 
 
5.2 
Pre-Treatment Criteria 
 
 
Cycle 1, Day 1 
 
Patients who completed screening assessments > 72 hours prior to cycle 1 day 1 should have 
cycle 1 day 1 laboratory values that re-meet eligibility criteria. If screening assessments were 
completed ≤ 72 hours prior to cycle 1 day 1, laboratory tests do not need to be repeated on cycle 
1 day 1 and the screening laboratory values can be used as the cycle 1 day 1 values. 


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Subsequent Cycles  
 
To be eligible to begin subsequent cycles of treatment, toxicity considered at least possibly 
related to the study regimen must have recovered to ≤ grade 2 or baseline. Management of 
specific toxicities considered at least possibly related to the study regimen is outlined in Section 
6.1. 
 
5.3 
Agent Administration 
 
 
MCS110 
 
MCS110 will be given once on day 1 of the 21 day cycle. On days where MCS110, 
dabrafenib, and trametinib are all to be given, order of administration does not matter.  
 
MCS110 will be administered via IV infusion.  
 
Mild infusion reactions were reported in 2 patients in the MCS110A2101 study, where all 
symptoms (dizziness, chills, hypotension) resolved within 1 hour. One patient was re-
challenged with MCS110 and did not have any infusion reactions during subsequent 
infusions. Patients should be monitored for hypersensitivity reactions according to local 
guidelines. Appropriate treatment for hypersensitivity reactions should be available at 
bedside and a physician readily available. Prophylaxis to prevent infusion reactions is 
only recommended for subsequent doses in patients who previously experienced an 
infusion reaction to MCS110. 
 
 
A pharmacy manual will be provided with details on how to administer MCS110 
 
 
Dabrafenib 
Dabrafenib will be given as per package instructions. Dabrafenib should be taken orally 
every 12 hours. A missed dose can be taken up to 6 hours prior to the next dose. Doses 
that would be administered outside of that timeframe should be considered missed and 
should not be taken. Tablets should not be crushed or chewed. A vomited dose should not 
be retaken, patients should continue with the next scheduled dose. Dabrafenib should be 
taken orally with approximately 200 mL of water under fasted conditions (an empty 
stomach either one hour before or two hours after a meal).  Do not replace water with 
juice (especially not orange, grapefruit or other fruit juices), soda or other beverages.  On 
days where MCS110, dabrafenib, and trametinib are all to be given, order of 
administration does not matter. 
 
 
Trametinib 
 
Trametinib will be given as per package instructions. Trametinib should be taken orally 
daily. A missed dose can be taken up to 12 hours prior to the next dose. Doses that would 
occur outside of this timeframe should be considered missed and should not be taken. 
Tablets should not be crushed or chewed. A vomited dose should not be retaken, patients 


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should continue with the next scheduled dose. Trametinib can be taken with or without 
food.  Trametinib should be taken with a cup of water (approximately 200 mL of water).  
Do not replace water with juice (especially not orange, grapefruit or other fruit juices), 
soda or other beverages.  On days where MCS110, dabrafenib, and trametinib are all to 
be given, order of administration does not matter. 
 
 
5.4 
Definition of Dose-Limiting Toxicity (DLT)  
 
Dose-limiting toxicity is based on version 4.0 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). DLT refers to toxicities experienced during the first cycle of 
treatment that are possibly, probably, or definitely related to the study medication regimen. A 
DLT will be defined as follows: 
 
• 
≥ Grade 3 non-hematological toxicity. Exceptions will be made for: 
• 
Nausea, vomiting, diarrhea, or constipation that can be controlled with appropriate care. 
Grade 3 and grade 4 nausea, vomiting, diarrhea, or constipation should be considered a 
DLT if persisting more than 48 hours despite maximum supportive intervention. 
• 
Grade 3 rash or photosensitivity lasting fewer than 8 days, or that can be controlled with 
appropriate care. Grade 3 rash or photosensitivity should be considered a DLT if it 
persists for more than 8 days and cannot be managed despite maximum supportive 
intervention. 
• 
Grade 3 thrombocytopenia with clinically significant bleeding 
• 
Grade 4 thrombocytopenia 
• 
≥ Grade 3 febrile neutropenia 
• 
Grade 4 anemia 
• 
Holding of any study medication due to toxicity for a period of greater than 8 consecutive 
days or two separate periods of any duration during the first cycle. 
• 
Any other significant toxicity deemed by the principal investigator to be dose limiting (for 
example, any toxicity that is at least possibly related to the study medication regimen that 
results in the withdrawal of the patient from the study during cycle 1). 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
In general, concomitant medications and therapies deemed necessary for the supportive care (e.g. 
such as anti-emetics, anti-diarrhea) and safety of the patient are allowed. The administration of 
bisphosphonates is permitted. 
 
Subjects should receive full supportive care during the study, including transfusions of blood and 
blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and analgesics, and 
other care as deemed appropriate, and in accordance with their institutional guidelines.  Use of 
anticoagulants such as warfarin is permitted however, caution should be exercised and additional 
International Normalized Ratio (INR) monitoring is recommended when dabrafenib is used 
concomitantly with warfarin. 


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The patient must be told to notify the investigational site about any new medications, herbal 
remedies and dietary supplements he/she takes after the start of the study treatment. All 
medications (other than study treatment) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered during the study must 
be listed in the subject’s study records. Prior antineoplastic therapies including medications, 
radiotherapy, and surgery are also to be recorded. Medication entries should be specific to trade 
name, dose and unit, the frequency and route of administration, the start and discontinuation date 
and the reason for therapy. 
Radiation skin injury has been reported with concurrent use of dabrafenib and radiation. It is 
recommended that dabrafenib be held for seven days before and two days after XRT in subjects 
receiving dabrafenib monotherapy or in combination with trametinib. These recommendations 
can be modified based on the physician’s assessment of the risk of radiation skin injury. 
 
 
 
MCS110 Guidelines 
 
Anticoagulation is permitted if the patients are already at stable doses of low molecular weight 
heparin (LMWH) for >2 weeks at time of first dose. However, ongoing anticoagulant therapy 
should be temporarily discontinued to allow tumor biopsy according to the institutional 
guidelines. 
 
Statins should be used with caution since CK elevations are commonly seen. 
 
Any other anticancer or investigational treatment is not permitted while on study treatment. 
Additionally, other biologics (e.g.: antibodies and proteins) and immunosuppressive medication 
are not permitted while on this study. 
 
Concomitant chronic corticosteroids (≥10 mg of prednisone or equivalent) are not allowed.  
 
Treatment with hematopoietic colony-stimulating growth factors (e.g. G-CSF), may not be 
initiated unless the investigator deems it necessary.  
 
The use of live vaccines is not allowed through the whole duration of the study. 
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
indefinitely or until one of the following criteria applies: 
 
• 
Disease progression, unless the patient is deriving clinical benefit as agreed upon with 
the principal investigator 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) including those described in Sections 5.4 and Section 


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6 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Dr. Elizabeth Buchbinder at DFCI pager number 40221.  
 
 
5.7 
Duration of Follow Up 
 
Participants will be followed for safety monitoring for 30 days after removal from protocol 
therapy.  After the 30 days they will enter into long term follow up and will be followed until 
death after removal from protocol therapy. This follow up will be performed by review of the 
medical record, contact with care providers, and/or telephone contact as needed every 3-4 
months. 
 
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff.  
 


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For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table. The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP website: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
6.1 
Specific Toxicity Management 
 
Dose delays and modifications due to toxicity considered at least possibly related to MCS110, 
dabrafenib, and/or trametinib will be made as indicated in the following tables. Please also see 
Sections 6.2 and 6.3 for further guidance on allowed treatment delays and dose modifications: 
 
Table 5: Management of Elevated AST 
AST (SGOT) and/or ALT (SGPT) Increase 
Medication Management 
≤ Grade 2 
No change. 
Grade 3, increase lasting less than 14 days 
without evidence of other hepatic injury 
Hold study medications until resolution to ≤ 
grade 1 or baseline. Resume study medications 
at the same dose level. 
Grade 3, increase lasting 14 or more days 
without evidence of other hepatic injury 
-OR- 
Grade 4, without evidence of other hepatic 
injury 
Hold study medications until resolution to ≤ 
grade 1; resume study medications with one 
dose level reduction. 
≥ Grade 3, with evidence of other hepatic 
injury 
Discontinue protocol therapy. 
 
Table 6: Management of Elevated ALT 
AST (SGOT) and/or ALT (SGPT) Increase 
Medication Management 
≤ Grade 2 
No change. 
Grade 3, without evidence of other hepatic 
injury 
-OR- 
Grade 4, without evidence of other hepatic 
injury 
Hold study medications until resolution to ≤ 
grade 1; resume study medications with one 
dose level reduction. 
≥ Grade 3, with evidence of other hepatic 
injury 
Discontinue protocol therapy. 
 
Liver transaminase elevations have been associated with all three study medications in previous 
clinical trials. Patients should be monitored for increases in their liver function tests and for other 
signs of possible hepatic injury (elevated bilirubin, coagulation abnormalities, encephalopathy, 


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etc.) as clinically appropriate and as indicated in the Study Calendar – Section 10. 
 
Table 7: Management of Neutropenia 
Neutrophil Count Decrease 
Medication Management 
≤ Grade 2 
No change. 
Grade 3, no associated fever or infection 
-OR- 
Grade 4, decrease lasting less than 8 
consecutive days 
Hold study medications until recovery to ≤ 
grade 2. Upon recovery, restart at the same 
dose level. 
≥ Grade 3, associated with a fever or 
infection 
-OR- 
Grade 4, decrease lasting 8 or more 
consecutive days 
Hold study medications until recovery to ≤ 
grade 2. Upon recovery, resume with one dose 
level reduction. 
 
