Clinical trial NCT02920996
Conditions: Carcinoma, Non-Small-Cell Lung Solid Tumor
Keywords: NSCLC MET Non-small cell lung cancer MET mutation NTRK rearrangement NTRK targeted therapy MET exon 14 NTRK1 NTRK2 NTRK3 merestinib LY2801653
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-11-11; Completion date: 2023-10-01
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is examining merestinib (a targeted therapy) as a possible treatment for non-small cell lung cancer (NSCLC) that was found to have a specific change in the MET gene (a MET exon 14 mutation); or as a treatment for solid tumors that have an alteration in the NTRK gene (an NTRK1, 2, or 3 rearrangement).

Detailed description:
This is an open-label, phase II study of merestinib in patients with advanced NSCLC with a MET exon 14 mutation or patients with advanced cancer harboring an NTRK1, 2, or 3 rearrangement. Twenty patients with a MET mutation will be evaluated in a single-arm design. A small separate cohort of 5 NTRK patients will be evaluated for exploratory purposes.

Merestinib (LY2801653) is a small molecule that has been shown in vitro to be a reversible type II ATP-competitive inhibitor of MET. Pre-clinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2 and the serine/threonine kinases MKNK1/2.

Arms: arm 1: Merestinib at the recommended phase II dose of 120 mg by mouth daily. arm 2: Merestinib at the recommended phase II dose of 120 mg by mouth daily.
Interventions: intervention 1: Merestinib
Intervention descriptions: intervention 1: Merestinib is a potent and selective type II MET/RON kinase inhibitor with the ability to achieve inhibition of MET activity both in vitro and in vivo.

Protocol documents:
Prot_SAP_000.pdf: 
 
Page 1 
NCI Protocol #:
N/A 
DF/HCC Protocol #: 16-374
 
TITLE:  A Phase II Study of Merestinib in Non-Small Cell Lung Cancers Harboring MET Exon 
14 Mutations and solid tumors with NTRK rearrangements
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute 
 
Principal Investigator (PI): 
Mark Awad MD, PhD 
 
Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute 
Mark_Awad@dfci.harvard.edu 
 
Other Investigators: 
Rebecca Suk Heist, MD 
 
Massachusetts General Hospital 
 
RHeist@partners.org 
 
Statistician: 
 
Project Manager:  
Suzanne Dahlberg, PhD 
 
Adrienne Anderson RN, BSN 
Dana-Farber Cancer Institute  
Dana-Farber Cancer Institute 
Telephone: 617-632-5580 
 
Telephone: 617-632-6594 
Fax: 617-632-2444 
 
Fax: 617-632-5152 
dahlberg@jimmy.harvard.edu  
Aanderson10@partners.org 
 
 
 
 
Agent: Merestinib (LY2801653) – Eli Lilly and Company 
 
IND #: 131154 
 
IND Sponsor: Investigator-Initiated Study, Mark Awad MD, PhD 
 
 
 
 
Protocol Type / Version # / Version Date: Revised, Version #8, 08 May 2019 




 
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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................2
1.
OBJECTIVES ......................................................................................................................6
1.1
Study Design............................................................................................................6
1.2
Primary Objective....................................................................................................6
1.3
Secondary Objectives...............................................................................................6
1.4
Exploratory Objectives ............................................................................................6
2.
BACKGROUND .................................................................................................................6
2.1
Study Diseases .........................................................................................................6
2.2
Merestinib (LY2801653) .........................................................................................7
2.3
Rationale ................................................................................................................20
2.4
Correlative Studies .................................................................................................20
3.
PARTICIPANT SELECTION ...........................................................................................22
3.1
Eligibility Criteria..................................................................................................22
3.2
Exclusion Criteria ..................................................................................................23
3.3
Inclusion of Women and Minorities ......................................................................25
4.
REGISTRATION PROCEDURES ...................................................................................25
4.1
General Guidelines for DF/HCC Institutions ........................................................25
4.2
Registration Process for DF/HCC Institutions .......................................................25
5.
TREATMENT PLAN........................................................................................................25
5.1
Treatment Regimen ................................................................................................25
5.2
Pre-Treatment Criteria ...........................................................................................26
5.3
Agent Administration.............................................................................................26
5.4
General Concomitant Medication and Supportive Care Guidelines......................27
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................27
5.6
Duration of Follow Up...........................................................................................28
5.7
Criteria for Taking a Participant Off Study ...........................................................28
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................29
6.1
Specific Toxicity Management..............................................................................29
6.2
Treatment Delays ...................................................................................................31
6.3
Dose Modifications................................................................................................31
6.4
Overdose Management ..........................................................................................31
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................31
7.1
Expected Toxicities ................................................................................................32
7.2
Adverse Event Characteristics...............................................................................32
7.3
Serious Adverse Events .........................................................................................33
7.4
Expedited Adverse Event Reporting ......................................................................34
7.5
Expedited Reporting to the Food and Drug Administration (FDA) ......................34


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7.6
Expedited Reporting to Hospital Risk Management .............................................34
7.7
Routine Adverse Event Reporting .........................................................................34
8.
PHARMACEUTICAL INFORMATION..........................................................................34
8.1
Merestinib (LY2801653) .......................................................................................34
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................37
9.1
Exploratory Pharmacodynamic Tumor Biopsies ...................................................37
9.2
Plasma Genotyping Correlative Studies ................................................................38
10.
STUDY CALENDAR .......................................................................................................39
11.
MEASUREMENT OF EFFECT........................................................................................40
11.1
Antitumor Effect – Solid Tumors ..........................................................................40
12.
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................48
12.1
Data Reporting .......................................................................................................48
12.2
Data Safety Monitoring..........................................................................................48
13.
STATISTICAL CONSIDERATIONS...............................................................................49
13.1
Study Design/Endpoints.........................................................................................50
13.2
Sample Size, Accrual Rate and Study Duration ....................................................51
13.3
Analysis of Primary and Secondary Endpoints .....................................................52
13.4
Analysis of Exploratory Endpoints........................................................................52
13.5
Reporting and Exclusions ......................................................................................52
14.
PUBLICATION PLAN .....................................................................................................52
REFERENCES ..............................................................................................................................53
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................55
LIST OF TABLES 
Table 1: Pharmacokinetic Parameters in Sprague-dawley rats and Beagle dogs ........................... 9
Table 2: Toxicokinetic Parameters in Sprague-dawley Rats ........................................................ 10
Table 3: Toxicokinetic Parameters in Beagle Dogs ...................................................................... 11
Table 4: Merestinib PK Parameters, Study JSBA ........................................................................ 16
Table 5: Summary of SAEs in Study JSBA Considered Possibly Drug-Related ......................... 18
Table 6: Treatment-Emergent Adverse Events Possibly Related to Merestinib........................... 19
Table 7: AST/ALT Management .................................................................................................. 29
Table 8: Nausea Management ....................................................................................................... 29
Table 9: Management of Vomiting ............................................................................................... 30
Table 10: Fatigue Management .................................................................................................... 30
Table 11: Management of Other Toxicity .................................................................................... 30
Table 12: Dose Modifications ....................................................................................................... 31


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Table 13: Study Calendar.............................................................................................................. 39


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1.
OBJECTIVES
1.1
Study Design
This is an open-label, phase II study of merestinib in patients with advanced non-small cell lung 
cancer (NSCLC) with a MET exon 14 mutation or patients with advanced cancer harboring an 
NTRK1, 2, or 3 rearrangement.  Patients with a MET mutation will be evaluated in a single-arm 
design. A small cohort of NTRK patients will be evaluated for exploratory purposes. 
1.2
Primary Objective 
Examine the overall response rate (ORR) utilizing RECIST 1.1 criteria in patients
harboring MET mutations following administration of merestinib. 
1.3
Secondary Objectives 
 
Evaluate the safety and tolerability of merestinib. 
 
Determine the overall survival (OS) rate, defined as the time from registration to death 
due to any cause (or censored at date last known alive), in patients harboring MET 
mutations.
 
Determine the progression-free survival (PFS) rate in patients harboring MET mutations, 
defined as the time from registration to disease progression or death due to any cause. 
Participants alive without disease progression will be censored at date of last disease 
evaluation. 
 
Determine the duration of response (DoR) in patients harboring MET mutations, defined 
as the time from documentation of response (by RECIST 1.1 criteria) to disease 
progression, or censored at date of last disease evaluation for those without progression.
 
1.4
Exploratory Objectives 
 
Explore the ORR, OS, PFS, and DoR in a small cohort of patients with advanced cancer 
harboring an NTRK1, 2, or 3 rearrangement.
 
Investigate the genomic determinants of response and resistance to merestinib by 
analyzing circulating free tumor DNA for identification of activating 
mutations/rearrangements in MET or NTRK as well as for detection of resistance 
mutations. 
 
Examine the mechanisms of resistance to prior tyrosine kinase inhibitors (TKIs) via a 
pre-treatment biopsy obtained on patients enrolling to the trial who have received a prior 
MET or NTRK inhibitor. 
 
Assess the genomic determinants of response and resistance to merestinib by analyzing 
tumor tissue obtained from patients at the time of disease progression. 
 
2.
BACKGROUND 
2.1
Study Diseases 
Lung cancer remains the third most prevalent cancer in the United States and more people die of 
lung cancer than any other form of cancer1. The application of molecularly targeted therapies in
subsets of lung cancer patients has revolutionized treatment for patients whose tumors harbor 


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mutations in genes such as EGFR, ALK, and ROS1. Activating mutations and genomic 
amplifications in the mesenchymal-to-epithelial transition (MET) gene have also been described 
as a potentially important therapeutic target in NSCLC2-4. Somatic mutations in the MET gene 
can lead to exon 14 skipping, and this mutant receptor can then subsequently increase c-Met 
signaling and oncogenic potential5,6. 
MET exon 14 mutations have been identified in approximately 3% of non-squamous NSCLCs. 
The mutation seems to occur primarily in older adults, a group that may not be able to receive 
full-dose chemotherapy due to comorbidities. Successful identification of targetable mutations 
may improve tolerability and ultimately treatment outcome in these patients7.   
Neurotrophic tyrosine receptor kinases (NTRK) belong to a group of tyrosine kinases that 
usually help regulate neural development. Chromosomal rearrangements that result in the 
expression of oncogenic NTRK fusions can induce cancer cell proliferation and engage critical 
cancer-related downstream signaling pathways. These rearrangements have been identified to 
occur in a subset of epithelial malignancies and can provide the basis for sensitivity to kinase 
inhibitors8,9. NTRK rearrangements are rare and are found among a diverse group of cancers, 
including thyroid and secretory breast carcinomas, NSCLC, sarcomas, and other epithelial 
malignancies10. 
2.2
Merestinib (LY2801653) 
Merestinib is a potent and selective type II MET/RON kinase inhibitor with the ability to achieve 
inhibition of MET activity both in vitro and in vivo. Merestinib has also been shown to be 
capable of inhibiting 14 receptor tyrosine kinases, including MET, MST1R [RON], AXL, ROS1, 
PDGFRA, FLT3, MERTK, TYR03, TEK, DDR1, DDR2, and NTRK1/2/3, as well as two
serine/threonine kinases (MKNK1/2) 11. Given that MET and other targets of merestinib may play 
critical roles in cancer progression, inhibition of MET and other targets by merestinib could have 
a significant impact on the treatment and survival of cancer patients12-17.
 
