Conditions: Non-Small Cell Lung Cancer
Keywords: Mirati MGCD265 MET NSCLC
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 68
Healthy volunteers: no

Brief summary:
MGCD265 is an orally administered receptor tyrosine kinase inhibitor that targets MET and other receptors. This study is a Phase 2 trial of MGCD265 in patients with locally advanced, unresectable or metastatic non-small cell lung cancer (NSCLC) that has activating genetic changes of the MET gene (mutation or amplification \[increase number of gene copies\]). Testing for tumor gene changes can be performed in tumor tissue or blood samples. Patients must have previously received treatment with chemotherapy. The number of patients to be enrolled will depend on how many enrolled patients experience tumor size reduction. MGCD265 will be administered orally, twice daily. The study is designed to evaluate whether the number of patients experiencing tumor size reduction is substantially higher than would be expected with other available treatments.

Detailed description:
If testing has not already been performed, the study will provide for the testing.

Arms:
arm 1: MGCD265 in patients with MET activating mutations in tumor tissue arm 2: MGCD265 in patients with MET gene amplifications in tumor tissue arm 3: MGCD265 in patients with MET activating mutations in blood (circulating tumor DNA) arm 4: MGCD265 in patients with MET gene amplifications in blood (circulating tumor DNA)

Interventions: intervention 1: MGCD265
Intervention descriptions: intervention 1: MGCD265 is a small molecule multi-targeted receptor tyrosine kinase inhibitor

Protocol document:
Prot_SAP_000.pdf: 
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CLINICAL RESEARCH PROTOCOL 
DRUG: 
MGCD265 
STUDY NUMBER(S): 
265-109 
PROTOCOL(S) TITLE: 
Phase 2, Parallel-Arm Study of MGCD265 in 
Patients with Locally Advanced or Metastatic 
Non-Small Cell Lung Cancer with Activating 
Genetic Alterations in Mesenchymal-Epithelial 
Transition Factor 
IND NUMBER: 
78394 
EUDRACT NUMBER: 
2015-002070-21 
SPONSOR: 
Mirati Therapeutics, Inc. 
9393 Towne Centre Drive, Suite 200 
San Diego, California, 92121, USA 
ORIGINAL PROTOCOL 
DATE: 
01 May, 2015 
VERSION NUMBER: 
V3.0 
VERSION DATE: 
23 March 2017 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This is a Mirati Therapeutics, Inc. document that contains confidential information.  It is intended solely 
for the use of the clinical Investigator(s) and other individuals involved in the study of MGCD265.  This 
document is not to be reproduced, abstracted, or quoted without written authorization from 
Mirati Therapeutics. 
 
 
 


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DOCUMENT HISTORY 
Document 
Version Date 
Summary of Changes 
Original Protocol, 
Version 1.0 
01 May 2015 
NA 
Protocol Amendment, 
Version 2.0 
17 May 2016 
• 
Added EUDRACT Number to protocol title page. 
• 
Updated protocol version and date. 
• 
Background information: 
o 
Updated clinical safety data from MGCD265 
clinical trials to be consistent with most recent 
version of Investigator’s Brochure. 
o 
Added Phase 1 safety and PK data using the SDD 
(spray-dried dispersion) tablet formulation of 
MGCD265 and compared to results using 
MGCD265 non-aqueous capsule formulation 
results. 
o 
Removal to trastuzumab as an example of a tyrosine 
kinase inhibitor. 
• 
Study population/patient eligibility: 
o 
Clarified prior receipt of at least one treatment to 
include a platinum-based chemotherapy regimen. 
o 
Reinforced and clarified text concerning collection 
and use of blood as well as tumor tissue to identify 
eligible tumor gene alterations.   
o 
Reinforced need for Sponsor approval of tumor 
genotyping laboratories. 
o 
Reinforced that patients entering the study based on 
Sponsor-approved local laboratory tumor 
genotyping using tumor tissue or blood must have a 
sample collected before dosing on study to submit 
for retrospective tumor genotyping by the central 
laboratory.  Results of the central laboratory test are 
not required prior to start of treatment on study.   
o 
Clarified that the exclusion criterion concerning 
prior positive EGFR mutation or ALK gene 
rearrangement requires known testing of patients 
with adenocarcinoma; testing for patients with 
non-adenocarcinoma is not required however, 
existing positive test is exclusionary. 
o 
Provided detailed list of tumor gene alterations 
qualifying for study entry (Section 7.1.1). 
o 
Updated list of central laboratories approved by 
Sponsor to perform tumor genotyping. 


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• 
Study objective:  Changed wording of primary objective 
from determination of the efficacy of MGCD265 to 
determination of tumor response to MGCD265 based on 
feedback from an ethics committee.   
• 
Region or country specific requirements added at 
request of Health Authorities or Ethics Committees: 
o 
Poland - screening pregnancy test must be 
completed within 7 days of Cycle 1, Day 1; Day 1 
(pre-dose) for all subsequent cycles and at the 28-
day follow up visit. 
o 
United Kingdom – screening pregnancy test must 
be completed within 7 days of Cycle 1, Day 1. 
o 
United Kingdom - pregnancy added as a criterion 
for discontinuation from study treatment. 
o 
European Union – contraception using condoms 
with spermicide is not an acceptable method for this 
study. 
• 
Assessments: 
o 
ctDNA – clarified that a sample should be collected 
at pre-screening for all patients, and additional 
samples may be requested if needed by the central 
laboratory.   
o 
PK – added unscheduled samples to be taken at 
least one week after any MGCD265 dose 
modification or change in study drug formation to 
strengthen population PK analysis. 
o 
PD – updated sample tubes from heparin to 
K2EDTA and, 5-mL to 10 mL vacutainers. 
o 
CT Scans – added CT of pelvis as required for 
routine disease evaluation (e.g., CT of chest, 
abdomen and pelvis at each assessment) to ensure 
sufficient evaluation to support central radiology 
review. 
o 
Bone Scans – clarified that one-half the frequency 
of other disease evaluations is equivalent to every 
12 weeks. 
o 
PET Scans – added guidance on limited role for use 
of PET scans in disease evaluations. 
o 
Triplicate ECGs – clarified two sets to be taken 
Cycle 1 Day 1 are to be within 30 minutes prior to 
dosing (e.g., at 15 minute intervals). 
o 
Single ECG – clarified this is done at end of 
treatment.   
o 
Lesion Flair Assessment – added a modification to 
RECIST 1.1 to allow suspension of conclusion of a 


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disease assessment until the outcome of an apparent 
tumor flair becomes clear.   
• 
Study Treatments: 
o 
Added details on formulation and packaging of both 
soft-gel capsule and SDD tablet formulations for 
MGCD265. 
o 
Added details on storage and stability of SDD tablet 
formulation. 
o 
Added starting dose and dose modification details 
concerning SDD tablet formation. 
o 
Amended the section regarding missed and vomited 
doses.  Missed doses may be allowed to be made up 
(not doubled up); but vomited doses should not be 
made up.   
o 
Added allowance to switch patients initially treated 
with soft-gel capsules to SDD tablets, at the 
discretion of the investigator. 
o 
Added expectation that ongoing food-effect 
evaluation may result in liberalizing fasting 
guidelines around dosing of MGCD265.  Any 
change in guidance will be communicated. 
• 
Concomitant Medications:  Reduced redundant text 
concerning use of anti-diarrheal medications. 
• 
Safety Reporting:  Added definition of Hy’s Law and 
guidance on patient management in such an event. 
• 
Study Analysis: 
o 
Changed mITT to include all patients that receive at 
least one dose of study treatment, eliminating 
caveats concerning specific eligibility criteria.  The 
option to replace patients and allowance for 10% 
non-evaluable rate based on these caveats were 
eliminated, adjusting the expectation for total 
enrollment from 320 to 290 patients, and 
corresponding adjustments per treatment arm.  This 
was modified throughout the protocol.   
o 
Further described the control of Type I error by use 
of the Bayesian designed applied to each study 
treatment arm separately. 
o 
Clarified evaluation of enrollment stopping rules 
with regard to inclusion of data under specified 
circumstances (e.g., exclusion from the denominator 
of patients just beginning treatment on study).  
Updated rules align with the IDMC Charter. 
o 
Added the possibility that the IDMC may elect to 
include only patients receiving the SDD formation 
in evaluating the enrollment stopping rules to 


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mitigate potential confounding effects from 
formulation change. 
• 
Addressed clerical errors and made minor clarifications 
of language. 
Protocol Amendment, 
Version 3.0 
23 Mar 2017 
• 
Updated protocol version and date. 
• 
Study Summary: 
o 
After discussion and acceptance by the Food and 
Drug Administration (FDA), the target population 
has been updated to include patients that have 
received either a platinum-based chemotherapy or 
licensed immunotherapy based on changing 
standard of care for first line therapy.   
o 
Added clarification that disease assessments must 
be based on a calendar schedule not cycle schedule.   
o 
Change cohorts from 1-4 to A-D for consistency 
with other study documents.   
• 
Schedule of Assessments: 
o 
Informed Consent - clarified that both pre-screening 
and full clinical screening consent must be obtained 
prior to entering full clinical screening.   
o 
Disease Evaluations – clarified the window for on-
study assessments are to start 6 weeks after dosing 
date (Cycle 1, Day 1).  Clarified that disease 
assessments should be done on a calendar schedule 
from first dosing.  Additional details provided on 
when brain and bone assessments need to be 
continued on-study (based on identification by 
investigator OR by the central radiology reviewer).   
o 
Adverse Events - additional details provided about 
reporting SAEs only to the safety vendor during the 
screening period.  The 28 day follow up as well as 
further survival follow up can be done via remote 
contact.   
o 
Long Term Follow up – clarified that long term 
follow- up is required every 2 months from the end 
of treatment visit.   
• 
Schedule for PK, Triplicate ECG, and PD Assessments: 
o 
Revised the table and footnotes to provide 
clarification and modifications on the timing of 
assessments for ECGs, PK and PD collections.   
• 
Introduction and Rationale: 
o 
Provided rationale to why immunotherapy has now 
been added to the eligibility requirement for prior 
therapy. 
 


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• 
Clinical Data: 
 
o 
Updated clinical data for single-agent studies with 
MGCD265 based on the revised Investigators 
Brochure. 
• 
Study Design: 
o 
Added clarification that disease assessments must 
be based on a calendar schedule not cycle schedule.   
o 
Changed cohorts from 1-4 to A-D for consistency 
with other study documents. 
• 
Inclusion Criteria: 
o 
Inclusion criteria #2 updated to include licensed 
immunotherapy as acceptable prior treatment.   
o 
Exclusion criteria #3 updated to include washout 
period for immunotherapy. 
o 
Exclusion criteria #8 updated to allow for a 2 week 
washout from stereotactic radiosurgery (gamma 
knife). 
• 
Study Treatment: 
o Formulation and Packaging – information regarding 
bottle size and tablet count have been removed from 
the protocol and will be detailed in the Pharmacy 
Manual.   
• 
Reporting of SAEs and AEs: 
o 
Reporting period - clarified that SAEs are reported 
from the time of main study informed consent.   
• 
References: 
o New reference added.   
• 
Addressed clerical errors and made minor clarifications 
of language. 


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STUDY SUMMARY 
Title:  
Phase 2, Parallel-Arm Study of MGCD265 in Patients with Locally 
Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with 
Activating Genetic Alterations in Mesenchymal-Epithelial Transition 
Factor (MET). 
Rationale:  
MET plays a central role in epithelial tissue remodeling and 
morphogenesis and is one of the most frequently dysregulated 
receptor tyrosine kinases (RTKs) in several human cancers.  
Oncology indications in which MET is reported to be genetically 
altered by mutation or gene amplification include lung, renal, 
colorectal, glioblastoma, gastric, and head and neck cancers.  MET 
mutations and/or gene amplification have recently been reported as 
part of the Cancer Genome Atlas program in approximately 7% of 
lung adenocarcinoma patients.  Furthermore, the expression of both 
MET and Hepatocyte Growth Factor (HGF), its sole, high-affinity 
ligand, was demonstrated to correlate with poor prognosis or 
metastatic progression in a number of major human cancers, 
including NSCLC.  Inappropriate activation of MET is involved in 
multiple tumor oncogenic processes such as cell growth, 
angiogenesis, invasive growth, and especially in the metastatic 
process.   
MGCD265 is a small molecule inhibitor of MET and Axl.  In vitro 
studies have demonstrated that MGCD265 is a potent inhibitor of 
tumor cell proliferation in cells where MET is overexpressed or 
activated, but not in cells that lacked MET expression/activation.  
These results are consistent with in vivo studies demonstrating 
activity of MGCD265 in human tumor xenograft-bearing mouse 
models including marked tumor regression in models exhibiting 
MET mutations and/or gene amplification.  Additionally, Axl 
dysregulation may contribute to tumor progression or further 
cooperate in drug resistance, and simultaneous inhibition of both of 
these targets may cooperate to overcome therapeutic resistance to 
selected anticancer agents. 
Target 
Population: 
Patients with locally advanced or metastatic NSCLC with activating 
genetic alterations of MET (mutations or gene amplifications), who 
have received at least one platinum-based chemotherapy or licensed 
immunotherapy regimen for advanced/metastatic NSCLC.   
Number in 
Primary Trial: 
Total enrollment up to approximately 290 patients  


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Primary 
Objective:  
• To determine the tumor response to MGCD265 in the selected 
patient population. 
Secondary 
Objectives: 
• To evaluate the safety and tolerability of MGCD265 in the 
selected population. 
• To evaluate secondary efficacy endpoints with MGCD265 
treatment in the selected population. 
• To assess correlation between selected tumor gene alterations 
using different analytical techniques in tumor tissue and 
circulating tumor deoxyribonucleic acid (ctDNA). 
• To assess change in genetic alteration status in ctDNA with 
MGCD265 treatment over time in the selected population.   
• To assess the population pharmacokinetics/pharmacodynamics 
(PK/PD) of MGCD265 in the selected population. 
Primary 
Endpoint 
• Objective Response Rate (ORR) as defined by Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). 
Secondary 
Endpoints 
• Safety characterized by type, incidence, severity, timing, 
seriousness and relationship to study treatment of adverse events 
and laboratory abnormalities. 
• Secondary efficacy endpoints: 
o Duration of Response (DR); 
o Progression-Free Survival (PFS); 
o 1-Year Survival Rate; and 
o Overall Survival (OS). 
• Gene alterations in tumor tissue and ctDNA at 
prescreening/baseline. 
• Change in ctDNA through time. 
• Blood plasma MGCD265 concentration. 
• Blood plasma concentration of selected soluble biomarkers. 
 
 


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Study Design: 
Study 265-109 is an open-label, parallel arm, Phase 2 trial evaluating 
the efficacy of MGCD265 in patients with locally advanced, 
unresectable or metastatic NSCLC exhibiting activating genetic 
alterations of MET. 
To be eligible for enrollment, patients must have documented 
evidence of a genetic alteration activating MET as determined by a 
Sponsor-approved central or local laboratory. 
The primary objective of the study is to determine the tumor 
response to MGCD265 as measured by ORR in accordance with 
RECIST 1.1.  Secondary objectives include evaluation of safety, 
secondary efficacy endpoints, genetic alterations in tumor tissue and 
ctDNA at pre-screening/baseline, change in ctDNA through time, 
and population PK/PD.  The Schedule of Assessments to be 
performed in the study is presented in Table 1, Table 2, and Table 3.   
MGCD265 will be administered as an oral therapeutic twice daily 
(BID) in 21-day cycles.  Guidelines for study drug administration 
and dose reduction in the event of toxicity are provided in the 
protocol.  Study treatment will continue until disease progression, 
unacceptable adverse events, patient refusal or death.   
Disease response and progression as documented by the investigator 
in the Case Report Form (CRF) will be the basis for patient 
management, study expansion decision making and secondary and 
supportive statistical analyses.  Central radiology review for disease 
response will be the basis for the primary statistical analyses to 
estimate the objective response rate and its confidence interval, as 
well as the duration of response and PFS.  The importance of timely 
and complete disease assessments in this study is critical for the 
efficacy endpoints.  The need to truncate treatment cycles to manage 
toxicity may result in inconvenient scheduling of disease 
assessments.  Disease assessments must be performed as scheduled 
according to the calendar to prevent the introduction of bias into the 
assessment of efficacy based on toxicity. 
This Phase 2, parallel-arm study will be conducted in four groups of 
patients having genetic tumor alterations activating MET:  
A. MET activating mutations in tumor tissue,  
B. MET gene amplifications in tumor tissue, 
C. MET activating mutations in ctDNA, and 
D. MET gene amplifications in ctDNA. 