 
Table 1: Management of Thrombocytopenia 
Platelet Count Decrease 
Medication Management 
≤ Grade 2 
No change. 
Grade 3, no clinically significant bleeding 
 
Hold study medications until recovery to ≤ 
grade 2. Upon recovery, restart at the same 
dose level. 
Grade 3, associated with clinically significant 
bleeding 
-OR- 
Grade 4 
Hold study medications until recovery to ≤ 
grade 2. Upon recovery, resume with one dose 
level reduction. 
 
 
 
Table 9: Management of Rash or Photosensitivity 
Rash or Photosensitivity 
Medication Management 
≤ Grade 2 
No change.* Implement appropriate supportive 
care (e.g., topical or oral antibiotics or steroids, 
use of protective clothing/sunscreen).  
Grade 3, not optimally managed or lasting 
fewer than 8 consecutive days 
 
Implement appropriate supportive care (e.g., 
topical or oral antibiotics or steroids). Hold 
study medications until recovery to ≤ grade 2. 
Upon recovery, restart at the same dose level. 
Grade 3, optimally managed or lasting 8 or 
more consecutive days 
-OR- 
Grade 4 
Hold study medications until recovery to ≤ 
grade 2. Upon recovery, resume with one dose 
level reduction. 
*If a patient is experiencing intolerable grade 2 rash or photosensitivity despite optimal medical 
management, their study medication may be held at the treating investigator’s discretion. Upon 
resolution to grade 1 or baseline, the study medication can be dose reduced at the treating 


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33 
investigator’s discretion. 
 
 
Table 10: Management of QTc Increase (Associated with Dabrafenib) 
QTc Interval Prolonged 
Dabrafenib Management 
≤ Grade 2 
No change. 
Grade 3, increase is ≤ 60 msec from pre-
treatment value or QTc ≥ 501 msec 
Hold dabrafenib until recovery to ≤ grade 2. 
Upon recovery, restart  at current dose level 
reduction.* 
Grade 3, increase is > 60 msec from pre-
treatment value 
-OR- 
Grade 4 
Discontinue dabrafenib. 
 
*Interrupt all study treatments until QTc prolongation resolves to grade 1 or baseline 
Test serum potassium, calcium, phosphorus and magnesium. If abnormal correct per routine 
clinical practice to within normal limits. 
Review concomitant medication usage for agents that prolong QTc. 
If event resolves, restart study treatment at current dose levelb 
If event does not resolve, permanently discontinue study treatments.  Consider evaluation with 
cardiologist. 
If event recurs, permanently discontinue study treatments.  Consider evaluation with 
cardiologist. 
 
Table 11: Management of Nausea 
Nausea 
Medication Management 
≤ Grade 2 
No change.* Implement appropriate supportive 
care (e.g., antiemetics) as clinically indicated. 
Grade 3, not optimally managed 
Hold study medication and implement 
appropriate supportive care (including 
antiemetics and IV hydration if indicated). 
Upon resolution to ≤ grade 2, resume study 
medication at the same dose level. 
≥ Grade 3, optimally managed 
-OR- 
Grade 4 
Hold study medication until resolution to ≤ 
grade 2; resume study medication with one 
dose level reduction if ≥ grade 3 nausea 
persisted for more than 48 hours despite 
maximum supportive intervention. 
*If a patient is experiencing intolerable grade 2 nausea despite optimal medical management, 
their study medication may be held at the treating investigator’s discretion. Upon resolution to 
grade 1 or baseline, the study medication can be dose reduced at the treating investigator’s 
discretion. 
 
 


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Table 12: Management of Vomiting 
Vomiting 
Medication Management 
≤ Grade 2 
No change.* Implement appropriate supportive 
care (e.g., antiemetics) as clinically indicated. 
Grade 3, not optimally managed 
Hold study medication and implement 
appropriate supportive care (including 
antiemetics and IV hydration if indicated). 
Upon resolution to ≤ grade 1, resume study 
medication at the same dose level. 
≥ Grade 3, optimally managed 
-OR- 
Grade 4 
Hold study medication until resolution to ≤ 
grade 1; resume study medication with one 
dose level reduction if ≥ grade 3 vomiting 
persisted for more than 48 hours despite 
maximum supportive intervention. 
*If a patient is experiencing intolerable grade 2 vomiting despite optimal medical management, 
their study medication may be held at the treating investigator’s discretion. Upon resolution to 
grade 1 or baseline, the study medication may be dose reduced at the treating investigator’s 
discretion. 
 
 
 
Table 13: Management of Diarrhea 
Diarrhea 
Medication Management 
≤ Grade 2 
No change.* Implement appropriate supportive 
care (e.g., antidiarrheals) as clinically 
indicated. 
Grade 3, not optimally managed 
Hold study medication and implement 
appropriate supportive care (including 
antidiarrheals and IV hydration if indicated). 
Upon resolution to ≤ grade 1, resume study 
medication at the same dose level. 
≥ Grade 3, optimally managed 
-OR- 
Grade 4 
Hold study medication until resolution to ≤ 
grade 1; resume study medication with one 
dose level reduction if ≥ grade 3 diarrhea 
persisted for more than 48 hours despite 
maximum supportive intervention. 
*If a patient is experiencing intolerable grade 2 diarrhea despite optimal medical management, 
their study medication may be held at the treating investigator’s discretion. Upon resolution to 
grade 1 or baseline, the study medication may be dose reduced at the treating investigator’s 
discretion. 
 
 
Table 14: Management of Constipation 
Constipation 
Medication Management 
≤ Grade 2 
No change.* Implement appropriate supportive 


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35 
care (e.g., laxatives) as clinically indicated. 
Grade 3, not optimally managed 
Hold study medication and implement 
appropriate supportive care (including 
laxatives and enemas if indicated). Upon 
resolution to ≤ grade 2, resume study 
medication at the same dose level. 
≥ Grade 3, optimally managed 
-OR- 
Grade 4 
Hold study medication until resolution to ≤ 
grade 2; resume study medication with one 
dose level reduction if ≥ grade 3 constipation 
persisted for more than 48 hours despite 
maximum supportive intervention. 
*If a patient is experiencing intolerable grade 2 constipation despite optimal medical 
management, their study medication may be held at the treating investigator’s discretion. Upon 
resolution to grade 1 or baseline, the study medication may be dose reduced at the treating 
investigator’s discretion. 
 
Table 15: Management of CK elevation 
CK elevation 
Medication Management 
CK elevation ≤ Grade 2 
No change.§  
CK elevation ≥ Grade 3 (CK ≥ 5XULN) 
Monitor CK-MB, troponin (I and T) and 
creatinine 
 
*If CK-MB and troponin (I or T) are normal, 
creatinine ≤ 1.5 baseline and patient 
asymptomatic continue treatment 
*If CK-MB and troponin (I or T) ere abnormal 
or creatinine ≥1.5X baseline and > ULN or 
patient symptomatic, hold therapy and explore 
alternative causes for elevated CK (for 
example myositis and rhabdomyolysis) 
After recovery of CK-MB, troponin (I or T) 
and creatinine to grade 1 or baseline, study 
treatment may be resumed with MCS110 at 
50% of the previous dose. 
§If a patient is experiencing a new grade 2 or greater increase in CPK, both urine and serum 
myoglobin laboratory tests should be performed. Additional tests may also be performed or 
repeated at the treating investigator’s discretion.   
* MCS110 treatment results in CK and AST elevations without any association to muscle 
damage (Radi 2011). The CK/AST elevations are caused by reduced clearance rate from the 
circulation due to the diminished numbers of macrophages (Kupffer cells) in the liver. 
 
Table 16: Managment of LVEF reduction 
LVEF decrease 
Medication Management 
 Asymptomatic with absolute LVEF 
decrease of > 10% compared to baseline and 
< LLN 
• 
Interrupt trametinib and repeat ECHO within 2 
weeksa,b   


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36 
• 
If the LVEF recovers within 4 weeks (defined 
as LVEF ≥LLN and absolute decrease ≤10% 
compared to baseline)  
• Consult with the GSK medical monitor 
• 
    and request approval for restart  
• 
 
• If approved, restart treatment with 
trametinib reduced by one dose level 
• 
 
• Repeat ECHO at 2 , 4, 8 and 12 weeks  
• 
   after re-start; continue in intervals of 12   
• 
   weeks thereafter 
• 
 
• 
If  LVEF does not recover within 4 weeks 
• Consult with cardiologist 
• Permanently discontinue trametinib 
• Report as SAE 
• Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolution 
 
Symptomatic, Grade 3: resting LVEF 39-
20% or >20% absolute reduction from 
baseline 
-OR- 
Grade 4: resting LVEF <20% 
• 
Permanently discontinue trametinib 
• 
Interrupt dabrafenib.d 
• 
Report as SAE  
• 
Consult with cardiologist 
Repeat ECHO after 2, 4, 8, 12, and 16 weeks or 
until resolutionb,d 
a. 
If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
b. If recurrent episodes of LVEF reduction occur in subjects receiving dabrafenib monotherapy, consult medical 
monitor. 
c. 
Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion and 
edema. 
d. 
Once LVEF recovers, including resolution of symptoms, restart of dabrafenib monotherapy only can be considered in 
consultation with GSK medical monitor. 
 