The first-in-human phase I study for merestinib (Study I3OMC-JSBA, hereby referred to as 
JSBA) was initiated in September 2009 and is currently ongoing. The objectives of this study 
were to evaluate the safety and tolerability of merestinib in patients with cancer and to determine 
the dose and schedule for phase II studies. As of 20 August 2015, 166 patients with advanced 
cancer have been enrolled and have received merestinib at dose levels ranging from 3 mg per day 
to 240 mg per day.
Study JSBA consists of six parts (A through F):
A. single agent dose-escalation testing in patients with advanced or metastatic solid tumors, 
B. single agent dose-confirmation testing, 
C. dose finding in combination with cetuximab, 
D. dose finding in combination with cisplatin, 
E. safety testing in combination with gemcitabine and cisplatin, and 
F. safety testing in combination with ramucirumab 
 
Enrollment has been completed for parts A-E. Based on the interim analysis of data from the 


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dose escalation, the 120 mg dose was investigated in part B of the study with merestinib as a 
single agent in patients with adenocarcinoma of the colon or rectum, squamous cell carcinoma of 
the head and neck (HNSCC), cholangiocarcinoma, and metastatic uveal melanoma. Additional 
parts of the study have enrolled patients to evaluate the safety of merestinib when administered 
in combination with other standard regimens. 
 
A clinical pharmacology study with merestinib (Study I3O-EW-JSBC, or JSBC) was initiated in 
November 2013 to determine the routes of elimination and extent of metabolism of merestinib, 
including identification of metabolites in plasma, urine, and feces in sterile healthy subjects after 
a single oral administration of merestinib containing 14C- merestinib. The total administered dose 
of merestinib was 120 mg. A total of five healthy subjects received merestinib containing 14C-
merestinib in this study. This study was completed on 18 September 2014. 
 
Another clinical pharmacology study with merestinib (Study I3O-EW-JSBD, or JSBD) was 
initiated in February 2015 to determine the relative bioavailability of two tablet formulations of 
merestinib, and the effect of a high-fat meal on the bioavailability of merestinib administered as 
three 40 mg tablets of the test formulation. A total of 23 subjects received merestinib. This study 
was completed on 06 October 2015. 
2.2.1
Merestinib Pre-Clinical Studies 
The plasma toxicokinetics of merestinib and its active N-desmethyl metabolite LSN2800870 
were evaluated in Sprague-dawley rats and Beagle dogs following daily oral administration of 
merestinib for 4 weeks. In rats, exposure to merestinib (defined as maximal concentration [Cmax]
and area under the concentration-time curve from time 0 to 24 hours [AUC0-24 hr]) generally
increased more than proportionally from 3 to 30 mg/kg/day. Exposure to merestinib in male rats
trended slightly lower than in females (< 2-fold). No accumulation was observed after multiple
doses. Merestinib was converted to an active metabolite, LSN2800870, with higher
concentrations in male rats than female rats.  
In dogs, merestinib Cmax and AUC0-24 hr increased less than dose proportionally from 2 to 250 
mg/kg/day. Potential accumulation of merestinib and LSN2800870 in dog plasma was observed 
following multiple dosing of merestinib at the 2 and 25 mg/kg dose levels. Gender differences in 
exposure were not marked (< 2-fold). Merestinib was not extensively converted to LSN2800870 
in dogs. 
 
Absorption, distribution, metabolism, and excretion of merestinib in rats and dogs have been 
determined following single doses of 14C- merestinib. Parent merestinib is absorbed and is the 
main component circulating in the plasma of both species. The N-desmethyl metabolite, 
LSN2800870, was observed in plasma, representing an approximately 9-fold lower exposure in 
rats and 27-fold lower in dogs when compared with the parent. More metabolites were observed 
in rat feces, bile, and plasma than in dog feces and plasma. Metabolic transformations observed 
in formation of the metabolites included oxidation, glucuronide conjugation, and N-
desmethylation. The radioactivity associated with 14C- merestinib was extensively distributed in 
tissues and organs and selectively associated with melanin-containing tissues in rats. The major 
path of excretion in rats and dogs was biliary/fecal based on the recovery of total radioactivity. 


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Less than 3% of the dose was excreted in the urine. 
Pre-clinical Pharmaco- and Toxicokinetics
The pharmacokinetic (PK) parameters of merestinib and merestinib-derived radioactivity were 
evaluated in male Sprague-dawley rats and male Beagle dogs following a single oral dose. On 
the basis of AUC versus time curve values, with time from 0 to infinity (AUC0- ), merestinib 
accounted for 64.9% and 83% of the plasma radioactivity in rats and dogs, respectively. The 
elimination half-life (t1/2) of merestinib was similar to the elimination t1/2 of radioactivity.
Table 1: Mean (± SD) Plasma Pharmacokinetic Parameters following a Single 10 mg/kg 
Oral Dose of 14C-merestinib in Sprague-dawley rats and Beagle dogs (n=3)
Due to the lower than expected exposure from the free-base dry blend capsule used in the 3 and 6 
mg cohorts in Study JSBA, a formulation study was conducted in dogs to evaluate the plasma
exposure of 5 alternative formulations and a tosylate salt compared with the free-base dry blend 
capsule at 6 mg/kg. The 5 alternative formulations were standard wet granulation with surfactant, 
polyvinylpyrrolidone vinylacetate (PVP-VA) solid dispersion with surfactant, HPMCAS solid 
dispersion with surfactant, PEG 3350 (polyethylene glycol)/10% Gelucire® 44/14 (9:1) 
semisolid, and -cyclodextrin with wet granulation. All formulations and the salt increased 
plasma exposure compared with the FHD capsule. The exposure increase was the highest for 
HPMC-AS solid dispersion with an AUC0-24 hr increase of 30-fold followed by the semi-solid
with a 20-fold increase. The PVP-VA solid dispersion led to a 13-fold increase and the tosylate 
salt to an 8.2-fold increase. The standard wet granulation with surfactant provided a 2.8-fold 
increase, and -cyclodextrins provided the smallest difference with only a 2.1-fold increase 
compared with the dry blend.
A study was conducted in Pgp and Bcrp knockout mice to determine the role of Pgp/Bcrp
transporters on the PK of merestinib following 0.1, 1, and 10 mg/kg oral administration. The
AUC0-24 hr in the individual Pgp (Mdr 1a/b) and Bcrp knockout mice was increased less than 2-
fold when compared with wild-type FVB mice. However, exposure increased 2.3-fold in 
Mdr1a/b/Bcrp triple-knockout mice. These data indicate that transporters, including Pgp and
Bcrp, appear to be involved in the absorption and/or clearance of merestinib in mice. 
 
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were evaluated on study days 1 and 28 following oral administration of 3, 10, or 30 mg/kg/day to 
rats for 4 weeks and is summarized in Table 2. 
In the rat, exposure to merestinib and its metabolite LSN2800870 (defined as Cmax and 
AUC0-24 hr) generally increased more than proportionally from 3 to 30 mg/kg/day. All animals in 
the high-dose group were euthanized prior to the study end and not available for blood draws on 
Day 28. In this study, merestinib was orally available, with time to maximal plasma 
concentration (tmax) ranging from 2 to 8 hours for the parent and 4 to 12 hours for the metabolite. 
The exposure to merestinib in male rats was slightly lower than the exposure in females, but the
difference was < 2-fold. The values for merestinib Cmax and AUC0-24 hr on day 28 were slightly
lower than those on day 1, but there was no evidence of total CYP induction after multiple
dosing, nor was the metabolite exposure increased. The Cmax and AUC0-24 hr values for the
metabolite were markedly (> 2-fold) higher in males than in females.
 
 
Table 2: Mean Toxicokinetic Parameters in Sprague-dawley Rats after Single and Multiple 
Oral Dose Administration of Merestinib for 4 Weeks
 
In Beagle dogs, the plasma toxicokinetics of merestinib and its N-desmethyl metabolite 
LSN2800870 were evaluated on study day 1 and again on either day 15 or day 28 following oral 
administrations of 2, 25, or 250/125 mg/kg/day to dogs for 4 weeks. Toxicokinetic parameters 


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are summarized in Table 3. 
Following oral administration, merestinib was available with mean tmax values ranging from 1.2
to 12.7 hours. Exposure increased less than dose proportionally from 2 to 250 mg/kg/day. 
Variability of AUC0-24 hr for the parent, as expressed by the percentage coefficient of variation
(%CV), ranged from 6% to 60%. No marked gender difference (< 2-fold) on exposure was
observed. Accumulation occurred following multiple dosing. Exposure of dogs to the metabolite 
was low. 
 
 
Table 3: Mean Toxicokinetic Parameters in Beagle Dogs after Single and Multiple Oral 
Dose Administrations of Merestinib for 4 Weeks 
Distribution 
 
In preliminary studies, merestinib was administered via gavage at 50 mg/kg to nude mice bearing
S114 tumors (derived from ovary cells). Merestinib was distributed into tumors with a tumor-to-
plasma ratio of 0.55 in mice at 2 hours post-dose. 
A quantitative whole-body autoradiographic disposition study was conducted in male and female 


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pigmented Long Evans rats and male non-pigmented Sprague-dawley rats following a single 10 
mg/kg oral dose of 14C-merestinib. Radioactivity related to 14C-merestinib was extensively 
distributed into tissues and was selectively associated with melanin-containing tissues. 
Maximum concentrations of radioactivity for Long Evans rats were observed at 4 hours post-
dose, and concentrations generally declined over time. The liver, uveal tract of the eye, 
epididymis (male), pigmented skin, small intestine, and thymus (female) were the tissues with 
the highest concentrations. Very low levels of radioactivity crossed the blood-brain barrier and 
blood-testis barrier. 
 
