Conditions: Melanoma
Keywords: Melanoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 5
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:

* LY3022855
* Vemurafenib
* Cobimetinib

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 LY3022855 as a treatment for any disease.

The FDA has approved vemurafenib and cobimetinib as treatment options for this disease.

LY3022855 is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor. It is a human monoclonal antibody. 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. By binding to the tumor cells, the antibody might prevent the tumor cell from growing and spreading. LY3022855 is being developed as a treatment for patients with advanced cancer.

Vemurafenib and cobimetinib attack different proteins that promote the growth of cancerous cells. Vemurafenib is a BRAF inhibitor that works by blocking altered BRAF proteins from stimulating the growth of melanoma cancer cells. Cobimetinib works by blocking a protein called MEK that has been known to promote melanoma growth. In order to participate in the study, participant's 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.

In this research study, the investigators are combining LY3022855 with vemurafenib and cobimetinib in the hopes that the LY3022855 will enhance how your cancer responds to vemurafenib and cobimetinib.

Arms:
arm 1: * Starting dose level of LY3022855 50mg IV administered intravenously every week
* Vemurafenib 960 mg BID administered by mouth twice daily
* Cobimetinib 60 mg administered by mouth once daily on days 1-21of each cycle arm 2: * LY3022855 50mg IV administered intravenously every week
* Vemurafenib 960 mg BID administered by mouth twice daily
* Cobimetinib 60 mg administered by mouth once daily on days 1-21of each cycle arm 3: * LY3022855 100mg IV administered intravenously every week
* Vemurafenib 960 mg BID administered by mouth twice daily
* Cobimetinib 60 mg administered by mouth once daily on days 1-21of each cycle arm 4: * MTD of LY3022855 was not established
* Vemurafenib planned 960 mg BID administered by mouth twice daily
* Cobimetinib planned 60 mg administered by mouth once daily on days 1-21of each cycle

Interventions: intervention 1: LY3022855 intervention 2: Vemurafenib intervention 3: Cobimetinib
Intervention descriptions: intervention 1: LY3022855 is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor intervention 2: Vemurafenib is a BRAF inhibitor that works by blocking altered BRAF proteins from stimulating the growth of melanoma cancer cells intervention 3: Cobimetinib works by blocking a protein called MEK that has been known to promote melanoma growth

Protocol document:
Prot_SAP_000.pdf: 
DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
 
 
 1 
 
NCI Protocol #: 
Not Applicable 
 
DF/HCC Protocol #: 17-030 
 
TITLE:  A Phase I/II Study of LY3022855 with BRAF/MEK Inhibition in Patients with 
Melanoma  
 
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 
Adrienne Anderson RN, BSN 
Dana-Farber Cancer Institute 
Dana-Farber Cancer Institute  
Telephone: 617-632-2193 
Telephone: 617-632-6594 
Fax: 617-632-2444 
Fax: 617-632-5152 
agiohur@jimmy.harvard.edu 
Aanderson10@partners.org 
 
 
 
 
Agents:  
LY3022855 – Eli Lilly and Company 
Vemurafenib – Commercial 
Cobimetinib – Commercial 
 
IND #: 130,965 
 
IND Sponsor: Investigator-Initiated Study, Dr. Elizabeth Buchbinder MD 
 
 
Protocol Type / Version # / Version Date: Revision, Version #6, 31 July 2017 


DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
2 
SUMMARY OF CHANGES 
 
DF/HCC Protocol #: 17‐030 
 
Protocol Date: 31 July 2017 
 
# 
Section(s) 
Change(s) 
1. TOC; Table 5; Section 
2.5.1 
Explanation of rationale for flat dosing of LY3022855; 
update of Table 5 to include non‐weight based cohorts for 
study JSCA; updated Table of Contents and added a List of 
Figures. Changes per FDA request for further information. 
2. 
1.3; 2.2.2; 2.3; 2.4; 
2.5.1; 2.5.2; 3.1.8; 
3.2.13; 5.1; 5.3.1; 5.4; 
5.5.2; 5.6; 5,8; 6.2; 6.3; 
7.1; 11.1; 13.1 
Secondary objective for the phase I portion of the trial 
further defined per FDA request; Background information 
on LY3022855 edited per updated IB; Background 
information on vemurafenib and cobimetinib edited; Rationale 
for flat-dosing of LY3022855 edited; Eligibility criterion 3.1.8 
edited to include additional parameters for defining 
adequate organ function per FDA request; Strong and 
moderate CYP3A inhibitors were prohibited for all portions 
of the trial per FDA request; Definition of the RP2D 
elaborated to include consideration of toxicity occurring 
outside of the DLT time window per FDA request,and dose 
level 3 removed; Hypersensitivity reaction section edited to 
include suggested medication intervention per FDA request; 
DLT criteria edited to include Grade 4 anemia and to 
remove allowance of Grade 3 AST/ALT increases lasting 
fewer than 8 days per FDA request; Modified criteria for 
taking participants off therapy to reference unacceptable 
AEs per FDA request; Clarified that tumor evaluations 
would continue on schedule in the event of dose delays as 
per FDA request; Added information that LY3022855 must 
be reduced as part of the 1st dose reduction for a toxicity 
and further clarified that patients undergoing intra‐patient 
dose escalation would not be allowed to escalate to a dose 
level beyond the MTD per FDA request; Added specification 
that vemurafenib and cobimetinib may be reduced per FDA 
prescribing information; Edited expected toxicities for 
clarity; Edited section 11 to include definition of evaluable 
disease for phase I enrollment purposes; Edited statistical 
section for clarity that the MTD will be defined in a 
minimum of 6 patients; General formatting updates to 
references to Tables/Sections throughout document. 


DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
3 
# 
Section(s) 
Change(s) 
3. Schema; 3.1.3; 5.1; 
5.3.1; 13 
Schema and Section 5.1 edited to reflect starting dose level 
of 50 mg for LY3022855 and removal of fallback dose level; 
Eligibility criterion 3.1.3 edited for clarity; Section 5.3.1 
hypersensitivity reaction guidelines edited; Section 13 
edited to reflect change in protocol sample size with altered 
dose levels. 
4. 
2.5.2; 2.6; 3.1.7; 7.1; 
12.1.2; 12.2; Study 
Calendar 
Protocol document edited to comply with DFCI 
departmental review comments. 
5. 3.2.2 
Clarification of washout for prior BRAF/MEK inhibitor 
therapy (applicable only to phase I participants). 


DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
 
 
4 
 
SCHEMA 
 
 
Phase I Portion: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase II Portion: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes 
No 
Enroll 
beginning 
with dose 
level 1 
Treat cohort 
(3 participants 
per cohort, with 1 
cycle = 28 days) 
No further escalation. 
Recruit 3 more 
participants 
Further 
DLTs? 
Escalate dose 
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 
No further escalation.  
2 or 3 
0 
Informed consent 
and confirmation 
of trial eligibility 
 
Participant 
receives 2 cycles 
of treatment 
(where 1 cycle = 
28 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 
Continue for another 2 cycles 


DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
 
 
5 
 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Study Design ............................................................................................................8 
1.2 
Primary Objectives ...................................................................................................8 
1.3 
Secondary Objectives ...............................................................................................8 
1.4 
Exploratory Objectives ............................................................................................8 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Disease ...........................................................................................................9 
2.2 
LY3022855 ..............................................................................................................9 
2.3 
Vemurafenib ..........................................................................................................27 
2.4 
Cobimetinib............................................................................................................27 
2.5 
Rationale ................................................................................................................28 
2.6 
Correlative Studies Background ............................................................................36 
3. 
PARTICIPANT SELECTION ...........................................................................................37 
3.1 
Eligibility Criteria ..................................................................................................37 
3.2 
Exclusion Criteria ..................................................................................................39 
3.3 
Inclusion of Women and Minorities ......................................................................40 
4. 
REGISTRATION PROCEDURES ...................................................................................40 
4.1 
General Guidelines for DF/HCC Institutions ........................................................41 
4.2 
Registration Process for DF/HCC Institutions .......................................................41 
4.3 
General Guidelines for Other Investigative Sites ..................................................41 
4.4 
Registration Process for Other Investigative Sites .................................................41 
5. 
TREATMENT PLAN ........................................................................................................41 
5.1 
Treatment Regimen ................................................................................................41 
5.2 
Pre-Treatment Criteria ...........................................................................................43 
5.3 
Agent Administration .............................................................................................43 
5.4 
Definition of Dose-Limiting Toxicity (DLT) ........................................................45 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................46 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................47 
5.7 
Duration of Follow Up ...........................................................................................48 
5.8 
Criteria for Taking a Participant Off Study ...........................................................48 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................49 
6.1 
Specific Toxicity Management ..............................................................................49 
6.2 
Treatment Delays ...................................................................................................53 
6.3 
Dose Modifications ................................................................................................53 
6.4 
Overdose management ...........................................................................................55 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................55 


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6 
7.1 
Expected Toxicities ................................................................................................55 
7.2 
Adverse Event Characteristics ...............................................................................55 
7.3 
Serious Adverse Events .........................................................................................56 
7.4 
Expedited Adverse Event Reporting ......................................................................57 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ......................57 
7.6 
Expedited Reporting to Hospital Risk Management .............................................57 
7.7 
Routine Adverse Event Reporting .........................................................................57 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................57 
8.1 
LY3022855 ............................................................................................................57 
8.2 
Vemurafenib ..........................................................................................................61 
8.3 
Cobimetinib............................................................................................................62 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................64 
9.1 
Collection of Archival Tissue ................................................................................64 
9.2 
Exploratory Fresh Tumor Biopsies ........................................................................64 
9.3 
Laboratory Correlative Studies ..............................................................................65 
10. 
STUDY CALENDAR .......................................................................................................65 
11. 
MEASUREMENT OF EFFECT........................................................................................70 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................70 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................77 
12.1 
Data Reporting .......................................................................................................78 
12.2 
Data Safety Monitoring ..........................................................................................78 
13. 
STATISTICAL CONSIDERATIONS...............................................................................78 
13.1 
Study Design/Endpoints.........................................................................................78 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................79 
13.3 
Analysis of Primary and Secondary Endpoints .....................................................80 
13.4 
Reporting and Exclusions ......................................................................................80 
14. 
PUBLICATION PLAN .....................................................................................................81 
15. 
REFERENCES ..................................................................................................................82 
16. 
APPENDIX A PERFORMANCE STATUS CRITERIA ..................................................85 
 
 
LIST OF TABLES 
 
Table 1: Single-Dose Pharmacokinetics of LY3022855 .............................................................. 11 
Table 2: Multi-Dose Pharmacokinetics in Cynomolgus Monkeys ............................................... 12 
Table 3: Single-Dose Toxicity and Toxicokinetics of LY3022855 in Cynomolgus Monkeys .... 14 
Table 4: Multi-Dose Toxicity and Toxicokinetics of LY3022855 in Cynomolgus Monkeys ...... 17 
Table 5: Lilly-Sponsored Clinical Studies .................................................................................... 19 
Table 6: Related TEAEs by Cohort for Study JSCA Occurring in ≥ 2 Patients (N = 29) ............ 25 


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7 
Table 7: Related TEAEs by Cohort for Study JSCB Occurring in ≥ 2 Patients (Safety Population, 
N = 14) .......................................................................................................................................... 26 
Table 8: Summary of Non-compartmental PK Parameters Following IV Infusion of Weight-
Based and Non-Weight-Based of Dosing LY3022855 in Cancer Patients during Cycle 1 for 
Study JSCA ................................................................................................................................... 29 
Table 9: Study JSCA:  Summary of Serious Treatment-Emergent Adverse Events for Flat Doses
....................................................................................................................................................... 35 
Table 10: Phase I Dose Escalation Schedule ................................................................................ 41 
Table 11: Phase I Dose Escalation Decision Criteria ................................................................... 42 
Table 12: Management of Elevated AST/ALT ............................................................................. 49 
Table 13: Management of Neutropenia ........................................................................................ 49 
Table 14: Management of Thrombocytopenia .............................................................................. 50 
Table 15: Management of Rash or Photosensitivity ..................................................................... 50 
Table 16: Management of QTc Increase (Associated with Vemurafenib) ................................... 50 
Table 17: Management of Nausea ................................................................................................ 51 
Table 18: Management of Vomiting ............................................................................................. 51 
Table 19: Management of Diarrhea .............................................................................................. 51 
Table 20: Management of Constipation ........................................................................................ 52 
Table 21: Management of Other Toxicity .................................................................................... 52 
Table 22: Dose Modifications ....................................................................................................... 54 
Table 23: Study Calendar.............................................................................................................. 67 
Table 24: Participants with Measurable Disease (i.e., Target Disease) ........................................ 76 
Table 25: Participants with Non-Measurable Disease (i.e., Non-Target Disease) ....................... 76 
Table 26: Accrual Targets ............................................................................................................. 80 
 
LIST OF FIGURES 
 
Figure 1: Mean concentration-versus-time profiles for LY3022855 following intravenous 
administration to patients with cancer on Day 1 (upper panel) and on Days 15 and 22 (lower 
panel) for Study JSCA. ................................................................................................................. 32 
Figure 2: Individual observed clearance versus patient body weight (upper panel) and 
LY3022855 dose (lower panel) for Study JSCA. ......................................................................... 33 


DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
8 
 
1. OBJECTIVES 
 
1.1 
Study Design 
 
This is an open-label phase I/II study looking at the combination of colony-stimulating factor-1 
receptor (CSF-1R) inhibition using LY3022855 with BRAF/MEK inhibitor therapy using 
vemurafenib and cobimetinib. The BRAF and MEK inhibition will be maintained at standard 
dosing with the addition of the LY3022855 in a typical 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 will move forward.   
 
1.2 
Primary Objectives 
 
Phase I:   
 
To determine the MTD and RP2D of the combination of LY3022855 with 
vemurafenib and cobimetinib. 
 