Table 17: Management of Renal Insufficiency 
Creatinine elevation 
Medication Management 
Grade 1, creatinine level increase of 
>0.3mg/dL, creatinine 1.5-2.0 X ULN 
 
 
• Recheck serum creatinine within 1 week 
• Serum creatinine increase > 1 week: contact 
Novartis Clinical Team.  If elevation persists 
beyond 4 weeks, recommend evaluation 
(consider renal biopsy) for etiology; consider 
nephrology consultation. 
• If pyrexia is present, treat as per Table 27. 
Continue study medication at same dose level 
Grade 2, creatinine 2-3 X ULN 
• Monitor serum creatinine ≥ 2-times per week  


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• Hospitalization may be necessary  if serum 
creatinine cannot be monitored frequently 
• If pyrexia is present, treat as per Table 27  
• Consult nephrologist if clinically indicated 
• Perform renal biopsy if clinically indicated, for 
example: 
o Renal insufficiency persists despite volume 
repletion or signs of hypersensitivity 
Hold study medication. Upon resolution to ≤ grade 
1, resume study medication at same dose level 
Grade 3, Creatinine >3XULN or  > 
4.0mg/dL 
Hold study medication. Upon resolution to ≤ 
grade 1, resume study medication with one 
dose level reduction. ** 
* NSAIDs can induce renal insufficiency, especially in subjects with dehydration; encourage oral fluids or 
consider intravenous fluids as clinically indicated. See guidelines for pyrexia Section 5.8.5.1. 
Investigator may restart at either the same or a reduced dose level.  Escalation of study treatment to 
previous dose level is allowed if another episode of renal insufficiency does not occur after 4 weeks of 
dose reduction.  Consultation with GSK Medical Monitor is required before restarting study treatment if 
there is evidence of thrombotic microangiopathy. 
 
Table 18: Management of Pneumonitis 
Pneumonitis 
Medication Management 
Grade 1 
• CT scan (high-resolution with lung 
windows) recommended 
• Clinical evaluation and laboratory work-up 
for infection 
• Monitoring of oxygenation via pulse-
oximetry recommended  
• Consultation of pulmonologist 
recommended 
Continue study medication at same dose level 
Grade 2 
• CT scan (high-resolution with lung 
windows) 
• Clinical evaluation and laboratory work-up 
for infection 
• Consult pulmonologist 
• Pulmonary function tests –if < normal, 
repeat every 8 weeks until ≥ normal 
• Bronchoscopy with biopsy and/or BAL 
recommended 
• Symptomatic therapy including 
corticosteroids if clinically indicated 
• Hold study medication. Upon resolution to ≤ 
grade 1, resume trametinib at one dose 
reduction.  
• Escalation to previous dose level after 4 


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weeks and consultation with Lead 
Investigator 
If no recovery to grade ≤1 within 4 weeks, 
permanently discontinue study treatment 
Grade 3 
• CT scan (high-resolution with lung 
windows) 
• Clinical evaluation and laboratory work-up 
for infection 
• Consult pulmonologist 
• Pulmonary function tests –if < normal, 
repeat every 8 weeks until ≥ normal 
• Bronchoscopy with biopsy and/or BAL 
recommended 
• Symptomatic therapy including 
corticosteroids if clinically indicated 
 
Hold study medication. Upon resolution to ≤ 
grade 1, resume trametinib at one dose 
reduction.  
 
If no recovery to grade ≤1 within 4 weeks, 
permanently discontinue study treatment 
Grade 4 
• CT scan (high-resolution with lung 
windows) 
• Clinical evaluation and laboratory work-up 
for infection 
• Consult pulmonologist 
• Pulmonary function tests –if < normal, 
repeat every 8 weeks until ≥ normal 
• Bronchoscopy with biopsy and/or BAL 
recommended 
• Symptomatic therapy including 
corticosteroids if clinically indicated 
Permanently discontinue trametinib 
 
Table 19: Management of Other Toxicity 
Other Toxicity 
Medication Management 
≤ Grade 2 
No change.* 
≥ Grade 3 
Hold study medication. Upon resolution to ≤ 
grade 2, resume study medication with one 
dose level reduction. ** 
*If a patient is experiencing intolerable grade 2 toxicity, their study medication may be held at 
the treating investigator’s discretion. Upon resolution to grade 1 or baseline, the study 
medication can be dose reduced at the treating investigator’s discretion. 
**Patients who experience a ≥ grade 3 infusion-related reaction should be discontinued from 


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39 
protocol therapy.  
 
 
MCS110 can cause periorbital edema which is generally mild but should be monitored: 
 
Periorbital edema 
Grade 2-3 
Delay treatment until resolved to ≤ Grade 1. Decrease 
MCS110 1 dose level. 
Grade 4 
Discontinue from treatment. 
 
Episodes of visual changes have been observed in subjects receiving trametinib, dabrafenib, and 
combination therapy. An ophthalmologist should be consulted if changes in vision develop.  
However, if the visual changes are clearly unrelated to study treatment (e.g., allergic 
conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic examination. 
 
Treatment with dabrafenib has been associated with the development of uveitis, including iritis. 
Monitor patients for visual signs and symptoms (such as, change in vision, photophobia and eye 
pain) during therapy. Special attention should be given to retinal findings (e.g., retinal pigment 
epithelial detachment (RPED) or retinovascular abnormalities (i.e., branch or central retinal vein 
occlusions (RVO).  For events of visual changes (regardless of severity) for which an ophthalmic 
examination is conducted, a blood sample for PK analysis must be drawn as close as possible to 
the time of the event. Guidelines regarding management and dose reduction for visual changes 
and/or ophthalmic examination findings considered to be related to study treatment are provided 
in Appendix B. 
 
Dose modifications and action for toxicities suspected to be related to 
MCS110 
Toxicity 
CTCAE 
Grade 
Action 
CK 
elevation 
Grade ≥3 
(CK>5 x 
ULN) 
Monitor CK-MB, troponin (I or T) and creatinine. 
● If CK-MB and troponin (I or T) are normal, creatinine < 1.5 x 
baseline and patient asymptomatic, maintain dose level. 
● If CK-MB and troponin (I or T) are abnormal or creatinine (> 1.5 x 
baseline and > ULN) or patient symptomatic, withhold drugs and 
explore alternative causes for elevated CK (for example myositis 
and 
rhabdomyolysis) according to local guidelines. 
After recovery of CK-MB, troponin (I or T) and creatinine to Grade 1 
or baseline, study treatment may be resumed: chemotherapy at 
previous doses and MCS110 at 50%a of the previous dose 
 
 
  
 
Episodes of pyrexia have been observed in subjects receiving dabrafenib monotherapy, and is 
increased in incidence and severity in subjects receiving dabrafenib in combination with 
trametinib (see dabrafenib and trametinib FDA Labels). In a minority of cases the pyrexia was 
accompanied by symptoms such as severe chills, dehydration, hypotension, dizziness or 
weakness.  


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40 
 
Subjects should be instructed on the importance of immediately reporting febrile episodes.  In 
the event of a fever, the subject should be instructed to take anti-pyretics (e.g. ibuprofen or 
acetaminophen/paracetamol) as appropriate to control fever.  The use of oral corticosteroids 
should be considered in those instances in which anti-pyretics are insufficient. Monitor serum 
creatinine and other evidence of renal function during and following severe events of pyrexia. 
 
6.2 
Treatment Delays 
 
The study medications may be held for toxicity for up to four weeks before the participant must 
be removed from the study. Exceptions to this requirement are possible should the principal 
investigator agree that the patient may continue despite the length of time off drug.  Treatment 
may be held for grade 2 AST and/or ASLT increases at the treating investigator’s discretion 
following the DLT period.  
 
Study medications may be held independently of each other if toxicity is felt by the treating 
investigator to be attributed to one or two of the three medications (e.g., a patient may continue 
to receive their MCS110 on schedule while holding their dabrafenib and/or trametinib). 
 
If the study medication(s) is/are placed on hold for toxicity, the counting of cycle days and 
assessment schedule will continue without interruption (including tumor evaluations). For 
example, a patient who does not receive their cycle 2 day 1 infusion of MCS110 due to toxicity 
will proceed with their next scheduled infusion and visit (cycle 3 day 1). Additional interim visits 
will be conducted as clinically necessary to manage toxicity. The cycle will not restart for dosing 
delays due to toxicity. Exceptions to this are possible for significant treatment delays (≥ 2 weeks) 
after a discussion with the principal investigator. 
 
 
6.3 
Dose Modifications 
 
The first dose reduction for any specific toxicity must include a reduction in MCS110 unless the 
toxicity is clearly causes by dabrafenib or trametinib in which case these medications should be 
reduced. Further dose reductions will be based on the offending medication(s) according to the 
schedule outlined in table 20. In the event the treating investigator feels all three medications are 
responsible for the toxicity, all medications can be reduced. Dose reductions below 25 mg once 
per week of MCS110 will not be permitted. Reductions below 50 mg BID of dabrafenib or 1 mg 
daily of trametinib will not be permitted.  
 
A maximum of two dose reductions will be allowed with any one of the medications. If a patient 
requires more than two dose reductions with any one of the study medications, they should be 
discontinued from protocol therapy. Exceptions are possible in the event a patient is not 
tolerating the dabrafenib and/or trametinib despite maximal dose reductions but is deriving 
clinical benefit. In this circumstance, a patient may be allowed to continue on protocol therapy 
and receive MCS110 either alone or in combination with just the dabrafenib or trametinib if 
agreed upon with the principal investigator. 
 
Patients undergoing dose reductions for toxicities may not be re-escalated. 


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41 
 
Participants enrolled to the phase I portion of the trial may undergo intra-patient dose escalation 
if subsequent higher dose levels are proven safe as per the guidelines in Section 5.1 and 5.4. 
Participants may only undergo dose escalations to a dose level where ≤ 1 DLT have been 
observed among 6 patients, two dose levels below a dose level where < 1 out of 3 patients have 
experienced DLTs, or the dose level that has been declared the RP2D. Under no circumstances 
may a patient escalate to a dose level above the MTD. Patients must have been on study for at 
least two cycles with no DLTs or DLT-equivalent toxicity to be eligible for dose escalation. If 
toxicities at a lower dose level are observed and make the dose intolerable, intra-patient dose 
escalation will stop and patients on higher dose levels will need to dose to reduce to a tolerable 
level.  
 