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The Phase 2 study will use a Bayesian Predictive Probability Design 
(Lee-2008), applied separately and using the same assumptions in 
each treatment arm (see Statistical Considerations).  Emerging 
efficacy data will be evaluated continuously beginning after 
10 patients in each treatment arm have completed their first on-study 
disease assessment and are considered part of the Modified 
Intent-to-Treat (mITT) population (defined under Statistical 
Considerations).  Stopping rules for futility are described under 
Statistical Considerations.  Assuming the stopping rules are not 
triggered, the total sample size to be evaluated in each treatment arm 
of the Phase 2 study is 45 patients.  The primary analysis will be 
conducted in the mITT population.   
There is potential for one or more arms of the Phase 2 study to yield 
results indicating that MGCD265 should be considered to provide an 
important advancement in treatment in this setting of unmet medical 
need.  If emerging data indicate that an accelerated approval market 
application may be undertaken for MGCD265 for one or more of the 
selected patient populations, an analysis of the combined populations 
may be undertaken, or additional patients may be enrolled into the 
study, to increase the precision of the 95% confidence interval 
around the ORR endpoint and/or to increase the size of the safety 
database in the target patient population.  As many as 55 additional 
patients included in the mITT population may be enrolled in up to 
two treatment arms to ensure collection of sufficient data to support 
an accelerated approval market application.   
Considering the sample size planned for the four treatment arms in 
the Phase 2 study (45 patients each) and the possible addition of 
patients to prepare for market application in this setting (55 patients 
in each of two treatment arms), the ultimate sample size for this 
study could include as many as 290 patients.  Enrollment through the 
stages of this study will proceed without planned interruption while 
data are accruing.  Decisions will be made expeditiously by the 
Internal Data Monitoring Committee to prevent excessive 
over-enrollment and include only outcomes among the specified 
number of patients according to the stopping rules. 
Statistical 
Considerations 
This Phase 2, parallel-arm study will use a Bayesian Predictive 
Probability Design (Lee-2008) that minimizes the number of patients 
enrolled to test the hypothesis.  The design will be applied separately 
and using the same assumptions in each of four treatment arms.   


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ORR in accordance with RECIST 1.1 is the primary endpoint.  With 
currently available treatments, ORR is assumed to be 20% (p0); thus 
this rate is considered uninteresting.  The target ORR using 
MGCD265 in this study is 40% (p1).  The trial will monitor the 
number of observed responses continuously after evaluating the first 
on-study disease assessments of the first 10 patients in each 
treatment arm in the mITT population.  In creating the statistical 
design, the Type 1 error (α) is constrained to < 0.05 and Power (1-β) 
is constrained to ≥ 0.90. 
Using the parameters identified, the ultimate sample size for each 
treatment arm is as many as 45 patients in the mITT population.  The 
stopping rules (rejection regions), expressed as number of responses 
per patients treated, are 0/10, 1/14, 2/18, 3/22, 4/26, 5/29, 6/32, 7/35, 
8/37, 9/39, 10/41, 11/43, 12/44, and 13/45.  Thus, if more than 
13 responses are observed among the first 45 patients enrolled who 
meet the criteria for the mITT population, the drug will be declared 
efficacious.  If the true ORR is 20% (null hypothesis), the probability 
of early termination during the study is 0.92, and the expected 
sample size prior to termination is 28 patients; the Type 1 error equal 
to 0.0499 and Power equal to 0.9065.  If the true ORR is 40% and 
N=45, the exact 95% confidence interval (Clopper-Pearson) around 
the point estimate for ORR will be (25.7; 55.7).   
If the outcome is promising and the option is taken to enroll an 
additional number of patients up to 100 in the mITT population in a 
specific treatment arm to increase the size of the safety database and 
narrow the confidence interval around the ORR point estimate, the 
95% confidence interval around a true ORR of 40% will be (30.3; 
50.3).  Data collected in patients enrolled beyond the planned Phase 
2 sample size will be used in secondary and supportive analyses. 
For the purpose of making decisions for continued enrollment and 
for conduct of the final analysis for the Phase 2, the mITT population 
is defined as all patients who receive at least one dose of MGCD265. 
 


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Table 1: 
Pre-screening Assessments 
To establish potential eligibility for future enrollment into Study 265-109, pre-screening for tumor genotype may be performed in 
advance of anticipated clinical screening for study entry, e.g., during treatment with chemotherapy required prior to study entry.   
 
Guidance 
Informed Consent for Tumor Genotyping Pre-screening 
Informed consent must be obtained prior to sending tumor tissue or blood for 
Sponsor-approved local or central laboratory genotyping.  The informed consent form and 
process may be performed in accordance with documented institutional practice or using 
the study-specific, IRB-approved pre-screening ICF.  An IRB/EC approved process for 
obtaining consent from patients who are remotely located may be used. 
Tumor Tissue Genotyping for MET Gene Alteration 
Testing Samples from the most recent biopsy or excision are preferred; however if no 
recently obtained materials are available, samples from any time during patient’s prior 
disease course are accepted.  If study enrollment is based on Sponsor-approved local 
laboratory results, a tumor tissue sample for confirmatory testing by the central laboratory 
is expected to be available. 
Circulating Tumor DNA Genotyping for MET Gene Alteration 
Samples consisting of two 10 mL tubes of whole blood are collected in Streck brand 
Cell-Free DNA Blood Collection tubes allowing shipping and stability at ambient 
temperatures. 
Evaluation of overall health status for future clinical trial 
participation 
Study eligibility requires adequate performance status and organ function.  Patients 
undertaking pre-screening for tumor /genotype with the goal of considering Study 265-109 
should have health status consistent with meeting eligibility criteria in the future when they 
may become a candidate for the study. 
 
 
 


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Table 2: 
Schedule of Assessments – During Study 
The Schedule of Assessments provides an overview of the protocol visits and procedures.  Refer to Section 7 for detailed information 
on each assessment.  Additional, unplanned assessments should be performed as clinically indicated, including for the purpose of fully 
evaluating adverse events. 
Assessments 
Screen/ 
Baseline 
Cycle 1 
Cycle 2 
≥ Cycle 3 
End of Treatment14 
Within  
28 days 
Day 1 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
Day 15 
(± 2 days) 
Day 1 
(± 2 days) 
End of 
Treatment/ 
Withdrawal 
Post 
Treatment 
Follow Up 
Study Participation Informed 
Consent1 
Before study 
specific assessments 
 
 
 
 
 
 
 
Tumor Tissue for 
Genotyping2 
X 
 
 
 
 
 
 
 
Medical History, Disease 
History, Prior Therapy  
X 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
 
 
 
 
X 
 
Abbreviated Physical Exam3 
 
X 
X 
X 
X 
X 
 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test5 
X 
As clinically indicated 
Hematology6,7 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation6,7 
X 
As clinically indicated 
 
Serum Chemistry6,7 
X 
X 
X 
X 
X 
X 
X 
 
PK Sampling8 
 
X 
X 
X 
X 
 
 
 
PD Sampling9 
 
X 
X 
X 
X 
 
 
 
ctDNA10 
X 
 
 
At assessment for confirmation of disease response 
(PR or CR) 
X 
 
12-Lead ECG11 
X 
X 
X 
X 
 
 
X 
 
Disease Evaluation12 
X 
Q 6 weeks until Week 49 (~1 year) and then Q 12 weeks 
 
Study Treatment Dispensing 
and/or Reconciliation 
 
X 
 
X 
 
X 
 
 
Adverse Events13 and 
Concomitant Medications 
SAEs only 
Throughout 
Long Term Follow-Up15 
 
 
 
 
 
 
 
X 
Footnotes located on the following page. 


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1. 
Study Participation Informed Consent (ICF): May be performed prior to 28 days before first dose of study treatment.  Patients entering full clinical screening must have both 
the pre-screening ICF as well as the clinical screening ICF signed.  
2 
Tumor Tissue for Genotyping: Collection of tumor tissue may occur well prior to the study screening period (See Table 1).  The informed consent process may be performed 
in accordance with documented institutional practice or using the study-specific, IRB-approved pre-screening ICF.  Tumor tissue samples preferred for testing are the most 
recent tumor sample available; however, testing may be performed on samples taken any time during the disease course.  Testing may be performed on primary, recurrent, or 
metastatic lesions.  If study enrollment is based on Sponsor-approved local laboratory results, a tumor tissue sample for retrospective confirmation by the central laboratory is 
expected to be available and to be collected prior to dosing.   
3 
Physical Examinations: A complete physical examination required at Screening and End of Treatment only.  Height will be recorded at screening only.  All other evaluations 
will be symptom-directed, abbreviated evaluations. 
4 
Vital Signs: Weight, temperature, blood pressure, respiratory rate, and pulse rate to be assessed prior to dosing as indicated. 
5 
Pregnancy Test: If the patient is a woman of childbearing potential, negative serum or urine pregnancy test performed by the local laboratory at screening will be required.  
The informed consent process must include discussion of the risks associated with pregnancy and adequate contraception methods.  Additional pregnancy testing may be 
necessary if required by local practices or regulations, or if potential pregnancy is suspected. For patients enrolled in the United Kingdom, a pregnancy test must be completed 
within 7 days of Cycle 1 Day 1 (as part of screening or a repeat test).   For patients enrolled in Poland, a pregnancy test must be completed within 7 days of Cycle 1 Day 1 
(as part of screening or a repeat test), Day 1 (pre-dose) for all subsequent cycles and at the 28-day follow up visit.  
6 
Indicated Cycle 1, Day 1 Assessments: Repeat assessment on Cycle 1, Day 1 not required if screening assessment performed within 7 days before the first dose.   
7 
Safety Laboratory Assessments: Hematology, coagulation, and chemistry evaluations will be performed by local laboratories.   
8 
PK Sampling: Samples to be taken following vital signs and electrocardiograms (ECGs).  See Table 3 for details of timing related to ECGs.  In the event of significant 
toxicities or withdrawal due to toxicity, an additional unscheduled PK blood sample should be drawn as soon as possible. In the event of a dose modification or formulation 
change, an additional unscheduled PK sample should be drawn at least one week after the modification or change.  Each PK blood sample will consist of a 4 milliliter (mL) 
whole blood draw collected in one 6-mL K2EDTA tube. 
9 
PD Sampling: Samples to be taken as detailed in Table 3.  Each PD sample will consist of whole blood draw collected in one 10-mL K2EDTA tube. 
10 ctDNA: Collection of ctDNA for eligibility purposes may occur well prior to the study screening period (See Table 1).  The informed consent process may be performed in 
accordance with documented institutional practice or using the study-specific, IRB-approved pre-screening ICF.  If study enrollment is based on prospective testing by the 
central laboratory, an additional sample may be requested prior to dosing to ensure enough material is available for all protocol defined analyses.  If study enrollment is based 
on Sponsor-approved local laboratory results, a ctDNA sample for retrospective confirmation by the central laboratory is expected to be available and to be collected prior to 
dosing. On-study samples to be taken at the time of disease assessment to confirm response (PR or CR) and at End of Treatment visit.  Samples consisting of two 10mL tubes 
of whole blood collected in Streck brand Cell-Free DNA Blood Collection tubes allowing shipping and stability at ambient temperatures. 
11 ECGs: Assessments will include an evaluation of rhythm, heart rate, and PR, QRS, QT, and QTc intervals.  Single ECG to be performed at screening and at the end of 
treatment visit.  Triplicate ECGs at Cycles 1 and 2 as described in Table 3.   
12 Disease Evaluations: To be performed at screening (28-day window allowed) and every 6 weeks from dosing date [Cycle 1, Day 1] (-7/+10 days window allowed for first 
on-study assessment, ± 10 days window for all other assessments) until Week 49 (~1 year) and then every 12 weeks.  All on-study disease assessments should be based on a 
calendar schedule beginning from the first day of dosing.  In general, assessments at screening/baseline as well as on-study are to include Computed Tomography (CT) scan 
with contrast or Magnetic Resonance Imaging (MRI) of the chest abdomen and pelvis.  In addition, at screening/baseline, a MRI with and without gadolinium or CT with 
contrast of the brain, a whole-body bone scan and evaluation of any superficial lesions will be performed.  Subsequent disease assessments should also include whole body 
bone scans and/or MRI of the brain if metastatic disease is identified at screening/baseline by either the investigator OR the central radiology reviewer.  Bone scans may be 
performed at one-half the frequency of other radiology evaluations (every 12 weeks) and should be performed during assessment for confirmation of disease response.  All 
scans will be sent to the central radiology reviewer.  More detailed guidance on exceptional circumstances is provided in the protocol (Section 7.3).   


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13 Adverse Events: SAEs are to be reported from the time of informed consent for study participation (i.e., excluding prescreening informed consent) until resolution of all SAEs 
observed on study (SAEs occurring during the screening period are only reported to the safety vendor).  Adverse events will be reported from the first day of study treatment 
until at least 28 days after last dose of study drug, and until resolution or stabilization of acute AEs and/or ongoing SAEs.  Post-treatment 28-day follow-up and beyond may 
be performed by remote contact (e.g., telephone call).   
14 End of Treatment: Assessments that have been completed in the previous 3 weeks do not need to be repeated (6 or 12 weeks for tumor assessments in accordance with 
schedule).   
15 Long Term Follow-up: Survival status and subsequent therapies will be collected by telephone contact every 2 months (±14 days) from end of treatment visit until death or 
lost to follow-up. 
 
 


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Table 3: 
Schedule of PK, Triplicate ECG, and PD Assessments 
 
Cycle 1, Days 1 and 15 (± 2 days Day 15 only) 
Cycle 2, Days 1 or 15 (± 2 days) 
Collection Time and  
Allowable Window 
Pre-dose 
2 hour  
(1-3 hour) 
6 hour 
(4-8 hour) 
Pre-dose 
(-0.5-0 hour) 
6 hour 
(4-8 hour) 
Triplicate ECG  
X 
(-1 - 0 hour) 
X 
(-0.5-0 hour) 
X 
X 
X 
X 
PK Sample  
X 
(-0.5-0 hour) 
X 
X 
X 
X 
 
Cycle 1, Days 1 and 15 (± 2 days Day 15 only) 
Cycle 2, Days 1 and 15 (± 2 days) 
Collection Time and 
Allowable Window 
Pre-dose 
(-0.5-0 hour) 
Pre-dose 
(-0.5-0 hour) 
PD Sample 
X 
X 
• 
On Cycle 1, Day 1 Pre-dose, two sets of triplicate ECGs should be done to firmly establish the baseline for the patient.   
o 
Example:  ~1.0 hr (Triplicate ECGs); ~30 mins (Triplicate ECGs); ~15 mins (Vitals/PK) 
• 
Vital signs should be assessed prior to blood sampling. 
• 
ECGs should be taken in triplicate, each reading approximately 2 minutes apart.   
• 
In Cycle 2, Pre-dose and 6 hour samples may be collected on either Day 1 or Day 15.  Flexibility has been provided so if samples are missed on Day 1, they 
can be done on Day 15 (pre-dose and/or 6 hour).  Steady-state exposure is expected, so samples should be representative regardless of when they are 
collected.   
• 
If the MGCD265 dose is taken before arrival in the clinic, special care is needed to collect the exact dosing time from the patient. 
• 
In the event of significant toxicities or withdrawal due to toxicity, an additional unscheduled PK blood sample should be drawn as soon as possible.  In the 
event of a dose modification or formulation change, an additional unscheduled PK sample should be drawn at least one week after the modification or 
change.   
 