Phase II:   
 
To evaluate the progression-free survival (PFS) rate in patients with BRAF V600E 
or V600K mutated melanoma. 
 
1.3 
Secondary Objectives 
 
Phase I:  
 To evaluate the preliminary overall response rate (ORR) and PFS rate of 
LY3022855 with vemurafenib and cobimetinib in patients with melanoma 
harboring BRAF V600E or V600K mutations. 
 
Phase II: 
 To evaluate the ORR of the combination of LY3022855 with vemurafenib and 
cobimetinib in patients with BRAF V600E or V600K mutated melanoma. 
 To evaluate the overall survival (OS) in patients with BRAF V600E or V600K 
melanoma to the combination of LY3022855 with vemurafenib and cobimetinib. 
 To continue to evaluate the safety and tolerability of LY3022855 in combination 
with vemurafenib and cobimetinib. 
 
 
1.4 
Exploratory Objectives 
 To investigate the effect of the combination of LY3022855 with vemurafenib and 
cobimetinib on mitogen-activated protein kinase (MAPK) pathway signaling and 
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 


DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
9 
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 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 vemurafenib or dabrafenib 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 
LY3022855 
 
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-1R has the potential to limit cancer 
progression. 
 
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, 


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10 
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-1R treatment. 
 
A recombinant human immunoglobulin type G1 (IgG1) that targets human CSF-1R, LY3022855 
was originally identified from a screen of hybridoma candidates that were generated following 
immunization of MEDAREX HuMAb™ human immunoglobulin G (IgG)-transgenic mice with 
human CSF-1R expressing NIH-3T3 cells and soluble CSF-1R protein. The antibody comprises 
two identical gamma (γ) heavy chains and two identical kappa (κ) light chains. 
 
Since LY3022855 does not inhibit murine CSF-1R, a recombinant rat IgG1 antibody specific for 
murine CSF-1R (designated as CS7) was developed and utilized as a surrogate antibody to 
evaluate the effects of targeting CSF-1R on macrophages in murine models of cancer. 
LY3022855 and CS7 were shown to inhibit the binding of both CSF-1 and IL-34 to human and 
mouse CSF-1R, respectively. In addition, LY3022855 and CS7 inhibited the phosphorylation 
both of their respective CSF-1R as well as of downstream signaling molecules. The effects of 
CS7 were evaluated in several mouse tumor models of cancer established with both human and 
murine tumor cells. Using CS7 as a single agent to target CSF-1R on macrophages effectively 
reduced tumor volume in three human xenograft breast cancer models and two syngeneic murine 
mammary cancer models. In line with the potential utility of LY3022855 as a combination 
therapy, CS7 increased the antitumor effects of targeted agents such as trastuzumab, 
doxorubicin, paclitaxel, and docetaxel in preclinical models. When comparing the effect of CS7 
in a range of animal models, antitumor efficacy correlated with CSF-1-secreting tumors, 
supporting the potential use of CSF-1 levels as a predictor of responsiveness to therapy. 
 
On the basis of the above non-clinical findings, LY3022855 was considered to be a candidate for 
clinical development as a treatment for cancer. A phase I trial to evaluate the safety, MTD, 
pharmacokinetics (PK), antitumor activity, immunogenicity, and pharmacodynamics (PD) of 
LY3022855 is currently ongoing. 
 
2.2.1 
Non-Clinical Studies 
 
2.2.1.1 
Pharmacokinetics 
 
The pharmacokinetics (PKs) of LY3022855 were characterized in mice after a single 
intraperitoneal injection of 20 mg/kg and in cynomolgus monkeys after a single intravenous (IV) 
infusion at dose levels of 10, 40, and 140 mg/kg. The PKs of CS7 were evaluated in mice after a 
single intraperitoneal injection (20 mg/kg). CS7 was produced to validate the strategy of 
targeting CSF-1R in mouse cancer models because LY3022855 does not cross-react with mouse 
CSF-1R. The half-life (t1/2) of LY3022855 in mice was 110.4 hours, approximately three-fold 
greater than that of CS7. However, in the IV single-dose cynomolgus monkey study, the t1/2 of 
LY3022855 was greater than that observed in mice, ranging from 183.3 to 275.2 hours (group 
means). In the primate study, LY3022855 exposure was generally dose proportional. The group 
means volume of distribution (Vd) in the primate study ranged from 60.8 to 63.6 mL/kg, 


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11 
indicating that the distribution of LY3022855 is limited to the vasculature. LY3022855 exposure 
was continuous throughout the duration of the primate study and no sex differences were 
observed. In the repeat-dose toxicology study, the PK parameters for LY3022855 after the 
administration of the first dose were consistent with the single-dose study (see Table 1). 
 
Table 1: Single-Dose Pharmacokinetics of LY3022855 
 
 
 
In a repeat-dose monkey toxicology study, LY3022855 was administered to cynomolgus 
monkeys IV once weekly over four weeks via a 15 minute infusion at four different dose levels: 
0 (control), 20, 60, and 180 mg/kg. The serum concentrations of LY3022855 were more 
sustained over the sampling period after the fourth dose compared with the first dose, with mean 
concentrations at 168 hours post dose ranging from 23 to 43% of the maximum serum 
concentration (Cmax); time to maximum serum concentration (Tmax) generally occurred by 1 hour 
post end of infusion. The group means t1/2 after the fourth dose was between 158 and 470 hours 
among recovery animals. The group means Vd for recovery animals was between 29.2 and 51.2 
mL/kg and indicated limited distribution beyond the vasculature. Exposure after the fourth dose 
was moderately higher than after the first dose, with accumulation ratios of approximately two 
for the area under the curve from time 0 to 168 hours (AUC0-168hr) and 1.5 for Cmax. The exposure 
parameters for the Cmax and AUC0-168hr generally increased proportionally with the increase in 
dose level, and no notable sex differences were apparent (Table 2). Anti-LY3022855 antibodies 
(anti-drug antibodies [ADA]) were detected in 12 of 30 animals that were evaluated after 
administration of LY3022855. The apparent concentration of LY3022855 was reduced in two of 
the 12 animals compared with that of animals from the same dose group that were negative for 
ADA. 
 
The concentration of CSF-1 increased in animals treated with LY3022855 in a similar manner to 
that observed in the single-dose primate study. After the first administration of LY3022855, 


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12 
CSF-1 serum concentrations increased quickly between 0.5 and 24 hours post infusion but then 
increased only slightly until 168 hours post infusion. CSF-1 concentrations were comparable 
among all treatment groups after the first and fourth doses, suggesting that maximal increases in 
CSF-1 were achieved with the lowest dose level studied. The concentrations of CSF-1 were 
sustained during the study, as high levels were still present prior to the fourth dose 
administration. After the fourth dose, concentrations generally decreased after approximately 504 
hours post infusion in the 20 mg/kg group and after approximately 672 hours post the end of 
infusion for the 60 mg/kg group. Exposure to CSF-1 was similar during the first and fourth 
doses, with no notable accumulation or sex differences. 
 
Table 2: Multi-Dose Pharmacokinetics in Cynomolgus Monkeys 
 
 
Metabolism and Disposition 
 
Formal studies to characterize the metabolism and disposition of LY3022855 have not been 
conducted. As a monoclonal antibody, LY3022855 will be largely confined to the extracellular 
space, which is supported by data from numerous investigations and is consistent with the PK 
evaluation of LY3022855. No formal metabolism studies of LY3022855 have been performed 
because the catabolism of antibodies by mammalian systems is largely understood and formal 
studies of the metabolic degradation of these molecules are not warranted. 
 
Excretion 
 
Formal excretion studies of LY3022855 have not been conducted. 
 
2.2.1.2 
Safety Pharmacology and Toxicology 
 
A standard non-clinical toxicology program for advancement of a monoclonal antibody into 
clinical trials in oncology indications was conducted to assess the safety and toxicity of 


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13 
LY3022855. The non-clinical safety assessment of LY3022855 was conducted in cynomolgus 
monkeys. This species was considered a relevant model for the safety evaluation of LY3022855 
based on a preliminary cross-species evaluation of tissue/receptor binding and/or functional in 
vitro pharmacological activity in human and cynomolgus monkey test systems and in a 
subsequent comprehensive tissue cross-reactivity study using full panels of monkey and human 
tissues. The toxicology studies conducted with LY3022855 included exploratory single-dose 
toxicity and toxicokinetic (TK) dose range-finding study and a pivotal four week repeat-dose 
Good Laboratory Practice toxicity, TK, and immunogenicity study with a six week recovery 
period.  
 
Animals were administered LY3022855 by IV infusion, the intended clinical method of 
administration, using the dosing schedule (once weekly) in the planned initial clinical 
investigations of LY3022855. The pivotal study included evaluations of relevant safety 
pharmacology parameters. Due to an anticipated effect of LY3022855 on circulating levels of the 
target ligand, CSF-1, the level of CSF-1 was also measured in the study animals as a potential 
marker of the PD activity of the antibody. A thorough assessment of peripheral blood and spleen 
mononuclear cell subsets and an immunohistochemical analysis of CD68+ cells (cellular marker 
of monocytes/macrophages) in liver and spleen were also included to determine the effects that 
blockade of the CSF-1R might have on these endpoints. 
 
Tissue Cross-Reactivity 
 
A comprehensive tissue cross-reactivity study was conducted in cryosections of normal human 
and cynomolgus monkey tissues using a fluorescein isothiocyanate (FITC)-labeled form of 
LY3022855, designated LY3022855-FITC, applied to cryosections of normal human and 
cynomolgus monkey tissues at 2 concentrations (5 and 0.5 µg/mL).  
 
The tissue-binding and distribution profile of LY3022855-FITC staining observed in the human 
and cynomolgus monkey tissue panels was generally consistent with reported sites of CSF-1R 
expression, and no important unexpected (i.e., off-target) binding was observed. Staining with 
LY3022855-FITC was present in the cytoplasm, cytoplasmic granules, and membrane granules 
of mononuclear cells and cells of myeloid and mononuclear phagocytic lineage. In human 
peripheral blood smears, staining of monocytes was observed. Additionally, staining of the 
cytoplasm and cytoplasmic granules of hematopoietic precursor cells was observed in one human 
bone marrow sample. In cynomolgus monkey kidney, cytoplasmic staining of glomerular tuft 
cells consistent with mesangial cells was present. In human placenta, staining of the cytoplasm, 
cytoplasmic granules, and membrane of trophoblastic epithelium was observed. Although CSF-
1R is expressed mainly by cells of myeloid and mononuclear phagocytic lineage (e.g., 
macrophages, monocytes, and glomerular mesangial cells), expression has also been reported in 
cells of neuroepithelial lineage, including trophoblasts23-25. 
 
Single-Dose Toxicity 
 
Single-dose administration of LY3022855 at dose levels of 10, 40, and 140 mg/kg administered 
by IV infusion over a 15 minute period was well tolerated in cynomolgus monkeys (two 
monkeys per sex per group) during the 14 day observation period. Sustained dose-proportional 


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Protocol Version Date: 31 July 2017 
 
14 
exposure to LY3022855 was generally observed throughout the 14 day observation period at all 
dose levels following administration, with no apparent sex differences. A relatively long t1/2 was 
observed for LY3022855, ranging from approximately 183 to 275 hours. 
 
The key toxicological findings after a single administration of LY3022855 were elevations in 
serum transaminases (ALT and AST) and LDH on days 2, 7, and 15 following dosing. 
Elevations in ALT were generally minimal at the lowest dose level (10 mg/kg), whereas 
generally minimal to moderate elevations were observed in ALT at 40 and 140 mg/kg and in 
AST and LDH across all dose groups. The elevations in ALT, AST, and LDH observed on day 7 
generally declined towards baseline levels in most animals by the end of the observation period, 
suggesting reversibility of these effects. No histological changes in the liver were noted to 
correlate with the increases in ALT, AST, and LDH, nor were any changes noted in liver 
functional parameters (i.e., alkaline phosphatase, bilirubin, or coagulation). Based on the small 
magnitude of the elevations and the absence of histological or functional changes, the increases 
in ALT, AST, and LDH were not considered adverse. Similar elevations in serum enzyme levels 
have also been observed when treating with other pharmacological agents targeting CSF-1R26,27. 
 
No other adverse clinical signs or effects on food consumption, body weight, hematology, or 
organ weights were associated with administration of LY3022855. 
 
The no-observed-adverse-effect level (NOAEL) in this study was considered to be the highest 
dose tested, 140 mg/kg. This dose corresponded to a dosing day 1 mean serum concentration at 
168 hours (C168hr) of 1097 μg/mL, mean Cmax of 4010 µg/mL, and mean AUC0-168hr of 303127 
μg·hr/mL for males and females (Table 3). 
 
Table 3: Single-Dose Toxicity and Toxicokinetics of LY3022855 in Cynomolgus Monkeys 
 
 
 


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15 
Multi-Dose Toxicity 
 
In the pivotal repeat-dose toxicity, TK, and immunogenicity study of LY3022855, doses of 0 
(control), 20, 60, and 180 mg/kg/dose of LY3022855 were administered by IV infusion once 
weekly to cynomolgus monkeys (5 monkeys per sex per group) for four weeks, followed by a six 
week recovery period. Standard toxicological and relevant safety pharmacology (cardiovascular, 
central nervous, and respiratory systems) endpoints were assessed. As in the single-dose study, 
circulating levels of CSF-1 were measured. A thorough assessment of peripheral blood and 
spleen mononuclear cell subsets and an immunohistochemical analysis of CD68+ mononuclear 
cells in liver and spleen were also conducted. 
 