 
Table 20: Dose Modifications 
Original Dose Level 
MCS110 Reduction 
Dabrafenib 
Reduction* 
Trametinib 
Reduction* 
-1 
1st Reduction: 0.625 
mg/kg IV every 3 
weeks 
1st Reduction: 100 mg 
BID 
1st Reduction: 1.5 mg 
once daily 
2nd Reduction: 
Discontinue protocol 
therapy 
2nd Reduction: 50 mg 
BID 
2nd Reduction: 1 mg 
once daily 
1 
1st Reduction: 1.25 
mg/kg IV every 3 
weeks 
2nd Reduction: 100 
mg BID 
1st Reduction: 1.5 mg 
once daily 
2nd Reduction: 0.625 
mg/kg IV every 3 
weeks 
2nd Reduction: 50 mg 
BID 
2nd Reduction: 1 mg 
once daily 
2 
1st Reduction: 2.5 
mg/kg IV every 3 
weeks 
1st Reduction: 100 mg 
BID 
1st Reduction: 1.5 mg 
once daily 
2nd Reduction: 1.25 
mg/kg IV every 3 
2nd Reduction: 50 mg 
BID 
2nd Reduction: 1 mg 
once daily 


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42 
weeks 
3 
1st Reduction: 5 
mg/kg IV every 3 
weeks 
1st Reduction: 100 mg 
BID 
1st Reduction: 1.5 mg 
once daily 
2nd Reduction: 2.5 
mg/kg IV every 3 
weeks 
2nd Reduction: 50 mg 
BID 
2nd Reduction: 1 mg 
once daily 
*: Dabrafenib and trametinib may be reduced as per the FDA prescribing information 
 
 
6.4 
Overdose management 
 
There are no known antidotes for over-dosage of MCS110, dabrafenib, or trametinib. In the case 
of suspected overdose, monitor hematologic parameters, serum chemistry, vital signs, cardiac 
function, and provide supportive care as necessary. 
 
In the event of a dabrafenib overdose, defined as administration of more than 300 mg as a single 
dose or 600 mg per day (the highest dose tested in clinical studies to date), and/or a trametinib 
overdose, defined as administration of more than 3.0 mg once daily (the maximum tolerated dose 
defined in the MEK111054 Study), the investigator should contact the NOVARTIS Clinical 
Team immediately and closely monitor the subject for AEs/SAEs and laboratory abnormalities.  
NOVARTIS does not recommend specific treatment.  The investigator will use clinical judgment 
to treat any overdose.  Haemodialysis is not expected to enhance the elimination of either 
dabrafenib or trametinib as both are highly bound to plasma proteins. 
 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the NOVARTIS Clinical Team based on the clinical evaluation of the subject. 
A plasma sample for PK analysis may be requested by the NOVARTIS Clinical Team on a case-
by-case basis.  This plasma sample should be collected as soon as possible, but within 10 days 
from the date of the last dose of on-study dosing. 
Information regarding the quantity of the excess dose as well as the duration of the overdosing 
should be documented in the eCRF. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Sections 7.2 and 7.3) will determine whether the event requires expedited 
reporting in addition to routine reporting. 
 


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43 
 
 
 
7.1 
Definition 
 
 
Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience 
that develops or worsens in severity after starting the first dose of study treatment or any 
procedure specified in the protocol, even if the event is not considered to be related to the 
study. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
 
 
7.2 
Expected Toxicities 
 
MSC110 
 
 
“Adverse Events considered to be Expected for Reporting 
Purposes” 
MedDRA system 
organ class 
Event 
n/N (%) 
Frequency 
Category* 
General disorders and 
administration site 
conditions 
Swelling (peripheral, 
general) 
3/16 (19%)** 
Very common 
Investigations 
CK (CPK, creatine 
kinase) increased 
*** 
Very common 
Skin and 
subcutaneous 
disorders 
Periorbital edema** 
7/16 (44 %) 
Very common 
Rash 
4/16 (25%) 
Very common 
 
* frequency category for each adverse drug reaction is based on the following convention 
(CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to 
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Unknown - insufficient data to 
determine the frequency of the ADR 
** 3 out of the 7 patients with periorbital edema also developed peripheral or general swelling;  
*** not consistently reported as AE 
There is no “Adverse Events with a fatal outcome considered to be Expected for Reporting 
Purposes”.  Information from MCS110 Investigator’s Brochure Edition 11, Dated 14 April 2016 
 
 
Trametinib 
 
 
“Adverse Events considered to be Expected for Reporting 


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44 
Purposes” 
MedDRA system 
organ class 
Event 
 
Frequency 
Category* 
Infections and 
infestations 
Folliculitis, paronychia, cellulitis, rash 
pustular 
Common 
Blood and lymphatic 
system disorders 
Anaemia 
Common 
Immune system 
disorders 
Hypersensitivity 
May present with symptoms such as fever, 
rash, increased liver function tests, and visual 
disturbances 
Uncommon 
Metabolism and 
nutrition disorders 
Dehydration 
Common 
Eye disorders 
Vision blurred, periorbital oedema, visual 
impairment 
Common 
Chorioretinopathy, retinal vein occlusion, 
papilloedema, retinal detachment 
Uncommon 
Cardiac disorders 
Left ventricular dysfunction, ejection fraction 
decreased, bradycardia 
Common 
Cardiac failure 
Uncommon 
Vascular disorders 
Hypertension, haemorrhage 
The majority of bleeding events were mild. 
Major events, defined as symptomatic 
bleeding in a critical area or organ, and fatal 
intracranial haemorrhages have been 
reported. 
Very common 
Lymphoedema 
Common 
Respiratory, thoracic 
and mediastinal 
disorders 
Cough, dyspnoea 
Very common 
Epistaxis, pneumonitis 
Common 
Interstitial lung disease 
Uncommon 
Gastrointestinal 
disorders 
Diarrhoea, nausea, vomiting, constipation, 
abdominal pain, dry mouth 
Very common 
Stomatitis 
Common 
Colitis, gastrointestinal perforation 
Uncommon 
Skin and 
subcutaneous tissue 
disorders 
Rash, dermatitis acneiform, dry skin, pruritus, 
alopecia 
Very common 
Skin chapped, erythema, palmar-plantar 
erythrodysaesthesia syndrome, skin fissures 
Common 
Musculoskeletal and 
connective tissue 
disorders 
Blood creatinine phosphokinase increased 
Common 
General disorders and 
administration site 
conditions 
Fatigue, oedema peripheral, pyrexia 
Very common 
Face oedema, mucosal inflammation, asthenia Common 
Investigations 
Aspartate aminotransferase increased, alanine 
aminotransferase increased, blood alkaline 
Common 


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45 
phosphatase increased 
* frequency category for each adverse drug reaction is based on the following convention 
(CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to 
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Unknown - insufficient data to 
determine the frequency of the ADR.  Information taken from Trametinib Investigator’s 
Brochure Edition 8, Dated 11 August 2016.  New events to IB Edition 8 are in bold font. 
 
 
 
Dabrafenib 
 
 
“Adverse Events considered to be Expected for Reporting 
Purposes” 
MedDRA system 
organ class 
Event 
 
Frequency 
Category* 
Infections and 
infestations 
Nasopharyngitis 
Common 
Neoplasms benign 
and malignant 
(including cysts and 
polyps) 
Papilloma 
Very common 
Acrochordon (skin tags), cutaneous squamous 
cell carcinoma (SCC) including SCC of the 
skin, SCC in situ (Bowen’s disease) and 
keratoacanthoma, seborrhoeic keratosis 
Common 
New primary melanoma 
Uncommon 
Immune system 
disorders 
Hypersensitivity 
Uncommon 
Metabolism and 
nutrition disorders 
Decreased appetite 
Very common 
Hypophosphataemia 
Hyperglycaemia 
Common 
Nervous system 
disorders 
Headache 
Very common 
Eye disorders 
Uveitis 
Uncommon 
Respiratory, thoracic 
and mediastinal 
disorders 
Cough 
Very common 
Gastrointestinal 
disorders 
Nausea, vomiting, diarrhoea 
Very common 
Constipation 
Common 
Pancreatitis 
Uncommon 
Skin and 
subcutaneous tissue 
disorders 
Skin effects (rash, hyperkeratosis), alopecia, 
palmarplantar erythrodysaesthesia syndrome 
Very common 
Skin effects (actinic keratosis, skin lesion, dry 
skin, erythema, pruritus) 
Common 
Panniculitis 
Uncommon 
Musculoskeletal and 
connective tissue 
disorders 
Arthralgia, myalgia, pain in extremity 
Very common 
Renal disorders 
Renal failure, acute renal failure 
Uncommon 


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Tubulointerstitial nephritis 
Rare 
General disorders and 
administration site 
conditions 
Asthenia, chills, fatigue, pyrexia 
Very common 
Influenza-like illness 
Common 
*frequency category for each adverse drug reaction is based on the following convention 
(CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to 
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Unknown - insufficient data to 
determine the frequency of the ADR.  Information taken from the Dabrafenib Investigator’s 
Brochure Edition 8, Dated 16 August 2016.  
 
Dabrafenib in combination with Trametinib 
 
 
“Additional Adverse Events considered to be Expected for 
Reporting Purposes - observed in clinical development programs 
in Dabrafenib in combination with Trametinb” 
MedDRA system 
organ class 
Event 
n/N (%) 
Frequency 
Category* 
Hepatobiliary 
disorder 
Liver 
disorders1 
41/5866 (0.69%) 
Uncommon 
 
1. Liver disorders include Hepatotoxicity, Hepatitis, Hepatocellular injury, Liver disorder, 
Jaundice, Hepatomegaly, Hepatitis toxic, Hepatorenal syndrome, Hepatitis fulminant, Drug-
induced liver injury and Liver injury. 
 