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TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ..........................................................................1 
DOCUMENT HISTORY ..................................................................................................2 
STUDY SUMMARY ..........................................................................................................7 
TABLE OF CONTENTS ................................................................................................17 
TABLE OF TABLES .......................................................................................................20 
LIST OF ABBREVIATIONS .........................................................................................21 
1 
INTRODUCTION AND RATIONALE .................................................................24 
1.1 
Disease and Therapeutic Strategy ...............................................................24 
1.1.1 
Non-Small Cell Lung Cancer .....................................................24 
1.1.2 
Tyrosine Kinase Inhibitors ........................................................25 
1.1.3 
Dysregulation of Receptor Tyrosine Kinases in Cancer .........25 
1.1.4 
Tumor Gene Sequencing Using Blood Plasma .........................27 
1.2 
MGCD265 ......................................................................................................28 
1.2.1 
Drug Substance ...........................................................................28 
1.2.2 
Non-Clinical Data .......................................................................28 
1.2.3 
Clinical Data ................................................................................28 
1.3 
Study Rationale .............................................................................................31 
2 
STUDY OBJECTIVES ............................................................................................31 
2.1 
Objectives ......................................................................................................31 
2.1.1 
Primary Objective ......................................................................31 
2.1.2 
Secondary Objective ...................................................................32 
2.2 
Endpoints .......................................................................................................32 
2.2.1 
Primary Endpoints .....................................................................32 
2.2.2 
Secondary Endpoints ..................................................................32 
3 
STUDY DESIGN ......................................................................................................33 
4 
SUBJECT SELECTION AND ENROLLMENT ..................................................35 
4.1 
Inclusion Criteria ..........................................................................................35 
4.2 
Exclusion Criteria .........................................................................................36 
4.3 
Life Style Guidelines .....................................................................................37 
4.4 
Enrollment into Study ..................................................................................38 
5 
STUDY TREATMENT ............................................................................................38 
5.1 
Study Drug Management .............................................................................38 
5.1.1 
Formulation and Packaging .......................................................38 
5.1.2 
Drug Storage and Accountability ..............................................39 
5.1.3 
Preparation and Dispensing .......................................................39 
5.1.4 
Compliance ..................................................................................40 
5.1.5 
Destruction ..................................................................................40 
5.2 
Administration ..............................................................................................40 
5.2.1 
Dose Modification .......................................................................41 
5.2.2 
Adverse Event Management Guidelines ...................................41 


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5.2.2.1 
Management of Diarrhea ........................................42 
5.2.2.2 
Management of Increased Transaminases ............42 
5.2.2.3 
Management of Hy’s Law Cases ............................43 
5.3 
Medication Error ..........................................................................................43 
5.4 
Concomitant Therapies ................................................................................43 
5.4.1 
Concomitant Medication(s) ........................................................43 
5.4.2 
Concomitant Surgery or Radiation Therapy ...........................44 
5.4.3 
Other Anticancer or Experimental Therapy ...........................44 
6 
STUDY ASSESSMENTS .........................................................................................44 
6.1 
Screening .......................................................................................................44 
6.2 
Study Period ..................................................................................................45 
6.3 
End of Treatment Assessment .....................................................................45 
6.4 
Long-Term Follow-up and End of Study Assessment ...............................45 
6.5 
Patient Discontinuation/Withdrawal ..........................................................45 
7 
PROCEDURES .........................................................................................................46 
7.1 
Molecular Testing for MET Mutations and Amplifications .....................46 
7.1.1 
Genetic Tumor Alterations Required for Study Entry ...........46 
7.2 
Molecular Testing Methods .........................................................................48 
7.3 
Efficacy ..........................................................................................................49 
7.4 
Safety Assessments ........................................................................................51 
7.4.1 
Adverse Events ............................................................................51 
7.4.2 
Physical Examination and Vital Signs ......................................51 
7.4.3 
Laboratory Safety Assessments .................................................51 
7.4.4 
Electrocardiogram (ECG) ..........................................................52 
7.5 
Laboratory Studies .......................................................................................52 
7.5.1 
Pharmacokinetic Evaluation......................................................53 
7.5.2 
Pharmacodynamic Evaluation ..................................................53 
7.5.3 
Circulating Tumor DNA ............................................................53 
7.6 
Post-treatment Follow-up ............................................................................54 
8 
ADVERSE EVENT REPORTING .........................................................................54 
8.1 
Sponsor Medical Monitor Personnel ..........................................................54 
8.2 
Adverse Events ..............................................................................................54 
8.2.1 
Laboratory Abnormalities .........................................................55 
8.2.2 
Severity Assessment ....................................................................55 
8.2.3 
Causality ......................................................................................55 
8.3 
Serious Adverse Events ................................................................................56 
8.3.1 
Definition of a Serious Adverse Events .....................................56 
8.3.2 
Exposure During Pregnancy ......................................................57 
8.4 
Reporting of SAEs and AEs .........................................................................58 
8.4.1 
Reporting Period .........................................................................58 
8.4.2 
Reporting Requirements ............................................................58 
9 
STATISTICS .............................................................................................................59 
9.1 
Hypothesis and Sample Size ........................................................................59 
9.2 
Data Handling ...............................................................................................60 
9.3 
Analysis Populations .....................................................................................60 


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9.3.1 
Modified Intent-to-Treat Population ........................................60 
9.3.2 
Safety Population ........................................................................60 
9.3.3 
Molecular Marker Evaluable Population .................................60 
9.3.4 
Pharmacokinetic Evaluable Population ...................................61 
9.3.5 
Pharmacodynamic Evaluable Population ................................61 
9.4 
Efficacy Endpoint Definitions and Analyses ..............................................61 
9.4.1 
Objective Response Rate ............................................................61 
9.4.2 
Duration of Response .................................................................61 
9.4.3 
Progression Free Survival ..........................................................62 
9.4.4 
Overall Survival ..........................................................................62 
9.5 
Safety Data Presentations and Summaries .................................................62 
9.5.1 
Adverse Events ............................................................................62 
9.5.2 
Prior and Concomitant Medications .........................................62 
9.5.3 
Clinical and Laboratory Assessments .......................................62 
9.5.4 
Patient Demographics, Baseline Characteristics and 
Disposition ...................................................................................63 
9.5.5 
Analysis of MGCD265 Dosing ...................................................63 
9.6 
Other Study Endpoints.................................................................................63 
9.6.1 
Pharmacokinetic/Pharmacodynamic Analysis ........................63 
9.6.2 
Gene Alterations in Tumor DNA ..............................................64 
9.7 
Interim Analysis ............................................................................................64 
9.8 
Internal Data Management Committee ......................................................64 
9.9 
Evaluation of Enrollment Stopping Rules ..................................................64 
10 ETHICS AND RESPONSIBILITIES .....................................................................66 
10.1 
Ethical Conduct of the Study .......................................................................66 
10.2 
Obligations of Investigators .........................................................................66 
10.3 
Institutional Review Board/Ethics Committee/Research Ethics 
Board (IRB/EC) ............................................................................................66 
10.4 
Informed Consent Form ...............................................................................67 
10.5 
Confidentiality...............................................................................................67 
10.6 
Reporting of Serious Breaches of the Protocol or ICH GCP ....................67 
11 RECORDS MANAGEMENT..................................................................................68 
11.1 
Source Documentation .................................................................................68 
11.2 
Study Files and Records Retention .............................................................68 
12 QUALITY CONTROL AND QUALITY ASSURANCE ......................................68 
12.1 
Monitoring Procedures ................................................................................68 
12.2 
Auditing and Inspection Procedures ...........................................................69 
13 CHANGES IN STUDY CONDUCT .......................................................................69 
13.1 
Protocol Amendments ..................................................................................69 
13.2 
Protocol Deviations .......................................................................................69 
14 END OF TRIAL ........................................................................................................70 
14.1 
End of Trial in a European Union Member State .....................................70 
14.2 
End of Trial in all other Participating Countries ......................................70 
14.3 
Premature Termination ...............................................................................70 
15 STUDY REPORT AND PUBLICATION POLICY ..............................................70 


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16 REFERENCES .........................................................................................................71 
Appendix 1. 
ECOG PERFORMANCE STATUS .........................................74 
Appendix 2. 
ABBREVIATED PRESENTATION OF RECIST 
 
VERSION 1.1 GUIDELINES ....................................................75 
 
 
TABLE OF TABLES 
Table 1: 
Pre-screening Assessments ......................................................................12 
Table 2: 
Schedule of Assessments – During Study ..............................................13 
Table 3: 
Schedule of PK, Triplicate ECG, and PD Assessments ........................16 
Table 4: 
Pharmacokinetic Parameters of MGCD265 Soft Gel Capsules and 
SDD after Single and Multiple BID Administration under 
Fasting Conditions ...................................................................................30 
Table 5: 
Dose Adjustment Guidelines Soft Gel Formulation .............................41 
Table 6: 
Dose Adjustment Guidelines Spray Dried Dispersion Formulation ...41 
Table 7: 
Dose Modifications – Treatment-Related Toxicities .............................42 
Table 8: 
Treatment Modification for Increased Hepatic Transaminase ...........43 
Table 9: 
Laboratory Safety Parameters ...............................................................52 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC0-12 
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 
12 Hours 
BID 
Twice daily  
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Plasma Concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography Scan 
CTA 
Clinical Trial Application 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating Tumor Cell DNA 
DNA 
Deoxyribonucleic Acid 
DR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
EIU 
Exposure In-Utero 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed, Paraffin-Embedded  
FISH 
Fluorescent In Situ Hybridization 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HDPE 
High-Density Polyethylene 
HGF 
Hepatocyte Growth Factor 
IB 
Investigator’s Brochure 
 
 


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LIST OF ABBREVIATIONS 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Internal Data Monitoring Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ration 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
Mesenchymal-Epithelial Transition Factor 
mg 
Milligram 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NGS 
Next-Generation Sequencing 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Objective Progression of Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PR 
Partial Response 
PTT 
Partial Thromboplastin Time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
ROC 
Receiver Operating Characteristic 
RTK 
Receptor Tyrosine Kinase 
 
 


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LIST OF ABBREVIATIONS 
RTPCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SDD 
Spray-Dried Dispersion 
SOC 
System Organ Class 
t1/2 
Plasma Half-Life 
TCGA 
The Cancer Genome Atlas Research 
Tmax 
Time to Maximum Observed Concentration 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR 
Vascular Endothelial Growth Factor Receptor 
WBC 
White Blood Cell 
WOCBP 
Women of Child Bearing Potential 


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1 INTRODUCTION AND RATIONALE 
1.1 
Disease and Therapeutic Strategy 
1.1.1 
 Non-Small Cell Lung Cancer 
Lung cancer remains the leading cause of cancer-related death in the United States (US).  
Approximately 221,200 new cases of lung cancer are expected to be diagnosed in the US 
in 2015, and approximately 158,040 deaths will be attributed to lung cancer 
(Cancer Facts and Figures-2015).  Non-small cell lung cancer (NSCLC) accounts for 
approximately 83% of lung cancer cases (Cancer Facts and Figures-2015), of which 
approximately half are classified as adenocarcinoma of the lung; squamous cell 
carcinoma accounts for approximately one-third of NSCLC cases and large cell 
carcinoma is less frequently diagnosed. 
In 1995, the use of cisplatin-based chemotherapy was reported to lead to modest 
improvement in survival in patients with advanced NSCLC as compared to best 
supportive care, with a 27% reduction in death as reported in a meta-analysis of 11 trials 
(NSCLC Collaborative Group-1995).  Subsequently, other chemotherapeutic agents have 
been reported to be active in NSCLC, leading to a comparison of 4 platinum-based 
doublets in the first-line treatment setting, all of which demonstrated similar activity 
(Schiller-2002).  The importance of histology in the selection of first-line treatment for 
NSCLC was later described in the development of bevacizumab and pemetrexed.  In a 
Phase 3 clinical trial, treatment with bevacizumab, a monoclonal antibody directed 
against vascular endothelial growth factor (VEGF), demonstrated an improvement in 
survival when added to doublet chemotherapy, specifically in patients with 
non-squamous NSCLC (Sandler-2006).  Similarly, treatment with pemetrexed, an 
antifolate chemotherapeutic agent, results in an improvement in survival when used as 
part of a chemotherapy doublet in patients with non-squamous NSCLC, but with a 
probable decrease in survival among patients with squamous cell NSCLC 
(Scagliotti-2008).  Based on the results of these and other trials, platinum-based 
chemotherapy doublets, with or without bevacizumab in selected patients, remain a 
standard of care for most patients with advanced NSCLC in the first-line treatment 
setting.  More recently, a trial of pembrolizumab, a humanized monoclonal antibody 
directed against PD-1, demonstrated an advantage of pembrolizumab over standard 
chemotherapy in patients with untreated, advanced NSCLC characterized by ≥ 50% 
tumor PD-L1 expression.  Improvement was reported across multiple efficacy endpoints 
including survival along with a favorable safety profile (Reck-2016), leading to the 
approval of pembrolizumab in the first-line treatment setting in this patient population in 
the US. 
Non-clinical and clinical studies have led to increased understanding of the molecular 
mechanisms underlying the pathogenesis of NSCLC.  Abnormalities of genes involving 
signaling pathways have been described primarily in adenocarcinoma, and have included 
mutations in EGFR, HER2, ROS, RON, MET, KRAS, and BRAF, as well as translocations 


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such as EML4-ALK.  In tumors harboring gene mutations in these pathways, the 
activation of the involved pathway is critical for the survival and maintenance of the 
malignancy.  Such observations have been made in concert with the development and 
market authorization of several drugs targeting these pathways, including gefitinib 
(Mok-2009), erlotinib (Shepherd-2005; Rosell-2012), and afatinib (Sequist-2013) 
inhibiting the EGFR (Epidermal Growth Factor Receptor) pathway; as well as crizotinib 
(Shaw-2013) and ceritinib (Shaw-2014) inhibiting the ALK pathway.  Clinical trials with 
these targeted agents have demonstrated that patient selection on the basis of tumor 
genetics can result in high disease response rates in all lines of treatment and have 
revolutionized the treatment of NSCLC, with targeted agents rapidly becoming standard 
of care among those patients with sensitizing tumor mutations (NCCN-2016).  These 
observations have led to the paradigm whereby adenocarcinoma of the lung often occurs 
in the setting aberrant signaling pathways, and the identification and targeting of these 
pathways lead to significant improvements in outcomes for these patients. 
Ongoing studies indicate that aberrations in the MET pathway may be similarly important 
in identifying patients with NSCLC, particularly those with adenocarcinoma, for targeted 
therapy.  The MET pathway may be dysregulated through many mechanisms in NSCLC, 
including focal gene amplification, mutations leading to aberrant splicing such that the 
amino acid sequence correlating to exon 14 is deleted from the protein, or other 
activating mutations.  As a consequence of these abnormalities, the MET pathway is 
overactive and acts as a tumor driver.  Agents targeted to exploit the dependency on the 
MET pathway may be associated with significant activity, and with the potential for a 
better safety profile as compared to current treatment options. 
1.1.2 
Tyrosine Kinase Inhibitors 
Receptor tyrosine kinases (RTKs) provide ideal targets for cancer therapeutics.  The 
rationale for use of kinase inhibitors to treat cancer is supported by a well-established 
paradigm in oncology that robust clinical efficacy can be achieved with well-tolerated 
inhibitors directed toward oncogenic tyrosine kinases that are genetically altered through 
activating mutations, gene translocations, or gene amplification.  Examples of tyrosine 
kinase inhibitors that have become standards of care in cancer diseases include imatinib 
in gastrointestinal stromal tumors with mutant c-KIT or chronic myelogenous leukemia 
with BCR-ABL gene translocations, erlotinib in NSCLC with mutant EGFR, sunitinib 
targeting the VHL (von Hippel-Lindau)-dependent VEGF pathway in renal cell 
carcinoma, and vemurafenib in BRAFV600E mutation-positive melanoma. 
1.1.3 
Dysregulation of Receptor Tyrosine Kinases in Cancer 
RTKs are families of kinases involved in the transmission of signals that regulate cell 
growth, survival, and migration.  Dysregulation of RTKs through genetic alteration or 
ectopic or uncontrolled expression is implicated in cell proliferation and tumor 
progression.   


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MET is one of the most frequently mutated or otherwise abnormally activated RTKs in 
several human cancers (Christensen-2005).  Malignancies in which MET has been 
reported to be genetically altered by mutation or gene amplification include lung, renal, 
colorectal, glioblastoma, gastric, and head and neck cancers (Christensen-2005).  MET 
mutations and high level gene amplification were also recently identified as significant 
cancer gene alterations in lung adenocarcinoma studies performed as part of the Cancer 
Genome Atlas consortium project (TCGA-2014a).  In the Cancer Genome Atlas lung 
adenocarcinoma genomics analysis, MET dysregulation resulted from exon 14 skipping, 
which results in increased protein stability, overexpression, and activation.  
Approximately 6.5% of lung adenocarcinoma sample demonstrated MET exon 14 splice 
site mutations with exon 14 skipping or high level amplification of the MET gene.  
Furthermore, the expression of both MET and HGF, its sole, high-affinity ligand, were 
demonstrated to correlate with poor prognosis or metastatic progression in a number of 
major human cancers including NSCLC (Christensen-2005).  Inappropriate activation of 
MET is involved in multiple tumor oncogenic processes such as cell growth, 
angiogenesis, invasive growth, and especially in the metastatic process.  MET has also 
been implicated as a key factor in resistance to both targeted agents and 
chemotherapeutics.  A key example is illustrated by the amplification of MET or the 
overexpression of MET or HGF in patients whose disease failed to respond or acquired 
resistance to EGFR inhibitors, including erlotinib, gefitinib and cetuximab 
(Engelman-2007; Yano-2011).  The simultaneous inhibition of MET and EGFR in 
nonclinical lung cancer models with acquired resistance to erlotinib through 
dysregulation of MET, circumvented resistance and led to tumor regression 
(Engelman-2007; Yano-2011).   
Overexpression or ectopic expression of the Axl RTK and its ligand Gas6 has been 
reported in a wide array of human cancers including lung, colon, head and neck, breast, 
ovarian, hepatocellular, and glioblastoma (Li-2009; Rankin-2010).  The ectopic 
expression of high levels of Axl in fibroblasts or epithelial cells resulted in a tumorigenic 
phenotype implicating it as a transforming oncogene (O’Bryan-1991; Li-2009; 
Rankin-2010).  Axl has been demonstrated to regulate tumor cell proliferation and 
survival and has also been implicated in tumor angiogenesis (Li-2009; Rankin-2010).  
Axl expression was correlated with clinical stage and lymph node status in NSCLC.  
Furthermore, a fusion of AXL with MBIP was recently reported in NSCLC.  Through this 
fusion, MBIP provided Axl with dimerization motifs enabling Axl kinase to be 
constitutively activated and become a primary oncogenic driver (Seo-2012).  Moreover, 
recent data have implicated Axl in the resistance to EGFR inhibitors such as erlotinib in 
NSCLC and cetuximab in HNSCC (Zhang-2012; Byers-2013). 
Collectively, the dysregulation of MET and Axl through genetic alterations and ectopic 
expression in multiple cancers and during cancer drug resistance provides an important 
opportunity to utilize MGCD265 in the therapeutic intervention in these cancers. 