IV infusion of LY3022855 was generally well tolerated at all dose levels. Sustained dose-
proportional to slightly-greater-than-dose-proportional increases in exposure to LY3022855 were 
observed, and no sex differences in exposure were apparent. Moderate accumulation 
(approximately two-fold) of LY3022855 occurred after repeated administration. ADA were 
detected in 12 of 30 animals treated with LY3022855 (six were positive after the first dose and 
an additional six were positive after the last dose). In two of the animals with ADA after the last 
dose, the presence of ADA appeared to decrease the concentration of LY3022855, thus 
impacting the TK analysis. The ADA in the other animals did not appear to affect serum 
LY3022855 concentrations. 
 
As noted in the single-dose exploratory study, circulating concentrations of CSF-1 increased 
shortly after LY3022855 administration. CSF-1 was not detected in any control animals. In 
contrast to LY3022855, the concentration of CSF-1 did not vary with dose, as comparable 
maximum levels were reached in all three dose groups. Toward the end of the recovery period, 
CSF-1 levels generally decreased in the 20 and 60 mg/kg dose groups, but remained elevated in 
the 180 mg/kg dose group. 
 
The key toxicological findings attributed to LY3022855 administration in this study were 
periorbital swelling, increases in serum transaminases as noted in the exploratory study, changes 
in leukocyte populations (monocytes, neutrophils, CD68+ mononuclear cells, natural killer [NK] 
cells), as well as target organ effects in the liver (Kupffer cell hypertrophy/hyperplasia), spleen 
(follicular hypertrophy/dendritic cell hyperplasia), and bone marrow (hypercellularity). The 
immunomodulatory effects on leukocytes, Kupffer cells, spleen, and bone marrow likely reflect 
an exaggerated pharmacological response to LY3022855, possibly associated with elevations in 
circulating CSF-1 levels noted during the study.  
 
Elevations in ALT after the last dosing of LY3022855 were generally minimal in the lowest dose 
group (20 mg/kg) and minimal to moderate at the 60 and 180 mg/kg dose groups. AST levels 
were minimally to moderately increased in all dose groups. ALT and AST returned to baseline in 
the 20 mg/kg group and trended toward baseline in the 60 and 180 mg/kg groups during the 
recovery period, but remained increased in some individual animals compared with baseline. No 
histological changes in the liver were noted to correlate with the transaminase increases, nor 
were any changes noted in liver functional parameters (alkaline phosphatase, bilirubin, or 
coagulation). Based on the small magnitude of the elevations and the absence of histological or 
functional changes, the increases in ALT and AST were not considered adverse. 


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16 
 
Increases in circulating white blood cells due to increases in neutrophils and monocytes were 
observed in both sexes at 60 and 180 mg/kg. Flow cytometry analysis of spleen and peripheral 
blood revealed increases in monocytes in spleen and blood at 60 and 180 mg/kg and reductions 
in splenic NK cells in all LY3022855 treated groups. Variability in NK cell numbers in the 
peripheral blood of animals in all dose groups (including control) precluded assigning a 
definitive relationship with LY3022855 treatment. These changes in white blood cell counts, in 
conjunction with minimal reversible increases in serum globulin concentrations with a 
corresponding decrease in albumin to globulin ratio, are consistent with the presence of an 
inflammatory response. However, no histopathological evidence of inflammation was observed. 
The monocyte, neutrophil, and globulin changes were reversible by the end of the recovery 
period, while the splenic NK cell reductions were still apparent in some animals. These changes 
were not considered adverse because of their small magnitude. 
 
Anatomic pathology changes attributed to the administration of LY3022855 at the end of the 
dosing period included increased spleen weights in females in all dose groups, which generally 
correlated with splenic follicular hypertrophy (males at 60 and 180 mg/kg; females at 20 and 180 
mg/kg), bone marrow hypercellularity (all female dose groups, 1 male at 60 mg/kg), bone 
marrow lymphoid aggregates (1 male, 1 female at 180 mg/kg), and Kupffer cell 
hypertrophy/hyperplasia (primarily minimal, all male dose groups, 1 female at 60 mg/kg). 
Immunohistochemical analyses confirmed the presence of increased size or number of CD68+ 
Kupffer cells in the liver and increased numbers of CD68+ mononuclear cells in the spleen at all 
dose levels. The CD68+ cells in the spleen were likely follicular dendritic cells. The 
immunohistochemical findings in liver and spleen generally correlated with the histopathological 
diagnoses of Kupffer cell hypertrophy/hyperplasia and splenic follicular hypertrophy. Similar 
anatomic pathology findings in spleen, liver, and bone marrow were observed after the recovery 
period. These changes were not considered adverse because of their small magnitude. 
 
Slight to moderate periorbital swelling was observed primarily during the recovery phase in all 
LY3022855 treated groups (20, 60, and 180 mg/kg/dose). This clinical sign has been reported to 
occur in humans with another antibody to CSF-1 and may thus represent a delayed response to 
LY3022855 in the treated monkeys. Watery feces was observed only in the 60 mg/kg/dose 
animals, but is considered possibly related to the administration of LY3022855. These clinical 
signs were not considered adverse based on their limited impact to the overall health of the 
animal. No adverse effects were noted in assessments of the central nervous (neurological 
behavioral examination), respiratory (rate), or cardiovascular (heart rate, blood pressure, 
electrocardiogram) systems. In addition, no evidence of an adverse reaction or intolerance 
attributable to LY3022855 was apparent at the injection sites after IV infusion in the cynomolgus 
monkey repeat-dose toxicity studies. 
 
Based on the absence of any definitive LY3022855 related adverse findings, the NOAEL for 
LY3022855 administered via 15 minute IV infusion weekly on four occasions was considered to 
be 180 mg/kg/dose. The dose corresponded to a dosing day 22 mean Cmax of 7985 µg/mL, C168hr 
of 2945 µg/mL, and mean AUC0-168hr of 711340 µg·hr/mL (Table 4). 
 
 


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17 
 
Table 4: Multi-Dose Toxicity and Toxicokinetics of LY3022855 in Cynomolgus Monkeys 
 
 
2.2.1.3 
Efficacy Pharmacology 
 
A series of in vitro studies determined the pharmacodynamic (PD) properties of LY3022855 
toward its target, CSF- 1R. LY3022855 bound in a dose-dependent manner to human CSF-1R 
and blocked CSF-1 and IL-34 binding in a solid-phase ligand-blocking assay. In addition to 
blocking ligand-induced receptor phosphorylation, LY3022855 inhibited ligand-induced 
phosphorylation of the downstream-signaling molecules AKT and MAP kinase in a CSF-1R 
transfected cell line. In vitro studies further demonstrated that LY3022855 inhibited monocyte 
proliferation and monocytic-to-macrophage differentiation. 
 
LY3022855 does not cross-react with murine CSF-1R, and thus cannot be used in efficacy 


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Protocol Version Date: 31 July 2017 
 
18 
studies in mice to explore the effects of targeting TAMs as a mechanism of inhibiting tumor 
growth. Therefore the surrogate rat monoclonal antibody CS7, which antagonizes murine CSF-
1R, was identified. CS7 binds murine CSF-1R with high affinity (Kd = 0.8nM) and neutralizes 
CSF-1 binding activity in a solid-phase ligand-blocking assay. Cell-based assays utilizing 
RAW264.7 cells, a murine macrophage-like cell line, showed CS7 blocked activation of CSF-1R 
in a dose-dependent manner with similar efficacy to LY3022855. In addition, in the presence of 
CS7, monocytes failed to differentiate into macrophages and had reduced proliferative 
properties. Thus, CS7, by neutralizing activation of CSF-1R, can inhibit the proliferation and 
differentiation of murine monocytes into macrophages in a manner similar to LY3022855 acting 
on human monocytes/macrophages and is an appropriate surrogate antibody for in vivo studies. 
 
Non-clinical PD studies with CS7 demonstrated the potential for CSF-1R targeted therapy in 
oncologic indications by reducing the number of TAMs in the tumor stroma and inhibiting the 
growth of tumor cells. Animal tumor model studies focused initially on breast cancer models 
because scientific literature indicates that breast cancers have high macrophage infiltration of the 
tumor stroma28. Also, CSF-1 is often highly secreted in breast cancer, and elevated circulating 
CSF-1 is an indicator of poor prognosis and high tumor grade28. Therefore, the hypothesis that 
the growth of tumors established with cell lines that secrete significant amounts of CSF-1 would 
be inhibited by an antibody targeting mouse CSF-1R (CS7) to a greater extent than tumors 
established with cell lines that express very little or no detectable CSF-1 was investigated. Two 
human breast cancer cell lines, MDA-MB-231LP-OSPT and HCC1954, were chosen for 
xenograft animal models because of their high CSF-1 secretion levels. In both tumor models, 
CS7 showed a statistically significant dose-dependent suppression of tumor growth over those 
animals treated with the rat IgG control antibody. 
 
Staining of the tumor and surrounding stroma with a macrophage-specific antibody revealed a 
dramatic decrease in macrophage infiltration in both MDA-MB-231LP-OS-PT and HCC1954 
tumor stroma. Thus, treatment of tumor-bearing animals with CS7 leads to a decrease in 
macrophage infiltration, as anticipated. Similarly, non-tumor bearing Balb/c mice treated with 
CS7 demonstrated a decrease in Kupffer cells (tissue-resident macrophages in liver) within two 
weeks of thrice-weekly administration. 
 
To estimate target serum concentrations for efficacy in initial clinical investigations, trough 
concentrations associated with efficacy were determined in human breast cancer (HCC1954) and 
human leukemia (NKM-1) models established in mice. LY3022855 was evaluated in the 
leukemia model established following IV injection of CSF-1R expressing NKM-1 cells. The rat 
surrogate, CS7, was used in the breast cancer model established following subcutaneous 
injection of CSF-1R negative HCC1954 cells. The results from the two studies identified 
markedly different efficacious concentrations for the antibodies in the different models. The 
human NKM-1 model appeared very sensitive to the anti-tumor effect of LY3022855, as efficacy 
was achieved at mean trough concentrations down to 0.2 µg/mL. For CS7, notably higher doses 
and concentrations were required to inhibit human HCC1954 breast cancer tumor growth, as a 
mean trough concentration of 425 µg/mL was associated with efficacy. Because the initial 
clinical investigation was in solid tumors, the higher concentration is regarded as a conservative 
target concentration for efficacy. 
 


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19 
 
2.2.2 
Clinical Studies 
 
As of 28 January 2016, data are available from 43 patients who have received treatment in two 
Lilly-sponsored phase I studies of LY3022855 (Study I5F-IE-JSCA hereby referred to as JSCA 
and Study I5F-MC-JSCB hereby referred to as JSCB), as summarized in Table 5. A third Lilly-
sponsored phase Ia/Ib study of LY3022855 (JSCC) will be initiated in 2016; no patients have 
been treated as of 28 January 2016. Please refer to the most recent investigator’s brochure (IB) 
for further information. 
 
Table 5: Lilly-Sponsored Clinical Studies 
Study Number and 
Title 
Study Design 
Treatment Regimen 
Number of 
Patients 
Treated and 
Study Status
15F-IE-JSCA (JSCA) 
Phase I Study of 
LY3022855, a Monoclonal 
Antibody Targeted to the 
CSF-1 Receptor (CSF-
1R), in Patients With 
Advanced Solid Tumors 
Refractory to Standard 
Therapy or for Which No 
Standard Therapy Is 
Available 
Phase I, 
single-agent 
(monotherapy), 
dose-escalation 
study 
LY3022855 administered by IV infusion at 
the following dosages: 
 
Part A (weight-based dosing): 
Cohort 1 - 2.5 mg/kg weekly 
Cohort 2 - 0.3 mg/kg weekly 
Cohort 3 - 0.6 mg/kg weekly 
Cohort 4 - 1.25 mg/kg every 2 weeks 
Cohort 5 – 1.25 mg/kg weekly 
 
Part B (non-weight based dosing): 
Cohort 6a – 100 mg weekly (completed) 
Cohort 7a – 150 mg weekly (ongoing) 
Study is 
ongoing. 
I5F-MC-JSCB (JCSB) 
Phase I Study to Identify 
the Immunomodulatory 
Activity of LY3022855 
(IMC-CS4) in Patients 
with Advanced, Refractory 
Breast or Prostate Cancer 
Phase I, single-
center, open-label, 
nonrandomized, 
noncontrolled study 
LY3022855 administered by IV infusion at 
the following dosages: 
Dosage A - 1.25 mg/kg every 2 weeks 
Dosage B - 1 mg/kg on weeks 1, 2, 4, and 
5 of every 6 week cycle 
Study is 
ongoing. 
15F-MC-JSCC 
 
A Phase Ia/Ib Trial 
Investigating the CSF-1R 
Inhibitor LY3022855 in 
Combination with 
Durvalumab (MEDI4736) 
or Tremelimumab in 
Patients with Advanced 
Solid Tumors 
Phase 1a/1b, 
multicenter, 
nonrandomized, 
open-label, dose-
escalation study 
followed by dose 
expansion (5 disease 
specific expansion 
cohorts) of IV 
LY3022855 in 
combination with IV 
In Part A (Dose Escalation, Phase 1a) of 
the study, LY3022855 QW, in 
combination with Durvalumab Q2W or 
Tremelimumab Q4W (after 6 doses, 
tremelimumab Q12W until 
discontinuation), is planned. 
Part B (Disease-Specific Expansion, Phase 
1b) of the study will include 5 expansion 
cohorts. Patients will be treated at the 
MTD identified for each combination in 
Study is 
ongoing. 


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20 
durvalumab or IV 
tremelimumab in 
patients with 
advanced cancer. 
Part A, unless otherwise specified by the 
sponsor. 
 