 
7.3 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 


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47 
7.4 
Serious Adverse Events 
 
A serious adverse event (SAE) is any adverse event during this study that results in one of the 
following outcomes: 
 
• Death 
• Hospitalization for greater than 24 hours 
• Prolonging an existing inpatient hospitalization 
• A life-threatening experience (that is, immediate risk of dying) 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• Considered significant by the investigator for any other reason 
 
• 
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT ≥3xULN and bilirubin ≥ 2xULN (>35% direct) (or ALT ≥ 3xULN and INR>1.5, 
if INR measured) or termed ‘Hy’s Law’ events (INR measurement is not required and 
the threshold value stated will not apply to patients receiving anticoagulants). 
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin 
elevations and suggesting liver injury. If testing is unavailable and a subject meets the 
criterion of total bilirubin ≥ 2xULN, then the event is still reported as an SAE. If INR is 
obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury. 
• 
Any new primary cancers and treatment emergent malignancies (including squamous 
cell carcinoma and new primary melanoma) with the exception of basal cell carcinoma 
(BCC).  BCC should be reported as an AE or SAE based on the discretion of the 
investigator. 
• 
Symptomatic LVEF decrease that meets stopping criteria or asymptomatic LVEF 
decrease that does not recover. 
• 
Retinal pigment epithelial detachment (RPED) or retinal vein occlusion (RVO) 
 
Previously planned (prior to signing the informed consent form) surgeries, and non-disease 
related elective surgeries planned during the course of the study, should not be reported as SAEs 
unless the underlying medical condition has worsened or appeared during the course of the 
study. 
 
Preplanned hospitalizations or procedures for preexisting conditions that are already recorded in 
the patient’s medical history at the time of study enrollment should not be considered SAEs. 
Hospitalization or prolongation of hospitalization without a precipitating clinical AE (e.g., for 
the administration of study therapy or other protocol-required procedure) should not be 
considered SAEs. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 


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48 
outcomes listed in this definition. 
 
Death due to disease progression should not be reported as an SAE unless the investigator deems 
it to be related to the use of study drug. 
 
Study site personnel must alert Novartis of any SAE as soon as possible and no later than 24 
hours of the investigator and/or institution receiving notification of the SAE experienced by a 
patient participating in the study.  The SAE reports are to be sent to Novartis via fax at 1-877-
778-9739. 
 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E) by fax 
(877-778-9739). Pregnancy follow-up should be recorded on the same form and should include 
an assessment of the possible relationship to the study treatment any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment 
in this study. Consent to report information regarding these pregnancy outcomes should be obtained 
from the mother. If a pregnancy occurs while on study treatment, the newborn will be followed 
for at least 3 months. 
 
7.5 
Expedited Adverse Event Reporting  
 


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49 
 Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days of 
the last dose of treatment on the local institutional SAE form. Each serious adverse 
event must be reported by the investigator to Novartis within 24 hours of learning of 
its occurrence, even if it is not felt to be treatment-related. Follow-up information 
about a previously reported serious adverse event must also be reported to Novartis 
within 24 hours of receiving it. If the serious adverse event has not been previously 
documented (new occurrence) and it is thought to be related to study drug (or therapy), 
the Medical Safety Expert of the Drug Safety & Epidemiology (DS&E) Department 
may contact the investigator to obtain further information. If warranted, an investigator 
alert may be issued, to inform all investigators involved in any study with the same 
drug (or therapy) that this serious adverse event has been reported.  
 
The investigator must complete the FDA MedWatch 3500a form and Novartis SAE 
coversheet in English, assess the relationship to study treatment and send the initial 
completed MedWatch form and Novartis SAE coversheet by fax 1.877.778.9739 
within 24 hours to the local Novartis Drug Safety & Epidemiology (DS&E) 
Department.  The investigator must then ensure that the form and coversheet are 
accurately and fully completed with follow-up information and fax those to Novartis 
DS&E Department within 2 to 3 calendar days for deaths or life-threatening events 
and 5 calendar days for other serious adverse events. The original and the duplicate 
copies of the FDA MedWatch form, Novartis SAE coversheet, and the fax 
confirmation sheet must be kept with the case report forms at the study site.  
 
Follow-up information should describe whether the event has resolved or continues, if 
and how it was treated, and whether the patient continued or discontinued study 
participation. The MedWatch form, Novartis SAE coversheet, and fax confirmation 
sheet must be retained. Pregnancy follow-up should describe the outcome of the 
pregnancy, including any voluntary or spontaneous termination, details of the birth, 
and the presence or absence of any congenital abnormalities or birth defects. 
 
 
DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.6 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.7 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  


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50 
 
7.8 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
8. BIOMARKER, CORRELATIVE, SPECIAL STUDIES, AND PHARMACEUTICAL INFORMATION 
 
8.1 
Collection of Archival Tissue 
 
Archival tumor tissue will be collected on all patients enrolling to the trial as described in 
Section 2.6 - Correlative Studies. Patients who do not have archival tissue available will be 
allowed to enroll at the discretion of the principal investigator.  
 
Depending on availability, 10 - 20 unstained slides will be collected. Less than the goal amount 
of tissue is acceptable if archival tissue is limited. The slide collection should be labeled with the 
protocol number and study subject number. Slides should be mailed to the following address for 
analysis: 
 
ATTN: CIO Laboratory Manager 
Center for Immuno-Oncology Laboratory 
Jimmy Fund Building Room 406 
1 Jimmy Fund Way 
Boston, MA 02115 
 
  
8.2 
Exploratory Fresh Tumor Biopsies 
 
Optional fresh tumor biopsies will be obtained from patients enrolled during either phase of the 
trial, as described in Section 2.6 – Correlative Studies. The biopsies will only be obtained if the 
treating investigator believes the biopsy to be clinically feasible and if the patient is willing to 
undergo the biopsy procedures.  
 
The optional on-treatment biopsy can be collected anytime between Cycle 1 Day 15 and Cycle 2 
Day 7. An additional optional biopsy at the time of disease progression will also be offered to 
patients if deemed clinically feasible. Preferably, time of progression biopsies should be obtained 
prior to the initiation of another cancer treatment. However, in the event that it is not possible to 
perform the biopsy before another treatment is begun, the biopsy can be obtained up to 30 days 
after the last dose of MCS110. 
 
Core biopsy samples should be obtained for analysis. Three-to-four biopsy passes utilizing a 16-
18 gauge needle are preferable, but a 20 gauge core needle biopsy is also acceptable. Less than 
the goal amount of tissue is acceptable for the biopsy procedures, and should be based upon the 
clinical judgment of the treating investigator and the clinician performing the procedure. 
 
Biopsy samples should be formalin-fixed and paraffin embedded per institutional standards. 


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51 
 
Both the pre and on-treatment tumor biopsy samples should be labeled with the protocol number 
and study subject number, and should be sent to the CIO lab for analysis: 
 
ATTN: CIO Laboratory Manager 
Center for Immuno-Oncology Laboratory 
Jimmy Fund Building Room 406 
1 Jimmy Fund Way 
Boston, MA 02115 
 
 
8.3 
Laboratory Correlative Studies 
 
A cell-free DNA (cfDNA) plasma sample and a circulating immune cell (CIC) sample will be 
collected at baseline (prior to the first dose of MCS110, dabrafenib, and trametinib), at visits 
immediately following restaging scans (i.e., cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc.), and 
at the off study visit. Samples collected on days where study medication dosing will occur can be 
collected anytime pre-dosing.  
 
 
Cell-free DNA (cfDNA) and Circulating Immune Cell (CIC) Sample Collection Procedure: 
 
1. Blood samples should be labeled with the protocol number, study subject 
number, date of the draw, and the label, “cfDNA/CIC.” 
2. Draw venous blood into three 10 mL EDTA tubes, immediately gently invert 
the tube 3-4 times. 
3. Send tubes to the CIO lab for processing within 6 hours of blood draw (tubes 
sent outside of this window due to shipping or scheduling difficulties will not 
be considered protocol violations): 
 
ATTN: CIO Laboratory Manager 
Center for Immuno-Oncology Laboratory 
Jimmy Fund Building Room 406 
1 Jimmy Fund Way 
Boston, MA 02115 
 
 
8.4 
MCS110 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in section 7.1. 
 
8.4.1 Description 
 
Molecular Structure: MCS110 is a IgG1/κ high affinity, humanized monoclonal antibody 
directed against human macrophage colony stimulating factor (M-CSF; also known as colony-
stimulating factor-1 [CSF-1]). It is a polypeptide composed of 1324 amino acid residues with 
two heavy chains and two light chains in heterodimeric arrangement.   


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52 
Molecular mass: MCS110 has a non-glycosylated molecular mass of 144.9 kDa. 
 
pH: 5.5- 6.5 
 
8.4.2 Form 
 
The MCS110 150 mg/7.5 mL solution for infusion is formulated as a sterile solution intended 
for intravenous (IV) administration. Each vial of MCS110 150 mg/7.5 mL solution for 
infusion contains 150 mg MCS110 drug substance and the following excipients: L-histidine, 
NaCl, Polysorbate 80, HCl, and water for injection. 
 
8.4.3 Storage 
 
Drug product should be stored at 2-8°C.  Only qualified individuals should be responsible for 
drug access and storage. 
 
If not used immediately, the MCS110 20mg/mL Concentrate for Solution for Infusion and 
MCS110 Solution for Infusion might be stored at 2- 8°C for not longer than 24 hours. The 
standing time of 24 hours is defined as the time from the first vial has been pierced until the end 
of administration. Upon storage, allow the Solution for Infusion to come to room temperature for 
5-10 minutes but not more than 15 minutes before administration 
 
8.4.4 Compatibility 
 
Drug product should be diluted with a 0.9% NaCl solution before administration to patients.  
Compatible materials for infusion and dilution instructions are listed in the pharmacy manual for 
CMCS110ZUS01T. 
 
8.4.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
8.4.6 Availability 
 
MCS110 is provided by Novartis for use in this clinical trial. 
 
8.4.7 Preparation 
 
Instructions for preparation are listed in the pharmacy manual for CMCS110ZUS01T.  Drug 
product should be diluted with a 0.9% NaCl solution before administration to patients. 
 