Metabolism 
 
The metabolism of merestinib was studied in vitro in rat, dog, and human cryopreserved 
hepatocytes, and in vivo in rats and dogs. The parent compound undergoes oxidative metabolism 
producing 2 predominant metabolites: LSN2800870 (N-desmethylation) and LSN2887652 
(oxidation of methylpyridone). LSN2800870 and LSN2887652 are both active metabolites. 
 
The metabolism of merestinib was examined in intact or biliary cannulated male Sprague-dawley 
rats following a single 10 mg/kg oral dose of 14C-merestinib, and male Beagle dogs following a 
single 1 mg/kg intravenous or 10 mg/kg oral dose of 14C- merestinib. More metabolites were 
observed in rat feces, bile, and plasma (a total of 22) than in dog feces and plasma (total of 9). 
Urine was not profiled due to the low renal excretion of total radioactivity. The primary 
metabolic pathways observed in rats involved N-desmethylation of the N-methylindazole 
followed by oxidation and/or glucuronide conjugation on either the indazole or pyrazole moiety, 
and oxidation of the methyl substituent on the methylpyridone. An additional pathway that 
involved direct N-linked glucuronide conjugation was observed in dogs. 
 
Excretion 
 
Excretion studies using 14C- merestinib were conducted following administration of a single oral 
or intravenous dose to rats and dogs. The majority of the dose was excreted in the bile or feces. 
Renal excretion was negligible.
 
Pre-Clinical Safety 
 
Merestinib was evaluated in one month daily oral dosing studies in rats and dogs (with 1 month
reversibility) at dose levels predicted to be biologically efficacious in humans, as well as at doses 
well in excess of those predicted to be biologically efficacious. In addition, a standard battery of 
safety pharmacology, genetic toxicity, and embryo-fetal development studies were performed. 
 
Daily administration of merestinib in rats caused non-formed feces at a tolerated dose level, 
which became more severe (liquid feces) at dose levels that exceeded the maximum tolerated 
dose (MTD). Target organ toxicity was observed at both tolerated and non-tolerated dose levels 
in both species. Target organ toxicities at tolerated dose levels included renal glomerulopathy, 
characterized by expansion of the renal glomerular mesangium. This change was observed in rats 
at all dose levels (primarily minimal to slight at the low dose, with increasing severity with
increasing doses), accompanied by minimal to slight proteinaceous tubular casts mainly at the


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high dose. This change was not reversible. Although there were no adverse functional effects
(based on clinical chemistry), this change might be predicted to lead to adverse effects on
glomerular function over time. However, similar effects were not observed in dogs. These
changes may be related to the anti-angiogenic effects of merestinib.
 
Additional target organ toxicities observed at tolerated dose levels included lymphoid organ 
necrosis, ovarian granulosa cell necrosis, bone physeal effects, bone marrow hypercellularity and 
increased myeloid-erythroid ratio, and testicular degeneration. Additional target organ toxicities 
observed at dose levels that exceeded the MTD included: adrenal gland congestion/hemorrhage; 
bone metaphyseal necrosis; myocardial degeneration/inflammation; vascular degeneration in the 
heart, gastrointestinal system, and pancreas; and male mammary gland necrosis. Merestinib also
causes complete post-implantation loss at higher dose levels in rats exposed during the period of 
organogenesis.  
 
Most of the toxicity observed in non-clinical species was reversible and is clinically monitorable: 
tremors, inflammatory leukogram, soft feces, lymphoid organ injury, adrenal gland injury, liver 
injury, and heart functional effects. The renal glomerular changes were not reversible; however, 
they did not have adverse functional consequences. The bone effects may be relevant only in 
growing bone (e.g., in children). Heart, vascular, and male mammary gland effects were only 
observed in a single species at dose levels well in excess of the MTD. Ovarian/testicular injury is 
a common toxicity observed with anti-cancer treatments. 
 
Pre-clinical Pharmacology 
 
The hepatocyte growth factor (HGF)/MET signaling pathway regulates a wide variety of normal 
cellular functions that can be subverted to support neoplasia including cell proliferation, survival, 
apoptosis, scattering and motility, invasion, and angiogenesis. For these reasons, merestinib was 
developed through a strategy of targeting the MET receptor. Additional biochemical and cell-
based assay testing have demonstrated that merestinib is a type II adenosine triphosphate
competitive inhibitor of 14 receptor tyrosine kinases (MET, MST1R [also known as RON], AXL, 
ROS1, PDGFRA, FLT3, MERTK, TYR03, TEK [also known as TIE2], DDR1, DDR2, NTRK1, 
NTRK2, and NTRK3) and two serine/threonine kinases (MKNK1/2). The two main circulating 
metabolites of merestinib (LSN2800870 and LSN2887652) found in both non-clinical studies in 
rats and dogs and the clinical Study JSBC were found to have similar kinase inhibitory activity 
as the parental compound in all the above targets when screened in vitro against a 456-kinase 
panel (DiscoveRx scanMax™). 
 
Merestinib inhibits autophosphorylation of the human MET receptor with a concentration 
producing 50% inhibition (IC50) of 0.2 µM and an inhibition binding constant (Ki) of 0.002 µM. 
It is a compound with a slow off-rate and a t1/2 of 525 minutes in vitro in a dissociation assay. 
Merestinib inhibits phosphorylation of MET in HGF-stimulated H460 lung cancer cells with IC50
of 0.035 µM. It also inhibits MET phosphorylation in an autocrine cell line S114 with IC50 of 
0.059 µM. Merestinib is active against 13 mutant forms of MET (Y1248C, D1246N, V1110I, 
M1268T, V1206L, L1213V, K1262R, M1149T, V1238I, S1058P, H1124D, G1137V, and 
H1112Y) with similar potency11. With the exception of S1058P, which is a mutation in the 
juxtamembrane domain, the remaining 12 mutations are in the MET kinase domain. 


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Merestinib demonstrates anti-angiogenic activity in vitro in human umbilical vein endothelial
cell (HUVEC) migration assays and endothelial cell cord formation assays.  
 
Merestinib demonstrates phospho-MET (p-MET) inhibition in nude mice bearing S114 xenograft 
tumors with a threshold effective dose of 50% inhibition (TED50) of 1.24 mg/kg, and a TED90 
(threshold effective dose of 90% inhibition) of 7.4 mg/kg. Sustained target inhibition (94% p-
MET inhibition) was observed at 8 hours after a single 120 mg/kg dose (TED95 [threshold
effective dose of 95% inhibition]). 
When dosed as a single agent, merestinib has demonstrated inhibition of tumor proliferation in 
U87MG glioblastoma, NSCLC (H441, A549, H1299, EBC-1), colon cancer (HT-29, HCT-116, 
KM-12, EL-1989), renal cell carcinoma (Caki-1, 786-0), MV4-11 acute myeloid leukemia, KP4 
pancreatic cancer, cholangiocarcinoma (EGI-1, SNU-869, SNU-1196, CTG-0011, CTG-0399), 
pediatric cancer (SJCRH30, RD-ES), and MKN45 gastric cancer xenograft tumor models 
following oral administration with either a daily or intermittent dosing regimen (9 days on, 5 
days off or 5 days on, 2 days off). Merestinib treatment also demonstrates anti-tumor activity in 
both the H441 and H1299 non-small cell lung orthotopic mouse models18. When studied in the 
H441 orthotopic model, merestinib reduced primary tumor growth and lymph node metastasis 
and was associated with a prolongation of survival in tumor-bearing animals.  
In addition to cell line-derived xenograft and orthotopic tumor models, merestinib demonstrated 
anti-tumor efficacy in human primary tumor-derived xenograft models of lung, pancreas, liver, 
breast, colorectal, cholangiocarcinoma (CCA), and kidney. Both KM-12 and EL-1989 bear the 
TPM3-NTRK1 fusion as a result of chromosomal translocation. In both cell line-derived and 
human primary tumor-derived animal models, merestinib demonstrated anti-tumor activity in 
tumors bearing both wild-type and activating mutations of KRAS. In MET-dependent xenograft 
models (autocrine MET activation or MET over expression), merestinib displayed anti-
proliferation effects on tumor cells and anti-angiogenesis effects on tumor vasculature. 
Combination treatment of merestinib with anti-vascular endothelial growth factor receptor 2 
(VEGFR2) antibody DC101 (a surrogate of ramucirumab) in xenograft models for gastric cancer 
(MKN45), pediatric cancer (SJCRH30, A204, Y79, RD-ES), and CCA (EGI-1, SNU-1196) 
resulted in further anti-tumor effect. 
 
Enzyme Inhibition 
 
The potential for drug-drug interactions (DDIs) was evaluated in vitro in human microsomes 
where merestinib exhibited a potential for competitive inhibition of CYP2C19, CYP2C9, and 
CYP2C8 yielding an apparent Ki of 0.97, 0.65, and 0.29 µM, respectively. The Ki for CYP3A4, 
CYP2D6, CYP2B6, and CYP1A2 were not calculated due to < 50% inhibition at the highest 
concentration tested (3 µM) in the assay. Merestinib was not tested at higher concentrations due 
to insolubility in the system at concentrations >3 µM. Since a steady-state Cmax in the range of 
502 ng/mL (0.9 µM) merestinib was observed in Study JSBA, there may be a potential for DDIs
when merestinib is co-administered at doses of 80 mg or higher with substrates of CYP2C19, 
CYP2C8, and CYP2C9.
 


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While initial screening data with merestinib suggested possible mechanism-based inhibition of
CYP3A4 (testosterone) and CYP2C9 at a concentration of 3 µM, a more rigorous assessment of
mechanism-based inhibition of CYP3A in the concentration range of 0.375 to 12 µM indicated 
that merestinib is not a time-dependent inhibitor of CYP3A. No mechanism-based inhibition was 
observed with CYP2D6, CYP2C19, CYP2C8, CYP2B6, or CYP1A2. 
 
Enzyme Induction 
 
The ability of merestinib to induce catalytic activities associated with CYP1A2, CYP2B6, and 
CYP3A was examined in primary cultures of fresh human hepatocytes. The results indicated that 
merestinib is unlikely to cause clinically relevant in vivo induction of CYP1A2, CYP2B6, or 
CYP3A within the concentration range examined (0.005 to 5 µM). 
 