 
2.2.2.1 
Pharmacokinetics 
 
As of 28 January 2016, LY3022855 serum concentrations for non-compartmental analysis were 
available from 27 patients enrolled in Study JSCA within 5 Cohorts: 0.3 mg/kg QW (n=4), 0.6 
mg/kg QW (n=3), 1.25 mg/kg QW (n=5), 1.25 mg/kg Q2W (n=9), and 2.5 mg/kg QW (n=6), and 
from 14 patients enrolled in Study JSCB within 2 Cohorts: 1.25 mg/kg Q2W (n=9) and 1 mg/kg 
on Weeks 1, 2, 4, and 5 of every 6-week cycle (n=5). Note that for patients in Study JSCA 
Cohort 4 and Study JSCB, only nominal time data (i.e., the intended sample collection time, 
rather than the actual collection time) were available. 
 
In addition to non-compartmental analysis, LY3022855 PK data were analyzed using a PK 
modeling approach. LY3022855 in cancer patients exhibited moderate total body clearance (CL) 
(mean values on Day 1 ranged from 0.0378 to 0.0651 L/h), low volume of distribution at steady 
state (Vss) (mean values on Day 1 ranged from 2.85 to 4.93 L) and moderate t1/2 (mean values on 
Day 1 ranged from 30.8 to 92.2 hours). 
 
While the values for CL and t1/2 appeared to be slightly larger and smaller, respectively, than 
those typically observed for an IgG1 monoclonal antibody, the estimates of both CL and t1/2 were 
likely confounded by the limited sampling period (between 168 hours and 336 hours, dependent 
on dosing frequency), and the high incidence of samples reported as below the quantifiable lower 
limit of the assay (BLQ) at lower doses. 
 
By comparison of the non-compartmental PK parameters across each dose cohort, the CL 
ofLY3022855 appeared to be non-linear with respect to LY3022855 concentration, with 
higherdoses of LY3022855 exhibiting lower CL values. Non-linearity of LY3022855 CL with 
respect to concentration was also observed in the model structure used for the PK/PD modeling 
analysis. However, this apparent non-linearity was confounded by the high incidence of 
concentrations reported as BLQ which could artificially inflate the calculated CL at lower doses. 
 
The intra-patient accumulation ratio (RA) for the 2.5-mg/kg QW regimen (1.97) was 
approximately twice that observed for the 1.25-mg/kg Q2W regimen (0.998). While this was 
approximately equal to the difference in the theoretical calculated accumulation index for a 
molecule with a 7-day t1/2 which was dosed QW versus Q2W, the 2 cohorts also received 
different dose levels, and thus the potential effect of dose non-linearity in CL on this difference 
in RA could not be disregarded. 
 
An apparent lack of relationship between patient body weight and LY3022855 CL resulted in an 
amended dose escalation plan for Study JSCA to evaluate the safety, PK, and immunogenicity of 
LY3022855 using a flat dosing approach (i.e., mg as opposed to mg/kg). Please see IB for further 
information. 
 


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21 
2.2.2.2 
Pharmacodynamics 
 
All patients receiving LY3022855 in Study JSCA exhibited elevated serum CSF-1 and IL-34 
levels, suggesting CSF-1R target engagement across a 0.3 to 2.5-mg/kg dose range. The extent of 
serum CSF-1 and IL-34 elevation increased with increasing dose. The duration of serum CSF-1 
and IL-34 elevation was dependent on dosing frequency, where dosing every week yielded 
increased and sustained serum CSF-1 and IL-34 elevations over dosing every 2 weeks. At higher 
serum concentrations of LY3022855 (i.e., higher doses and earlier time points), inter-individual 
variability in patient CSF-1 PD response was reduced. 
 
In addition, inhibition of non-classical CD14dimCD16bright monocytes occurred with increasing 
dose and was sustained with increased dosing frequency, where dosing every week yielded 
increased and sustained suppression of CD14dimCD16bright monocytes over dosing every 2 weeks. 
This indicated that sustained target engagement yielded sustained biological response, as 
measured by inhibition of CD14dimCD16bright monocytes. 
 
2.2.2.3 
Pharmacokinetic/Pharmacodynamic Model 
 
Patients receiving LY3022855 across the dose range tested (0.3 to 2.5 mg/kg) exhibited 
increased levels of serum CSF-1 after single and multiple doses of LY3022855, with the extent 
of CSF-1 elevation increasing with increasing dose level and dosing frequency. Since CSF-1 is a 
ligand of CSF-1R, it is thought that the increase in serum concentrations of this marker showed 
evidence of CSF-1R target engagement. A PK/PD model was therefore developed to quantify the 
relationship between LY3022855 dose, LY3022855 serum concentrations, and serum CSF-1 
levels. 
 
The PK/PD dataset comprised PK and CSF-1 data which were available as of 28 January 2015. 
This dataset included 24 patients enrolled on Study JSCA: 2.5 mg/kg QW (n=6), 0.3 mg/kg QW 
(n=4), 0.6 mg/kg QW (n=3), 1.25 mg/kg Q2W (n=6) and 1.25 mg/kg QW (n=5). Rich sampling 
was performed for both PK and CSF-1 across single and multiple doses of LY3022855. 
 
The PK of LY3022855 was characterized by a two-compartment model with non-linear 
clearance. The Michaelis-Menten constant (KM) for non-linear LY3022855 clearance was 
approximately equal to 30 µg/mL, corresponding to doses above 1.25 mg/kg. However, this 
apparent non-linearity in CL may have been confounded by the high incidence of concentrations 
reported as BLQ which could have artificially inflated the calculated CL at lower doses. 
 
LY3022855-mediated elevations of CSF-1 were best described by an indirect response model, 
where the action of LY3022855 was incorporated as inhibition of CSF-1 elimination. The model 
indicated potent and complete inhibition of CSF-1 elimination by LY3022855, and a steep 
concentration-response curve. The model-estimated LY3022855 concentration at which 50% 
inhibition of CSF-1 elimination occurs (IC50) (approximately equal to 1.4 µg/mL) was lower 
than the PK assay limit of quantification, and thus the lowest dose that could sustain this 
LY3022855 concentration across the dosing period is not known, but is predicted to be as low as 
0.3 mg/kg QW. However, model simulations showed that, of the doses tested, the 1.25-mg/kg 
QW dose was the lowest dose associated with sustained CSF-1 elevation across the dosing 
interval in the majority of patients. 


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22 
 
Although the PK/PD model suggests complete inhibition of CSF-1 elimination by LY3022855, 
the extent of serum CSF-1 elevation continued to increase with increasing dose. The model 
suggests that this phenomenon is due to continued production of serum CSF-1, rather than 
insufficient inhibition of the target, CSF-1R. 
 
2.2.2.4 
Safety 
 
Study JSCA 
 
As of 09 September 2016  total of 369 patients have received LY3022855 in the phase I dose 
escalation study of LY3022855 in advanced solid tumors (study JSCA). This study is currently 
ongoing. 
 
In cohort 1, two of the first three patients experienced Common Terminology Criteria for 
Adverse Events (CTCAE) grade 2 elevations of serum CPK, AST (Grade 1 - 2) and LDH. Due 
to these serum enzyme elevations and the general conditions of the patients involved, two of the 
first three patients enrolled did not complete cycle 1. 
 
Per protocol, three additional patients were treated in cohort 1. These additional patients also 
exhibited elevated levels of CPK, AST, and LDH. In one patient, serum levels of CPK and AST 
reached grade 3; however, this was not classified as a dose-limiting toxicity (DLT) upon 
comprehensive clinical evaluation of the patient due to the lack of clinical signs and symptoms 
of organ toxicity. Furthermore, enzyme levels decreased upon discontinuation of LY3022855, 
indicating that these effects were reversible. 
 
Since pre-clinical studies with LY3022855 in monkeys demonstrated a dose-response correlation 
between the dose of LY3022855 and the increase in serum enzyme levels, continued dose 
escalation in the JSCA trial was considered likely to result in a DLT. Therefore, it was 
considered medically prudent not to dose escalate beyond cohort 1 with the originally planned 
dosage schedule, which was 5, 10, 20, and 30 mg/kg once weekly. In order to better characterize 
the LY3022855 dose-response effect on the monocyte/macrophage system and on various 
serologic and hematologic parameters, the dosing scheme and schedule for study JSCA were 
revised to reflect dose reductions and prolonged administration intervals. 
 
Under the revised dose-escalation plan, the dosages for subsequent dose explorations were as 
follows: cohort 2 (0.3 mg/kg QW), cohort 3 (0.6 mg/kg QW), Cohort 4 (1.25 mg/kg Q2W), 
Cohort 5 (1.25 mg/kgQW), and Cohort 6 (2.5 mg/kg Q2W). The addition of every-2-week 
dosing was considered appropriate based on the relatively long t1/2 observed in cynomolgus 
monkeys. 
 
In cohort 4, a DLT for LY3022855 was declared in one patient with a history of cardiac 
dysfunction who developed a grade 3 left ventricular systolic dysfunction after one dose of 
LY3022855. Two DLT events were observed in cohort 5: one patient developed grade 4 
rhabdomyolysis and acute renal failure and one patient developed grade 3 pancreatitis. The 
original recommended phase II dose for LY3022855 was determined to be 1.25 mg/kg every 2 


DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
23 
weeks. However, subsequent analysis of clinical data suggested sub-maximal target engagement 
on a Q2W schedule as opposed to QW dosing. Additionally, exploratory graphical analysis of 
the PK of LY3022855 in weight-based dosing Cohorts 1 to 5 indicated no clear relationship 
between body weight and drug clearance. Therefore, additional cohorts were added (Part B of the 
study) in a protocol amendment, Version 7.0, to evaluate safety, PK, and PD of non-weight 
based dosing of LY3022855 administered on a weekly schedule. 
 
Study JSCB 
 
Study JSCB is a Phase 1 study to identify the immunomodulatory activity of LY3022855 in 
patients with advanced, refractory breast or prostate cancer. As of the data cut-off date, 28 
January 2016, 9 patients have been treated with 1.25 mg/kg LY3022855 Q2W of every 6-week 
cycle and 5 patients have been treated with 1 mg/kg LY3022855 on Weeks 1, 2, 4, and 5 of 
every 6-week cycle. Patients treated with 1.25 mg/kg LY3022855 Q2W were observed to have 
elevated CK, AST, and LDH levels. In 1 patient, serum levels of CK reached Grade 3 on 2 
occasions. For each of these occasions, study drug was subsequently held and the event resolved. 
Please refer to the IB for more information.  Enrollment to this study is ongoing. 
 
Deaths 
 
As of the data cut-off date of 28 January 2016, three deaths occurred on the JSCA study or 
within 30 days after the last dose of LY3022855. One death each, due to progressive disease, 
occurred in patients enrolled in the 0.3 mg/kg weekly dose cohort (cohort 2), 0.6 mg/kg weekly 
dose cohort (cohort 3), and 1.25 mg/kg weekly dose cohort (cohort 5). In addition, two deaths 
were reported post completion of the study. The patients died after more than 30 days of 
receiving the last dose of LY3022855 due to progressive disease. One of the patients was 
enrolled in the 0.3 mg/kg weekly dose cohort (cohort 2), and the other in the 1.25 mg/kg every 2 
weeks dose cohort (cohort 4).No deaths occurred while patients were on study treatment in trial 
JSCB or within 30 days after the last dose of LY3022855, and no deaths were reported post 
completion of study participation. 
 
Serious Adverse Events 
 
As of the data cut-off date of 28 January 2016, Nine patients who received at least one dose of 
LY3022855 in study JSCA experienced a total of 15 treatment-emergent serious adverse events 
(SAEs): grade 2 toxicity to various agents and tremor, and grade 3 ascites (cohort 2, 0.3 mg/kg 
QW); grade 3 tachycardia, pneumothorax, and hypotension and grade 5 sudden death (cohort 3, 
0.6 mg/kg QW); grade 3 left ventricular dysfunction, confusional state, and small intestinal 
obstruction (cohort 4 and the MTD expansion cohort, 1.25 mg/kg Q2W); and grade 2 fatigue and 
mental status changes, grade 3 pancreatitis, and grade 4 rhabdomyolysis and acute renal failure 
(cohort 5, 1.25 mg/kg QW).  
 
Of these 15 SAEs, 8 SAEs reported in 5 patients were considered at least possibly related to 
LY3022855: tachycardia, hypotension, and sudden death (1 patient, Cohort 3); left ventricular 
dysfunction (1 patient, Cohort 3); rhabdomyolysis and acute renal failure (1 patient, Cohort 5); 
pancreatitis (1 patient, Cohort 5); and confusional state (1 patient, MTD expansion cohort). The 


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24 
sudden death occurred after the patient had completed the DLT assessment period (i.e., had 
received all scheduled treatments for cycle 1 and completed the observation period, as needed). 
The treating investigator felt that the death was most likely related to disease progression of the 
underlying sarcoma.  
 
In study JSCB, two patients with breast cancer who received at least 1 dose of LY3022855 (1.25 
mg/kg Q2W) experienced 8 treatment-emergent SAEs: anemia, cardiomyopathy, confusional 
state, encephalopathy, femur fracture, hemorrhage, pain, and pain in the extremity (all Grade 3). 
Of the 8 SAEs, 2 SAEs (cardiomyopathy and encephalopathy) reported in 1 patient were 
considered by the investigator to be at least possibly related to LY3022855. 
 
Treatment-Emergent Adverse Events 
 
As of 28 January 2016, 28 of the 29 patients (96.6%) treated with LY3022855 in study JSCA 
experienced at least one treatment-emergent adverse event (TEAE). Please refer to the IB for a 
comprehensive list of adverse events. Of the 29 patients treated with LY3022855, 22 patients 
(75.9%) experienced at least one AE considered at least possibly related to treatment with 
LY3022855. This data is summarized below. The most commonly reported possibly study drug-
related TEAEs (≥ 20% of patients) regardless of grade were fatigue, AST increased, and blood 
CPK increased, and nausea. Among all grade 3 and grade ≥ 4 AEs, the following AEs reported in 
a total of 7 patients (24.1%) were considered related to LY3022855: grade 3 AST increased and 
blood CPK increased (cohort 1); grade 3 hypotension, subcutaneous abscess, and tachycardia 
(cohort 3); grade 5 sudden death (cohort 3); grade 3 confusional state and left ventricular 
dysfunction (cohort 4 and the MTD expansion cohort); grade 3 hypophosphatemia and 
pancreatitis (cohort 5); and grade 4 acute renal failure and rhabdomyolysis (cohort 5). 
 