8.4.8 Administration 
 
MCS110 will be given once on day 1 of the 21 day cycle via IV infusion.  MCS110 should be 


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53 
administered in a 1 hour (±5 min) infusion.  On days where MCS110, dabrafenib, and trametinib 
are all to be given, order of administration does not matter.    
 
Only 0.9% normal saline should be used for dilution and post-infusion flushing of the infusion 
line. Post-infusion, the infusion line must be flushed with 0.9% normal saline, with a volume 
equal to or greater than the hold-up volume of the infusion line. 
 
Further instructions for administration are listed in the pharmacy manual for CMCS110ZUS01T. 
 
8.4.9 Ordering 
 
Drug product will be ordered from Novartis by site pharmacy personnel. 
 
8.4.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain 
a careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form. 
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.4.10 Destruction and Return 
 
The disposal or return transport of MCS110 will comply with DFCI institutional policies on 
handling and documentation.   
 
 
     
8.5 
Dabrafenib 
 
8.5.1 Description 
 
Dabrafenib mesylate is a kinase inhibitor.  
 
Chemical Name: N-{3-[5-(2-amino-4pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-
fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt 
 
Molecular Formula: C23H20F3N5O2S2 ∙ CH4O3S 
 
Molecular Weight: 615.68 
 
Dabrafenib mesylate is a white to slightly colored solid with three pKas: 6.6, 2.2, and -1.5. It is 
very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media. 
 
8.5.2 Form 
 


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54 
TAFINLAR (dabrafenib) capsules are supplied as 50 mg and 75 mg capsules for oral 
administration. Each 50 mg capsule contains 59.25 mg dabrafenib mesylate equivalent to 50 mg 
of dabrafenib free base. Each 75 mg capsule contains 88.88 mg dabrafenib mesylate equivalent 
to 75 mg of dabrafenib free base. 
 
8.5.3 Storage 
 
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled 
Room Temperature].  Only qualified individuals should be responsible for drug access and 
storage. 
 
8.4.4 Compatibility 
 
Review the full FDA Tafinlar (dabrafenib) Label for drug information. 
 
8.4.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
8.4.6 Availability 
 
Dabrafenib is commercially available. 
 
8.4.7 Preparation 
 
Instructions for preparation are listed in the full FDA Tafinlar (dabrafenib) Label. 
 
8.4.8 Administration 
 
Dabrafenib will be given as per package instructions.  Dabrafenib should be taken orally every 
12 hours. A missed dose can be taken up to 6 hours prior to the next dose. Doses that would be 
administered outside of that timeframe should be considered missed and should not be taken. 
Tablets should not be crushed or chewed. A vomited dose should not be retaken, patients should 
continue with the next scheduled dose. Dabrafenib should be taken orally with approximately 
200 mL of water under fasted conditions. On days where MCS110, dabrafenib, and trametinib 
are all to be given, order of administration does not matter. 
 
8.4.9 Ordering 
 
Dabrafenib is commercially available.  The investigator or designated study personnel are 
responsible for maintaining dispensing records of dabrafenib per institutional standards. 
 
8.4.10 Accountability 
 


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55 
The investigator, or a responsible party designated by the investigator, should maintain 
a careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form. 
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.4.10 Destruction and Return 
 
The disposal or return transport of dabrafenib will comply with DFCI institutional policies on 
handling and documentation.   
 
 
8.6 
Trametinib  
 
8.5.1 Description 
 
Trametinib dimethyl sulfoxide is a kinase inhibitor.  
 
Chemical Name: acetamide, N-[3-[3454 cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-
3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7455 trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, 
compound with 1,1’-sulfinylbis[methane] (1:1) 
 
Molecular Formula: C26H23FIN5O4 ∙ C2H6OS 
 
Molecular Weight: 693.53 
 
Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the 
pH range of 2 to 8 in aqueous media. 
 
8.5.2 Form 
 
MEKINIST (trametinib) tablets are supplied as 0.5 mg and 2 mg tablets for oral administration.  
Each 0.5 mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of 
trametinib non-solvated parent. Each 2 mg tablet contains 2.254 mg trametinib dimethyl 
sulfoxide equivalent to 2 mg of trametinib non-solvated parent. 
 
8.5.3 Storage 
 
Store refrigerated at 2° to 8°C (36° to 46°F). Do not freeze. Dispense in original bottle. Do not 
remove desiccant. Protect from moisture and light. Do not place medication in pill boxes. Only 
qualified individuals should be responsible for drug access and storage. 
 
8.4.4 Compatibility 
 
Review the full FDA Mekinist (trametinib) Label for drug information. 
 


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56 
8.4.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
 
8.4.6 Availability 
 
Trametinib is commercially available. 
 
8.4.7 Preparation 
 
Instructions for preparation are listed in the FDA Mekinist (trametinib) Label. 
 
8.4.8 Administration 
 
Trametinib will be given as per package instructions. Trametinib should be taken orally daily. A 
missed dose can be taken up to 12 hours prior to the next dose. Doses that would occur outside of 
this timeframe should be considered missed and should not be taken. Tablets should not be 
crushed or chewed. A vomited dose should not be retaken, patients should continue with the next 
scheduled dose. Trametinib can be taken with or without food. On days where MCS110, 
dabrafenib, and trametinib are all to be given, order of administration does not matter. 
 
8.4.9 Ordering 
 
Trametinib is commercially available.  The investigator or designated study personnel are 
responsible for maintaining dispensing records of dabrafenib per institutional standards. 
 
8.4.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain 
a careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form. 
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.4.10 Destruction and Return 
 
The disposal or return transport of trametinib will comply with DFCI institutional policies on 
handling and documentation.   
 
 
9. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with 
the exception of the informed consent, echocardiogram, ophthalmologic exam, and baseline 


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57 
tumor imaging which may be obtained up to 28 days prior to the start of protocol therapy. 
 
Assessments must be performed prior to administration of any study agent.


 
 
58 
 
 
 
Table 2: Study Calendar 
Pre-
StudyL 
Cycle 1 Day 1 
Cycle 1 Day 8M 
Cycle 1 Day 15M 
Cycle 2 Day 1M 
Cycle 3+ Day 1N,M 
Off StudyO 
Every 3 Months after 
Discontinuing 
Informed Consent 
X 
 
 
 
 
 
 
 
Archival Tumor Tissue 
CollectionA 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
X 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsB 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance 
Status 
X 
X 
 
X 
 
X 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
 
C-Reactive Protein 
(CRP) 
X 
Repeat as clinically indicated. 
 
PT-INR, PTT 
X 
Repeat as clinically indicated. 
 
Serum chemistryC 
X 
X 
X 
X 
X 
X 
X 
 
EKGD 
X 
X 
 
 
X 
XD 
 
 
EchocardiogramE 
X 
 
 
 
X 
XE 
 
 
Dermatologic 
Evaluation 
X 
Dermatologic evaluations to be performed to assess for suspicious skin lesions every 9 weeks (± 1 
week) while on dabrafenib/trametinib therapy or as per institutional standards. Evaluation can be 
performed and documented by treating investigator or by dermatologist. 
X 
 
Adverse event 
evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
 


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59 
 
Table 2: Study Calendar 
Pre-
StudyL 
Cycle 1 Day 1 
Cycle 1 Day 8M 
Cycle 1 Day 15M 
Cycle 2 Day 1M 
Cycle 3+ Day 1N,M 
Off StudyO 
Every 3 Months after 
Discontinuing 
Radiologic evaluation 
X 
CT or MRI imaging of any disease-involved site. Radiologic measurements should be performed at 
the end of cycle 2 (Cycle 2 Day 21) and at the end of every 2 cycles of treatment thereafter (i.e., 
Cycle 4 Day 21, Cycle 6 Day 21, and so on). There is a +/- 7 day scheduling window on imaging 
evaluations. 
X 
 
Serum β-HCGF 
X 
 
 
 
 
 
 
 
Urine Pregnancy TestP 
 
X 
 
 
X 
X 
X 
 
Ophthalmologic 
examination 
X 
 
 
 
X 
To be conducted at baseline, on cycle 2 day 1, and as 
clinically indicated – to be done at the treating 
investigator’s discretion based on institutional 
standards and the presence of symptoms. 
 
cfDNA SampleG 
 
X 
Samples to be collected at visits immediately following restaging scan visits (i.e., 
cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc.) 
X 
 
Plasma CIC SampleH 
 
X 
Samples to be collected at visits immediately following restaging scan visits (i.e., 
cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc.) 
X 
 
Fresh Tumor Tissue 
BiopsyI 
 
 
 
X 
 
 
 
MCS110 
Administration 
 
X 
MCS110 to be administered as described in Section 5. 
 
 
Dabrafenib 
AdministrationJ 
 
X 
Dabrafenib to be administered as described in Section 5 and as per institutional 
standards. 
 
 
Trametinib 
AdministrationJ 
 
X 
Trametinib to be administered as described in Section 5 and as per institutional 
standards. 
 