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1.1.4 
Tumor Gene Sequencing Using Blood Plasma 
Whereas analytical techniques evaluating tumor genes in tumor tissue have become 
accepted for identification of patients for clinical trials of targeted therapies, increasing 
evidence supports the genetic analysis of circulating DNA in the blood plasma of patients 
with cancer as an effective and quantitative method for evaluating tumor genetic mutation 
profiles.  Tumor cells release a significant amount of DNA into circulation during cancer 
progression; cell-free circulating tumor DNA (ctDNA) can comprise greater than 90% of 
total circulating plasma DNA (Bettegowda-2014, Diehl-2008).  Correlative analyses have 
demonstrated a high degree of concordance for detection of selected genetic mutations 
(e.g., EGFR, KRAS or multi-gene panels with annotated known cancer mutations) 
between tumor tissue and ctDNA with specificity for plasma vs. tissue concordance of 
99% for mutations with allelic fractions > 0.10% (Bettegowda-2014, Newman-2014).  
The clinical utility of a ctDNA-based assay to identify a patient population that benefits 
from treatment with a specific therapeutic agent was demonstrated using a plasma 
DNA-based companion diagnostic to detect EGFR mutations in the tumors of patients 
with NSCLC treated with gefitinib (Douillard-2014); the result was European regulatory 
approval for gefitinib in the indication.   
Availability of tumor tissue for tumor gene sequencing and other potentially interesting 
diagnostic testing is inherently limited in the NSCLC disease setting and becoming more 
problematic with the increasing number of targeted therapies under study and the 
required testing with multiple co-diagnostic tests.  The capability to evaluate tumor 
mutation status with non-invasive techniques has the potential to benefit a significant 
segment of the patient population.  In addition, specimens available for tumor tissue-
based analysis are frequently archival diagnostic biopsy tissue that are not necessarily 
reflective of tumor genetic status in more advanced and treated disease.  A benefit of 
analysis of ctDNA is that the sample represents a patient’s current tumor genetic profile.  
In addition, it allows ongoing monitoring to identify new mutations that may occur and 
indicate resistance to treatment. 
In the current study, a ctDNA-based targeted next-generation sequencing (NGS) platform 
will be used to identify patients having selected MET mutations and/or MET gene 
amplification.  The ctDNA-based NGS platform was evaluated in more than 150 paired 
tumor and plasma samples, collected across multiple clinical institutions.  The evaluation 
used 10 well-established genetic markers and demonstrated 97% diagnostic accuracy, 
98% specificity and more than 85% sensitivity for the comparison of tumor genes in 
tissue and plasma samples (data on file at central laboratory).  In addition, the analytical 
technique passed quality control analysis for 99.8% of the more than 500 samples tested.  
Based on this evidence of robust performance and concordance with tissue-based 
analyses, the method will be used to identify patients for two independent study treatment 
arms in the current study, patients having MET mutations or MET gene amplification. 


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1.2 
MGCD265 
MGCD265 is an orally administered multi-targeted RTK inhibitor that primarily targets 
the Axl and MET receptors.  Additional RTK targets potentially include the MERTK, 
DDR2, and PDGFRα and β receptors.   
1.2.1 
Drug Substance 
Generic Name: 
MGCD265 (free base) 
Chemical Name: 
N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridine-2-
yl)thieno[3,2-b]pyridine-7-yloxy)phenylcarbamothioyl)-2-(4-
fluorophenyl)acetamide 
Chemical 
Formula: 
C31H27F2N5O3S2 
Molecular Weight: 
619.71 g/mol 
 
1.2.2 
Non-Clinical Data 
MGCD265 has demonstrated potent, concentration-dependent inhibition of the kinase 
activity of MET, Axl family, PDGFR family, DDR2, in biochemical assays and inhibited 
phosphorylation in cell-based assays.  MGCD265 also inhibited MET-dependent cell 
viability and migration and endothelial tube formation and angiogenesis in cell-based 
experiments.  In a variety of human tumor xenograft models, MGCD265 has 
demonstrated anti-tumor efficacy including robust tumor regression in models exhibiting 
genetic alterations of the MET RTK including MET mutations and gene amplification. 
Based on cytochrome P450 inhibition, induction and metabolism experiments, 
MGCD265 is expected to have a low potential for drug-drug interactions.   
MGCD265 was evaluated in a toxicology program using oral administration to 
Sprague-Dawley rats and Beagle dogs.  In the 28-day rat study, target organ toxicity was 
observed in bone marrow, liver, kidney and reproductive organs; additional findings were 
noted in thymus, adrenal gland, exocrine glands, and spleen.  In the 28-day dog study, 
increased emesis and non-formed feces correlated with decreased food consumption and 
body weight gain; no target organs were identified during histopathology review. 
1.2.3 
Clinical Data 
MGCD265 has been evaluated using various oral formulations and regimens in Phase 1 
and 1/2 clinical trials in over 370 patients with advanced malignancies.  The safety 
profile of single agent administration and combinations of MGCD265 and docetaxel or 


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erlotinib has been evaluated.  Details on clinical trial experience are presented in the 
MGCD265 Investigator’s Brochure (IB). 
When MGCD265 was administered as a single agent, the most common related 
treatment-emergent adverse events (TEAEs) were diarrhea (62%), nausea (39%), fatigue 
(31%), vomiting (26%), aspartate aminotransferase increased (25%), and alanine 
aminotransferase increased (20%).  Grade 3 related TEAEs reported in more than one 
patient included diarrhea (8%), fatigue (5%), aspartate aminotransferase increased, 
alanine aminotransferase increased, lipase increased, nausea, and vomiting (2% each), 
and abdominal pain, anemia, blood alkaline phosphatase increased, blood phosphorus 
decreased, dehydration, hypertension, and hypokalemia (1% each); Grade 4 related 
TEAEs included lipase increased (1%) and amylase increased and lymphocyte count 
decreased (< 1%). 
The MGCD265 formulation and regimen to be used at the initiation of the current study 
is non-aqueous suspension capsules (MGCD265 free base suspended in Miglyol® in soft 
gelatin capsules and referred to as soft gel capsules), administered twice daily (BID) in a 
continuous regimen (delivered in 21-day cycles).  In the Phase 1 study, MGCD265 
systemic exposure increased with increasing dose from 600 to 1050 mg BID, with a less 
than dose proportional manner between 1050 and 1200 mg BID.  The maximum tolerated 
dose with the soft gel capsules was established at 1050 mg BID.  Following single dose 
administration of 1050 mg BID soft gel capsules, MGCD265 was absorbed, with 
maximum concentration (Cmax) occurring at a median time of 8 hours (4-12 hours range) 
after dosing.  The mean elimination half-life was 36.7 ± 13.6 hours (mean ± SD).  At 
steady state, the geometric mean Cmax,ss, Cave,ss and AUC0-12,ss  values were 510 ng/mL, 
464 ng/mL, and 5572 ng•h/mL, respectively.  Drug accumulation was observed after 
multiple dose administration, whereby Cmax and AUC0-12 were 3.9-fold and 5.2-fold 
higher, respectively, than single dose administration of 1050 mg soft gel capsules.  Mean 
peak to trough ratio at steady state was 1.18. 
A solid, oral MGCD265 drug product consisting of a spray-dried dispersion (SDD) tablet 
formulation was developed in order to reduce the number of unit doses (pill burden) and 
eliminate the Miglyol® excipient used in the soft gel capsule formulation.  The SDD 
tablet formulation was introduced into this study with Protocol Version 2.0.  The SDD 
tablet formulation was evaluated in the Phase 1 trial at doses of 500, 750 and 1000 mg 
BID; 750 mg BID was established as the maximally tolerated dose.  Following single 
dose administration of 750 mg SDD tablets, MGCD265 was absorbed, with Cmax 
occurring at a median time of 6 hours (2-24 hours range) after dosing.  The mean 
elimination half-life was 30.9 ± 13.9 hours (mean ± SD) hours.  At steady state, 
geometric mean Cmax,ss, Cave,ss and AUC0-12,ss  values were 432 ng/mL, 396 ng/mL, and 
4751 ng•h/mL, respectively.  Drug accumulation with this regimen was observed and was 
associated with a Cmax and AUC0-12 values 4.0-fold and 4.5-fold higher than single dose 
administration, respectively, and mean peak to through ratio at steady state was 
1.12.  The relative bioavailability comparing 750 mg BID SDD to 1050 mg BID capsules 
based on steady state dose normalized parameters was around 1.2.  The increase in 


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exposure from 500 mg BID to 750 mg BID at steady state was less than dose proportional 
with the 750 mg BID dose level yielding approximately 17% higher steady state exposure 
(geometric mean Cave,ss and AUC0-12,ss) than the 500 mg BID dose level.   
The rates of absorption and elimination of multiple dose administration of 750 mg BID 
SDD were comparable to 1050 mg BID soft gel capsules, while the extent of absorption 
at steady state was approximately 1.2 times greater with 1050 mg BID soft gel capsules 
as compared to 750 mg BID SDD tablet.   
Table 4: 
Pharmacokinetic Parameters of MGCD265 Soft Gel Capsules 
and SDD after Single and Multiple BID Administration under 
Fasting Conditions 
MGCD265 Dose 
Status 
Fasted 
Formulation 
Soft Gel Capsules 
Spray Dried Dispersion 
MGCD265 Dose 
1050 mg, BID 
750 mg, BID 
 
Single 
Steady 
Single 
Steady 
 
Dose 
State 
Dose 
State 
N 
28 
26 
4 
4 
Parameter 
Geometric Mean (CV% Geometric Mean) 
AUC0-12 
(ng•h/mL) 
1214 (63.6) 
5572 (44.9) 
1149 (76.2) 
4751 (60.1) 
AUC0-24 
(ng•h/mL) 
2513 (70.9) 
11110 (41.7) 
2251 (83.7) 
9257 (62.1) 
Cave,ss 
(ng/mL) 
- 
464 (44.9) 
- 
396 (60.1) 
Cmax 
(ng/mL) 
149 (65.8) 
510 (44.8) 
124 (85.1) 
432 (57.2) 
Tmaxa (h) 
8 (4, 12) 
4 (2, 12) 
6 (2, 24) 
2 (2, 4) 
t½b (h) 
36.7 ± 13.6 
- 
30.9 ± 13.9 
- 
a. 
Median (Min, Max);  
b. 
Mean ± SD  
Data Source: 265-101 Final Pharmacokinetic Data (02 May 2016)  
N = total number of patients 
Single dose = PK blood samples were collected up to 48 hours after the first dose in Cycle 
To date, the safety profile of the SDD formulation shows a trend for reduced frequency 
and severity of adverse events.  Based on this outcome from the SDD tablet dose 
escalation, the 750 mg BID dose was established as the recommended Phase 2 dose for 
the MGCD265 SDD tablet formulation.   


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Detailed background information concerning MGCD265 can be found in the 
MGCD265 Investigator’s Brochure. 
1.3 
Study Rationale 
MET plays a central role in epithelial tissue remodeling and morphogenesis and is one of 
the most frequently dysregulated RTKs in several human cancers.  Oncology indications 
in which MET was reported to be genetically altered by mutation or gene amplification 
include lung, renal, colorectal, glioblastoma, gastric, and head and neck cancers.  MET 
mutations and/or gene amplification have recently been reported as part of the Cancer 
Genome Atlas program in approximately 7% of lung adenocarcinoma patients.  
Furthermore, the expression of both MET and HGF, its sole, high-affinity ligand, was 
demonstrated to correlate with poor prognosis or metastatic progression in a number of 
major human cancers including NSCLC.  Inappropriate activation of MET is involved in 
multiple tumor oncogenic processes such as cell growth, angiogenesis, invasive growth, 
and especially in the metastatic process. 
MGCD265 is a small molecule inhibitor of MET and Axl.  In vitro studies have 
demonstrated that MGCD265 is a potent inhibitor of tumor cell proliferation in cells 
where MET is overexpressed or activated, but not in cells that lacked MET 
expression/activation.  These results are consistent with in vivo studies demonstrating 
activity of MGCD265 in human tumor xenograft-bearing mouse models, including 
marked tumor regression in models exhibiting MET mutations and/or gene amplification.  
Additionally, anti-tumor activity has been observed in patients treated with MGCD265 in 
the Phase 1 study. 
The current study is designed to evaluate the tumor response to MGCD265 in patients 
with NSCLC with activating genetic alterations of MET consisting of either MET 
activating mutations or MET amplification.  The primary endpoint of the study is 
Objective Response Rate (ORR). 
 
2 STUDY OBJECTIVES 
2.1 
Objectives 
2.1.1 
Primary Objective 
• To determine the tumor response to MGCD265 in the selected patient population. 
 
 


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2.1.2 
Secondary Objective 
• To evaluate the safety and tolerability of MGCD265 in the selected population. 
• To evaluate secondary efficacy endpoints with MGCD265 treatment in the selected 
population. 
• To assess correlation between selected tumor gene alterations using different 
analytical techniques in tumor tissue and ctDNA. 
• To assess change in genetic alteration status in ctDNA with MGCD265 treatment 
over time in the selected population.   
• To assess the population PK/PD of MGCD265 in the selected population. 
2.2 
Endpoints 
2.2.1 
Primary Endpoints 
• ORR as defined by RECIST 1.1. 
2.2.2 
Secondary Endpoints 
• Safety characterized by type, incidence, severity, timing, seriousness and relationship 
to study treatment of adverse events and laboratory abnormalities. 
• Secondary efficacy endpoints: 
o DR; 
o PFS; 
o 1-Year Survival Rate; and 
o OS. 
• Gene alterations in tumor tissue and ctDNA at prescreening/baseline. 
• Change in ctDNA through time. 
• Blood plasma MGCD265 concentration. 
• Blood plasma concentration of selected soluble biomarkers. 
 
 


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3 STUDY DESIGN 
Study 265-109 is an open-label, parallel arm, Phase 2 trial evaluating the tumor response 
to MGCD265 in patients with locally advanced, unresectable or metastatic NSCLC 
exhibiting activating genetic alterations of MET. 
To be eligible for enrollment, patients must have documented evidence of a genetic 
alteration activating MET, based on molecular testing performed by a Sponsor-approved 
central or local laboratory.   
The primary objective of the study is to determine the tumor response with MGCD265 as 
measured by ORR in accordance with RECIST 1.1.  Secondary objectives include 
evaluation of safety, secondary efficacy endpoints, tumor genetic alterations in tumor 
tissue and ctDNA at prescreening/baseline, change in ctDNA through time, and 
population PK/PD.  Schedule of Assessments to be performed in the study is presented in 
Table 1, Table 2, and Table 3.   
MGCD265 will be administered as an oral therapeutic twice daily (BID) in 21-day 
cycles.  Guidelines for study drug administration and dose reduction in the event of 
toxicity are provided in Section 5.2.  Study treatment will continue until disease 
progression, unacceptable adverse events, patient refusal or death.   
Disease response and progression as documented by the investigator in the CRF will be 
the basis for patient management, study expansion decision making, and secondary and 
supportive statistical analyses.  Central radiology review for disease response will be the 
basis for the primary statistical analyses to estimate the objective response rate and its 
confidence interval as well as the duration of response and PFS.  The importance of 
timely and complete disease assessments in this study is critical for the efficacy 
endpoints.  The need to truncate treatment cycles to manage toxicity may result in 
inconvenient scheduling of disease assessments.  Disease assessments must be performed 
as scheduled according to the calendar to prevent the introduction of bias into the 
assessment of efficacy based on toxicity. 
This Phase 2 parallel-arm study will be conducted in four groups of patients having 
genetic tumor alterations activating MET:  
A. MET activating mutations in tumor tissue,  
B. MET gene amplifications in tumor tissue, 
C. MET activating mutations in ctDNA, and 
D. MET gene amplifications in ctDNA 
Full and timely enrollment of patients into Treatment Arms A and B are central to this 
study meeting its objectives.  In addition, for patients enrolled based on a 


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Sponsor-approved local test, retrospective analysis by the central tissue testing laboratory 
is key.   
Treatment Arms C and D, based on documentation of target gene alteration using the 
ctDNA test, are intended to include patients for whom central laboratory tumor tissue 
testing fails for technical reasons, or the search for suitable tumor tissue or test results 
prove that none exist (to be documented in the patient records).   
Individual patients with gene alterations are likely to qualify for entry into two or more 
treatment arms.  The correlation between target gene mutations in tumor tissue and 
ctDNA is expected to be high.  In addition, patients may have both target gene mutation 
and amplification.  The priority for assignment to treatment arm will be in the order A to 
D listed above.   
The Phase 2 study will use a Bayesian Predictive Probability Design (Lee-2008), applied 
separately and using the same assumptions in each treatment arm (see Section 9.1).  
Emerging tumor response data will be evaluated continuously beginning after 10 patients 
in each treatment arm have completed their first on-study disease assessment and are 
considered part of the mITT population.  Stopping rules for futility are described in 
Section 9.1.  Assuming the stopping rules are not triggered, the total sample size to be 
evaluated in each treatment arm of the Phase 2 study is 45 patients.  The primary analysis 
will be conducted in the mITT (defined in Section 9.3.1).   
There is potential for one or more arms of the Phase 2 study to yield results indicating 
that MGCD265 should be considered to provide an important advancement in treatment 
in this setting of unmet medical need.  If emerging data indicate that an accelerated 
approval market application may be undertaken for MGCD265 for one or more of the 
selected patient populations, an analysis of the combined populations may be undertaken, 
or additional patients may be enrolled into the study, to increase the precision of the 95% 
confidence interval around the ORR endpoint and/or to increase the size of the safety 
database in the target patient population.  As many as 55 additional patients in the mITT 
population may be enrolled in up to two treatment arms to ensure collection of sufficient 
data to support an accelerated approval market application.  Whether additional 
enrollment will include patients with MET mutation and/or MET gene amplification will 
depend on the emerging efficacy data in the populations as the study progresses.   
Considering the sample size planned for the four treatment arms in the Phase 2 study 
(45 patients each) and the possible addition of patients to prepare for market application 
in this setting (55 patients in each of two treatment arms), the ultimate sample size for 
this study could include as many as 290 patients.  Enrollment through the stages of this 
study will proceed without planned interruption while data are accruing.  Decisions will 
be made expeditiously by the Internal Data Monitoring Committee to prevent excessive 
over-enrollment and include only outcomes among the specified number of patients 
according to the stopping rules. 