In study JSCB, all 14 participants treated with LY3022855 experienced at least 1 TEAE. Twelve 
of 14 patients experienced at least 1 AE considered at least possibly related to treatment with 
LY3022855. The most common TEAEs considered to be at least possibly study drug-related 
(≥20% of patients), regardless of grade, were: fatigue, nausea, blood CPK increased, decreased 
appetite, diarrhea, lipase increased, and periorbital edema. The following Grade 3 AEs reported 
in 5 of 14 patients were considered at least possibly related to LY3022855: amylase increased, 
blood alkaline phosphatase increased, blood CPK increased, cardiomyopathy, and 
encephalopathy, and fatigue. 
 
Of the 29 patients treated with LY3022855, 4 patients (13.8%) were discontinued from study 
drug due to AEs. One patient treated with LY3022855 at the weekly dose of 2.5 mg/kg (cohort 
1) was discontinued from study drug due to the AEs of elevated CPK, AST, and LDH; all AEs 
were considered probably related to the study drug. One patient was discontinued from study 
drug due to cognitive disorder (considered unrelated to the study drug). Two patients treated with 
LY3022855 at the weekly dose of 1.25 mg/kg (cohort 5) discontinued study therapy due to acute 
renal failure (as a consequence of rhabdomyolysis) and pancreatitis that were probably and 
possibly related to study drug, respectively. 
 
In study JSCB, no patient was discontinued from LY3022855 due to AEs. 


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Table 6: Related TEAEs by Cohort for Study JSCA Occurring in ≥ 2 Patients (N = 29) 
 
 
 


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Table 7: Related TEAEs by Cohort for Study JSCB Occurring in ≥ 2 Patients (Safety Population, N = 14) 


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27 
 
2.2.2.5 
Efficacy 
 
No efficacy information is available as of 28 January 2016. 
 
2.2.2.6 
Drug Interactions 
 
No formal drug interaction studies have been performed with LY3022855 in humans. 
 
 
2.3 
Vemurafenib 
 
Vemurafenib is a low molecular weight, orally available inhibitor of some mutated forms of 
BRAF serine threonine kinase, including BRAF V600E. Vemurafenib also inhibits other kinases 
in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar 
concentrations. Some mutations in the BRAF gene including V600E result in constitutively 
activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that 
would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and 
animal models of melanomas with mutated BRAF V600E. 
 
Vemurafenib has been FDA approved for patients with unresectable or metastatic melanoma 
with a BRAF V600E mutation and is commercially available. Please reference the FDA package 
insert for background information. Agent will be administered per standard of care guidelines in 
accordance with institutional standards and the FDA prescribing information. 
 
 
2.4 
Cobimetinib 
 
Cobimetinib (Cotellic) is a reversible inhibitor of MAPK/ MEK1 and MEK2. MEK proteins are 
upstream regulators of the extracellular signal related kinase (ERK) pathway, which promotes 
cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the 
BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines 
expressing BRAF V600E, cobimetinib inhibited tumor cell growth. 
 
Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. 
Compared to either drug alone, co-administration of cobimetinib and vemurafenib resulted in 
increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor 
cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated 
growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation 
model. 
 
Cobimetinib has been FDA approved for patients with unresectable or metastatic melanoma with 
a BRAF V600E or V600K mutation and is commercially available. Please reference the FDA 
package insert for background information. Agent will be administered per standard of care 
guidelines in accordance with institutional standards and the FDA prescribing information. 
 


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28 
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. 
 
2.5.1 
LY3022855 Flat Dosing Rationale 
 
LY3022855 was initially dosed per body weight. However, Study JSCA (Version 7.0) was 
amended to explore a non-weight based dosing scheme based upon clinical data.  
 
As of 14 August 2016, LY3022855 serum concentrations for non-compartmental analysis were 
available from 33 patients enrolled in Study JSCA within 7 cohorts:  0.3 mg/kg QW (N=4), 0.6 
mg/kg QW (N=3), 1.25 mg/kg QW (N=5), 1.25 mg/kg every 2 weeks (Q2W) (N=11), 2.5 mg/kg 
QW (N=6), 100 mg QW (N=3), and 150 mg QW (N=1).  The non-compartmental PK parameters 
stratified by dosing regimen and day of PK sample collection for Study JSCA are provided in 
Table 8.  Mean LY3022855 serum concentration-time profiles on Day 1 and on Day 15 or 22 for 
Study JSCA are presented in Figure 1. 
 


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29 
 
 
Table 8: Summary of Non-compartmental PK Parameters Following IV Infusion of Weight-Based and Non-
Weight-Based of Dosing LY3022855 in Cancer Patients during Cycle 1 for Study JSCA 
 
Geometric Mean 
(CV%)
Treatment 
0.3 mg/kg 
QW 
0.6 mg/kg 
QW 
1.25 mg/kg 
QW 
1.25 mg/kg 
Q2W 
2.5 mg/kg 
QW 
100 mg 
QW 
150 mg 
QW 
Cohort 
2 
3 
5 
4 
1 
6a 
7a 
Day 
1 
1 
1 
1 
15 
1 
22 
1 
84 or 99 
1 
N 
4 
3 
5 
11 
10 
6 
4 
3 
2 
1 
Parameter 
 
 
 
 
 
 
 
 
 
 
C168h, µg/mL 
NC 
NC 
 
(5.68 and 3.41)a 
3.32 
(11)b 
3.35 
(22)c 
14.4 
(34) 
50 
(25)d 
 
(1.77 and 6.11)a 
7.71e 
NC 
Cmax, µg/mL 
6.83 
(32) 
13.5 
(33) 
26.0 
(14) 
30.7 
(24) 
30 
(25) 
69.2 
(13) 
92.7 
(23) 
34.6 
(25) 
 
(42.8 and 31.2) 
42.7 
tmaxf, h 
0.01 
(0.01-
1.02) 
2.02 
(0.01-
2.08) 
1.01 
(0.01-21.6) 
0.01 
(0.01-2) 
1.00 
(0.01-2) 
0.75 
(0.01-8.00) 
0.97 
(0.50-2.00) 
0.960 
(0.01-2) 
 
(0.01 and 1.07) 
2.02 
t1/2g, h 
30.9d 
(25.2-44) 
30.8 
(23.6-
36.2) 
58.3 
(45.5-85.3) 
41.4 
(21.5-67.3) 
46.9h 
(24.3-109) 
85.0 
(56.6-126) 
196 
(132-346) 
48.2 
(35.9-69.9) 
82.8e 
38.7 
Cav,τ, µg/mL 
1.53d 
(15) 
2.91 
(24) 
10.8 
(21) 
4.72 
(50) 
5.06h 
(49) 
29.9 
(18) 
55.8 
(41) 
10.5 
(28) 
18.9e 
13.2 
AUC(0-∞), 
h·µg/mL 
264d 
(17) 
500 
(24) 
2130 
(28) 
1600 
(50) 
1730h 
(52) 
6860 
(26) 
21200 
(73) 
1970 
(37) 
4150e 
2330 
AUC(0-τ)i, 
h·µg/mL 
257d 
(15) 
489 
(24) 
1810 
(21) 
1590 
(50) 
1700h 
(49) 
5030 
(18) 
9370 
(41) 
1770 
(28) 
3170e 
2220 
CL, L/h 
0.107d 
(21)  
0.0720 
(30) 
0.0561 
(31) 
0.0559 
(33) 
0.0516h 
(36) 
0.0378 
(25) 
0.0203 
(34) 
0.0566 
(28) 
0.0315e 
0.0676 
Vss, L 
4.71d 
(9) 
3.15 
(10) 
4.72 
(12) 
3.39 
(22) 
3.37h 
(20) 
4.67 
(37) 
5.70 
(19) 
3.88 
(23) 
3.68e 
3.77 
RA 
NC 
NC 
NC 
NC 
1.04h, j 
(18) 
NC 
1.82c, k 
(27) 
NC 
2.29e, l 
NC 
Abbreviations:  AUC(0- τ) = area under the concentration versus time curve from time zero to τ; AUC(0- ∞) = area under the concentration versus time curve from time zero to ∞; C168h = serum 
concentration collected 168 hours following the start of infusion; Cav,τ = average serum concentration over dosing interval calculated using AUC(0-τ); CL = total body clearance; Cmax = maximum 


DF/HCC Protocol #: 17-030 
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30 
 
Table 8: Summary of Non-compartmental PK Parameters Following IV Infusion of Weight-Based and Non-
Weight-Based of Dosing LY3022855 in Cancer Patients during Cycle 1 for Study JSCA 
 
Geometric Mean 
(CV%)
Treatment 
0.3 mg/kg 
QW 
0.6 mg/kg 
QW 
1.25 mg/kg 
QW 
1.25 mg/kg 
Q2W 
2.5 mg/kg 
QW 
100 mg 
QW 
150 mg 
QW 
Cohort 
2 
3 
5 
4 
1 
6a 
7a 
Day 
1 
1 
1 
1 
15 
1 
22 
1 
84 or 99 
1 
N 
4 
3 
5 
11 
10 
6 
4 
3 
2 
1 
serum concentration; CV = coefficient of variation; h = hours; N = number of patients; NC = not calculable; Q2W = once every 2 weeks; QW = once weekly; RA = intrapatient accumulation 
ratio; t1/2 = terminal elimination half-life; tmax = time of maximum serum concentration; Vss = volume of distribution at steady-state. 
a 
N=2; reported as individual parameter estimates. 
b 
N=5. 
c 
N=4. 
d 
N=3. 
e 
N=1; reported as individual parameter estimate. 
f 
Median (Minimum – Maximum). 
g 
Geometric Mean (Minimum – Maximum). 
h 
N=9. 
i 
τ = 168 h for QW regimen; τ = 336 h for Q2W regimen. 
j 
RA = AUC(0-τ),day 15/ AUC(0-τ),day 1. 
k 
RA = AUC(0-τ),day 22/ AUC(0-τ),day 1. 
l 
RA = AUC(0-τ),day 84 or day 99/ AUC(0-τ),day 1. 
 


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31 
 
 
LY3022855 in cancer patients exhibits pharmacokinetic properties consistent with those 
typically expected for an IgG1 antibody, with mean total body clearance (CL) after a single dose 
ranging from 0.0378 to 0.107 L/h, mean volume of distribution at steady state (Vss) after a single 
dose ranging from 3.15 to 4.72 L, and mean half life (t1/2) after a single dose ranging from 30.8 
to 85.0 hours.  LY3022855 CL appears to be non-linear with respect to dose, with higher doses 
of LY3022855 exhibiting lower CL values (Figure 2).  These results are in accordance with the 
previous PK analysis for Cohorts 1 to 5, as detailed in the Investigator’s Brochure. 


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32 
 
Abbreviations:  h = hours; N = number of patients treated; QW = once weekly; Q2W = once every 2 
weeks. 
Figure 1: Mean concentration-versus-time profiles for LY3022855 
following intravenous administration to patients with cancer on Day 1 
(upper panel) and on Days 15 and 22 (lower panel) for Study JSCA. 


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33 
These updated results indicate an apparent lack of relationship between patient body weight and 
LY3022855 CL (Figure 2), consistent with previous analyses.  Moreover, the PK of LY3022855 
in patients receiving a non-weight-based dose of 100 mg QW (Cohort 6a) and the weight-based 
dose of 1.25 mg/kg QW (Cohort 5) appears comparable (Figure 1).  The AUC(0-τ), Cmax, tmax, and 
t1/2 values are consistent between the 2 cohorts, further demonstrating a lack of a relationship 
between patient body weight and serum LY3022855 concentration exposure. Taken together, 
these analyses provide support for the exploration of LY3022855 using a non-weight-based 
dosing approach. 
 
Similar findings with monoclonal antibodies have been reported by others35-38. Wang and 
colleagues investigated 12 monoclonal antibodies and found that fixed and body size-based 
Abbreviations:  N = number of patients treated; QW = once weekly; Q2W = once every 2 weeks. 
Figure 2: Individual observed clearance versus patient body weight 
(upper panel) and LY3022855 dose (lower panel) for Study JSCA. 


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34 
dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies36. In addition, 
they investigated 18 therapeutic proteins and peptides and showed that fixed dosing performed 
better for 12 of 18 in terms of reducing the between-subject variability in PK/pharmacodynamic 
parameters37. 
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar PK exposure and variability, we considered 
it feasible to switch to fixed dosing regimens. 
 
2.5.2 
LY3022855 Flat Dosing Safety 
 
Updated safety analyses for patients treated in the flat dosing cohorts for Study JSCA (data cut 
off date of  06 September 2016)  are available; including 3 patients treated in Cohort 6a (100 mg 
weekly [QW]) and 3 patients treated in Cohort 7a (150 mg QW).   
 