 
Telephone or Care 
Provider ContactK 
 
 
 
 
 
 
 
X 
A. 
Participants must have archival tumor tissue available for enrollment. Participants without archival tissue may be enrolled at the discretion of the principal investigator. See Section 9 for 
further detail. 
B. 
Vital signs to include heart rate, blood pressure, temperature, respiratory rate, and oxygen saturation (O2 sat). 
C. 
Serum chemistry to include: sodium, potassium, chloride, CO2, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, SGOT [AST], 
SGPT [ALT], globulin, phosphorus, magnesium, calcium, and creatinine phosphokinase (CPK). Other tests may be ordered as clinically indicated. If a patient experiences a new grade 2 
or greater increase in CPK, a CK-MB, troponin (I or T), urine and serum myoglobin and aldolase or other skeletal marker should also be obtained. 
D. 
EKG (single) to be performed during screening, at anytime pre-dose on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 day 1. EKGs to be collected every 3 months thereafter . EKGs can be 
performed more frequently as clinically indicated or as per institutional standards. 
E. 
Echocardiogram to be performed during screening, on Cycle 2 day 1, and then every 3 months thereafter.  Echo can be performed more frequently if clinically indicated. 
F. 
Serum pregnancy test only required for women of childbearing potential. Childbearing potential defined as any female who has experienced menarche and who has not undergone 


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60 
 
Table 2: Study Calendar 
Pre-
StudyL 
Cycle 1 Day 1 
Cycle 1 Day 8M 
Cycle 1 Day 15M 
Cycle 2 Day 1M 
Cycle 3+ Day 1N,M 
Off StudyO 
Every 3 Months after 
Discontinuing 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months; or women 
with a documented plasma follicle-stimulating hormone level >35µlU/mL). 
G. 
cfDNA plasma genotyping sample to be obtained anytime pre-dose on Cycle 1 Day 1. The exact time of the sample should be recorded. Additional samples to be collected at visits 
immediately following restaging scans (i.e., cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc.), and at the off study visit. Please see Section 9 for more detail. 
H. 
Plasma CIC sample to be obtained anytime pre-dose on Cycle 1 Day 1. The exact time of the sample should be recorded. Additional samples to be collected at visits immediately 
following restaging scans (i.e., cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc.), and at the off study visit. Please see Section 9 for more detail. 
I. 
Optional fresh tumor tissue biopsy to be obtained anytime between cycle 1 day 15 and cycle 2 day 7. An additional optional biopsy at the time of disease progression may be obtained up 
to 30 days after the last dose of MCS110. Please see Section 9 for more detail. 
J. 
Dabrafenib and trametinib to be dispensed and administered as described in Section 5 and as per institutional standards. 
K. 
Participants will be followed until death or withdrawal of consent after removal from protocol therapy. This follow up will be performed by review of the medical record, contact with care 
providers, and/or telephone contact as needed every 3-4 months. 
L. 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with the exception of the informed consent, echocardiogram, ophthalmologic exam, and baseline 
tumor imaging which may be obtained up to 28 days prior to the start of protocol therapy. 
M. 
A +/- 3 day scheduling window exists to accommodate holidays, adverse weather, vacations, or other scheduling requests. 
N. 
The start of a subsequent cycle may be delayed by up to 7 days to allow for vacations or other scheduling requests. 
O. 
Off-study evaluation to be completed within 30 days of the last dose of MCS110. Note: Follow up visits or other contact is required in order to identify SAEs during the 30 days following 
the end of study treatment.  
P. 
Urine pregnancy test only required for women of childbearing potential.  Childbearing potential defined as any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months; or women 
with a documented plasma follicle-stimulating hormone level >35µlU/mL). 
 
 


 
 
61 
 
10. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of the phase I portion of this trial, participants 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
participants should be re-evaluated every eight weeks.  In addition to a baseline scan, 
confirmatory scans will also be obtained not less than four weeks following initial 
documentation of an objective response. 
 
10.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:221-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
 Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable.  
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 


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Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 


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63 
followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 


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64 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
MIBG (meta-iodobenzylguanidine).The following is recommended, to assure high 
quality images are obtained.  
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds.  
Images from the head to the distal lower extremities should be obtained.  
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A 
large field of view dual head gamma camera with low energy collimators is preferred.  
 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 


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65 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances.  
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
10.1.3.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 


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increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
10.1.3.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
10.1.3.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
10.1.3.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 


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67 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 


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68 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
 Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
 Response Review 
 
Evaluation of scans will be done centrally at the DFCI using the Tumor Metrics Core.  
 
 
 
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
11.1 
Data Reporting 
 
 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
 Responsibility for Data Submission 
  
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
11.2 
Data Safety Monitoring 
 


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69 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
11.3 
Multicenter Guidelines 
 
Not Applicable. 
 
11.4 
Collaborative Agreements Language 
 
Not Applicable. 
 
12. STATISTICAL CONSIDERATIONS 
 
A standard 3+3 design is planned for the dose finding phase I portion of the trial. The phase I 
portion of the trial will require a minimum of six and a maximum of 18 patients to determine the 
MTD and RP2D. Following identification of the MTD and RP2D, a single-arm phase II trial will 
commence. A total of 25 patients with metastatic melanoma harboring a BRAF V600E or V600K 
mutation will be enrolled to the phase II portion of the trial.  
 
12.1 
Study Design/Endpoints 
 
Endpoints: 
 
Primary 
Phase I  
Dose-limiting toxicity of the combination of MCS110 with BRAF/MEK inhibition. 
 
Phase II 
Overall response (CR or PR as best overall response) according to RECIST criteria (Version 
1.1). At the time of each restaging, patients will be classified as achieving complete response 
(CR), partial response (PR), stable disease (SD), progressive Overall response will be determined 
by the best overall confirmed response designation recorded between the date of first dose of 
trial therapy and the date of objectively documented disease progression or cessation of trial 
therapy, whichever occurs first. For patients without documented progression or cessation of trial 


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therapy, all available response designations contributed to the objective response determination. 
 
Secondary Endpoints: 
 
Progression-free and overall survival are defined in Section 10.1.5. 
 
Toxicity will be assessed using the CTCAE version 4.0. 
 
Design: 
 
Phase I 
A conventional algorithm (3+3 design) will be used to identify the MTD, escalating on 0/3 or 1/6 
DLTs, and de-escalating if two DLTs are encountered. The MTD will be the highest dose level at 
which 0/3 or 1/6 subjects experience a DLT. If dose level 1 is discovered to be intolerable (with 
2/3 or ≥ 2/6 subjects experiencing a DLT), the trial will proceed with enrollment to the fallback 
dose level of -1. If the fallback dose level is also found to be intolerable, the trial will be 
discontinued. The probabilities of escalation if the true but unknown DLT rates are 10, 20, 30, 
40, and 50% are 91, 71, 49, 31, and 17%, respectively.  
 
Phase II 
The design of the phase II trial will be based on the endpoint of ORR.   
 
A Simon, two-stage design with a total of 25 patients will be used.  For this we assume a 
desirable response rate of 20% and a null rate of 1%. We will enroll 15 patients in the first stage.  
If no responses are observed then the trial will stop.  If one or more responses are observed, then 
10 additional patients will be enrolled.  If two or more of the 25 patients have response, then we 
will conclude that there is evidence of adequate response in this cohort.  If the true response rate 
is 1%, the probability is 0.86 that the study will stop at the end of the first stage.  The power of 
this design is 95% with a type-I error of 0.02 (target 0.1).   
 
 
12.2 
Sample Size, Accrual Rate and Study Duration 
 
The planned sample size is between six and 18 patients in the phase I portion of the trial, and 25 
patients in the phase II portion of the trial, for a total of six to 43 patients. The planned accrual 
rate is approximately 5 patients per quarter. Up to an additional one year of follow-up will be 
required for the last participant accrued to observe the patient’s response and survival following 
therapy, for a total study length of about four years. Participants will be identified via targeted 
NextGen sequencing using the DFCI/BWH OncoPanel or another CLIA-certified method for 
genotyping. 
 
 


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71 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
1 
= 
1 
Not Hispanic or Latino 
12 
+ 
24 
= 
36 
Ethnic Category: Total of all subjects 
12 
 
+ 
25 
 
= 
37 
 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
1 
= 
1 
Asian 
0 
+ 
0 
= 
0 
Black or African American 
0 
+ 
0 
= 
0 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
12 
+ 
24 
= 
36 
Racial Category: Total of all subjects 
12 
 
+ 
25 
 
= 
37 
 
 
 
 
 
 
 
 
12.3 
Analysis of Primary and Secondary Endpoints 
 
The primary and secondary analyses will include all eligible patients who started assigned 
therapy. The phase II evaluations will not include the patients enrolled in the phase I portion of 
this trial (see above for statistical analysis plan). The exception to this includes the planned 
analysis of toxicity data, which will include all patients who received study drug regardless of 
eligibility.  
 
Phase I:  The proportion of patients with DLTs will be summarized by dose cohort. 
 
Phase II:  The primary endpoint of ORR will be summarized and presented with a 95% 
confidence interval estimated using the method of Atkinson and Brown, which allows for the 
two-stage design.  PFS and OS will be summarized using the method of Kaplan-Meier.  Medians 
and PFS/OS estimates at pre-specified time points will be summarized and presented with 95% 
confidence intervals based on log(-log(endpoint)) methods. 
 
Exploratory Endpoints: 
Data from correlative studies will be summarized using descriptive statistics. Associations to 
clinical outcome between MAPK signaling, TAMs, and immune infiltrates will be compared and 
summarized by descriptive methods and may be explored graphically. 
 
Additionally, tumor DNA levels obtained from the serial collection of cfDNA samples will be 
examined to explore whether clinical outcome correlates to fluctuations following the 
administration of MCS110 combination therapy. 
 
 


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12.4 
Reporting and Exclusions 
 
 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of study 
medication. 
 
 Evaluation of the Primary Efficacy Endpoint 
 
All eligible participants included in the study will be assessed for response, even if 
there are major protocol therapy deviations. Each participant should be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 
4) progressive disease, 5) early death from malignant disease, 6) early death from 
toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database. 
 
13.  ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES 
 
13.1 
Ethics and good clinical practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
3. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
4. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms 
to. 
 
13.2 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC). A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC must be given to Novartis before 
study initiation. The name and occupation of the chairman and the members of the IRB/IEC will 
be supplied to Novartis. Any amendments to the protocol, other than administrative ones, must 
be approved by this committee. 
 
13.3 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 


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73 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC approval.  
 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that in 
order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
13.4 
Discontinuation of the study 
Novartis reserves the right to discontinue support for any study under the conditions specified in 
the clinical trial agreement. 
 
13.5 
Changes to the protocol 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by Novartis and the investigator before implementation. Amendments significantly 
affecting the safety of subjects, the scope of the investigation or the scientific quality of the 
study, require additional approval by the IRB/IEC. A copy of the written approval of the 
IRB/IEC must be sent to Novartis. 
 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC approval but the IRB/IEC of each center must be kept informed of such 
administrative changes.  
 