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4 SUBJECT SELECTION AND ENROLLMENT 
Patient eligibility must be reviewed and documented by an appropriately qualified 
member of the investigator’s study team before patients are included in the study.  No 
exceptions to the patient eligibility requirements will be granted by the Sponsor. 
4.1 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into 
the study: 
1. Histologically confirmed NSCLC with metastatic or unresectable, locally advanced 
disease. 
2. Receipt of at least one prior platinum-containing chemotherapy or licensed 
immunotherapy regimen in the advanced disease setting.   
3. Molecular analysis of patient-derived samples using a Sponsor- approved method and 
laboratory that demonstrates a genetic alteration activating MET in tumor tissue 
and/or ctDNA.  If eligibility is established using a Sponsor-approved local laboratory, 
a tumor tissue specimen and/or blood sample is expected to be available for 
retrospective sequencing in the central laboratory selected by the Sponsor.   
4. Measurable disease, as per RECIST version 1.1. 
5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 
(Appendix 1). 
6. Adequate bone marrow and organ function demonstrated by:  
a. Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 × 109/L) 
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5 × Upper Limit of Normal (ULN), or ≤ 5.0 × ULN for patients with 
documented liver metastases.  Alkaline phosphatase levels ≤ 2.5 × ULN.  In the 
presence of extensive bone metastases, there is no upper limit for alkaline 
phosphatase. 
c. Total bilirubin ≤ 1.5 × ULN or ≤ 3.0 × ULN for patients with Gilbert Syndrome 
or documented liver metastases.   
7. ≥ 18 years of age. 
8. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP 
agrees to use contraception while participating in this study, and for a period of 
6 months following termination of study treatment. 


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9. Completed informed consent process, including signing IRB/EC-approved informed 
consent form. 
10. Willing to comply with clinical trial instructions and requirements. 
4.2 
Exclusion Criteria 
Patients presenting with any of the following will not be included in the study: 
1. Prior treatment with a small molecule or antibody inhibitor of MET or HGF. 
2. Prior positive test for EGFR mutation or ALK gene rearrangement 
o Testing and documentation is required for patients with adenocarcinoma 
histology; 
o Testing is not required for patients with non-adenocarcinoma histology; however 
if documentation of a positive test is available, the patient will not be eligible. 
3. Most recent prior systemic therapy (e.g. chemotherapy or immunotherapy) or 
investigational agent discontinued ≤ 2 weeks before first dose date. 
4. Absence of recovery from the adverse effects of prior therapy at the time of 
enrollment to ≤ Grade 2 (excluding alopecia). 
5. History of stroke or transient ischemic attack within the previous 6 months. 
6. Any of the following cardiac abnormalities: 
a. Unstable angina pectoris, 
b. Congestive heart failure ≥ NYHA Class 3, or 
c. QTc > 480 msec. 
7. Known or suspected presence of another malignancy that could be mistaken for 
metastatic NSCLC during disease assessments. 
8. Symptomatic or uncontrolled brain metastases requiring current treatment (less than 
4 weeks from last cranial radiation, 2 weeks from stereotactic radiosurgery [gamma 
knife], or 2 weeks from last steroids).  Known conditions associated with significant 
risk of intracranial bleeding including but not limited to vascular malformations and 
pituitary adenoma. 
9. Inability to swallow oral medications or pre-existing gastrointestinal disorders that 
might interfere with proper absorption of oral drugs.   


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10. Known hypersensitivity to any of the components of the MGCD265 Drug Product. 
11. Pregnancy.  WOCBP must have a negative serum or urine pregnancy test documented 
within the screening period prior start of study drug. 
12. Breast-feeding or planning to breast feed during the study or within 6 months after 
study treatment. 
13. Any serious illness, uncontrolled inter-current illness, active or uncontrolled 
infection, or other medical history, including laboratory results, which, in the 
Investigator’s opinion, would be likely to interfere with the patient’s participation in 
the study, or with the interpretation of the results.   
4.3 
Life Style Guidelines 
Patients who are biologically capable of having children and sexually active must agree 
to use an acceptable method of contraception for the duration of the treatment period and 
for at least 6 months after the last dose of study treatment.  The investigator will counsel 
the patient on selection of contraception method and instruct the patient in its consistent 
and correct use.  Examples of acceptable forms of contraception may include: 
1. Oral, inserted, injected or implanted hormonal methods of contraception, provided it 
has been used for an adequate period of time to ensure effectiveness. 
2. Correctly placed copper containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide 
(Exception: in the European Union, this option does not meet criteria for highly 
effective contraception and therefore is not an acceptable form of contraception for 
this study; please refer to the following guidance:  
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01About_HMA/
Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.) 
4. Male sterilization with confirmed absence of sperm in the post-vasectomy ejaculate. 
5. Bilateral tubal ligation or bilateral salpingectomy. 
The investigator will instruct the patient to call immediately if the selected birth control 
method is discontinued or if pregnancy is known or suspected.   
Note: Women are considered post-menopausal and/or not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 


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6 months ago.  In case of any ambiguity, the reproductive status of the woman should be 
confirmed by hormone level assessment. 
4.4 
Enrollment into Study 
Genotyping of the tumor sufficient for establishing study eligibility may have been 
performed historically or more recently for the purpose of considering enrollment in this 
study.  In all cases, informed consent for tumor genotyping (using tumor tissue or 
ctDNA) must be documented prior to submission of samples for testing.  The informed 
consent for tumor testing may be performed in accordance with established institutional 
practice, or using the study-specific, IRB-approved pre-screening informed consent 
associated with this study.   
If the Sponsor-provided central laboratory is used to perform tumor genotyping to 
establish eligibility for the study, a 14-day turn-around time should be expected from the 
time of receipt of adequate samples at the central lab to test results returned to the study 
site.  Questions concerning adequacy of samples will cause delay beyond this timeframe.   
Following completion of the full, study-specific informed consent process and review of 
all screening procedures, patient eligibility will be confirmed by appropriately qualified 
staff at the investigational site.  Patients will be enrolled by entry into a patient 
registration log provided by the Sponsor and maintained by the study site and completion 
of the patient registration procedure detailed in the Study Manual.  Each patient will be 
assigned a sequential number by the study site.  The patient number must be used on all 
documentation and correspondence with the Sponsor, Contract Research Organization 
(CRO) and laboratory vendors. 
 
5 STUDY TREATMENT 
5.1 
Study Drug Management 
5.1.1 
Formulation and Packaging 
MGCD265 study drug will be supplied by the Sponsor.  At the beginning of the study, 
the presentation was soft gel capsules containing the free-base form of MGCD265 and 
inert excipients: Miglyol®, Labrafil®, fractionated coconut oil, Capsule Gel 60, Gelatin 
195 Acid Bone and glycerin.  Dosage strength is 150 mg (white opaque capsule), 
calculated as free-base corrected for purity.   
Soft gel capsules are supplied in 40 count, high-density polyethylene (HDPE) bottles 
with child resistant closures.  Bottles will be labeled in compliance with the legal 
requirements per country.  Labels will be printed in the languages required in the 
countries in which the study is conducted. 


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MGCD265 Spray-Dried Dispersion [SDD] tablet formulation is being introduced with a 
protocol amendment (Version 2.0).  Dosage strength will be 100 mg and 250 mg.  Inert 
excipients in the SDD tablet include hydroxypropylmethyl cellulose (HPMC), Avicel® 
(or equivalent), Kollidon® (or equivalent), sodium bicarbonate, sodium chloride, Syloid® 
(or equivalent), and magnesium stearate, as necessary. 
SDD tablets will be supplied in HDPE, white opaque bottles.  A tamper-proof heat 
induction seal and a child-resistant closure are used.  Tablet bottles will be received by 
the pharmacy in foil pouches that are to be kept intact until the bottles are dispensed to 
the patient.  Bottles will be labeled in compliance with the legal requirements per 
country.  Labels will be printed in the languages required in the countries in which the 
study is conducted.   
Refer to the Pharmacy Study Manual for details on available study drug presentations, 
unit dose strengths, bottle sizes, and number of units per bottle supplied. 
5.1.2 
Drug Storage and Accountability 
MGCD265 study drug should be stored as directed on the package labeling.  The storage 
area should be secure with limited access and monitored for temperature using a 
calibrated thermostat.  Shelf-life evaluation of the intact bottles is ongoing.  Available 
stability data for the soft-gel capsules support ≥ 24-months shelf-life when stored at room 
temperature (suggested temperature range 15-30°C, 59-86°F).   
SDD tablets, while stored in the study site pharmacy, should be kept in the unopened foil 
pouches under refrigerated conditions (suggested temperature range 2-8°C, 36-46°F).  
Once dispensed to patients, bottles should be stored at room temperature (suggested 
temperature range 15-30°C, 59-86°F).  Available stability data for the SDD tablets 
support > 12 months shelf-life for pharmacy storage at refrigerated conditions and 
> 4 months shelf-life when stored at room temperature after dispensation to the patient.   
All study treatment supplies will be accounted for in the drug accountability inventory 
forms supplied by the Sponsor or using forms according to local site procedures that 
include all required information.  The drug accountability inventory forms must identify 
the study drug, including batch or lot numbers and account for its disposition on a 
patient-by-patient basis, including specific dates and quantities.  The forms must be 
signed by the individual who dispensed the drug. 
5.1.3 
Preparation and Dispensing 
Only qualified personnel who are familiar with procedures that minimize undue exposure 
to them and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents. 
Study site personnel should dispense to patients the appropriate number of study drug 
units of each strength to support a 21-day cycle.  An additional number equivalent to 


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two dosing days may be dispensed at the discretion of the study site to provide for 
holidays or inclement weather.  Study drug should be dispensed in the Sponsor provided 
HDPE bottles with child resistant closures.  Patients should be made aware of the storage 
temperature requirements. 
5.1.4 
Compliance 
Study site personnel should provide each patient with dosing information and review it 
with the patient during clinic visits.  Patients will be asked to record their daily dosing on 
Sponsor provided diary cards and report any missed doses or lost study drug at the next 
clinic visit.  Patients will also be told to bring study drug bottle(s) (empty or not) with 
them to the clinic visit for a compliance check and unit count.  Study site personnel will 
record compliance information in the source document and on the CRF and retain the 
bottle(s) until a monitor has completed reconciliation.  See the Study Manual for 
additional details regarding compliance and reconciliation. 
5.1.5 
Destruction 
At the end of the study, all unused drug supplies must be destroyed in accordance with 
local Standard Operating Procedure provided to the Sponsor for the Trial Master File, or 
returned to the Sponsor or its appointed agent, as directed by the Sponsor. 
5.2 
Administration 
MGCD265 study drug will be administered orally twice daily (BID) in 21-day cycles.  
The starting dose of MGCD265 using the soft gelatin capsules was 1050 mg BID.  The 
starting dose using the SDD tablets will be 750 mg BID.  At the time of protocol 
amendment (Version 2.0) approval at each institution, newly enrolled patients will begin 
dosing at 750 mg BID with the SDD tablet formulation.  Ongoing patients who initiated 
treatment with soft-gel capsules will be allowed to switch to the SDD tablet formulation 
at their next treatment cycle.  The dose level of the SDD tablet will need to be discussed 
on a case-by-case basis with the Sponsor prior to the patient receiving the SDD tablet 
formulation. 
MGCD265 doses should be taken approximately every 12 hours at approximately the 
same times each day, on an empty stomach (1 hour fast before each dose and no food for 
a minimum of 1 hour after each dose).  Each dose should be taken with approximately 
200 mL of water.   
A food effect evaluation is currently being conducted in the MGCD265 Phase 1 study.  If 
the outcome of that evaluation indicates that patients may take MGCD265 SDD tablets 
with food, this change will be communicated to participating institutions. 
If the patient vomits after taking the study drug, s/he should not make up the missed dose 
or increase the next dose.   


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5.2.1 
Dose Modification 
Study treatment-related adverse events that are intolerable or severe will be managed by 
treatment interruption and/or dose reduction depending on the circumstance.  In response 
to observed toxicity, daily doses should be reduced by steps of at least 15-20% within the 
constraints of the available capsule or tablet dose strengths.  Necessary dose reductions 
will typically be made in sequential steps but, under some circumstances, dose reduction 
by two steps (i.e., 30-40%) may be advisable and may be considered in consultation 
between the investigator and Sponsor (See Table 5 and Table 6).  Dose reductions below 
the current guidelines may be allowed after consultation between the investigator and 
Sponsor.  Patients requiring greater than 3 weeks to recover from drug-related toxicity 
should be considered for discontinuation from study treatment.   
Table 5: 
Dose Adjustment Guidelines Soft Gel Formulation 
Soft Gel - Capsule Formulation 
Dose Level 
265 Daily Dose (BID Dose) 
Number of capsules 
(150 mg capsule strength) 
0 (Starting Dose) 
2100 mg (1050 mg BID) 
14 total (7 BID) 
-1 
1800 mg (900 mg BID) 
12 total (6 BID) 
-2 
1500 mg (750 mg BID) 
10 total (5 BID) 
 
Table 6: 
Dose Adjustment Guidelines Spray Dried Dispersion 
Formulation 
Spray Dried Dispersion – Tablet Formulation 
Dose Level 
265 Daily Dose (BID Dose) 
Number of tablets 
(100 mg and 250 mg tablet 
strength) 
0 (Starting Dose) 
1500 mg (750 mg BID) 
6 total (3 BID) 
[3-250 mg BID] 
-1 
1200 mg (600 mg BID) 
6 total (3 BID) 
[2-250 mg BID; 1-100 mg BID] 
-2 
1000 mg (500 mg BID) 
4 total (2 BID) 
[2-250 mg BID] 
 
Dosage interruptions to assess or treat intercurrent illnesses are allowed as needed in the 
judgment of the investigator. 
5.2.2 
Adverse Event Management Guidelines 
Management of toxicities ≥ Grade 3 and considered to be treatment-related should 
include treatment interruption until resolution of toxicity to ≤ Grade 1 or to baseline 


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value.  If the toxicity may be adequately managed by routine supportive care (such as 
anti-emetics, anti-diarrheals, or electrolyte supplementation), treatment may be resumed 
at the same dose; if not, treatment may be resumed at a reduced dose as described in 
Table 7.  Recurrence of the toxicity may be managed similarly.  If treatment is 
interrupted for more than 3 weeks, permanent discontinuation from study treatment 
should be considered. 
Table 7: 
Dose Modifications – Treatment-Related Toxicities 
Toxicity 
Treatment Delay 
Dose Modification 
< Grade 3  
May be implemented based on Investigator and patient discretion 
Grade 3 or 4, manageable with 
routine supportive care 
Hold until ≤ Grade 1 or return to 
baseline 
Not required 
Grade 3 or 4, not manageable 
with routine supportive care 
Hold until ≤ Grade 1 or return to 
baseline 
Resume at a dose level one or 
more levels below that inducing 
the toxicity  
 
5.2.2.1 
Management of Diarrhea 
Prevention and treatment of diarrhea should be aggressive to limit patient morbidity and 
to prevent potentially premature study drug discontinuation.  Example treatment 
regimens are recommended here and in Section 5.4.1, Concomitant Medications. 
Prophylactic anti-diarrheal treatment may be implemented at the discretion of the 
investigator.  A regimen recommended for primary prophylaxis for diarrhea is 
loperamide 2-4 mg beginning with the first dose of MGCD265, followed by 2 mg every 
6–8 hours.  Loperamide use may be titrated as needed. 
To date, diarrhea has been effectively managed after onset in most subjects by 
symptomatic treatment with Imodium® (loperamide) and, when indicated, with the 
addition of Lomotil® (diphenoxylate and atropine).  Patients treated with MGCD265 
should be given instructions to be aware of the potential of developing diarrhea while 
taking MGCD265 and to start treatment with loperamide immediately upon the first sign 
of diarrhea.  If there is no improvement in severity of symptoms within 24 hours, 
additional anti-diarrheal medication in the form of Lomotil® should be added.  If this does 
not effectively control symptoms, patients should be instructed to contact their physician 
and their dose held until resolution of symptoms followed by a dose reduction as 
indicated per protocol.  Patients with severe or prolonged diarrhea should be observed 
and treated for dehydration. 
5.2.2.2 
Management of Increased Transaminases 
Increased transaminases should be evaluated to determine whether confounding factors 
exist, such as metastatic lesions or biliary obstruction.  For cases where treatment-related 


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increases are likely, dose modifications may be made with investigator discretion in 
consideration of clinical factors.  Suggested recommendations are shown in Table 8.   
Table 8: 
Treatment Modification for Increased Hepatic Transaminase 
Toxicity 
Treatment Delay 
Dose Modification 
Grade 1 (> ULN to 3.0 × ULN) 
May be implemented based on Investigator and patient discretion 
Grade 2 (> 3.0 to 5.0 × ULN) 
Not required 
Decrease by 1 dose level 
Grade 3/4 (> 5.0 × ULN) 
Hold until ≤ Grade 1 or return to 
baseline 
Decrease by at least 2 dose 
levels for a first dose reduction; 
decrease by at least 1 dose level 
if dose is already reduced. 
 