Clearance 
 
A substrate depletion approach employing human recombinant CYPs indicated that CYP3A is 
responsible for 99% of hepatic clearance, and CYP1A2, CYP2B6, and CYP2J2 are each 
responsible for < 1% of hepatic CYP-mediated clearance of merestinib. The contributions of 
other non-CYP elimination pathways were not measured in this assay and must be accounted for 
when estimating total clearance and/or the potential for a co-administered drug to affect the 
clearance of merestinib. 
 
 
2.2.2 
Merestinib Clinical Studies 
As of 20 August 2015, a total of 166 patients in Study JSBA were treated with at least one dose 
of study drug. Merestinib has also been administered in a total of 28 healthy subjects (Studies
JSBC and JSBD).  
 
Human Pharmacokinetics 
 
Merestinib PK has been investigated with drug-in-capsule or enabled formulation at dose levels 
from 3 to 6 mg and from 5 to 240 mg, respectively. Pharmacokinetic interactions with 
concomitant drugs have not yet been assessed with merestinib. Data in patients from the first two 
cohorts in Study JSBA, who were dosed with the capsule formulation, indicated limited
absorption. To increase the bioavailability of drug, an enabled dosage form was introduced. Data 
from patients who received this formulation indicated that a significant increase in exposure was 
achieved compared to previous cohorts receiving the drug-in-capsule formulation.  
 
In a non-compartmental analysis comprising concentration data from 113 patients in Study JSBA 
through June 2015, observed Cmax and AUC0-24 hr indicate that exposure increases with dose of
the enabled formulation following single doses from 5 to 240 mg. The geometric mean of the 
oral apparent volume of distribution during the terminal phase (Vz/F) was 287 L (53% CV), and 
the apparent oral clearance (CL/F) was 19.3 L/h (36% CV), leading to a typical t1/2 of 10.3 hours 
(42% CV). Given the range of tmax, there is extensive variability in the rate of absorption and, in 
patients with cancer; variability in absorption and bioavailability contributes to the variability in 


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exposure. The mechanisms and covariates that may explain this variability (e.g., metabolism) 
remain under investigation. 
 
 
Table 4: Merestinib Non-compartmental PK Parameters Following First Dose, Study JSBA
 
 
Study JSBD was designed to investigate the relative bioavailability of a test formulation
compared to the reference formulation, as well as to investigate the effect of a high-fat meal on
the bioavailability of merestinib, administered as the test formulation. The PK analysis was
carried out with data from 23 individuals, and a comparison of fasted versus fed state (US Food 
and Drug Administration-defined high-fat meal) indicated a significant increase in bioavailability
of merestinib with concomitant food intake. 
Following administration of 120 mg merestinib in the fed state, geometric least squares mean 
merestinib AUC from time zero to the last measurable concentration after the first dose (AUC0-
tlast), AUC0- , and Cmax were, respectively, 2.29, 2.28, and 2.44 times that following 
administration of 120 mg merestinib in the fasted state, and these differences were statistically
significant. The median tmax of merestinib occurred 2 hours later in the fed states compared to the 


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fasted state. A similar increase in exposure was observed for the major metabolites. However, 
the mean merestinib exposures observed in the fasted state in Study JSBD was marginally lower 
compared to those observed at the same 120 mg dose level in Study JSBA (AUC0- 4930 
ng•h/mL vs. 6270 ng•h/mL, respectively), where a low-calorie meal was administered (minimum 
100 kcal). Study JSBD indicates that a high fat intake might enhance bioavailability of 
merestinib; however, the mechanism remains unclear.
 
Human Metabolism and Excretion 
 
The metabolic profile has been established in Study JSBC where healthy subjects (n=5) received
a 120 mg dose of merestinib containing approximately 100 µCi of radioactivity in the form of
14C-merestinib. The mean Cmax was 544 ng/mL (22% CV), the median tmax was 4 hours, and the 
mean t1/2 was 16.7 hours. The mean AUC0- was 6930 ng•h/mL (46% CV), which is similar to 
that observed in cancer patients who received a dose of 120 mg. Following Cmax, a secondary 
peak in total radioactivity was observed at approximately 10 hours in plasma and whole blood
(and also for merestinib and its metabolite, LSN2800870 in plasma), which may suggest
enterohepatic recirculation.  
The main route of elimination was in the feces with a total mean (± standard deviation [SD]) of 
96.2% (± 2.39%) of the dose excreted in the feces. Renal clearance is minimal (a mean [± SD] of 
2.8% [± 0.461%] of the radioactivity was excreted in urine through the last collection interval).
Only approximately 14% of the dose is excreted as intact parent drug which indicates absorption 
of merestinib is almost complete. A total of 14 circulating metabolites were detected across 
plasma, urine, and feces, with parent drug and major metabolites M1 (LSN2800870) and M2 
(LSN2887652) accounting for approximately 51%, 11%, and 18% of the circulating 
radioactivity, respectively. Merestinib is metabolized primarily through two routes, leading to the
N-desmethyl metabolite LSN2800870, the hydroxymethyl metabolite LSN2887652, and M6, a
product of both routes. These three metabolites account for 71% out of the 86% of the dose
recovered in feces and urine as metabolites. These metabolites are believed to express similar 
biological activity as parent drug, but the relative potency is currently under evaluation.
 
Clinical Safety – Serious Adverse Events 
 
As of 20 August 2015, a total of 57 serious adverse events (SAEs) in 37 patients have been 
reported. All were experienced by patients enrolled in Study JSBA. Six patients experienced a 
total of eight possibly study drug-related SAEs as assessed by the investigator or the sponsor. 
The events were graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) scale and included abdominal pain (grade 2), vomiting (grade 3), fatigue (grade 3), 
febrile neutropenia (grade 3), hyponatremia (grade 3), acute kidney injury (grade 3), and blood 
bilirubin increase (two events, both grade 3). 
 
 
 
 
 


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Table 5: Summary of SAEs in Study JSBA Considered Possibly Drug-Related
During Study JSBA 30 deaths have been reported; 27 were considered related to disease
progression. Three patients died due to AEs considered unrelated to the study drug (cardiac 
arrest, bacterial peritonitis, and liver failure). No study drug-related deaths have been reported in 
Study JSBA. No deaths occurred in Studies JSBC or JSBD. 
 
Dose-Limiting Toxicities and Maximum Tolerated Dose 
 
As of 20 August 2015, five dose-limiting toxicities (DLTs) were observed during the dose-
escalation phase (Part A) of study JSBA. All five were due to reversible grade 3 increases in
ALT and/or AST (1 of 10 patients at 120 mg, 2 of 12 patients at 160 mg, and 2 of 3 patients at 
240 mg). A dose of 120 mg by mouth daily has been declared the recommended phase II 
monotherapy dose.
 
Of the 69 patients treated in Part B, five patients experienced a reversible grade 3 ALT and/or 
AST increase. One additional patient with CCA, status post bile duct stent and right 
percutaneous biliary catheter drain, experienced a reversible grade 3 increase in bilirubin and 
grade 1 increases in AST/ALT and was included in the DLT list. After 8 days of merestinib (120 
mg), the patient was hospitalized with increased bilirubin and for persistent left duct dilatation. 
This patient was found to have a disease-related biliary tract obstruction which was treated with 
placement of a left biliary drain. The SAE was assessed by the investigators as related to the 
treated disease and possibly related to study drug treatment, since although the bilirubin level 
continued to improve, it did not return to baseline after drainage. The patient was removed from 
the study. 
 
In Part C of the study (merestinib in combination with cetuximab in patients with HNSCC), one 
patient out of 20 experienced a reversible grade 3 increase in ALT while receiving the 120 mg 
dose. In Part D of the study, testing began at a dose of 120 mg merestinib with cisplatin 25 
mg/m2. One of the three patients treated at this dose level experienced a grade 3 increase in blood 
bilirubin and testing shifted to subsequently enroll patients to a lower dose of merestinib (80 mg 
daily with 25 mg/m2 cisplatin). None of the 17 additional CCA patients who received the 80 mg 
dose were reported to have a DLT or DLT-equivalent event. 


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Based on available data, the increases in blood aminotransferase levels were reversible with
treatment interruption followed by either dose reduction or treatment discontinuation. 
Treatment-Emergent Adverse Events
Overall, 126 of the 166 patients (75.9%) treated in Study JSBA reported at least one treatment-
emergent adverse event (TEAE). Across all study parts and grades, the most frequent TEAEs 
 10% of patients and believed to be related to study drug treatment were fatigue 
(25.9%), ALT increase (22.9%), AST increase (21.1%), nausea (18.1%), vomiting (11.4%), limb 
edema (10.8%), and alkaline phosphatase increase (10.2%). 
 
 
Table 6: Treatment-Emergent Adverse Events Possibly Related to Merestinib Occurring in 
the Reduced Dose of 80 mg 
 
 
 
Three patients in Study JSBA discontinued treatment due to adverse events (AEs). These 
included AST increase, left ventricular systolic dysfunction, and blood bilirubin increase. The 
AE of left ventricular dysfunction occurred in the setting of antecedent concentric left ventricular 
hypertrophy in a patient who mistakenly increased his daily dose to a dose greater than was 
assigned. The AE of blood bilirubin increase in one patient occurred in the setting of a disease-
related biliary tract obstruction. Consequently, the investigator assessed this event as related to 
both the biliary tract obstruction and study drug treatment.
In Study JSBC, one subject reported 2 AEs that were considered to be related to study drug; 
these included headache and flatulence, which were both mild in severity. No subject 
discontinued the study because of an AE. 
 