LY3022855 administered at a flat dose on a weekly schedule has not resulted in any adverse 
events that led to permanent discontinuation of study treatment.  Only one patient who received 
flat weekly dosing of LY3022855 experienced an AE (elevated lipase) resulting in a dose 
reduction.  The most common treatment emergent adverse events (all grades, with a minimum 
incidence of 33%) for patients treated with flat weekly dosing were: anemia (4 – 67%), nausea (3 
– 50%), fatigue (3 – 50%), constipation (2 – 33%), lipase elevation (2 – 33%), hypoalbuminemia 
(2 – 33%), hypocalcemia (2 – 33%), and back pain (2 – 33%).  The majority of these TEAEs 
were Grade 1 or 2. The incidence of Grade 3 events were: anemia (2 – 33%), nausea (0%), 
fatigue (2 – 33%), constipation (0%), lipase elevation (1 – 17%), hypoalbuminemia (0%), 
hypocalcemia (0%), and back pain (0%).  A summary of all-cause serious treatment-emergent 
adverse events for flat doses are presented in the table below.  Two patients treated at a dose of 
100mg QW experienced 4 serious treatment-emergent AEs.  One patient  experienced an SAE of 
pulmonary hemorrhage (Medical Dictionary for Regulatory Activities Preferred Term [MedDRA 
PT]), and the second patient, experienced SAEs of abdominal discomfort, C-reactive protein 
increased, and upper gastrointestinal (GI) hemorrhage (all are MedDRA PTs). 
 
No DLT events were reported for patients treated at a dosage of 100mg QW.  One out of three 
patients treated at a dosage of 150mg QW experienced a DLT event of Grade 3 serum creatine 
kinase (CK) elevation associated with elevated urine and serum myoglobin.  As a result of this 
one DLT, 3 additional patients are planned to be enrolled to the 150mg QW dose level. 
 
Dose levels for LY3022855 in this protocol are detailed in 5.1 and are not planned to exceed the 
100 mg weekly dose that has thus far been shown to be tolerable in study JSCA. As a result 50 
mg QW is an appropriate initial dose for LY3022855 for this study. 
 
 


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Table 9: Study JSCA:  Summary of Serious Treatment-Emergent Adverse Events for Flat Doses 
Summary of Serious Treatment-Emergent Adverse Events for Flat Dose. - Study I5F-IE-JSCA/CP24-1001                      
Safety Population                                                                                                 13:51 07SEP2016 
                                                                                                                             TDTM 
 
     _______________________________________________________________________________________________________________________ 
                                                           100 mg weekly                          150 mg weekly 
                                                               (N=3)                                  (N=3) 
                                                                n(%)                                   n(%) 
                                               ______________________________________ ______________________________________ 
     SOC/Preferred Term                        All Grades   Grade =3     Grade >=4    All Grades   Grade =3     Grade >=4 
     _______________________________________________________________________________________________________________________ 
 
     Patients with any AE                        1 ( 33.3)    0            0            1 ( 33.3)    1 ( 33.3)    0 
 
     Gastrointestinal disorders                  0            0            0            1 ( 33.3)    1 ( 33.3)    0 
        ABDOMINAL DISCOMFORT                     0            0            0            1 ( 33.3)    1 ( 33.3)    0 
        UPPER GASTROINTESTINAL HAEMORRHAGE       0            0            0            1 ( 33.3)    1 ( 33.3)    0 
 
     Investigations                              0            0            0            1 ( 33.3)    0            0 
        C-REACTIVE PROTEIN INCREASED             0            0            0            1 ( 33.3)    0            0 
 
     Respiratory, thoracic and mediastinal       1 ( 33.3)    0            0            0            0            0 
     disorders 
        PULMONARY HAEMORRHAGE                    1 ( 33.3)    0            0            0            0            0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     _______________________________________________________________________________________________________________________ 
Note 1: For each SOC and Preferred Term, each patient was counted only once according to the worst grade of the TEAE. 
Note 2: All Grades column includes patients with missing CTC grades as well. 
Data cut-off date: September 6, 2016. 


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36 
 
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.  
Correlative studies are designed to both enable better understanding of the possible reasons that 
LY3022855 in combination with vemurafenib and cobimetinib 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 LY3022855 
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 LY3022855 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 microenvironment. 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 LY3022855 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. 


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37 
 
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-
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 LY3022855, 
vemurafenib, and cobimetinib 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. 
 
3.1.1 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. 
 


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38 
3.1.2 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 cannot have received prior BRAF or MEK inhibitor therapy. 
 
3.1.3 Participants enrolling to the phase I portion of the trial must have evaluable or 
measurable disease (see 11 for definitions). 
 
3.1.4 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 11 for the 
evaluation of measurable disease. 
 
3.1.5 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.  
 
3.1.6 ECOG performance status 0 - 1 (see APPENDIX A 
PERFORMANCE STATUS 
CRITERIA). 
 
3.1.7 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) 
 
3.1.8 Participants must have a left ventricular ejection fraction (LVEF) ≥ 50%. 
 
3.1.9 Participants must have a QTc of ≤ 470 msec on the screening EKG. 
 


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39 
3.1.10 The effects of LY3022855 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 and for the duration of 
study participation.  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 LY3022855 administration. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.12 Participants must have archival tumor tissue available. Participants without archival 
tissue may be enrolled at the discretion of the principal investigator. 
 
3.2 
Exclusion Criteria 
 
3.2.1 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. 
 
3.2.2 
For enrollment to the phase I portion: there is no required washout period for BRAF or MEK inhibitor 
therapy. 
 
3.2.3 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). 
 
3.2.4 For enrollment to the phase II portion: participants who have received prior BRAF or 
MEK inhibitor therapy. 
   
3.2.5 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. 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to LY3022855, vemurafenib, or cobimetinib. 
 
3.2.7 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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40 
3.2.8 Pregnant women are excluded from this study because LY3022855 is an anti-cancer 
agent with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with LY3022855, breastfeeding should be discontinued if the 
mother is treated with LY3022855.  These potential risks may also apply to the other 
agents used in this study. 
 
3.2.9 Participants with a known history of HIV are ineligible because of the potential for 
pharmacokinetic interactions with LY3022855, vemurafenib, and cobimetinib with 
antiretroviral agents.  In addition, these participants are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  Appropriate studies will be 
undertaken in participants receiving combination antiretroviral therapy when 
indicated. 
 
3.2.10 Participants with a personal or family history of long QT syndrome. 
 
3.2.11 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. 
 
3.2.12 Participants with impairment of GI function or GI disease that may significantly alter 
the absorption of vemurafenib and cobimetinib in the opinion of the treating 
investigator (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, small bowel resection). 
 
3.2.13 Participants who are unable to swallow or retain oral medication. 
 
3.2.14 Participants that require co-administration of strong or moderate CYP3A inhibitors, as 
these medications may alter vemurafenib and cobimetinib concentrations. 
 
3.2.15 Participants who require treatment with medications that are strong or moderate 
CYP3A inducers, as these medications may alter the concentration of cobimetinib. 
 
3.2.16 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. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
  


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41 
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 
 
The starting dose for the phase I portion of the trial will be dose level 1: LY3022855 50 mg IV 
weekly, vemurafenib 960 mg by mouth twice per day (BID), and cobimetinib 60 mg by mouth 
once daily on days 1-21 of the cycle. The dose escalation scheme is depicted in Table 10. One 
cycle is defined as 28 consecutive days. Treatment will be administered on an outpatient basis.  
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in 6.3.  No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the participant's 
malignancy, with the exception of palliative radiation therapy or surgical resection to non-target 
lesions with prior permission from the principal investigator. Bisphosphonate use is permitted. 
 
 
Table 10: Phase I Dose Escalation Schedule 
Dose Level 
Dose 


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42 
LY3022855 
Vemurafenib 
Cobimetinib 
1 (Starting Dose Level) 
50 mg IV weekly 
960 mg BID 
60 mg daily (taken 
on days 1-21) 
2  
75 mg IV weekly 
960 mg BID 
60 mg daily (taken 
on days 1-21) 
3 
100 mg IV weekly 
960 mg BID 
60 mg daily (taken 
on days 1-21) 
 
 
Three patients will be enrolled to dose level 1. The maximum dose of LY3022855 to be 
evaluated in the triplet combination will not exceed the recommended phase 2 flat dose of singe-
agent LY3022855. 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 5.4.    
 
Dose escalation will proceed in a standard 3+3 fashion according to the scheme in Table 11. 
 
Table 11: 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 
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 


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43 
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 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. 
 
In the event that dose level 3 is found tolerable (with ≤ 1 of 6 participants experiencing DLT); 
subsequent higher dose levels may be explored following a full protocol amendment as long as 
the LY3022855 dose does not exceed the identified RP2D of LY3022855 single-agent therapy. 
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 of the combination. 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. Patients enrolling into the phase II portion of the trial will 
be treated at the RP2D for the combination 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 vemurafenib and cobimetinib, and must complete at 
least three of the four LY3022855 infusions 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 
 
5.2.1 
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. 
 
5.2.2 
Subsequent Cycles  
 
Management of specific toxicities considered at least possibly related to the study regimen is 
outlined in 6.1. 
 
5.3 
Agent Administration 
 


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44 
5.3.1 
LY3022855 
 
LY3022855 will be given once per week on day 1, 8, 15, and 22 of the 28 day cycle. On 
days where LY3022855, vemurafenib, and cobimetinib are all to be given, order of 
administration does not matter.  
 
LY3022855 will be administered via IV infusion. The first infusion should be scheduled 
to occur over 90 minutes (± 5 minute infusion window). If no infusion-related reaction 
occurs, the second infusion can be scheduled to occur over 60 minutes (±5 minute 
window). If no infusion-related reaction occurs, the third and all subsequent infusions can 
be given over 30 minutes (± 5 minute window).  
 
Please see guidance regarding hypersensitivity reactions below. In the event that the 
infusion time takes longer than the above guidance (in the setting of a LY3022855 
infusion-related reaction), this will not be considered to be in violation of the protocol; 
however, in all cases the infusion must be completed within 4 hours of preparation. 
The exact infusion time should be accurately recorded. 
 
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. 
 
DO NOT FREEZE AND/OR SHAKE PREPARED LY3022855 DOSING 
SOLUTION FOR INFUSION. 
 
LY3022855 should be handled according to standard procedures and precautions 
consistent with a cytotoxic anti-cancer drug. 
 
Hypersensitivity Reactions 
 
As with other monoclonal antibodies, infusion-related reactions may occur during or 
following LY3022855 administration. As a precaution, during the first cycle of treatment 
with LY3022855 patients should be monitored by the medical staff for signs and 
symptoms of an infusion-related reaction from the start of the infusion until at least one 
hour after the end of the infusion. Monitoring should occur in an area where resuscitation 
equipment and other agents (e.g., epinephrine, prednisolone or equivalents) are available. 
After completion of the first cycle, if no infusion-related reactions have occurred the 
post-infusion observation period may be discontinued. 
 
Patients will not be premedicated prior to the first infusion of LY3022855. In the event of 
an infusion-related reaction, institutional guidelines for managing infusion reactions 
should be followed. In the case of a grade 1 infusion-related reaction, the infusion rate 
should be decreased by 50% for the duration of the infusion. In the event of a grade 2 
infusion-related reaction, the infusion must be stopped until resolution to ≤ grade 1; the 
infusion may then be resumed at 50% of the prior infusion rate. Note that the infusion 
must be completed within 4 hours of preparation. Patients should be monitored for 
worsening of condition in case of a grade 1 or 2 infusion-related reaction. Once the 


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45 
infusion rate has been reduced for a grade 1 or 2 infusion-related reaction, it is 
recommended to maintain the lower infusion rate for all subsequent infusions.  
 
If the patient experiences a grade 1 or grade 2 infusion-related reaction, premedication 
should be provided prior to subsequent infusions. The exact premedication regimen will 
be per institutional standards and investigator discretion, and should include use of 
diphenhydramine hydrochloride 50 mg IV (or equivalent) administered prior to the 
infusion.  
 
Patients who experience a ≥ grade 3 infusion-related reaction will be discontinued from 
protocol therapy. 
 
5.3.2 
Vemurafenib 
 
Vemurafenib will be given as per package instructions. Vemurafenib should be taken 
orally every 12 hours. A missed dose can be taken up to 4 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. 
Vemurafenib can be taken with or without food. On days where LY3022855, 
vemurafenib, and cobimetinib are all to be given, order of administration does not matter. 
 
5.3.3 
Cobimetinib 
 
Cobimetinib will be given as per package instructions. Cobimetinib should be taken 
orally once daily on days 1-21 of every 28 day cycle. For the purposes of this trial, there 
is a +/- 4 hour dosing window. 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. Cobimetinib can be taken with or without food. On days where LY3022855, 
vemurafenib, and cobimetinib 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 4.03 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 


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46 
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 
6.1, 6.2, and 6.3. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Investigators should use appropriate supportive medications to address toxicities that arise 
during the study, including but not limited to antiemetics, antidiarrheals, and blood product 
transfusion. 
 
Photosensitivity has occurred with use of both vemurafenib and cobimetinib. Patients on trial 
should be advised to avoid sun exposure, wear protective clothing, and use a broad-spectrum 
UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors. 
 
5.5.1 
LY3022855 Guidelines 
 
No formal drug interaction studies have been performed with LY3022855. 
 
5.5.2 
Vemurafenib Guidelines 
 
CYP3A4 Inhibitors or Inducers: Vemurafenib is a substrate of CYP3A4 based on in vitro 
data; therefore, co-administration of strong CYP3A4 inhibitors or inducers may alter 
vemurafenib concentrations. Co-administration of strong CYP3A4 inhibitors is 
prohibited (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, 
saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole).  
 
Concurrent use of strong or moderate CYP3A inducers is prohibited at any point during 
the trial due to their effects on cobimetinib (e.g., phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital). 
 
CYP1A2 Substrates: Concomitant use of vemurafenib with drugs with a narrow 
therapeutic window that are predominantly metabolized by CYP1A2 is not recommended 
as vemurafenib may increase concentrations of CYP1A2 substrates. If co-administration 
cannot be avoided, monitor closely for toxicities and consider a dose reduction of 
concomitant CYP1A2 substrates. 
 