5.2.2.3 
Management of Hy’s Law Cases 
In the event a patient develops concurrent increase in AST and/or ALT ≥ 3 × ULN, 
bilirubin ≥ 2 × ULN but without concurrent increases in alkaline phosphatase 
(i.e., alkaline phosphatase < 2 × ULN), that is not attributable to liver metastases or 
biliary obstruction, investigational study treatment should be permanently discontinued. 
5.3 
Medication Error 
Medication errors may involve patient exposure to a wrong study drug, at a wrong dosing 
frequency, or at a wrong dose level (e.g., a dose that is not planned in the study).  
Medication errors occurring during the conduct of this study will be documented as AEs 
(regardless of whether clinical signs or symptoms are observed) and if serious 
consequences are observed, will be reported on Serious Adverse Event (SAE) forms.  In 
all cases of medication error, the sponsor should be notified immediately.   
5.4 
Concomitant Therapies 
5.4.1 
Concomitant Medication(s) 
Concomitant medications must be locally-approved and used at doses and regimens that 
are considered standard of care.   
Treatment for co-morbidities, disease signs and symptoms and treatment emergent 
adverse events should be provided as necessary in the judgment of the investigator.  
Patients may continue to use any ongoing medications not prohibited by the 
inclusion/exclusion criteria or treatment plan.  Supportive medication (e.g., antiemetics, 
analgesics, anti-diarrheals, etc.) is permitted.   
Prophylactic anti-diarrheal medication may be administered at the discretion of the 
investigator as described in Section 5.2.2.1.   


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Antibiotics and analgesics should be used as needed.  Patients with neutropenic fever or 
infection should be treated promptly.  Therapeutic colony-stimulating factors should be 
used in accordance with American Society for Clinical Oncology guidelines.  Packed red 
blood cell and platelet transfusions may be administered as clinically indicated. 
5.4.2 
Concomitant Surgery or Radiation Therapy 
The use of surgery or radiation to manage cancer lesions during study treatment can 
jeopardize assessment of the primary objective of the study, evaluation of disease status; 
thus where clinically justified and possible, such treatment should be undertaken prior to 
study enrollment.   
Although bleeding events have been reported with MGCD265 treatment, there have been 
no reported bleeding complications following surgical procedures performed in subjects 
treated with MGCD265.  Significant inhibition of the VEGF receptor (VEGFR) pathway 
is not expected with MGCD265.  For patients requiring surgery while on-study, 
MGCD265 dosing should be held for 3-7 days prior to any applicable procedure when 
possible, and treatment should be re-initiated once adequate closure or healing of the 
surgical site is established.   
Any foreseeable need for palliative radiotherapy should be addressed before study entry, 
if possible and clinically appropriate (e.g., bone lesions at risk for spontaneous 
micro-fractures or painful lesions).  However, these treatments may be used on-study 
where it is medically necessary.  For patients requiring radiation while on-study, 
MGCD265 should be interrupted during the period that the patient is receiving radiation 
treatment.   
5.4.3 
Other Anticancer or Experimental Therapy 
Use of approved or investigational anticancer treatment will not be permitted during the 
study treatment period, including chemotherapy, biological response modifiers, hormone 
therapies or immunotherapy.  No other investigational drug may be used during treatment 
on this protocol.  Concurrent participation in another therapeutic clinical trial is not 
allowed.   
 
6 STUDY ASSESSMENTS  
6.1 
Screening 
Voluntary, written, dated, and signed informed consent must be obtained before any 
study specific procedures are performed.  Patients who completed the informed consent 
process but did not enroll on the study will be considered as screen failures.  Limited 
information will be recorded in the CRF for these patients.   


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6.2 
Study Period 
For details on procedures during the study period, see Schedule of Assessments as shown 
in Table 2.   
6.3 
End of Treatment Assessment 
All patients will be followed for adverse events and serious adverse events for at least 
28 days following the last dose of MGCD265.  See the Schedule of Assessments  
(Table 2) for evaluations to be performed at the End of Treatment visit.   
6.4 
Long-Term Follow-up and End of Study Assessment 
Patients will be followed for survival at two month intervals as outlined in the Schedule 
of Assessments (Table 2).  Treatments received following participation in the study will 
be collected in the CRF.   
6.5 
Patient Discontinuation/Withdrawal 
Patients may discontinue from study treatment or from the study at any time at their own 
request, or they may be discontinued at any time at the discretion of the investigator or 
Sponsor for safety, behavioral reasons, or the inability of the patient to comply with the 
protocol required schedule of study visits or procedures at a given study site.   
Criteria that may be used to discontinue patients from receipt of study medication will 
include, but will not be limited to: 
• Objective disease progression according to RECIST 1.1 as determined by the 
investigator (patients who may derive clinical benefit may continue on treatment at 
the discretion of the investigator); 
• Global deterioration of health status requiring discontinuation; 
• Adverse event; 
• Significant protocol violation; 
• Lost to follow-up; 
• Refusal for further treatment; 
• Study termination by Sponsor; 
• Pregnancy; 
• Death. 


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Reasons for discontinuation from study follow-up may include: 
• Study terminated by Sponsor; 
• Lost to follow-up; 
• Refusal for further follow-up for survival; 
• Death. 
If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient.  At least 2 attempts should be made to contact the patient, and each attempt 
should be recorded in the source documents.  In any circumstance, every effort should be 
made to document patient outcome, if possible.  The investigator should inquire about the 
reason for withdrawal, request that the patient returns for a final visit, and if applicable, 
follow-up with the patient regarding any unresolved adverse events.   
If the patient withdraws from the study treatment and also withdraws consent for 
disclosure of future information, no further evaluations should be performed, and no 
additional data should be collected.  The Sponsor may retain and continue to use any data 
collected before such refusal for further follow-up.   
 
7 PROCEDURES 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that there may be circumstances 
outside of the control of the investigator that may make it unfeasible to perform a 
protocol-specified assessment.  In these cases the investigator will take all steps 
necessary to ensure the safety and well-being of the patient.  When a protocol required 
test cannot be performed, the investigator will document in the source document and CRF 
the reason and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible.  The study team will be 
informed of these incidents in a timely fashion.   
7.1 
Molecular Testing for MET Mutations and Amplifications 
To be eligible for enrollment, patients must have documented evidence of a genetic tumor 
alteration activating MET.   
7.1.1 
Genetic Tumor Alterations Required for Study Entry 
Presence of an eligible MET gene alteration is defined as follows: 


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1. MET Mutations (based on human genome GRCh37/hg19 assembly and MET 
reference sequence NM_000245): 
o MET mutations that result in the alternative splicing or selective deletion of MET 
exon 14 as determined by gene sequencing or ribonucleic acid (RNA)-based 
reverse transcription polymerase chain reaction (qRT-PCR) analysis indicating: 
 point mutations involving c2888 or c3028 splice sites (or equivalent according 
to analytical reference standard), or  
 insertion or deletion mutations involving or proximal to c2888 or c3028 splice 
sites (or equivalent according to analytical reference standard), and/or  
 selective deletion of MET exon 14 
o MET activating mutations including but not limited to, P991S, Y1003F, Y1003N, 
Y1003*, V1070E, V1070R, V1092L, H1094L, H1094Y, H1094R, H1106D, 
M1131T, T1173I, V1188L, L1195V, V1220I, D1228H, Y1230C, Y1230H, 
Y1230D, Y1235D, Y1235H, M1250T.   
 Please note that these mutations have an alternative nomenclature based on 
GRCh37/hg19 assembly and MET reference sequence NM_001127500 as 
follows: P1009S, Y1021F, Y1021N, Y1021*, V1088E, V1088R, V1110L, 
H1112L, H1112Y, H1112R, H1124D, M1149T, T1191I, V1206L, L1213V, 
V1238I, D1246H, Y1248C, Y1248H, Y1248D, Y1253D, Y1253H, M1268T.   
2. MET Gene Amplification in tumor tissue defined by any of the following: 
o Loose or tight clusters of MET too numerous to count as determined by 
MET 2-color fluorescent in situ hybridization (FISH)  
o MET/CEP7 ratio of > 5.0 in > 10% of evaluated cells as determined by 
MET 2-color FISH 
o Greater than or equal to 10 copies of MET per nucleus as determined by 
MET 2-color FISH  
o Greater than 8 copies in an appropriate molecular assay (DNA sequencing-based 
platform).   
For ctDNA based analysis, a positive result for MET mutation or gene amplification by 
the Sponsor-provided central laboratory (Guardant) is required.   
The method used to establish eligibility and the result will be documented in the patient’s 
site source documents and the CRF.   


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7.2 
Molecular Testing Methods 
Potential study candidates will undergo molecular testing of tumor tissue or blood in 
order to first establish eligibility of molecular alterations; those patients with qualifying 
mutations will then undergo clinical screening, and eligible patients [based on both 
qualifying mutation(s) and clinical screening] will then be assigned into a patient 
treatment arm upon confirmation of study eligibility.   
Testing of tumor tissue is prioritized over ctDNA for the purpose of determining 
eligibility for this study.  Tumor tissue samples preferred for testing are the most recent 
tumor sample available; however, testing may be performed on samples taken any time 
during the disease course.  Testing may be performed on primary, recurrent, or metastatic 
lesions.  Biopsies having significant risk should not be performed for the purpose of 
determining patient eligibility, including but not limited to biopsies of the 
lung/mediastinum or endoscopic procedures extending beyond the esophagus, stomach, 
or bowel.  However, in the event that a patient desires to consider study participation and 
no tumor specimen is available, procedures having less risk may be considered.   
Tumor tissue or ctDNA may be tested using the Sponsor-provided central laboratory or a 
Sponsor-approved local laboratory to establish eligibility, with follow-up tissue or 
ctDNA sample(s) retrospectively analyzed in the Sponsor-provided central laboratory.   
Qualifying results by ctDNA testing may be the basis for study eligibility if the search to 
locate tumor tissue that is suitable for testing shows that none exists.   
The analytical techniques employed by the Sponsor-provided central laboratories and 
criteria for acceptable genetic tumor alterations for this study are described in the Study 
Laboratory Manual.  Included are: 
1. Gene panels for the next generation sequencing tests for tumor tissue and ctDNA 
samples,  
2. List of MET mutations known to be activating,  
3. Description and use of RT-PCR for detection of MET exon 14 deletion mutations, and 
4. Definitions for quantitative thresholds for positive test results. 
If study eligibility is to be based on tumor tissue or ctDNA testing at the 
Sponsor-provided central laboratory, a 14-day turn-around time should be expected from 
the time of receipt of adequate samples at the central lab to test results returned to the 
study site.  Questions concerning adequacy of samples will result in delays beyond this 
timeframe.  It is possible that testing could be more rapid, e.g., 8-10 days, but the patient 
and site should be prepared to wait for confirmation of eligibility for the full duration. 


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The laboratories employed by the Sponsor to perform initial or retrospective 
confirmatory evaluation of tumor gene alterations are certified by Clinical Laboratory 
Improvement Amendments (CLIA).  Guidance on sample preparation and submission 
can be found in the Study Laboratory Manual. 
The following laboratories are considered Sponsor-approved local laboratories for this 
study and prospective confirmation of eligibility from our central laboratory is not 
required prior to enrollment.  Additional Sponsor-approved local laboratories may be 
added during the study.  Tissue and ctDNA samples for retrospective analysis are 
requested for all patients that are enrolled based on a Sponsor-approved local laboratory 
test: 
• FoundationOne®, a commercially available next generation gene sequencing test for 
tumor tissue performed by Foundation Medicine, Inc. 
• Caris Molecular Intelligence ®, a commercially available next generation gene 
sequencing test for tumor tissue performed by Caris Life Sciences.   
• Guardant360®, a commercially available next generation gene sequencing test for 
ctDNA performed by Guardant Health. 
On a case-by-case basis, information in addition to what is typically reported for 
commercial tests may be needed from Foundation Medicine, Caris Life Sciences and 
Guardant to make a final determination of eligibility (e.g., quantitative results for gene 
amplification). 
Positive results from a site-specific local laboratory that may meet the criteria for 
molecular profiling eligibility will need to be confirmed by the Sponsor-provided central 
laboratory prior to full clinical screening.   
7.3 
Efficacy 
All patients enrolled in the study are to be evaluated for disease activity as outlined in the 
Schedule of Assessments (Table 2).  Disease assessments are to be performed as 
scheduled according to the calendar days regardless of treatment delays.  On-study 
assessments will be performed at 6 week intervals until approximately 1-year and then 
every 12 weeks.  The allowable windows for assessments are 4 weeks prior to first study 
treatment for screening/baseline assessments and ±10 days for on-study disease 
assessments.  CT scans should be performed with contrast agents unless contraindicated 
for medical reasons.  If intravenous contrast is medically contraindicated, the imaging 
modality to be used (either CT without contrast or MRI) should be the modality which 
best evaluates the disease, and the choice should be determined by the investigator in 
conjunction with the local radiologist.  Depending on the adequacy for evaluation of 
disease, a combination of CT without contrast and MRI should most often be used.  CT 
without contrast is preferred for evaluation of lesions in lung parenchyma.  MRI is not 


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adequate for evaluation of lung parenchyma but should also be performed to evaluate all 
other aspects of the chest.  MRI of the abdomen and pelvis should substitute for CT with 
contrast unless the method does not adequately depict the individual’s disease, in which 
case CT without contrast is preferred.   
For patients having effusions or ascites, cytological proof of malignancy should be 
obtained prior to selection of the effusion as a non-target lesion.  Effusions that have not 
been evaluated using cytology or were found to be non-malignant should not be 
considered to be cancer lesions. 
Screening/baseline tumor assessments should include CT or MRI of the chest and 
abdomen, pelvis, whole body bone scan, MRI of the brain and evaluation of any 
superficial lesions.  For those sites that routinely use PET scans for assessment of bone 
lesions in lieu of skeletal scintigraphy, PET scans may be used on-study, with the same 
modality planned throughout the study for any given patient.  CT or MRI of the chest, 
abdomen, and pelvis will be conducted at every subsequent assessment.  Disease 
assessments subsequent to baseline assessment should also include whole body bone 
scans and/or MRI of the brain if metastatic disease is identified at screening/baseline by 
either the investigator OR the central radiology reviewer.  Bone scans may be performed 
at one-half the frequency (every 12 weeks) of other disease assessments.  All other 
suspected sites of disease should be evaluated at each assessment.  Disease response will 
be assessed in accordance with RECIST 1.1 (Eisenhauer-2009).  Appendix 2 provides 
guidance in using the response criteria and includes a modification to RECIST 1.1 to 
address potential temporary treatment effects such as tumor lesion cavitation.  
Assessments will be performed until objective disease progression is documented by the 
investigator, or subsequent anti-cancer therapy is begun.   
Patients experiencing tumor response (Partial Response [PR] or Complete Response 
[CR]) should undergo confirmatory assessment at least 4 weeks after initial 
documentation of response.  It is acceptable to perform confirmatory assessments at the 
next appointed evaluation per protocol.  Bone scan is required as an element of the 
assessment of PR or CR response confirmation if bone lesions were identified at the 
baseline assessment.  When bone scans are not protocol-specified, assessment for time 
point response will be based on assessment of all other lesions with imputation of 
Non-CR/Non-PD for bone lesions recorded as non-target lesions. 
The investigator’s assessment of disease response and progression will be the basis for 
patient management and study expansion decision making.  Potential exists for individual 
tumor lesions to cavitate or become otherwise difficult to evaluate for a period of time as 
the result of beneficial study treatment impact.  For example, tumor necrosis and 
cavitation may result in minor increase in overall individual lesion size or unclear tumor 
margins prior to recovery to a smaller lesion, development of scar tissue, or complete 
resolution.  For this reason, investigators may delay reaching the conclusion of disease 
progression until subsequent on-study disease assessments are performed.   