In Study JSBD, of 23 subjects who received one or more doses of merestinib, nine TEAEs were 
reported that were related to merestinib as judged by the investigator. Overall, the most common 
TEAEs were headache (3 subjects), constipation (4 subjects), and raised liver enzymes, which 


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included ALT increase (3 subjects), AST increase (3 subjects), and GGT increase (2 subjects). 
All incidences of constipation and raised liver enzymes were considered to be related to study 
drug treatment, whereas the majority of headaches were considered to be unrelated. Most AEs 
were of mild severity with moderate AEs of ALT increase and AST increase reported in one 
subject each and one severe AE of ALT increase reported in one subject. Of the six patients who 
discontinued from the study, three discontinued due to AEs (elevated liver enzymes, chest 
discomfort, and elevated liver enzymes and increased platelet count), all of which (except
platelet count increase) were related to study treatment. During the course of the study, three 
subjects experienced AEs related to elevations in liver enzymes following treatment with
merestinib in the fed state, each of which were considered to be related to study treatment.
Efficacy
Due to the early phase of development of merestinib, comparative efficacy has not yet been 
demonstrated but will continue to be evaluated. In Study JSBA, 166 patients with advanced 
cancer have received merestinib. Among the 100 patients with measurable disease at baseline 
 120 mg, 33 have had a best overall response of stable disease, with a 
median duration of 126 days (minimum = 43 days; maximum = 485 days). One confirmed 
complete response has been observed among the relapsed or refractory CCA patients who have 
received merestinib as an 80 mg once daily dose in combination with cisplatin in Part D. Among 
the 6 first-line CCA evaluable patients in Part E, one partial response and two stable disease 
responses have been observed. 
 
 
2.3 
Rationale 
Identification of targetable genomic alterations in NSCLC has led to the development of 
effective small molecule inhibitors of mutated proteins such as EGFR, ALK, ROS1, and BRAF.  
Mutations in MET exon 14 occur in approximately 3% of NSCLCs7, and these cancers are 
sensitive to treatment with c-Met inhibitors such as crizotinib; however, there are no FDA-
approved drugs for this mutational subset of lung cancers.  Furthermore, mechanisms of 
resistance to these drugs have not yet been described, and it is not known if treatment with a 
different MET inhibitor can overcome resistance to drugs like crizotinib2-4,19,20. Merestinib is a 
potent oral MET inhibitor which has already been evaluated in a phase I clinical trial11,18,21.
 
Inhibition of the additional oncokinase targets of merestinib has the potential to demonstrate 
anti-cancer effects in non-MET mutated cancers as well. Rearrangements in NTRK have been 
described in lung cancer and other solid tumor malignancies, and these cancers appear to respond 
to NTRK inhibitors such as LOXO-101. Similarly, there are no approved agents for cancers with 
NTRK alterations and mechanisms of resistance to NTRK inhibitors have also not been 
reported8,22. 
2.4
Correlative Studies 
Fresh Tumor Tissue Biopsies 


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NSCLCs harboring somatic mutations in kinases are often sensitive to small molecule kinase 
inhibitors.  For example, crizotinib, an ALK/ROS1/MET inhibitor is approved for use in NSCLC
and has antitumor activity in NSCLCs with genomic alterations in ALK, ROS1, and MET. 
Unfortunately, the efficacy of these kinase inhibitors has been limited by the invariable 
development of acquired drug resistance. The identification of resistance mechanisms has been 
instrumental in the development of strategies aimed at preventing or overcoming resistance23.  In 
the case of ALK-rearranged NSCLC, a greater understanding of the various mechanisms of 
resistance to crizotinib has led to the approval of several next generation ALK inhibitors that are 
able to overcome resistance24.
In order to retrospectively explore the determinants of response and resistance to merestinib, a 
mandatory fresh tumor biopsy will be obtained from patients who enroll on trial who have 
received a prior MET or NTRK inhibitor. Biopsy samples will be submitted for Next Generation 
Sequencing (NGS) at the Center for Advanced Molecular Diagnostics (CAMD) at Brigham and 
Women’s Hospital to determine mechanisms of resistance to prior TKIs, including the 
development of alternate kinase domain mutations or bypass signaling tract activation. These 
results will be correlated with clinical outcome to investigate whether merestinib can overcome 
certain resistance mechanisms. This testing will further identify the characteristics of patients 
who respond to treatment with merestinib versus patients that do not, helping with future 
selection of patient populations appropriate for treatment with MET or NTRK inhibitor therapy. 
 
In addition, patients will be offered an optional biopsy at the time of progression if deemed safe 
and feasible by the treating investigator. This tissue will also be submitted for targeted 
sequencing and NGS to identify genetic mechanisms of resistance. The testing will help with 
both the creation and selection of future treatment strategies following the development of 
resistance to merestinib.  
 
Patients undergoing a biopsy either prior to starting merestinib or at the time of disease 
progression will be given the option to have tissue sent to the Dana-Farber Cancer Institute 
Translational Research Laboratory under the team of 
-
derived cell lines and mouse xenograft models. There are few available cell lines harboring MET 
exon 14 mutations or NTRK rearrangements. These patient-derived samples will be extremely 
valuable for testing various drugs or drug combinations both in vitro and in vivo. 
 
Quantitative Non-Invasive Genotyping 
 
Analysis of circulating free DNA for identification of activating mutations/rearrangements in 
MET and NTRK as well as resistance mutations will be conducted. This data will be correlated 
with clinical outcome to identify indicators of sensitivity or resistance. Using digital PCR 
techniques, the Belfer Center at the Dana-Farber Cancer Institute has designed methods to 
quantitatively evaluate the levels of circulating free plasma DNA. Tumor DNA is preferentially 
identified by selecting for key oncoproteins which would only be present in the tumor genome 
(such as activating mutations/rearrangements in MET or NTRK). Previously, this methodology 
was developed for important EGFR mutations (del 19, L858R and T790M), KRAS (four most 
common mutations), and BRAF (V600E). The Belfer Center has demonstrated that levels of 
tumor DNA will decline longitudinally over time if there is a response to the treatment 


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administered. To further assess this concept, plasma will be collected from participants to 
evaluate whether circulating free plasma DNA declines or increases with the administration of 
merestinib in MET and NTRK mutant/rearranged tumors in patients who either respond or 
progress on therapy. Plasma samples will also be evaluated for detection of possible resistance 
mutations (e.g., kinase domain mutations or bypass tract activation).
 
 
3. PARTICIPANT SELECTION
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with 
the exception of the informed consent and baseline tumor imaging which may be obtained up to 
28 days prior to the start of protocol therapy. 
 
3.1 
Eligibility Criteria
3.1.1
For enrollment into the MET cohort: Participants must have a histologically or 
cytologically confirmed advanced NSCLC and must have received at least one prior line 
of therapy in the metastatic setting.
3.1.2
For enrollment into the NTRK cohort: Participants must have a histologically or 
cytologically confirmed advanced solid tumor and must have received at least one prior 
line of therapy in the metastatic setting. 
 
3.1.3 Participants enrolling into the MET cohort must have a MET exon 14 mutation as 
confirmed by targeted NextGen Sequencing using the DFCI/BWH OncoPanel or another
CLIA-certified method. Participants whose NSCLC specimens contain actionable genetic 
mutations/alterations (e.g. ALK/EGFR) should receive appropriate targeted therapies 
prior to enrollment in the trial.
3.1.4
Participants enrolling into the NTRK cohort must have an NTRK1, 2, or 3 rearrangement 
as confirmed by targeted NextGen Sequencing using the DFCI/BWH OncoPanel or 
another CLIA-certified method. 
 
3.1.5 Participants 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  20 mm with conventional techniques 
or as  10 mm with spiral CT scan, MRI, or calipers by clinical exam.  See Section 11 for 
the evaluation of measurable disease. 
 
3.1.6 Participants enrolling to the MET cohort who have received treatment with a prior MET
inhibitor must be able and willing to undergo a baseline tumor biopsy.
3.1.7
Participants enrolling to the NTRK cohort who have received treatment with a prior 
NTRK inhibitor must be able and willing to undergo a baseline tumor biopsy.


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3.1.8
Age 
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.
3.1.9
ECOG performance status 
1 (see Appendix A). 
3.1.10 Participants must have normal organ and marrow function as defined below:
 
 
Absolute neutrophil count 
1.5 K/uL
 
Platelets  
100 K/uL
 
Hemoglobin
 
Total bilirubin
AST(SGOT)/ALT(SGPT)
2.5 
institutional ULN, unless liver metastases are
 
 
Serum creatinine
 
 
3.1.11 The effects of merestinib on the developing human fetus are unknown.  For this reason 
and because MET inhibitor 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 merestinib administration. 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document.
 
3.1.13 Participants must be able to swallow and retain oral medication or have an enteral feeding 
tube in place for study drug administration. 
 
3.1.14 Participants who have received prior oral tyrosine kinase inhibitors (TKIs) will be 
allowed on study if at least 5 half-lives have elapsed since the date of their last dose of 
TKI. 
 
3.2
Exclusion Criteria 
3.2.1
Participants who have had chemotherapy, immune therapy, other investigational therapy, 
major surgery, or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) 
prior to entering the study.
3.2.2
Participants who have not recovered to eligibility levels from adverse events due to 
agents administered prior to study entry. 
 
3.2.3
Participants who are receiving any other investigational agents.


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3.2.4
Participants with 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 
following the last date of 
treatment are permitted. Note: a brain MRI is required during the screening period. 
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to merestinib. 
3.2.6
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.
3.2.7
Pregnant women are excluded from this study because merestinib is an 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 merestinib, breastfeeding should be discontinued if the mother is treated with 
merestinib. 
 
3.2.8 Known HIV-positive participants are ineligible because 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. 
 
3.2.9 Participants enrolling to the MET cohort who have received a prior MET inhibitor may 
not be on anticoagulant therapy unless the investigator has deemed it safe to temporarily 
hold to facilitate the baseline tumor biopsy. 
 
3.2.10 Participants enrolling to the NTRK cohort who have received a prior NTRK inhibitor may 
not be on anticoagulant therapy unless the investigator has deemed it safe to temporarily 
hold to facilitate the baseline tumor biopsy. 
 
3.2.11 Participants with uncontrolled high blood pressure, defined as a blood pressure during 
s
 
 
3.2.12 Participants must not have any clinically significant gastrointestinal abnormalities that in 
the opinion of the treating investigator may alter absorption of oral medications, such as 
malabsorption syndrome or major resection of the stomach or bowels. 
 
3.2.13 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. 


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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 
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.   
 
5.
TREATMENT PLAN 
5.1
Treatment Regimen 
Participants will take merestinib at the recommended phase II dose of 120 mg by mouth daily. 
Patients will take merestinib continuously through the 28 day treatment cycle. 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 Section 6.  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 to 
non-target lesions when pre-approved by the principal investigator. Treatment with 
bisphosphonates will be permitted. 
 
Participants will be requested to maintain a study medication diary that will indicate each dose of 
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. 
 
 


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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 
co
1 day 1 and the screening laboratory values can be used as the cycle 1 day 1 values. 
 