13.7 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC. Study documents provided by 
Novartis (investigators' brochures and other material) will be stored appropriately to ensure their 
confidentiality. The information provided by Novartis to the investigator may not be disclosed to 
others without direct written authorization from Novartis, except to the extent necessary to obtain 
informed consent from patients who wish to participate in the trial. 
 
13.8 
Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 


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74 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request 
or can be accessed via the website of the World Medical Association at 
http://www.wma.net/en/10home/index.html 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and prior to any outside submission.  Novartis must receive copies of any 
intended communication in advance of publication (at least twenty-one working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the scientific 
content and conclusions of such publications or presentations.  The Principal 
Investigator/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the interests 
of Novartis and, in accord with the trial contract and shall not permit disclosure of Novartis 
confidential or proprietary information. 
 
 


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75 
REFERENCES 
 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-
30. 
2. 
Chapman PB, Hauschild A, Robert C, et al. Improved survival with dabrafenib in 
melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516. 
3. 
Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations 
of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239-1246. 
4. 
Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with 
combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39. 
5. 
Larkin J, Ascierto PA, Dréno B, et al. Combined dabrafenib and trametinib in BRAF-
mutated melanoma. N Engl J Med. 2014;371(20):1867-1876. 
6. 
Kacinski BM. CSF-1 and its receptor in ovarian, endometrial and breast cancer. Ann 
Med. 1995;27(1):79-85. 
7. 
Sasmono RT, Oceandy D, Pollard JW, et al. A macrophage colony-stimulating factor 
receptor-green fluorescent protein transgene is expressed throughout the mononuclear 
phagocyte system of the mouse. Blood. 2003;101(3):1155-1163. 
8. 
Bourette RP, Rohrschneider LR. Early events in M-CSF receptor signaling. Growth 
Factors. 2000;17(3):155-166. 
9. 
Pixley FJ, Stanley ER. CSF-1 regulation of the wandering macrophage: complexity in 
action. Trends Cell Biol. 2004;14(11):621-638. 
10. 
Lin H, Lee E, Hestir K, et al. Discovery of a cytokine and its receptor by functional 
screening of the extracellular proteome. Science. 2008;320(5877):807-811. 
11. 
Nowicki A, Szenajch J, Ostrowska G, et al. Impaired tumor growth in colony-stimulating 
factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of 
CSF-1-dependent macrophages in formation of tumor stroma. Int J Cancer. 
1996;65(1):112-119. 
12. 
Lewis CE, Pollard JW. Distinct role of macrophages in different tumor 
microenvironments. Cancer Res. 2006;66(2):605-612. 
13. 
Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour 
progression: implications for new anticancer therapies. J Pathol. 2002;196(3):254-265. 
14. 
Lin EY, Nguyen AV, Russell RG, Pollard JW. Colony-stimulating factor 1 promotes 
progression of mammary tumors to malignancy. J Exp Med. 2001;193(6):727-740. 
15. 
Dubreuil P, Torrès H, Courcoul MA, Birg F, Mannoni P. c-fms expression is a molecular 
marker of human acute myeloid leukemias. Blood. 1988;72(3):1081-1085. 
16. 
Kacinski BM, Scata KA, Carter D, et al. FMS (CSF-1 receptor) and CSF-1 transcripts 
and protein are expressed by human breast carcinomas in vivo and in vitro. Oncogene. 
1991;6(6):941-952. 
17. 
Tang R, Beuvon F, Ojeda M, Mosseri V, Pouillart P, Scholl S. M-CSF (monocyte colony 
stimulating factor) and M-CSF receptor expression by breast tumour cells: M-CSF 
mediated recruitment of tumour infiltrating monocytes? J Cell Biochem. 1992;50(4):350-
356. 
18. 
Kacinski BM. CSF-1 and its receptor in breast carcinomas and neoplasms of the female 
reproductive tract. Mol Reprod Dev. 1997;46(1):71-74. 
19. 
Mroczko B, Groblewska M, Wereszczyńska-Siemiatkowska U, et al. Serum macrophage-
colony stimulating factor levels in colorectal cancer patients correlate with lymph node 
metastasis and poor prognosis. Clin Chim Acta. 2007;380(1-2):208-212. 


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76 
20. 
Zhu XD, Zhang JB, Zhuang PY, et al. High expression of macrophage colony-stimulating 
factor in peritumoral liver tissue is associated with poor survival after curative resection 
of hepatocellular carcinoma. J Clin Oncol. 2008;26(16):2707-2716. 
21. 
Scholl SM, Pallud C, Beuvon F, et al. Anti-colony-stimulating factor-1 antibody staining 
in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates 
and prognosis. J Natl Cancer Inst. 1994;86(2):120-126. 
22. 
Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. 
Nat Rev Cancer. 2004;4(1):71-78. 
23. 
Guo JK, Cantley LG. Cellular maintenance and repair of the kidney. Annu Rev Physiol. 
2010;72:357-376. 
24. 
Hume DA. The mononuclear phagocyte system. Curr Opin Immunol. 2006;18(1):49-53. 
25. 
Watanabe S, Yoshimura A, Inui K, et al. Acquisition of the monocyte/macrophage 
phenotype in human mesangial cells. J Lab Clin Med. 2001;138(3):193-199. 
26. 
Wang T, Papoutsi M, Wiesmann M, et al. Investigation of correlation among safety 
biomarkers in serum, histopathological examination, and toxicogenomics. Int J Toxicol. 
2011;30(3):300-312. 
27. 
Radi ZA, Koza-Taylor PH, Bell RR, et al. Increased serum enzyme levels associated with 
kupffer cell reduction with no signs of hepatic or skeletal muscle injury. Am J Pathol. 
2011;179(1):240-247. 
28. 
Leek RD, Harris AL. Tumor-associated macrophages in breast cancer. J Mammary Gland 
Biol Neoplasia. 2002;7(2):177-189. 
29. 
Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate 
resistance to RAF inhibitors through HGF secretion. Nature. 2012;487(7408):500-504. 
30. 
Wilson TR, Fridlyand J, Yan Y, et al. Widespread potential for growth-factor-driven 
resistance to anticancer kinase inhibitors. Nature. 2012;487(7408):505-509. 
31. 
Mok S, Tsoi J, Koya RC, et al. Inhibition of colony stimulating factor-1 receptor 
improves antitumor efficacy of BRAF inhibition. BMC Cancer. 2015;15:356. 
32. 
Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. 
Immunity. 2014;41(1):49-61. 
33. 
Wang T, Xiao M, Ge Y, et al. BRAF Inhibition Stimulates Melanoma-Associated 
Macrophages to Drive Tumor Growth. Clin Cancer Res. 2015;21(7):1652-1664. 
34. 
Hu-Lieskovan S, Mok S, Homet Moreno B, et al. Improved antitumor activity of 
immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci Transl 
Med. 2015;7(279):279ra241. 
35. 
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of 
pertuzumab in cancer patients based on population pharmacokinetic analysis. Pharm Res. 
2006;23(6):1275-1284. 
36. 
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based 
dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 
2009;49(9):1012-1024. 
37. 
Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing 
of therapeutic peptides and proteins in adults. J Clin Pharmacol. 2012;52(1):18-28. 
38. 
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferon-α monoclonal antibody, in systemic lupus erythematosus. 
Clin Pharmacokinet. 2013;52(11):1017-1027. 
39. 
Garraway LA, Lander ES. Lessons from the cancer genome. Cell. 2013;153(1):17-37. 


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40. 
Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, Dudley ME, Rosenberg SA. 
Myeloid cells obtained from the blood but not from the tumor can suppress T-cell 
proliferation in patients with melanoma. Clin Cancer Res. 2012;18(19):5212-5223. 
 
 
 


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78 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 


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79 
APPENDIX B  
BRAF/MEK Ophthalmic Exam Source Worksheet 
 
Subject Name: ______________________________________________Note to 
examiner:  Please assess particularly for visible retinal pathology. 
 
* Optical coherence tomography is highly recommended  For patients in whom retinal abnormalities are noted, 
color fundus photos, and fluorescein angiography if clinically indicated, are recommended.   
 
OPHTHALMIC EXAMINATION 
1. Date of Examination:
 
 
 
 
 
   
_ _/_ _ _ /_ _ _ _ 
   dd  /   mmm   /    yyyy 
VISUAL ACUITY 
Enter corrected visual acuity 
OD: 
 
OS: 
TONOMETRY 
Enter IOP (mmHg) 
 
OD: 
OS: 
INDIRECT FUNDOSCOPY 
Indirect Exam: Indicate 
normal or specify abnormalities 
OD: 
OS: 
CONFRONTATION VISUAL FIELD EXAM  OR AUTOMATED PERIMETRY 
(e.g., Humphrey 24-2 or 30-2 or equivalent if using a non-Humphrey instrument) 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
OPTICAL COHERENCE TOMOGRAPHY (strongly recommended) 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
COLOR FUNDUS PHOTOS (recommended if retinal abnormalities are noted)* 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
FLORESCEIN ANGIOGRAPHY (suggested if retinal abnormalities are noted and 
test clinically indicated)* 
Indicate normal or specify any 
abnormalities 
OD: 
OS: 
Were any of the following noted on ocular history or exam? 
Yes No 
• 
History of CSR? 
 
 
• 
Evidence of new optic disc cupping? 
 
 
• 
Evidence of new visual field defects? 
 
 
EXCLUSION CRITERIA 
Yes No 
• 
History of RVO? 
o If yes, patient is not eligible for the study. 
 
 
 
Signature of Examiner: _____________________________   


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80 
Printed Name: _________________________      Date: ______________ 
 
 
 


DF/HCC Protocol #: 17-656 
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81 
Dabrafenib, Trametinib, or Dabrafenib-Trametinib Treatment Modification for Visual 
Changes