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Central radiology review for disease response and progression will be performed in this 
study and will be the basis for the primary statistical analysis used to estimate the 
objective response rate and its confidence interval as well as the duration of response and 
PFS.  Materials to be forwarded for independent review will be all imaging studies 
performed at screening and on study, preferably in digital format, using an electronic 
transfer through a portal to the review vendor or transfer on compact disc or optical disc.  
All digital media must be in DICOM format.  Films may be forwarded for review if 
necessary; all films must be originals (second original films acceptable) rather than 
copies of films.  Further information on materials to be forwarded for independent review 
is provided in the core imaging laboratory Study Manual. 
7.4 
Safety Assessments 
7.4.1 
Adverse Events 
Assessment of adverse events will include type, incidence, severity (graded by the 
National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events 
[CTCAE, Version 4.03]), timing, seriousness, and relatedness to study treatment. 
Signs and symptoms of the patient’s cancer diagnosis and/or comorbidities present at 
baseline will be recorded in the CRF as adverse events.  Treatment-emergent adverse 
events will be reported separately from signs and symptoms of the patient’s cancer 
diagnosis and/or comorbidities that are present at Day 1.  The actual date of onset should 
be recorded in all cases.  Ongoing AEs that change in attribution or severity should have 
the date of change entered as the “end date” and a new AE record should be opened with 
the changed details.   
7.4.2 
Physical Examination and Vital Signs 
A physical examination including all major body systems is mandated at Screening and 
End of Treatment Visits only.  During study treatment, symptom directed physical 
examinations will be performed.   
Vital signs to be assessed include weight, body temperature, blood pressure, and pulse 
rate.  Height will be recorded at screening only.  On days when both vital signs and PK 
sampling are scheduled, the vital signs should be assessed prior to blood sampling.   
Clinically significant findings noted during screening will be reflected on the medical 
history CRF, while those noted during study treatment will be collected on the AE CRFs.   
7.4.3 
Laboratory Safety Assessments 
Laboratory safety assessments for which data will be collected in this study will include 
hematology, coagulation, and chemistry parameters presented in Table 9.   


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Laboratory tests will be drawn at the time points described in the Schedule of Assessment 
table and analyzed at local laboratories.  Additional laboratory tests may be performed 
per standard of care, at the investigator's discretion for the purpose of planning treatment 
administration, dose modification, following adverse events, or as clinically indicated.   
Table 9: 
Laboratory Safety Parameters 
Hematology Panel 
Blood Chemistry Panel 
Hemoglobin 
Aspartate aminotransferase (AST) 
Platelet count 
Alanine aminotransferase (ALT) 
White blood cell count (WBC) 
Alkaline phosphatase 
Neutrophil count 
Total bilirubin 
Lymphocyte count 
Creatinine 
Eosinophil count 
Uric acid 
Basophil count 
Albumin 
Monocyte count 
Sodium 
 
Potassium 
Coagulation 
Chloride 
International normalized ration (INR) 
Total calcium 
Partial thromboplastin time (PTT) 
Phosphate 
 
Magnesium 
 
Pregnancy Testing: For patients of childbearing potential, a serum or urine pregnancy test 
will be performed at screening.  Pregnancy tests will also be done whenever pregnancy is 
suspected during the study.  Additional pregnancy testing may be necessary if required by 
local practices or regulations.   
7.4.4 
Electrocardiogram (ECG)  
Single and triplicate ECGs are to be performed as outlined in the Schedule of 
Assessments.  It is preferable that the machine used has a capacity to calculate the 
standard intervals automatically.  Assessments reported by automated read as 
prolongation of QTc > 480 msec should be over-read by a cardiologist to ensure accuracy 
of interpretation. 
7.5 
Laboratory Studies 
Laboratory studies for which blood will be collected include evaluation of PK, PD and 
ctDNA.  The schedules for sample collection are outlined in Table 2 and Table 3.  Blood 
samples will be collected using an in-dwelling catheter or venipuncture into specified 


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vacutainer tubes.  Full details on sample processing, storage and shipment are presented 
in the Study Laboratory Manual. 
7.5.1 
Pharmacokinetic Evaluation 
The PK of MGCD265 will be determined using plasma samples collected at specified 
time points prior to and following study treatment dosing.  Every effort will be made to 
collect these PK samples at the exact nominal times relative to dosing.  A variation 
window is allowed for each time point as outlined in Table 3.  The actual time of drug 
administration and each PK sample collection will be recorded in the patient’s source 
document and the CRF. 
At each PK time point, blood samples will be collected into 6-mL K2EDTA tubes.  For 
PK analysis, a total of approximately 48 mL of blood will be collected from each patient.  
Analysis of plasma samples for MGCD265 will be performed using specific validated 
bioanalytical methods.   
7.5.2 
Pharmacodynamic Evaluation 
Pharmacodynamic parameters that may be investigated in this study include but are not 
limited to plasma levels of hepatocyte growth factor (HGF) and shed-MET receptor, prior 
to and during treatment.  At each PD time point, whole blood samples will be collected 
into 10-mL K2EDTA tubes.  For PD analysis, a total of approximately 40 mL of blood 
will be collected from each patient. 
7.5.3 
Circulating Tumor DNA 
Blood samples for ctDNA analysis will be collected at pre-screening or baseline, at the 
time of disease evaluation to confirm a disease response (PR or CR) and at the End of 
Treatment visit, as outlined in Table 2.  For patients who are enrolled based on 
prospective ctDNA testing, an additional sample may be requested prior to dosing to 
ensure adequate amounts of blood have been received to complete the remainder of 
analyses required per protocol.  Parameters that will be evaluated include but are not 
limited to MET mutations, MET gene amplification, MET gene rearrangement, and other 
genetic mutations or gene copy number changes associated with the pathogenesis of 
human cancers.   
At each ctDNA time point, blood samples will be collected into two 10mL Streck brand 
Cell-Free DNA Blood Collection tubes allowing shipping and stability at ambient 
temperatures.  For ctDNA analysis, the total volume of blood to be collected between 
pre-screening and End of Treatment will be up to approximately 60 mL of blood.   


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7.6 
Post-treatment Follow-up 
Post-treatment follow-up for survival will be conducted by telephone contact or other 
methods every 2 months (± 14 days) until death or lost to follow-up.  Treatments received 
subsequent to study participation will be collected and recorded in the CRF. 
 
8 ADVERSE EVENT REPORTING 
8.1 
Sponsor Medical Monitor Personnel 
The contact information for the sponsor's Medical Monitor personnel for this trial is 
available in the study contact list located in the Study Manual. 
8.2 
Adverse Events 
An adverse event (AE) is any reaction, side effect or other undesirable medical event that 
occurs during participation in a clinical trial, regardless of treatment group or suspected 
causal relationship to study treatment.  All observed or volunteered AEs will be recorded 
in source documents and reported in the CRF.  The best available medical terminology 
should be used to describe AEs in source documents and CRFs.  Terms describing the 
diagnosis are preferred over individual signs and symptoms of the diagnosis.  If 
determination of the diagnosis is delayed, record signs and symptoms and add the 
diagnosis as an additional AE when available; follow all recorded AEs to resolution.  
Examples of AEs include but are not limited to:   
• Signs or symptoms of co-morbidity, illness, or toxicity of study treatment; 
• Signs or symptoms of worsening malignancy under study (disease progression 
assessed by measurement of malignant lesions should not be reported as an AE). 
• Laboratory abnormalities (see Section 8.2.1 for guidance for reporting in CRF); 
• Hypersensitivity; 
• Drug abuse, dependency, overdose, withdrawal or misuse; 
• Signs or symptoms of drug interactions; 
• Extravasation; 
• Exposure during pregnancy or via breastfeeding; 
• Medication error; or 
• Occupational exposure. 


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8.2.1 
Laboratory Abnormalities 
An abnormal laboratory test results should be reported as an AE in the CRF only if it is 
associated with one or more of the following:  
• Clinical symptoms; 
• Requires additional tests (beyond repeats), treatment or intervention; 
• Results in change in study treatment dosing; 
• Requires discontinuation from study treatment; and/or 
• Considered by the investigator or Sponsor to be an AE. 
Hy’s Law 
Hepatic function abnormality defined by an increase in AST and/or ALT to ≥ 3 × ULN 
concurrent with an increase in total bilirubin to ≥ 2 × ULN but without increase in 
alkaline phosphatase (i.e., alkaline phosphatase < 2 × ULN) meets the criteria for Hy’s 
Law and raises the concern for drug-induced liver injury when no other cause of the 
abnormal laboratory results is identified.  Follow-up investigations and inquiries will be 
initiated promptly by the investigational site to determine whether the findings are 
reproducible and/or whether there is objective evidence that clearly supports causation by 
a disease (e.g., cholelithiasis and bile duct obstruction with distended gallbladder) or an 
agent other than the investigational product. 
Cases meeting Hy’s Law should be reported as SAEs.  Study drug should be permanently 
discontinued for a Hy’s Law case.   
8.2.2 
Severity Assessment 
AEs occurring during this study will be graded in accordance with the NCI CTCAE 
Version 4.03.  Documentation of AE grading in the source documents and CRF should be 
consistent with provided definitions. 
8.2.3 
Causality 
For each AE, the investigator should determine and document whether there exists a 
reasonable possibility that the study treatment caused or contributed to the AE.  The 
investigator’s assessment should be recorded in the source document.  The CRF will 
provide the options for attribution to study treatment as “related” and “not related.” If the 
investigator's causality assessment is "unknown but not related to investigational 
product," this should be recorded in the CRF as “not related.” If the investigator does not 
know whether or not the study treatment is causally-related to the event, reporting for 
study purposes will be as “related” to study treatment.   


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Collection of causal relationship for AEs associated with study procedures (e.g., tumor 
biopsy) is provided for separately in the CRF.   
8.3 
Serious Adverse Events 
8.3.1 
Definition of a Serious Adverse Events 
An SAE is any event that meets any of the following criteria: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/permanent damage (substantial 
disruption of the ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
• Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon 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.  
Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
Progression of the malignancy under study, including any signs or symptoms of 
progression that may require hospitalization, should not be reported as an SAE unless the 
outcome is fatal within the safety reporting period.   
Definition of Terms 
Life threatening: An AE is life threatening if the patient was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a 
more serious form might have caused death.  For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening 
even though drug-induced hepatitis can be fatal. 
Hospitalization: Hospitalization for elective surgery or routine clinical procedures that are 
not the result of AE (e.g., elective surgery for a pre-existing condition that has not 


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worsened) need not be considered AEs or SAEs.  If anything untoward is reported during 
the procedure, that occurrence must be reported as an AE, either 'serious' or 'non-serious' 
according to the usual criteria. 
In general, hospitalization signifies that the patient has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient 
setting.  When in doubt as to whether 'hospitalization' occurred or was necessary, the AE 
should be considered serious. 
Disability/permanent damage: An AE is disabling or caused permanent damage if it 
resulted in a substantial disruption of a person’s ability to conduct normal life functions, 
e.g., a significant, persistent or permanent change, impairment, damage or disruption in 
body function/structure, physical activities and/or quality of life.   
8.3.2 
Exposure During Pregnancy 
Exposure during pregnancy (i.e., exposure in-utero [EIU]) may occur in a female study 
participant, the female partner of a male study participant or study site personnel working 
with the investigational product (e.g., occupational exposure) if: 
• A female becomes or is found to be pregnant during treatment or within 6 months 
after discontinuing treatment or having been directly exposed to the investigational 
product;  
• A male is exposed to the investigational product prior to or around the time of 
conception or during the pregnancy of his partner. 
If exposure in-utero occurs, the investigator must submit an SAE form and an EIU 
Supplemental Form within 24 hours of awareness of the exposure, regardless of whether 
an AE or SAE has occurred.   
In the event of pregnancy in a female study participant, if the pregnancy is continued, 
study treatment will be immediately discontinued. 
In the event of exposure of the pregnant partner of a male study participant, the study 
participant should be asked to deliver an EIU Pregnant Partner Release of Information 
Form to his partner.  The Investigator must document on the EIU Form that the patient 
was given this letter to provide to his partner. 
Follow-up to obtain pregnancy outcome information is to be conducted for all EIU 
reports.  In the case of a live birth, the health of the neonate should be assessed at the 
time of birth and for up to 3 months after birth.  Further follow-up of birth outcomes will 
be handled on a case-by-case basis (e.g., follow-up on preterm infants to identify 
developmental delays).  In the event the pregnancy is terminated, the reason(s) for 


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termination should be reported and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection. 
If the outcome of the pregnancy meets the criteria for an SAE (i.e., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly), 
an SAE report should be submitted to the Sponsor. 
8.4 
Reporting of SAEs and AEs 
8.4.1 
Reporting Period 
The active reporting period for SAEs begins from the time that the patient provides main 
study informed consent (i.e., prior to undergoing any study-specific procedure or 
assessment) and continues until all SAEs have resolved or stabilized to a chronic 
condition, whichever is later.  Death must be reported if it occurs during the active 
reporting period for SAEs regardless of whether a subsequent anticancer therapy is 
administered.  Serious adverse events occurring to a patient after the active reporting 
period has ended should be reported to the Sponsor if the investigator becomes aware of 
them and if the investigator assesses at least a reasonable possibility of being related to 
study drug.   
The reporting period for non-serious AEs begins from the day of first dose of study 
treatment and continues until at least 28 days after last administration of study treatment 
and/or until recovery from all acute toxicities associated with the drug administration to a 
chronic condition, whichever is later.  If a patient begins a subsequent anticancer therapy, 
the AE reporting period ends at the time the new treatment is started.   
8.4.2 
Reporting Requirements 
All SAEs must be reported within 24 hours of Investigator/site knowledge of the event, 
irrespective of the extent of available AE information, by faxing the SAE report to the 
Sponsor’s pharmacovigilance representative designated in the Study Manual.  The 
24-hour timeframe also applies to additional new information (follow-up) on previously 
forwarded SAE reports and to the initial and follow-up reporting of exposure during 
pregnancy and exposure via breastfeeding.  The need for an expedited report to 
regulatory authorities will be determined by the Sponsor and necessary reporting will be 
performed by the Sponsor.  The Sponsor will notify study investigators of all Suspected, 
Unexpected (as judged against the Investigator Brochure) Serious Adverse Reaction 
(SUSAR) reports.  The investigator is responsible for reporting all SUSARs to the 
IRB/EC.   
All AE (including SAEs) must be documented in source documents and reported in the 
CRF.  Please note that the CRF and SAE report forms may collect information in 
somewhat different formats.  Where the requested data overlap in different formats, the 
information should be consistent between the two forms.   


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9 STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be maintained 
by the Sponsor.  The SAP may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 
9.1 
Hypothesis and Sample Size 
This Phase 2, parallel-arm study will use a Bayesian Predictive Probability Design 
(Lee-2008) that minimizes the number of patients enrolled to test the hypothesis.  The 
design will be applied separately and using the same assumptions in each of 
four treatment arms.  As many as 45 patients are planned for inclusion in the primary 
analysis for each treatment arm.  The study also provides for the addition of up to 
55 patients to each of two treatment arms to provide sufficient safety and/or efficacy data 
to support an accelerated approval market application in two study populations.  Thus, 
the ultimate sample size for this study could include as many as 290 patients. 
ORR in accordance with RECIST v1.1 is the primary endpoint.  With currently available 
treatments, ORR is assumed to be 20% (p0), thus this rate is considered uninteresting.  
The target ORR using MGCD265 in this study is 40% (p1).  The trial will monitor the 
number of observed responses continuously after evaluating the first on-study disease 
assessments of the first 10 patients in each treatment arm in the mITT population.  In 
creating the statistical design, the Type 1 error (α) is constrained to < 0.05 and Power 
(1-β) is constrained to ≥ 0.90. 
Using the parameters identified, the ultimate sample size for each treatment arm is as 
many as 45 patients in the mITT population.  The stopping rules (rejection regions), 
expressed as number of responses per patients treated, are 0/10, 1/14, 2/18, 3/22, 4/26, 
5/29, 6/32, 7/35, 8/37, 9/39, 10/41, 11/43, 12/44, and 13/45.  Thus, if more than 
13 responses are observed among the first 45 patients enrolled who meet the criteria for 
the mITT population, the drug will be declared efficacious.  If the true ORR is 20% (null 
hypothesis), the probability of early termination (under H0) during the study is 0.92 and 
the expected sample size prior to termination is 28 patients.  The Type 1 error is equal to 
0.0499 and Power equal to 0.9065.  If the true ORR is 40%, the probability of rejecting 
the hypothesis at each evaluation of the stopping rules varies, but cumulatively is 0.0935.  
If the true ORR is 40% and N=45, the exact 95% confidence interval (Clopper-Pearson) 
around the point estimate for ORR will be (25.7, 55.7).  If the outcome in a treatment arm 
is promising and the option is taken to enroll up to 100 patients in the mITT in a specific 
treatment arm (45 patients in the initial arm plus 55 patients), to narrow the confidence 
interval around the ORR point estimate and to increase the size of the safety database, the 
exact 95% confidence interval around a true ORR of 40% will be (30.3, 50.3).  Data 
collected in patients enrolled beyond the planned Phase 2 sample size will be used in 
secondary and supportive analyses.  The primary analysis includes independent 


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evaluation of each of the four treatment arms in the first 45 patients; study expansion 
enables confirmation of the results of the primary analysis.  The use of the Bayesian 
Predictive Probability Design within each arm effectively controls the overall Type I 
error to a maximum of 5% for each population of interest. 
9.2 
Data Handling 
Listings of all patient data will be prepared.  Data summaries will be presented in tabular 
and/or graphical format and summarized descriptively, by the four groups of patients 
having genetic tumor alterations activating MET, where appropriate.  If some (or all) of 
those four groups of patients show similar objective response rate, data summaries 
(efficacy and safety) will also be presented for those groups combined as supportive 
analyses.  Response rates will be considered similar between groups, if they are within 
± 10%.  Further details of planned analyses will be described in the SAP.   
For all variables, only the observed data from patients will be used in the statistical 
analyses; there is no plan to estimate missing data.  Patients without a valid clinical 
response assessment will be assigned a best overall response of not evaluable (NE).  Data 
from patients who are lost to follow-up or have missing observations before reaching an 
endpoint in any of the time-to-event analyses will be treated as censored with specific 
rules defined in the SAP. 
9.3 
Analysis Populations 
9.3.1 
Modified Intent-to-Treat Population 
The Modified Intent-to-Treat (mITT) population is defined in each arm as all patients 
who receive treatment at least one dose of MGCD265 on this study. 
The primary efficacy analyses of the primary and secondary efficacy endpoints will be 
performed in the mITT population.   
9.3.2 
Safety Population 
The Safety population is defined as all patients who received at least 1 dose of 
MGCD265 and will be equivalent to the mITT population for this study.  The Safety 
population will be used for all safety analyses. 
9.3.3 
Molecular Marker Evaluable Population 
The molecular marker evaluable population will consist of all patients in the mITT 
population for whom results of gene alteration tests in tumor tissue and/or ctDNA are 
available. 