5.2.2
Start of Subsequent Cycles 
To be eligible to begin subsequent cycles of treatment, toxicity considered at least possibly 
related to merestinib must have recovered
 or baseline. Management of specific 
toxicities considered at least possibly related to merestinib are outlined in Section 6.1. 
5.3
Agent Administration 
5.3.1
Merestinib 
Participants will take merestinib at the recommended phase II dose of 120 mg by mouth 
daily. Merestinib should be taken with food or within one hour of a meal. Doses of 
merestinib should be taken approximately 24 hours apart, there is a +/- 4 hour dosing 
window. Doses that would be outside of this time range should be considered missed and 
should not be taken. Vomited doses should not be retaken. Tablets of merestinib should 
be swallowed whole and should not be chewed or crushed (unless administered via 
feeding tube).
 
All persons should be instructed to wash their hands after handling the study drug tablets. 
 
Administration via Feeding Tube
 
Merestinib tablets may be prepared for administration per enterostomy feeding tubes. 
Tablets corresponding to the appropriate dose should be crushed with an Ezy Dose Tablet 
Crusher (or an equivalent device) and prepared into a slurry with the addition of 10 mL of 
water in the device. The resulting tablet slurry should be transferred to the feeding tube 
using a syringe ensuring that all contents are transferred. Crushing device and syringe 
should be flushed with additional small quantities of water (~25 mL). Rinsing may be 
repeated to ensure transfer of all tablet contents. The total volume of water used should 
not exceed 100 mL. Tablet slurry should be administered via the feeding tube within 4 
hours of slurry preparation. With use of this technique, non-clinical testing has 
demonstrated recovery of  97.6% of merestinib.  
 
Administration Guidelines 
 
Administration of merestinib may cause minor changes in heart rate and blood pressure. 


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During clinical study participation patients should be carefully monitored as described in 
the Study Calendar in Section 10. 
 
Due to the potential for changes in vasculature in actively growing bone observed in non-
clinical studies, careful monitoring of bone repair and healing may be warranted in 
individuals who incidentally develop bone fractures or injuries through trauma, surgery, 
or other means. 
 
 
5.4 
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.  
 
It is recommended that strong CYP3A4 inhibitors and inducers be avoided within 2 weeks before 
the start of study drug treatment and for the duration of trial treatment unless medically 
necessary. In addition, merestinib may increase the concentrations of P-gp substrates, and 
increased monitoring is recommended for patients taking digoxin. 
 
Based on the available non-clinical data, there is a possible risk of clinical DDIs when merestinib 
is co-administered with substrates of cytochrome P450 (CYP)2C8, CYP2C9, and CYP2C19. In 
the absence of more data to refine the risk of interaction, caution is warranted in the concomitant 
use of merestinib with CYP2C8, CYP2C9, and CYP2C19 substrates known to have a narrow 
therapeutic range (e.g., warfarin, phenytoin, tricyclic antidepressants, tolbutamide, etc.). When, 
in the clinical investigator’s opinion, concomitant use of these medications is indicated, use of 
these agents should be carefully monitored. 
 
The chemical structure of merestinib is consistent with the potential for photosensitivity. While 
photosensitivity has not been reported among patients who have received merestinib, patients 
should be advised to minimize or avoid exposure to strong sunlight, sunlamps, or other sources 
of ultraviolet radiation for long periods of time and are advised to use sunscreen and sunglasses. 
 
 
5.5 
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 events, treatment may continue 
indefinitely or until one of the following criteria applies: 
 
Disease progression (unless the participant is exhibiting clinical benefit as agreed 
upon with the principal investigator)
 
 
Intercurrent illness that prevents further administration of treatment
 
 
Unacceptable adverse event(s)
 


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Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
 
Participant decides to withdraw from the protocol therapy 
 
 
Pregnancy 
 
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/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 
Treatment/Off Study information in OnCore. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Mark Awad MD, PhD at 617-632-3468.
 
 
5.6 
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. 
 
 
5.7 
Criteria for Taking a Participant Off Study 
Participants will be removed from study when any of the following criteria apply:
 Lost to follow-up
 Withdrawal of consent for data submission 
 Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff.  


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For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
6.
DOSING DELAYS/DOSE MODIFICATIONS 
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 merestinib
will be made as indicated in the following tables:
 
Table 7: AST/ALT Management 
AST (SGOT) and/or ALT (SGPT) Increase
Merestinib Management
No change.
Grade 3, increase lasting less than 8 days
Hold study medication
grade 1 or baseline. Resume study medication 
at the same dose level.
Grade 3, increase lasting 8 or more days 
-OR-
Grade 4 
grade 1; resume study medication with one 
dose level reduction. 
AST and/or ALT > 3 × the institutional 
ULN AND 
institutional ULN
Permanently discontinue merestinib therapy.
As a precaution, patients with baseline elevation of hepatic transaminases or with increasing 
(compared with baseline) hepatic transaminases during merestinib therapy should be monitored 
closely for evidence of progressive hepatic injury and disease-associated biliary obstruction. In
addition, as merestinib is anticipated to be predominately metabolized by the liver with biliary 
excretion of its metabolites, patients with reduced hepatic function may exhibit decreased
clearance of merestinib. 
 
Table 8: Nausea Management
Nausea
Merestinib Management
No change.* Implement appropriate supportive 
care (e.g., antiemetics) as clinically indicated.
, not optimally managed 
Hold study medication and implement 
appropriate supportive care (including 
antiemetics and IV hydration if indicated). 
medication at the same dose level.


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optimally managed 
grade 2; resume study medication with one 
dose level reduction. 
*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 9: Management of Vomiting
Vomiting
Merestinib Management
No change.* Implement appropriate supportive 
care (e.g., antiemetics) as clinically indicated.
not optimally managed 
Hold study medication and implement 
appropriate supportive care (including 
antiemetics and IV hydration if indicated). 
 grade 1, resume study 
medication at the same dose level.
optimally managed 
grade 1; resume study medication with one 
dose level reduction. 
*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 10: Fatigue Management
Fatigue 
Merestinib Management
No change.* 
grade 2, resume study medication with one 
dose level reduction. 
*If a patient is experiencing intolerable grade 2 fatigue, 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 11: Management of Other Toxicity 
Other Toxicity 
Merestinib Management
rade 2
No change.* 


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grade 2, resume study medication with one 
dose level reduction. 
*If a patient is experiencing intolerable grade 2 toxicity, their study medication may be held at 
the treating investigator’s discretion. Upon resolution to grade 1 or baseline, the study 
medication can be dose reduced at the treating investigator’s discretion.
6.2
Treatment Delays
Participants who are benefiting from merestinib in the opinion of the treating investigator may 
have their study medication held for up to 4 weeks to allow for recovery of toxicity. Participants 
requiring a longer hold should be removed from the trial. Exceptions to this requirement are 
possible should the principal investigator agree that the patient may continue despite the length 
of time off drug. 
 
If the study medication is placed on hold for toxicity, the counting of cycle days and pre-planned 
assessment schedule will continue without interruption. For example, a patient who does not 
receive their cycle 3 day 15 – cycle 3 day 19 doses of merestinib due to toxicity would restart on 
cycle 3 day 20 and will proceed with their next regularly scheduled visit (cycle 4 day 1). 
Additional interim visits can be conducted as clinically necessary to manage toxicity; however 
once resolved, the cycle will not restart for dosing delays due to toxicity. Exceptions to this are 
possible after discussion with the principal investigator. 
 
 
6.3 
Dose Modifications 
A maximum of one dose reduction is allowed. If a patient requires more than one dose reduction, 
they should be removed from the trial. Once a patient’s dose has been reduced, it must be 
maintained at the reduced dose and it cannot be re-escalated. 
Table 12: Dose Modifications
Dose Reduction Level
Merestinib Dose
-1 
80 mg Daily
6.4
Overdose Management 
There is no known antidote for over-dosage of merestinib. In case of suspected overdose, 
monitor hematology, chemistry, and vital signs and give 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 (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 


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addition to routine reporting. 
 
7.1 
Expected Toxicities
7.1.1
Adverse Events List
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 2.2.2, in Table 6, and in the investigator’s 
brochure (IB). Fatigue has been the most frequent toxicity following treatment with merestinib, 
followed by elevation in hepatic transaminases.
Elevation in liver transaminases (AST and/or ALT) were noted to occur in patients at the highest 
tested dose levels of merestinib, and these events defined the upper range of dose testing. 
Although the grade 3 changes in transaminases tended to occur at higher exposures, no direct 
relationship between these events and merestinib exposure was noted. Of the 69 patients given 
merestinib at the recommended phase II dose in the monotherapy expansion of the phase I trial, 
eight patients experienced a reversible grade 3 ALT and/or AST increase. Based on available 
data, these changes were reversible with treatment interruption followed by either dose reduction 
or treatment discontinuation. 
For the purposes of suspected unexpected serious adverse reaction (SUSAR) reporting, there are 
no adverse drug reactions listed for merestinib; therefore any serious adverse event deemed 
related to merestinib will be reported as a SUSAR per local regulatory requirements.
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.
 
 For expedited reporting purposes only:   
- 
Expedited reporting of AEs for merestinib should be done only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided or if it fits under the definition of a Serious Adverse Event defined in 
Section 7.3. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.


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7.3
Serious Adverse Events
A serious adverse event (SAE) is any adverse event that occurs following the initiation of study 
treatment 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 (for 
example, for the administration of study therapy or other protocol-required procedure) should not 
be considered SAEs. Events that occurred prior to the first dose of study treatment should not be 
reported as 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 
patient participating in the study. The SAEs should be reported using a standard SAE reporting 
form (e.g. CIOMS form, Medwatch 3500a form, or similar). The SAE reports are to be sent to 
Eli Lilly via fax at 1-866-644-1697.
 
 
7.3.1 Investigators must report to the Overall PI any 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.  
 
 


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7.4
Expedited Adverse Event Reporting 
7.4.1
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 administered in 
this study can be found in Section 7.1. 
8.1
Merestinib (LY2801653) 
8.1.1
Physical and Chemical Characteristics 
Chemical Name: N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-
yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 
 
Chemical Structure: 


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Molecular Weight: 552.5 
 
Molecular Formula: C30H22F2N6O3 
 
Physical Description: White solid
 
pKa: 1.61 (in water) 
 
pH: 6.82 (water slurry at 2 mg/mL concentration)
 
Solubility: < 0.001 mg/mL in water 
 0.340 mg/mL in methanol 
 1.560 mg/mL in ethanol 
 
8.1.2 
Form 
Merestinib (LY2801653) is supplied for clinical trial use as tablets. The beige tablets are 
composed of merestinib and the inactive ingredients hydroxypropyl methylcellulose 
acetate succinate, microcrystalline cellulose, lactose monohydrate, croscarmellose 
sodium, sodium lauryl sulphate, colloidal silicon dioxide, magnesium stearate, and 
Opadry® II Tan. Each tablet contains merestinib equivalent to 40 or 80 mg of the base 
compound.  
 