P-gp Substrates: Co-administration of vemurafenib with digoxin, a sensitive P-gp 


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47 
substrate, increased digoxin systemic exposure by 1.8-fold. Avoid concurrent use of P-gp 
substrates known to have narrow therapeutic indices. If use of these medications is 
unavoidable, consider dose reduction of P-gp substrates with narrow therapeutic indices. 
 
Concentration-dependent QT prolongation occurred in an uncontrolled, open-label 
vemurafenib QT substudy in previously treated patients with BRAF V600E mutation-
positive metastatic melanoma. Patients that require medications that are known to 
prolong the QTc interval should be changed to alternative drugs whenever possible. If in 
the opinion of the treating investigator, co-administration cannot be avoided, patients 
should be closely monitored for QT prolongation. 
 
5.5.3 
Cobimetinib Guidelines 
 
CYP3A Inducers: Co-administration of cobimetinib with a strong CYP3A inducer may 
decrease cobimetinib systemic exposure by more than 80% and reduce its efficacy. For 
this reason, concurrent use of strong or moderate CYP3A inducers is prohibited at any 
point during the trial (medications including but not limited to phenytoin, carbamazepine, 
efavirenz, rifampin, and St. John’s Wort). 
 
CYP3A Inhibitors: Co-administration of cobimetinib with itraconazole (a strong 
CYP3A4 inhibitor) increased cobimetinib systemic exposure by 6.7-fold. During the 
phase I portion of the trial, co-administration of strong or moderate CYP3A inhibitors is 
prohibited. Following the phase I portion of the trial, avoid concurrent use of cobimetinib 
and strong or moderate CYP3A inhibitors where possible. If concurrent short term (14 
days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., 
erythromycin, ciprofloxacin) is unavoidable for patients who are taking cobimetinib 60 
mg, reduce cobimetinib dose to 20 mg. After discontinuation of a moderate CYP3A 
inhibitor, resume cobimetinib at the previous dose. Use an alternative to a strong or 
moderate CYP3A inhibitor in patients who are taking a reduced dose of cobimetinib. 
 
 
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 5.4 and 6.1 
 
 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 


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48 
 
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. 
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment 
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.  
 
For Decentralized Subject Registrations, the research team updates the relevant Off Treatment  
information 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 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 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.  
 
For Decentralized Subject Registrations, the research team updates the relevant Off Study 
information in OnCore.  
 
 


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49 
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 4.03 will be utilized for dose delays and dose modifications. A copy of the 
CTCAE version 4.03 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 LY3022855, 
vemurafenib, and/or cobimetinib will be made as indicated in the following tables. Please also 
see 6.2 and 6.3 for further guidance on allowed treatment delays and dose modifications: 
 
Table 12: Management of Elevated AST/ALT 
AST (SGOT) and/or ALT (SGPT) Increase 
Medication Management 
≤ Grade 2 
No change. 
Grade 3, increase lasting less than 8 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 8 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. 
 
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 as clinically appropriate and as indicated in the Study Calendar –
Table 23. 
 
Table 13: 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. 
 


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50 
 
Table 14: 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 15: 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 
investigator’s discretion. 
 
 
Table 16: Management of QTc Increase (Associated with Vemurafenib) 
QTc Interval Prolonged 
Vemurafenib Management 
≤ Grade 2 
No change. 
Grade 3, increase is ≤ 60 msec from pre-
treatment value 
Hold vemurafenib until recovery to ≤ grade 2. 
Upon recovery, restart with one dose level 
reduction. 
Grade 3, increase is > 60 msec from pre-
treatment value 
-OR- 
Grade 4 
Discontinue vemurafenib. 
 
 
Table 17: Management of Nausea 


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51 
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. 
 
 
Table 18: 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 19: Management of Diarrhea 
Diarrhea 
Medication Management 
≤ Grade 2 
No change.* Implement appropriate supportive 
care (e.g., antidiarrheals) as clinically 
indicated. 


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52 
Diarrhea 
Medication Management 
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 20: Management of Constipation 
Constipation 
Medication Management 
≤ Grade 2 
No change.* Implement appropriate supportive 
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 21: 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 


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medication can be dose reduced at the treating investigator’s discretion. 
**Patients who experience a ≥ grade 3 infusion-related reaction should be discontinued from 
protocol therapy.  
§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.   
 
 
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.  
 
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 LY3022855 on schedule while holding their vemurafenib and/or cobimetinib). 
 
If the study medication(s) is/are placed on hold for toxicity, the counting of cycle days and 
assessment schedule will continue without interruption. For example, a patient who does not 
receive their cycle 2 day 15 infusion of LY3022855 due to toxicity will proceed with their next 
scheduled infusion and visit (cycle 2 day 22). 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. If an exception is made to restart the cycle for a 
participant in the phase II portion of the trial, tumor evaluations should continue as previously 
scheduled (tumor evaluations should not be delayed). 
 
 
6.3 
Dose Modifications 
 
The first dose reduction for any toxicity must include a reduction in LY3022855. Further dose 
reductions will be based on the offending medication(s) according to the schedule outlined in 
Table 22. 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 
LY3022855 will not be permitted. Reductions below 480 mg BID of vemurafenib or 20 mg daily 
of cobimetinib 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 vemurafenib and/or cobimetinib despite maximal dose reductions but is deriving 
clinical benefit. In this circumstance, a patient may be allowed to continue on protocol therapy 
and receive LY3022855 either alone or in combination with just the vemurafenib or cobimetinib 
if agreed upon with the principal investigator. 
 


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Patients undergoing dose reductions for toxicities may not be re-escalated. 
 
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 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. 
 
 
Table 22: Dose Modifications 
Original Dose Level 
LY3022855 
Reduction 
Vemurafenib 
Reduction* 
Cobimetinib 
Reduction* 
1 
1st Reduction: 25 mg 
weekly 
1st Reduction: 720 mg 
BID 
1st Reduction: 40 mg 
once daily 
2nd Reduction: 
Discontinue protocol 
therapy 
2nd Reduction: 480 
mg BID 
2nd Reduction: 20 mg 
once daily 
2 
1st Reduction: 50 mg 
weekly 
2nd Reduction: 720 
mg BID 
1st Reduction: 40 mg 
once daily 
2nd Reduction: 25 mg 
weekly 
2nd Reduction: 480 
mg BID 
2nd Reduction: 20 mg 
once daily 
3 
1st Reduction: 75 mg 
weekly 
1st Reduction: 720 mg 
BID 
1st Reduction: 40 mg 
once daily 
2nd Reduction: 50 mg 
weekly 
2nd Reduction: 480 
mg BID 
2nd Reduction: 20 mg 
once daily 
*: Vemurafenib and cobimetinib may be reduced as per the FDA prescribing information 
 
 
6.4 
Overdose management 
 


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There are no known antidotes for over-dosage of LY3022855, vemurafenib, or cobimetinib. In 
the case of suspected overdose, monitor hematologic parameters, serum chemistry, vital signs, 
cardiac function, and provide supportive care as necessary. 
 
 
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 (7.1) and the characteristics of an observed AE 
(7.2 and 7.3) will determine whether the event requires expedited reporting in addition to 
routine reporting. 
 
7.1 
Expected Toxicities 
 
Please refer to the FDA prescribing information for vemurafenib and cobimetinib, along with the 
IB for LY3022855 for the most comprehensive information regarding expected toxicities 
associated with treatment. 
 
Reasonably anticipated serious adverse events for patients with advanced melanoma who receive 
LY3022855 include: 
 Fatigue 
 Nausea/vomiting/anorexia 
 Diarrhea 
 Elevation of hepatic transaminases 
 Increases in LDH 
 Increases in blood creatine phosphokinase 
 Lymphopenia 
 
Fatigue has been the most frequent toxicity reported following treatment with LY3022855, 
followed by elevation in hepatic transaminases and increases in blood creatine phosphokinase 
(CPK). Increased creatinine has been the most frequently reported AE for patients treated with 
the combination of vemurafenib and cobimetinib, followed by increased CPK, and liver 
transaminase increases. 
 
Reasonably anticipated overlapping toxicities for the combination may include hepatotoxicity, 
CK elevations, and cardiomyopathy.  
 
7.2 
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 
4.03 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03.  A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


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 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. 
 
7.3 
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 
 
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 
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 Eli Lilly 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 


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57 
patient participating in the study.  The SAE reports are to be sent to Eli Lilly via fax at 1-866-
644-1697. 
 
7.4 
Expedited Adverse Event Reporting  
 
7.4.1 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.  
 
7.4.2 
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.  
 
7.5 
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. 
 
7.6 
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.  
 
7.7 
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. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in 7.1. 
 
8.1 
LY3022855 
 


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8.1.1 
Description 
 
Molecular Structure: LY3022855 is an anti-CSF-1R recombinant human monoclonal 
antibody of the IgG1 class, composed of 4 polypeptide chains: 2 identical heavy (γ) 
chains consisting of 450 amino acids each, and 2 identical light (κ) chains consisting 
of 214 amino acids each. The heavy chain subunit contains 1 consensus glycosylation 
site for N-linked oligosaccharides at position N300 in the Fc region. There are no O-
linked glycosylation sites. 
 
Molecular mass: 148 kDa 
 
pH: 6.0 at a concentration of 5 mg/mL 
 
Osmolality: 293 mmol/kg 
 
The LY3022855 active ingredient is an aqueous solution at a pH of approximately 6.0 
at a concentration of 5 mg/mL. The monomeric purity of LY3022855 is > 90% by 
size-exclusion chromatography. 
 
LY3022855 drug product is a sterile, preservative-free injection for infusion of 
LY3022855 formulated in an aqueous solution at a concentration of 5 mg/mL (100 
mg/20 mL vial). The buffer contains 10mM histidine, 100mM glycine, 100mM 
arginine, and 0.01% polysorbate 80. LY3022855 drug product is a clear or slightly 
opalescent liquid, without visible particles. All excipients used for the manufacture of 
LY3022855 drug product are of pharmacopeial grade. No animal-derived components 
are used in the manufacture of LY3022855 drug product excipients. 
 
8.1.2 
Form 
 
LY3022855 drug product is supplied in single-use, 20 mL nominal volume, United 
States Pharmacopeia (USP) Type I glass vials. Each vial contains 100 mg of 
LY3022855 at a concentration of 5 mg/mL in a sterile, preservative-free solution. 
Each vial is stoppered with a coated chlorobutyl latex-free rubber stopper and sealed 
with an aluminum seal and a flip-off cap. 
 
8.1.3 
Storage and Stability 
 
LY3022855 Drug Product 
 
The drug product must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) with 
protection from direct light. DO NOT FREEZE AND/OR SHAKE LY3022855 
DRUG PRODUCT. Stability studies have demonstrated that the drug product can 
withstand transient excursion to room temperature without adverse effect; however, 
storage at this temperature is not recommended. 
 
LY3022855 Prepared Dosing Solution for Infusion 
 


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Chemical and physical in-use stability for the prepared LY3022855 dosing solution 
has been demonstrated for up to 24 hours below 25°C (77°F). However, it is 
recommended that the prepared dosing solution be used immediately in order to 
minimize the risk of microbial contamination. If not used immediately, the prepared 
LY3022855 dosing solution should be stored under refrigeration at 2°C to 8°C (36°F 
to 46°F) for no longer than 24 hours. If the prepared solution is held at room 
temperature (below 25°C [77°F]) it must be used within 4 hours. Store protected from 
light. Brief exposure to ambient light is acceptable while preparation and 
administration is taking place. DO NOT FREEZE AND/OR SHAKE PREPARED 
LY3022855 DOSING SOLUTION FOR INFUSION. 
 
8.1.4 
Compatibility 
 
The following have been found to be compatible for LY3022855 drug product 
infusion: 
 A polyethylene-lined PVC infusion set with a 0.22-µm downstream high-
pressure, protein-sparing in-line filter made of polyethersulfone of 10-cm2 
surface area 
 A PVC (with di(2-ethylhexyl)phthalate) infusion set with a 0.2-µm protein-
sparing filter made of polyethersulfone of 4.2-cm2 surface area 
 A polyethylene-lined PVC infusion set with a 0.2-µm protein-sparing in-line 
filter made of polyethersulfone of 10-cm2 surface area 
 A polyurethane infusion set with a 0.2-µm protein-sparing in-line filter made 
of polyethersulfone of 10-cm2 surface area 
 A polybutadiene tubing with 0.2-µm in-line filter made of polysulfone of 9-
cm2 surface area 
 
Only 0.9% normal saline should be used for dilution and post infusion flushing of the 
infusion line. 
 
8.1.5 
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.  
 
8.1.6 
Availability 
 
LY3022855 is an investigational agent that will be supplied by Eli Lilly and Company. 


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60 
 
8.1.7 
Preparation 
 
The dose of LY3022855 should be aseptically withdrawn from the vial and transferred 
to a sterile IV container. LY3022855 is compatible with infusion containers composed 
of polyolefin, polyvinyl chloride (PVC), ethylene vinyl acetate, and evacuated glass 
(USP Type II or local equivalent). An infusion bag composed of polyolefin, 
polypropylene, and polyethylene prefilled with 0.9% sodium chloride injection, such 
as AVIVA, may also be used. 
 
 To administer using pre-filled IV infusion containers: 
Calculate the respective dose and remove the corresponding volume of 0.9% normal 
saline from the prefilled 250 mL container of the correct composition. Aseptically 
transfer the calculated dose of LY3022855 drug product to the container to bring the 
final volume in the container back to 250 mL. Gently invert the container to mix. 
 
To administer using empty IV infusion containers: 
Aseptically transfer the calculated dose of LY3022855 drug product into an empty IV 
container of the correct composition and add a sufficient quantity of sterile normal 
saline (0.9% weight/volume) to the container to bring the total volume to 250 mL. 
Gently invert the container to mix. 
 
For dose volumes greater than 250 mL, the addition of sterile normal saline is not 
required. Only 0.9% normal saline should be used for dilution and post infusion 
flushing of 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. 
 