In addition 40 mg blue nonagon tablets may be supplied that are composed of merestinib 
and the following inactive ingredients: silicon dioxide, croscarmellose sodium, 
hypromellose acetate succinate, mannitol, microcrystalline cellulose, sodium lauryl 
sulfate, sodium stearyl fumarate.  The proprietary color mix contains blue hypromellose, 
titanium dioxide, triacetin, and FD&C Blue 2 indigo carmine. 
 
8.1.3 
Storage and Stability 
 
Merestinib (LY2801653) is stable when stored at room temperature, defined as 
-
. 
 
The investigator or pharmacist will ensure that all investigational products are stored in a 
secure area, under recommended storage conditions and in accordance with applicable 
regulatory requirements. The site should monitor the minimum and maximum 
temperature and maintain temperature logs to confirm the correct storage of all 


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investigational products used in the trial. 
 
8.1.4 
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. 
Anyone who handles merestinib tablets should be instructed to wash their hands 
following contact.  
 
8.1.5 
Availability 
Merestinib (LY2801653) is an investigational agent that will be supplied by Eli Lilly and 
Company.
 
8.1.6 
Administration 
Participants will take merestinib at the recommended phase II dose of 120 mg by mouth 
daily. Patients will take merestinib continuously through the 28 day treatment cycle. 
Treatment will be given on an outpatient basis.
 
Merestinib should be taken with food or within one hour of a meal. Doses of merestinib 
should be taken approximately 24 hours apart, there is a +/- 4 hour dosing window. Doses 
that would be outside of this time range should be considered missed and should not be 
taken. Vomited doses should not be retaken. Tablets of merestinib should be swallowed 
whole and should not be chewed or crushed (unless administered via feeding tube, please 
see Section 5.3 for guidance on feeding tube administration). 
 
8.1.7
Ordering 
Drug supply will be ordered from Eli Lilly by site pharmacy personnel. 
 
8.1.8
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.) 
 
8.1.9 
Destruction and Return 
 
Expired supplies of merestinib 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 merestinib should also be destroyed according to 
institutional policies and destruction will be documented in the Drug Accountability 
Record Form.


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9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Exploratory Pharmacodynamic Tumor Biopsies
9.1.1
OncoPanel Testing (All Participants) 
A mandatory fresh tumor biopsy will be obtained from patients enrolling to the trial who have 
received a prior MET or NTRK inhibitor, as described in Section 2.4 – Correlative Studies. The 
biopsy is to be obtained at baseline (prior to the first dose of study medication). 
An optional biopsy will be offered at the time of disease progression if judged by the treating 
investigator to be safe and feasible. Preferably, time of progression biopsies should be obtained 
prior to the initiation of another cancer treatment. However, in the event that it is not possible to 
perform the biopsy before another treatment is begun, biopsies can be obtained up to 30 days 
after the last dose of merestinib. 
 
Whenever possible, core biopsy samples should be collected for analysis. Three-to-four biopsy 
passes utilizing a 16-18 gauge needle are preferable, but 20 gauge core needle biopsies are also 
acceptable at the discretion of the interventionalist performing the biopsy procedure.  
 
If a core biopsy is judged to be too unsafe or difficult for the participant in the opinion of the 
treating investigator, a fine needle aspirate (FNA) or cytology sample can also be collected. The 
goal for a thoracentesis or paracentesis procedure will be 500 – 1000 mL collected in a standard 
collection tube. The goal for an FNA will be three distinct passes. Less than the goal amount of 
tissue is acceptable for any of the biopsy collection methods, and should be based upon the 
clinical judgment of the treating investigator and the clinician performing the procedure. 
 
Handling of samples for NGS/OncoPanel testing:  
 Samples should be formalin-fixed and paraffin embedded (FFPE) per routine local 
procedures.  
 A minimum of 10 unstained slides and 1 H&E slide of 5 – 10 micron thickness should be 
labeled with the protocol number, study subject number, and the date of sample 
collection.  
 Blocks should not be sent to CAMD for analysis, blocks should be processed into slides 
prior to shipment. 
 Samples should be sent to the Center for Advanced Molecular Diagnostics (CAMD) at 
Brigham and Women’s Hospital for performance of the NGS with the specimen drop-off 
form: 
Center for Advanced Molecular Diagnostics
Brigham & Women's Hospital
Shapiro Cardiovascular Building 
70 Francis Street, 5th Floor
Boston, MA 02115 


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9.1.2
Optional Generation of Cell Lines and Xenograft Models (DFCI Participants Only)
  
Optionally and if enough tissue remains, one-to-two biopsy passes should be placed in PBS per 
standard procedures. The sample should be labeled with the protocol number, subject number, 
and the date of sample collection. The samples should be sent to the Dana-Farber Cancer 
Institute Translational Research Laboratory for generation of cell lines and xenograft models at: 
 
360 Longwood Avenue 
4th floor, LC-4101
Boston, MA 02215 
9.2
Plasma Genotyping Correlative Studies (All Participants) 
Plasma will be collected from patients at the following intervals: 
Anytime pre-dose on Cycle 1 Day 1
 
On the first day of each subsequent cycle* 
 
At the off study visit
*After completion of cycle 6, plasma can be collected on day 1 of every odd cycle – coinciding 
with restaging scan visits (i.e., Cycle 7 day 1, Cycle 9 day 1, Cycle 11 day 1, and so on). 
The exact date and time of every sample should be recorded.
Plasma collection protocol
NOTE: Time period from draw to freezing of plasma must be less than 3 hours. 
1. Draw venous blood into one (1) 10 mL EDTA tubes labeled CFDNA and immediately 
gently invert the tubes 8-10 times. Write the patient and draw date number on the tube.  
2. Immediately centrifuge for 10 minutes at 1500 (+\- 150) x g. NOTE: Brake switch must 
be off so the cell/plasma interface is not disturbed. 
 
3. Pipette the plasma layer into a 15 mL tube labeled “CFDNA/with patient #”. Do not ship. 
NOTE: Do not dip the tip of the pipette into the plasma/cell interface.  Leave a thin 
plasma layer intact over the interface. 
 
4. Centrifuge the 15 mL tube containing the plasma only for 10 minutes at 3000 (+/- 150) x 
g. 
 
5. Transfer using a fresh pipette, the supernatant into a second 15 mL tube labeled “CFDNA 
super.do not ship”. NOTE: Leave about 0.3 mL of supernatant in the centrifuged 15 mL 
tube. This leftover 0.3 mL contains cellular debris. 
 
6. Using a fresh pipette, transfer 1 mL of plasma from the “super.do not ship” tube into max 
four (4) 2 mL cryovials labeled CFDNA.ship.patient#/ 
 


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7. Freeze immediately upright at -70ºC or colder until shipping. 
 
Samples should be sent on dry ice to:
 
Julianna Supplee 
Translational Research Laboratory
Belfer Center for Applied Cancer Research 
360 Longwood Avenue LC-4202 
Boston, MA 02215 
617-582-8723 
Julianna_supplee@dfci.harvard.edu
10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with 
the exception of the informed consent 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. 
 
Table 13: Study Calendar
 
Pre- 
StudyA
Cycle 1 Day 1 
Cycle 1 Day 15B 
Cycles 2+  
Day 1C 
End of 
Treatment 
D 
Every 3 Months 
after 
DiscontinuingE 
Informed 
consent
X 
 
 
 
 
 
Demographics
X
 
 
 
Medical history 
X
 
 
 
Physical examF
X
X
X
X
X
 
Vital signsG
X
X
X
X
X
 
Height 
X
 
 
 
Weight 
X
X
 
X
X
 
ECOG 
performance 
status
X 
X 
 
X 
X 
 
CBC w/diff, plts
X
X
X
X
X
 
Serum 
chemistryH 
X 
X 
X 
X 
X 
 
Adverse event 
evaluation 
X----------------------------------------------------X 
X 
 
Radiologic 
evaluation 
X 
CT or MRI imaging of any disease-involved site. 
Radiologic measurements should be performed at 
X 
 


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Table 13: Study Calendar
 
Pre- 
StudyA
Cycle 1 Day 1 
Cycle 1 Day 15B 
Cycles 2+  
Day 1C 
End of 
Treatment 
D 
Every 3 Months 
after 
DiscontinuingE 
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 window on imaging evaluations.
Brain MRI
X
Repeat brain imaging as clinically indicated.
Serum -HCGI
X
X
MerestinibJ
X
X
Fresh Tumor 
BiopsyK
X 
 
 
 
X 
 
Plasma 
GenotypingL
X 
 
X 
X 
 
Telephone or 
Care Provider 
Contact 
 
 
 
 
X 
A.
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with the exception of the informed 
consent and baseline tumor imaging which may be obtained up to 28 days prior to the start of protocol therapy. 
B. 
Cycle 1 Day 15 has a +/- 3 day scheduling window to accommodate adverse weather, holidays, vacations, etc. 
C. 
The start of a subsequent cycle may be delayed by up to 7 days for scheduling issues (vacations, holidays, adverse weather, etc.). 
Following completion of cycle 6, at the treating investigator’s discretion clinic visits may occur every other cycle.  
D. 
End of treatment evaluation to be completed within 30 days of the last dose of study medication. Note: follow up visits or other 
contact is required in order to identify SAEs during the 30 days following the end of study treatment. 
E. 
Participants will be followed until death or withdrawal of consent after removal from protocol therapy. This follow up will be 
performed by review of the medical record, contact with care providers, and/or telephone contact as needed every 3-4 months. 
F. 
Routine physical exam. Screening physical exam should include a neuromuscular examination with focus on monitoring for 
tremors. 
G. 
Vital signs to include heart rate, blood pressure, temperature, respiratory rate, and oxygen saturation (O2 sat). 
H. 
Sodium, potassium, chloride, CO2, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, 
total bilirubin, SGOT [AST], SGPT [ALT], and globulin. Other tests may be ordered as clinically indicated. 
I. 
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). 
J. 
Merestinib to be taken daily as described in Section 5.3. Adequate supply should be dispensed at the beginning of each new cycle to 
accommodate any pre-planned scheduling delays. 
K. 
A fresh tumor biopsy is required at baseline from patients who have received prior therapy with a MET or NTRK inhibitor. An 
optional biopsy at the time of disease progression will be offered to any patient. Please see Section 9 for more detail. 
L. 
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 any time on the first day of each subsequent cycle (the exact time of the sample should be 
recorded) and at the off study visit. Please see Section 9 for more detail. 
11. MEASUREMENT OF EFFECT 
11.1
Antitumor Effect – Solid Tumors 
For the purposes of this study, participants should be re-evaluated for response every 
approximately every 8 weeks.  In addition to a baseline scan, confirmatory scans should also be 
obtained not less than 4 weeks following initial documentation of objective response. 


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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.
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.  
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 may 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.
 


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42 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
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 


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43 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
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), 


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44 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
MIBG (meta-iodobenzylguanidine).The following is recommended, to assure high 
quality images are obtained. 
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds.  
Images from the head to the distal lower extremities should be obtained.  
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
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. 


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45 
 
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. 
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. 


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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 
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. 
 
 
For 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-
No
SD
Documented at least once >4 


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47 
PD/not 
evaluated
wks from baseline**
PD 
Any
Yes or No
PD
no prior SD, PR or CR
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions
New Lesions
Overall Response 
CR
No
CR
Non-CR/non-PD 
No
Non-CR/non-PD* 
Not all evaluated
No
not evaluated 
Unequivocal PD
Yes or No 
PD 
Any 
Yes
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
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.  
 


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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 Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1
Data Reporting 
12.1.1 Method 
The Office of Data Quality (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 ODQ according to the schedule set by the ODQ.
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 


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49 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
13. STATISTICAL CONSIDERATIONS 
This is a single arm phase II study examining the anti-tumor activity of merestinib in patients 
with advanced cancer exhibiting a MET exon 14 mutation. The primary goal of the study will be 
to examine the ORR utilizing RECIST 1.1 criteria in patients harboring MET mutations 
following administration of merestinib. Secondary efficacy measures will include assessment of 
the safety and tolerability of merestinib in both MET and NTRK patients, as well as the OS rate, 
the PFS rate, and the DoR in patients with tumors harboring MET mutations.
 
A total of 14 patients with MET exon 14 mutations will be enrolled in the first stage of a Simon 
2-stage design. If three or more responses are observed an additional six patients will be 
enrolled, for a total of 20 patients. If two or fewer responses are observed among the first 14 
patients, the study will close for lack of efficacy.  Merestinib will be deemed promising if a total 
of four or more responses are observed among all 20 patients. This design has an 84% chance of 
stopping early under the null, and has an 86% power to detect a response rate of 32% while 
testing at the one-sided 0.10-level against the historical control rate of 10%. 
 
An additional 5 patients with an NTRK1, 2, or 3 rearrangement will be enrolled to a separate 
exploratory group. As NTRK rearrangements are rare and a large cohort may be difficult to fill, 
the initial substudy is planned to look at a small number of patients. If responses are observed, a 
larger multi-center study may then be undertaken. Additionally if the MET cohort is found 
promising and the cohort fills to capacity (20 patients) prior to the NTRK cohort filling, the 
remaining NTRK slots may be re-distributed to allow more participants to enroll to the MET 
cohort at the principal investigator’s discretion. For example, if 20 participants have enrolled to 
the MET cohort and the treatment is considered promising (with four or more responses) but only 
three participants have been enrolled to the NTRK cohort, the remaining two NTRK slots may be 
shifted to enroll an additional two participants with MET exon 14 mutations instead (bringing the 
total MET enrollment to 22). The intent behind this is to avoid difficulties with slow accrual 
prolonging the overall duration of the trial.  
 
The exploratory endpoints for the NTRK cohort will include the ORR, OS, PFS, and DoR in 
patients with advanced cancer harboring an NTRK rearrangement. Among this cohort of 5 
patients with NTRK rearrangements, if the cohort fills to capacity there is a 0.83 probability that 
we observe at least 1 response if the true but unknown response rate associated with merestinib is 
30%. In reality, if the associated response in this population is low (3%), then the probability that 
we observe at least 1 response in this cohort is low (0.14). 
 
For the analysis of the response efficacy measures among both the MET and NTRK groups, 


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50 
participants will be censored if they are alive and without disease progression at the date of the
last disease evaluation. In the case of OS, participants will be censored if they are living at the 
date last known alive. 
 
Statistical Analysis Plan for Correlative Studies: 
 
The role of the diagnostic specimen is identification of mutations for the purpose of enrollment 
onto this trial; however, when paired with genomic results obtained from the biopsy at 
progression, it is of interest to identify new alterations that were not present at baseline. Initial 
analyses of these data will utilize tests for association comparing the frequency of a particular 
genomic aberration at baseline and at progression (for example, using McNemar’s test) and 
association between alterations and baseline characteristics (for example, using Fisher’s exact 
test). More sophisticated analyses may include multivariable logistic regression modeling and/or 
competing risks analysis, however it is expected that analyzable results will not be obtained from 
100% of patients (either due to things like assay failure, inability to biopsy at progression due to 
poor patient health, etc).   
 
For the aims related to plasma genotyping and serial plasma collection, we may employ a variety 
of statistical techniques for the analyses of these data. The rate of change at a particular time 
point may be compared to baseline measures of cfDNA and that measure will be analyzed for 
association with patient demographics and/or disease characteristics using the Kruskal Wallis 
test. Landmark analyses of PFS and OS in which the landmark time is defined by the cfDNA 
measurements at a particular time point, may be used as well. Presence or absence of mutations 
in plasma will be analyzed for association with other variables using Fisher’s exact test. To 
account for the repeated measures of plasma over time, we may potentially use these data as time 
varying covariates in multivariable Cox models to study their impact on outcomes like PFS and 
OS.  
If at least 50% of patients (n=10) yield analyzable laboratory results, then this sample size 
provides 76% power to detect differences in the rate of another binary variable (such as baseline 
characteristics or abnormality) with frequencies of 5% and 70%, respectively, while testing with 
a one-sided 0.15-level Fisher’s exact test; this also assumes that the underlying prevalence of the 
genomic marker is 50%, thus splitting the cohort into two groups with 5 patients in each. It is 
worth noting that the Fisher’s test for association between the presence/absence of baseline 
samples and resistant samples assumes independence between those samples. Given what is 
known about tumor heterogeneity, the likelihood that the cancer may be altered genomically over 
time and due to therapy, and the low chance that the same area of a patient’s tumor will be 
biopsied at progression, we believe that independence could be an appropriate assumption. We 
will, however, explore results via sensitivity analysis using a McNemar’s test. 
 
 
13.1 
Study Design/Endpoints 
Primary Efficacy Measure: 
 
Investigate the ORR in patients with tumors exhibiting a MET exon 14 mutation.


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51 
Secondary Efficacy Measures: 
Evaluate the safety and tolerability of merestinib.
 
Determine the OS, PFS, and DoR in patients harboring MET mutations. 
Exploratory Endpoints: 
Explore the ORR, OS, PFS, and DoR in a small cohort of patients with advanced cancer 
harboring an NTRK1, 2, or 3 rearrangement.
 
Investigate the genomic determinants of response and resistance to merestinib by 
analyzing circulating free tumor DNA for identification of activating mutations in MET 
as well as for detection of resistance mutations.
Examine the mechanisms of resistance to prior TKIs via a pre-treatment biopsy obtained 
on patients enrolling to the trial who have received a prior MET or NTRK inhibitor.
 
Assess the genomic determinants of response and resistance to merestinib by analyzing 
tumor tissue obtained from patients at the time of disease progression. 
13.2
Sample Size, Accrual Rate and Study Duration 
The planned sample size is 20 patients in the single-arm phase II study of merestinib in patients 
with MET exon 14 mutations. An additional 5 patients will be enrolled into a separate 
exploratory NTRK cohort, for a total of 25 patients.  
 
The planned accrual rate is approximately 3 patients per quarter. Up to an additional year of 
follow-up will be required on the last participant accrued to observe the patient’s response and 
survival following study therapy, for a total study length of approximately three years. 
Participants will be identified for enrollment via targeted NextGen Sequencing using the 
DFCI/BWH OncoPanel or another CLIA-certified method for genotyping. 
 
Accrual Targets
Ethnic Category 
Sex/Gender
Females
Males
Total
Hispanic or Latino
1
+
1
=
2 
Not Hispanic or Latino 
11 
+
12 
=
23
Ethnic Category: Total of all subjects
12 
+
13  
=
25
Racial Category 
 
American Indian or Alaskan Native 
0
+
0
=
0 
Asian
0
+
0
=
0 
Black or African American
0
+
1
=
1 
Native Hawaiian or other Pacific 
Islander
0 
+
0 
=
0 
White
12 
+
12 
=
24
Racial Category: Total of all subjects
12 
+
13 
=
25
 
 
 


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52 
13.3
Analysis of Primary and Secondary Endpoints
The primary and secondary analyses will include all eligible patients who started assigned 
therapy. The exception to this includes the planned analysis of toxicity data, which will include 
all patients who received study drug regardless of eligibility. 
13.4
Analysis of Exploratory Endpoints
Analysis for the NTRK cohort will include all eligible patients who started assigned therapy.
The results of the NGS obtained on the fresh tissue biopsies and plasma will be compared to the 
clinical outcomes of the patients. It will help to further identify the genetic characteristics of 
patients who will respond to treatment with merestinib versus patients who will not, and whether 
merestinib is able to overcome certain resistance mechanisms in patients who have already 
received prior MET or NTRK inhibitors. This data may help with future selection of patient 
populations appropriate for treatment with MET inhibitor therapy. 
 
 
13.5 
Reporting and Exclusions 
13.5.1 Evaluation of Toxicity 
All participants will be evaluable for toxicity from the time of their first dose of study 
medication. 
 
13.5.2 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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Kong-Beltran M, Seshagiri S, Zha J, et al. Somatic mutations lead to an oncogenic 
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Awad MM, Oxnard GR, Jackman DM, et al. MET Exon 14 Mutations in Non-Small-Cell 
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Amplification and c-Met Overexpression. J Clin Oncol. 2016. 
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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.