Different lot numbers of LY3022855 must not be mixed in a single infusion. 
 
 
8.1.8 
Administration 
 
LY3022855 will be given once per week on day 1, 8, 15, and 22 of the 28 day cycle. 
On days where LY3022855, vemurafenib, and cobimetinib are all to be given, order of 
administration does not matter.  
 
LY3022855 will be administered via IV infusion. The first infusion should be 
scheduled to occur over 90 minutes (± 5 minute infusion window). If no infusion-
related reaction occurs, the second infusion can be scheduled to occur over 60 minutes 
(±5 minute window). If no infusion-related reaction occurs, the third and all 
subsequent infusions can be given over 30 minutes (± 5 minute window).  
 
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. 
 


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DO NOT FREEZE AND/OR SHAKE PREPARED LY3022855 DOSING 
SOLUTION FOR INFUSION. 
 
LY3022855 should be handled according to standard procedures and precautions 
consistent with a cytotoxic anti-cancer drug. 
 
8.1.9 
Ordering 
 
Drug supply will be ordered from Eli Lilly and Company by site pharmacy personnel. 
 
8.1.10 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.) 
 
8.1.11 Destruction and Return 
 
Expired supplies of LY3022855 should be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record Form. At 
the end of the study, unused supplies of LY3022855 should also be destroyed 
according to institutional policies and destruction will be documented in the Drug 
Accountability Record Form. 
 
8.2 
Vemurafenib 
 
8.2.1 
Description 
 
Chemical Name: propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-
b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide 
 
Chemical Structure: 
 
 
 
Molecular Weight: 489.9 
 
Molecular Formula: C23H18ClF2N3O3S 


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62 
 
Solubility: Insoluble in aqueous media 
 
The inactive ingredients of the tablet core are hypromellose acetate succinate, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and 
hydroxypropyl cellulose. The ingredients of the coating are poly (vinyl alcohol), 
titanium dioxide, polyethylene glycol 3350, talc, and iron oxide red. 
 
8.2.2 
Form 
 
Vemurafenib is available as 240 mg film-coated tablets with VEM debossed on one 
side. 
 
8.2.3 
Storage and Stability 
 
Store at room temperature between 20°C–25°C (68°F–77°F); excursions permitted 
between 15°C and 30°C (59°F and 86°F), See USP Controlled Room Temperature. 
Store in the original container with the lid tightly closed. 
 
8.2.4 
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. 
 
8.2.5 
Availability 
 
Vemurafenib is commercially available. 
 
8.2.6 
Administration 
 
Vemurafenib will be given as per package instructions. Vemurafenib should be taken 
orally every 12 hours. A missed dose can be taken up to 4 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. 
Vemurafenib can be taken with or without food. 
 
8.2.7 
Ordering 
 
Vemurafenib is commercially available. The investigator or designated study 
personnel are responsible for maintaining dispensing records of vemurafenib per 
institutional standards. 
 
8.3 
Cobimetinib 
 


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63 
8.3.1 
Description 
 
Chemical Name: (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-
hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone hemifumarate 
 
Chemical Structure: 
 
 
 
Molecular Weight: 1178.71 as a fumarate salt 
 
Molecular Formula: C46H46F6I2N6O8 (2 C21H21F3IN3O2 . C4H4O4) 
 
The inactive ingredients of the tablet core are microcrystalline cellulose, lactose 
monohydrate, croscarmellose sodium, magnesium stearate. The inactive ingredients of 
the tablet coating are polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, 
talc. 
 
8.3.2 
Form 
 
Cobimetinib is available as 20 mg white, round, film-coated tablets with COB 
debossed on one side. Each 20 mg tablet contains 22 mg of cobimetinib fumarate, 
which corresponds to 20 mg of the cobimetinib free base. 
 
8.3.3 
Storage and Stability 
 
Store at room temperature below 30°C (86°F). 
 
8.3.4 
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. 
 
8.3.5 
Availability 
 
Cobimetinib is commercially available. 
 


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8.3.6 
Administration 
 
Cobimetinib will be given as per package instructions. Cobimetinib should be taken 
orally once daily on days 1-21 of every 28 day cycle. For the purposes of this trial, 
there is a +/- 4 hour dosing window. 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. Cobimetinib can be taken with or without food. 
 
8.3.7 
Ordering 
 
Cobimetinib is commercially available. The investigator or designated study personnel 
are responsible for maintaining dispensing records of cobimetinib per institutional 
standards. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Collection of Archival Tissue 
 
Archival tumor tissue will be collected on all patients enrolling to the trial as described in 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 
 
  
9.2 
Exploratory Fresh Tumor Biopsies 
 
Optional fresh tumor biopsies will be obtained from patients enrolled during either phase of the 
trial, as described in 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 1. 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 


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perform the biopsy before another treatment is begun, the biopsy can be obtained up to 30 days 
after the last dose of LY3022855. 
 
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. 
 
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 
 
 
9.3 
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 LY3022855, vemurafenib, and cobimetinib), 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.  
 
9.3.1 
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 
 
 
10. STUDY CALENDAR 
 


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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. 
 
Assessments must be performed prior to administration of any study agent.


DF/HCC Protocol #: 17-030 
Protocol Version Date: 31 July 2017 
 
 
 
67 
 
 
 
Table 23: Study Calendar 
Pre-
StudyL 
Cycle 1 
Day 1 
Cycle 1 Day 
8M 
Cycle 1 Day 
15M 
Cycle 1 Day 
22M 
Cycle 2+ 
Day 1N 
Cycle 2+ 
Day 8M 
Cycle 2+ Day 
15M 
Cycle 2+ Day 
22M 
Off 
TreatmentO 
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 
 
X 
 
Vital signsB 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance 
Status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
CBC w/diff, plts 
X 
X 
X 
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 
X 
X 
X 
 
EKGD 
X 
 
 
X 
 
X 
 
 
 
 
 
EchocardiogramE 
X 
 
 
 
 
X 
 
 
 
 
 
Dermatologic 
Evaluation 
X 
Dermatologic evaluations to be performed to assess for suspicious skin lesions every 2 months while on 
vemurafenib/cobimetnib 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 
 


DF/HCC Protocol #: 17-030 
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68 
 
Table 23: Study Calendar 
Pre-
StudyL 
Cycle 1 
Day 1 
Cycle 1 Day 
8M 
Cycle 1 Day 
15M 
Cycle 1 Day 
22M 
Cycle 2+ 
Day 1N 
Cycle 2+ 
Day 8M 
Cycle 2+ Day 
15M 
Cycle 2+ Day 
22M 
Off 
TreatmentO 
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 28) and at the end of every 2 cycles of treatment thereafter (i.e., Cycle 4 Day 28, Cycle 6 Day 28, and so on). There is 
a +/- 7 day scheduling window on imaging evaluations. 
X 
 
Serum β-HCGF 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic 
examination 
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 
 
 
 
 
X 
 
LY3022855 
Administration 
 
X 
LY3022855 to be administered as described in 5.3.1. 
 
 
Vemurafenib 
AdministrationJ 
 
X 
Vemurafenib to be administered as described in 5.5.2 and as per institutional standards. 
 
 
Cobimetinib 
AdministrationJ 
 
X 
Cobimetinib to be administered as described in 5.3.3 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 9.1 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 urine and serum myoglobin should also be obtained. 
D. 
EKG to be performed during screening, at anytime pre-dose on Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 3 day 1. EKGs to be collected every 3 months thereafter (i.e., Cycle 6 Day 1, 
Cycle 9 Day 1, and so on). EKGs can be performed more frequently as clinically indicated or as per institutional standards. 
E. 
Echocardiogram (echo) to be performed during screening, on Cycle 2 day 1, and then every 3 cycles thereafter (i.e., Cycle 5 Day 1, Cycle 8 Day 1, and so on). 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 
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 treatment visit. Please see 9.3.1 for more detail. 


DF/HCC Protocol #: 17-030 
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69 
 
Table 23: Study Calendar 
Pre-
StudyL 
Cycle 1 
Day 1 
Cycle 1 Day 
8M 
Cycle 1 Day 
15M 
Cycle 1 Day 
22M 
Cycle 2+ 
Day 1N 
Cycle 2+ 
Day 8M 
Cycle 2+ Day 
15M 
Cycle 2+ Day 
22M 
Off 
TreatmentO 
Every 3 Months 
after Discontinuing 
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 1. An additional optional biopsy at the time of disease progression may be obtained up 
to 30 days after the last dose of LY3022855. Please see 9.2 for more detail. 
J. 
Vemurafenib and cobimetinib to be dispensed and administered as described in 5.3.2 and 5.3.3 and as per institutional standards. 
K. 
Participants will be followed until death or withdrawal of consent after removal from protocol therapy for survival status only. 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 +/- 1 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-treatment evaluation to be completed within 30 days of the last dose of LY3022855. Note: Follow up visits or other contact is required in order to identify SAEs during the 30 days 
following the end of study treatment.  
 


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70 
 
11. 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. 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every eight 
weeks.  In addition to a baseline scan, confirmatory scans should also be obtained not less than 
four weeks following initial documentation of objective response. 
 
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 45:228-247, 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. 
 
Participants enrolling to the phase I portion of the trial who do not have measurable disease at 
baseline per RECIST 1.1 guidelines may be enrolled if they have evaluable disease. Evaluable 
disease includes non-measurable disease: small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses that cannot be accurately measured by CT or MRI are all considered non-
measurable. For the purposes of the phase I portion of the trial a participant who exhibits one or 
more non-measurable disease parameters but does not meet the definition for measurable disease 
may be enrolled assuming that they meet the other eligibility requirements of the protocol. 
 
11.1.1 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.  
 


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71 
11.1.2 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. 
 
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 


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72 
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.  
 
11.1.3 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 
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 


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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 
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.  


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74 
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 
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. 
 


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75 
11.1.3.1 
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 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.3.2 
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). 
 
11.1.3.3 
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 


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76 
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. 
 
11.1.3.4 
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. 
 
Table 24: Participants with Measurable Disease (i.e., Target Disease) 
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. 
 
 
Table 25: 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 


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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 
 
11.1.4 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). 
 
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.  
 
11.1.5 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. 
 
11.1.6 Response Review 
 
Evaluation of scans will be done centrally at the DFCI using the Tumor Metrics Core.  
 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in 7.1 (Adverse 


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78 
Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
  
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the InForm application designed by CTRIO according to the schedule set 
by CTRIO. 
 
12.2 
Data Safety Monitoring 
 
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 within 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.  
 
 
13. 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.  
 
13.1 
Study Design/Endpoints 
 
Primary Endpoints: 
 
For the phase I portion of the trial: 
 
A conventional algorithm (3+3 design) will be used to identify the MTD, escalating on 0/3 or 1/6 


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79 
DLTs, and de-escalating if two DLTs are encountered. The MTD will be the highest dose level at 
which  ≤ 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 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.  
 
Data will be summarized using descriptive statistics for continuous variables and frequencies, 
percentages for discrete variables, and presented by dose group, as appropriate.  
 
For the phase II portion of the trial: 
 
Primary Endpoint: 
 
For the phase II portion of the trial, the primary endpoint will be PFS, defined as the time from 
study enrollment until the identification of disease progression by RECIST 1.1 criteria or death. 
Patients who have not experienced an event of interest by the time of analysis will be censored at 
the date they are last known to be progression-free. 
 
Power is based on the Wald test of the log failure rate. We assume uniform accrual for 12 
months, 12 additional months of follow-up, and a null median PFS of 10 months. A sample of 25 
subjects, with 12 observed PFS events, will have 85% power to detect an alternative median PFS 
of 20 months (hazard ratio = 2), The design assumes a one-sided, type-I error of 10%. The null 
median PFS of 10 months will be rejected if the observed median PFS is at least 14.5 months. 
 
Secondary Endpoints: 
 
Overall response rate (ORR) will be assessed by RECIST 1.1 criteria and will be graded as 
complete response, partial response, stable disease and progressive disease. Overall survival 
(OS) will be defined as the time from study enrollment to death from any cause. Patients who are 
alive at the time of analysis will be censored at the date of last vital status. 
 
Toxicity will be assessed using the CTCAE version 4.03. 
 
Exploratory Endpoints: 
 
Data from correlative studies will be summarized using descriptive statistics. Associations 
between MAPK signaling, TAMs, and immune infiltrates will be compared to clinical outcome 
and will be 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 LY3022855 combination therapy. 
 
13.2 
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 


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80 
patients in the phase II portion of the trial, for a total of 31 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. 
 
 
Table 26: Accrual Targets
Ethnic Category 
Sex/Gender
Females
Males
 
Total
Hispanic or Latino 
0 
+
1 
= 
1 
Not Hispanic or Latino 
15 
+
27 
= 
42 
Ethnic Category: Total of all subjects 
15 
 
+
28 
 
= 
43 
 
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 
15 
+
27 
= 
42 
Racial Category: Total of all subjects 
15 
 
+
28 
 
= 
43 
 
 
 
 
 
 
 
13.3 
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 to the phase I portion of 
this trial. The exception to this includes the planned analysis of toxicity data, which will include 
all patients who received study drug regardless of eligibility.  
 
Overall response rate will be presented with a 90% exact binomial confidence interval.  For a 
sample of size 25, the confidence interval will be no wider than 0.35.  The distributions of 
overall survival and progression-free survival will be described using the method of Kaplan-
Meier.  Median PFS and OS will be summarized with 90% confidence intervals estimated using 
log (-log(endpoint)) methodology. 
 
In the event that there are missing data points, no imputation of the missing data will be 
conducted.  
 
13.4 
Reporting and Exclusions 
 
13.4.1 Evaluation of Toxicity 
 


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All participants will be evaluable for toxicity from the time of their first dose of study 
medication. 
 
13.4.2 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. 
 
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.  


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82 
 
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16. 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.