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9.3.4 
Pharmacokinetic Evaluable Population 
The Pharmacokinetic evaluable population will consist of all patients in the mITT 
population who had sufficient concentration-time data to permit population PK analysis 
for MGCD265.  For patients who were noncompliant with respect to administration of 
MGCD265, or for patients with incomplete data, a decision as to their inclusion in the 
analysis will be made on a case-by-case basis. 
9.3.5 
Pharmacodynamic Evaluable Population 
The Pharmacodynamic evaluable population will consist of all patients in the mITT 
population for whom PD samples are collected. 
9.4 
Efficacy Endpoint Definitions and Analyses 
9.4.1 
Objective Response Rate 
Objective disease response will be categorized in accordance with RECIST v1.1 
(Appendix 2).  Objective Response Rate (ORR) is defined as the percent of patients 
documented to have a confirmed Complete Response (CR) or Partial Response (PR), as 
reported by the central review laboratory.  The primary analysis will be conducted 
approximately 12 weeks after the last patient is enrolled, allowing for observation of an 
early disease response and confirmation of PR or CR.  ORR as reported by the 
investigator in the CRF will be used in secondary and supportive analyses as well as by 
the Internal Data Monitoring Committee for purpose of decision making using the 
Bayesian Predictive Probability Design. 
Descriptive statistics (frequency and percentage) for ORR, CR, and PR will be presented.  
The exact 95% confidence interval of these response rates will be constructed.  An exact 
test for single proportion (two-sided α=5%) will be performed to test H0: ORR ≤ 20% 
against H1: ORR > 20%.  Other details will be described in the SAP. 
9.4.2 
Duration of Response 
Duration of Response (DR) is defined as the time from date of the first documentation of 
objective tumor response (CR or PR) to the first documentation of Objective Progression 
of Disease (PD) or to death due to any cause in the absence of documented PD.  
Censoring for the DR endpoint will be assigned on the date of the last tumor assessment 
if no assessment of tumor progression is identified by the central radiology review and 
the patient does not die while on study.  DR will only be calculated for the subgroup of 
patients with an objective response.  The Kaplan-Meier method will be used to obtain the 
estimate of median DR.   


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9.4.3 
Progression Free Survival 
Progression-free survival (PFS) is defined as the time from date of first study treatment to 
first PD or death due to any cause in the absence of documented PD.  Censoring for the 
PFS endpoint will be assigned on the date of the last tumor assessment if no assessment 
of tumor progression is identified by the central radiology review and the patient does not 
die while on study.  For patients in whom two or more sequential assessments are missed, 
followed by the finding of tumor progression, the PFS endpoint will be censored on the 
date of the last tumor assessment before the gap.  Patients lacking an evaluation of 
disease after first study treatment will have their PFS time censored on the date of first 
dose with duration of 1 day.  Patients who start a new anti-cancer therapy prior to 
documented PD will have the endpoint censored at the date of the last tumor assessment 
prior to the start of the new therapy.  The Kaplan-Meier method will be used to obtain the 
estimate of median progression-free survival time.   
9.4.4 
Overall Survival 
Time to death is defined as the time from date of first study treatment to death due to any 
cause.  Censoring for the survival endpoint will be assigned on the date of the last 
on-study follow-up that the patient is reported to be alive.  The Kaplan-Meier method 
will be used to estimate the median OS and 1-year Survival Rate; the 95% confidence 
interval of the 1-year survival rate will also be reported.   
9.5 
Safety Data Presentations and Summaries 
9.5.1 
Adverse Events 
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  Listings will include the verbatim term, preferred term, 
and system organ class (SOC).  The number of patients with AEs and the incidence of 
AEs by SOC and preferred term will be summarized.  AEs will be summarized by 
maximum intensity and relationship to study therapy.  Separate summaries will be 
provided for AEs, SAEs, treatment-related AEs, treatment-related SAEs, and other 
significant AEs (e.g., AEs leading to study discontinuation). 
9.5.2 
Prior and Concomitant Medications 
Collected prior and concomitant medications will be coded by WHO medical dictionary; 
patients who received these medications will be listed and summarized.   
9.5.3 
Clinical and Laboratory Assessments 
Clinical and laboratory assessments include clinical laboratory tests (hematology, 
coagulation, and chemistry), vital signs, and 12-lead ECGs.   


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Clinical laboratory results will be listed by patient and, as appropriate, summarized 
descriptively, which will include a display of change from baseline.  Selected parameters 
will be presented in shift tables of baseline against worst grade test result.  Laboratory 
values outside of the normal ranges will be identified.  Laboratory values that meet Grade 
3 or 4 criteria according to NCI CTCAE v.4.03 will be listed and summarized. 
ECG assessments will be evaluated for change of QTc from baseline as an exposure: 
response analysis.  The investigator’s interpretation of QTc will be used in the clinical 
management of patients.  The study analysis will use Fridericia’s formula applied 
programmatically to the ECG data collected in CRFs.   
Vital signs and ECG measurements will be listed for each patient at each visit.  
Descriptive statistics of observed values and changes from baseline will be summarized 
by treatment group. 
9.5.4 
Patient Demographics, Baseline Characteristics and Disposition 
Presentations of patient characteristics will include a summary of the following for all 
patients enrolling in the study: 
• Demographics 
• Baseline disease characteristics 
• Pre-existing conditions/concurrent illness 
• Prior therapies/surgeries 
A summary of patient enrollment and disposition will include reasons for study 
discontinuation. 
9.5.5 
Analysis of MGCD265 Dosing 
MGCD265 administration will be described in terms of the total number of cycles 
administered, the median (range) of cycles administered, dose intensity, and reasons for 
the deviations from planned therapy. 
9.6 
Other Study Endpoints 
9.6.1 
Pharmacokinetic/Pharmacodynamic Analysis 
The PK exposure and PD data from this study may be used in the development of 
population PK and PK/PD models for MGCD265.  Additional PK parameters may be 
defined and described in the Pharmacokinetic Analysis Plan.  Plasma concentrations will 
be listed by subject for the PK Population.  Summary statistics of MGCD265 
concentrations will be reported by Day and Cycle.  Only samples with acceptable PK 


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(as defined in the Pharmacokinetic Analysis Plan) will be included in the summary 
statistics and a listing of individual data points or subjects excluded from the analysis will 
be presented.   
9.6.2 
Gene Alterations in Tumor DNA 
Tumor tissue and ctDNA genetic alterations activating MET will be presented 
descriptively, by treatment arm.  Moreover, change-from-baseline in ctDNA will be 
presented by visit and treatment arm to assess change in genetic alteration status in 
ctDNA with MGCD265 treatment over time. 
A concordance analysis will be conducted between target gene alterations identified in 
tumor tissue versus ctDNA in individual patients at prescreening/baseline.  Cohen's 
Kappa, sensitivity and specificity will be estimated for ctDNA as well as Spearman's 
correlations between tumor tissue and ctDNA.   
An analysis of covariance will be performed on changes in ctDNA through time 
including Time and Treatment as fixed effects and ctDNA at baseline as covariate. 
Further details of the analyses will be presented in the SAP.   
9.7 
Interim Analysis 
No interim statistical analysis is planned during this study.  However, ORR will be 
evaluated throughout the study as per the Bayesian Predictive Probability Design in order 
to decide whether or not a group should be stopped for lack of tumor response. 
9.8 
Internal Data Management Committee 
Interim data will be reviewed for the purpose of study expansion decision making.  The 
Internal Data Monitoring Committee (IDMC) will be comprised of a limited group of 
Sponsor representatives not directly involved in the conduct of the study.  The IDMC will 
review emerging data in accordance with a separate charter.  Investigators will be 
informed of enrollment decisions but details of efficacy results will be protected until 
communication points specified in the IDMC charter.   
9.9 
Evaluation of Enrollment Stopping Rules 
Disease response and progression as documented by the investigator in the CRF will be 
the basis for evaluation of the enrollment stopping rules.  The following guidelines will 
apply to each treatment arm when determining number of events in the numerator and 
denominator in the stopping rules: 
 
 


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1. The numerator will include patients with objective responses (PR or CR) at any time 
prior to disease progression as assessed by the investigator and documented in the 
CRF.  Unconfirmed responses will be included until sufficient time has elapsed to 
allow confirmation of response; if the response is not confirmed, the response will be 
excluded from the numerator during subsequent reviews.   
2. The denominator will include:  
a. Patients included in the numerator;  
b. Patients discontinued from treatment;  
c. Patients at the second or subsequent on-study disease assessment (scheduled after 
4 treatment cycles, at Week 13) without PR, CR or PD (i.e., patient has Stable 
Disease [SD] or Not Evaluable [NE]).   
3. The denominator will exclude:  
a. Patients on treatment that have not yet reached the first on-study disease 
assessment;  
b. Patients on treatment with SD or NE at the first on-study disease assessment 
(scheduled after 2 treatment cycles, at Week 7).   
At each evaluation of stopping rules, the contribution of each participant’s experience to 
the numerator or denominator will be updated based on current data.  For example, a 
patient having SD at Week 13 may contribute only to the denominator at one evaluation, 
but be included also in the numerator at the next evaluation based on new data 
documenting PR or CR at Week 19. 
A degree of discordance is expected between investigator assessments of disease 
response/progression and central review of disease response/progression.  No attempt 
will be made to retrospectively apply the later emerging central review assessments to the 
enrollment stopping rules.   
The IDMC may elect to apply the Bayesian Predictive Probability Design only to those 
patients taking the SDD formulation in order to mitigate the potential confounding effects 
from formulation change.  These details are outlined in the IDMC charter. 
 
 
 


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10 ETHICS AND RESPONSIBILITIES 
10.1 Ethical Conduct of the Study 
This study will be conducted in accordance with International Ethical Guidelines for 
Biomedical Research Involving Human Patients (Council for International Organizations 
of Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International 
Conference on Harmonization [ICH] 1996), and concepts that have their origin in the 
Declaration of Helsinki (World Medical Association 1996, 2008 & 2013).  Specifically, 
this study is based on adequately performed laboratory and animal experimentation; the 
study will be conducted under a protocol reviewed and approved by an IRB/EC; the study 
will be conducted by scientifically and medically qualified persons; the benefits of the 
study are in proportion to the risks; the rights and welfare of the patients will be 
respected; the physicians conducting the study do not find the hazards to outweigh the 
potential benefits; and each patient will give his or her written informed consent before 
any protocol-driven tests or evaluations are performed. 
10.2 Obligations of Investigators 
The Investigator is responsible for complying with the protocol and all applicable 
regulations and guidelines governing clinical research.  Additionally, he/she is 
responsible for ensuring that all participating staff members are adequately trained and 
competent to perform his/her assigned tasks. 
All Investigators must provide the sponsor with a current curriculum vitae.  Only 
Investigators and designated Sub-Investigators are permitted to sign CRFs and 
examination findings (e.g., laboratory results or ECGs). 
The Investigator or designee is responsible for informing the patient of all available 
information relevant to his/her safety and obtaining signed, written consent from all 
participating patients.  Additionally, the Investigator is responsible for monitoring patient 
safety and providing periodic and requested reports to the IRB/EC. 
The Investigator is responsible for the accuracy and completeness of all study records 
including CRFs, source documents, and the Site Trial Master File.  The Investigator will 
allow the study monitor, Sponsor, auditor, regulatory agencies, and IRB/EC full access to 
the study and source documents. 
10.3 Institutional Review Board/Ethics Committee/Research Ethics Board 
(IRB/EC) 
Prior to the shipment of clinical supplies or initiation of the study, the clinical trial 
protocol along with the informed consent form (ICF), Investigator’s Brochure, and any 
other written information or instructions for the patient must be submitted to the IRB/EC 
for written approval.  The Investigator will provide the Sponsor with a copy of the 
IRB/EC’s written approval, as well as the membership list or a compliance statement 


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from the IRB/EC.  The Investigator is responsible for notifying the IRB/EC of any 
Sponsor-approved amendments to the protocol or ICF, SAEs occurring in patients treated 
at the study site in accordance with local IRB/EC practice, and all expedited safety 
reports from SAEs occurring at other study sites participating in the drug development 
program. 
10.4 Informed Consent Form 
The ICF must contain all elements required by the Food and Drug Administration (FDA) 
under 21 Code of Federal Regulations (CFR) Part 50 and the ICH GCP guidelines (ICH 
E6) in addition to any other elements required by applicable national, state, provincial, 
and local regulations, or institutional policies. 
All patients who choose to participate in the study must provide written consent after 
having had adequate time to consider whether they will participate in the study.  The 
written consent must be obtained prior to any protocol-related procedures that are not part 
of the patient’s normal medical care.  The patient must be advised of his/her right to 
withdraw from the study at any time.   
Written documentation of consent must be recorded in the patient’s source documents, 
study records and CRF indicating the date the consent was signed.  The patient should 
receive a signed copy of the consent form according to GCP guidelines. 
10.5 Confidentiality 
All information generated in this study is considered confidential, is subject to applicable 
privacy rules and regulations, and must not be disclosed to any person or entity not 
directly involved with the study unless prior written consent is gained from the Sponsor 
and otherwise except in accordance with applicable law or regulations.  However, 
authorized regulatory officials, IRB/EC personnel, the Sponsor and its authorized 
representatives (as and to the extent authorized in the patient’s ICF) are allowed access to 
the records. 
Identification of patients in CRFs shall be by study assigned patient numbers only.  If 
required, the patient's full name may be made known to an authorized regulatory agency 
or other authorized official. 
10.6 Reporting of Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction (i.e., clinical hold) imposed by an applicable 
Regulatory Authority, or if the investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the 
Sponsor must be informed immediately.  In addition, the investigator will inform the 
Sponsor immediately of any serious breaches of this protocol or of ICH GCP of which 
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11 RECORDS MANAGEMENT 
11.1 Source Documentation 
Source documents include hospital or clinical patient charts, pertinent historical medical 
records, laboratory test reports, ECG tracings, pathology reports, radiographs, etc.  All 
source documents must be legible.  Data reported in CRFs and evidence of patient’s 
informed consent must be documented in source documents.   
11.2 Study Files and Records Retention 
A CRF must be completed for each patient for whom informed consent for the study is 
obtained.  The CRFs must be maintained by properly trained and delegated site 
representatives.  The Principal Investigator has responsibility for ensuring the 
authenticity, accuracy, completeness and timeliness of all data collected in the CRF.  
CRFs must be signed by the Principal Investigator or by an authorized Sub-Investigator 
to attest that the information included is true.   
The study site will maintain a Site Trial Master File in accordance with GCPs. 
The Investigator shall retain all records for the longest of the following periods: (i) 
15 years; (ii) the period of time that conforms to ICH GCP guidelines; (iii) the period of 
time required by applicable law or regulations, or (iv) the period of time specified in the 
Clinical Research Agreement. 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Monitoring Procedures 
Sponsor appointed Site Monitor(s) must be allowed access to all study records, original 
source documents, and investigational products throughout the duration of the study.  
These personnel are responsible to assess compliance with the protocol, appropriate 
health authority regulations, ICH GCP guidelines, and Sponsor requirements. 
The study monitor is responsible for complying with the monitoring guidelines 
established by the Sponsor for the study, assessing the site’s needs, and liaising with the 
assigned Sponsor staff. 
Source documents are defined as all medical records, medical notes, pathology or 
radiology reports, laboratory results, ECG tracings, and any additional documents that 
have original patient information contained within it.   


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If the Investigator withdraws from the study and relinquishes his/her responsibility for the 
maintenance and retention of records, he/she must notify the Sponsor in writing so 
arrangements can be made to properly store the study materials. 
12.2 Auditing and Inspection Procedures 
The Sponsor’s Quality Assurance representatives, IRB/EC reviewers, or inspectors from 
regulatory agencies may perform an audit or inspection at any time during or after 
completion of the clinical study.  All study-related documentation must be made 
available to the designated auditor.  In addition, representatives of applicable regulatory 
health authorities may choose to inspect a study.  A Sponsor representative will be 
available to assist in the preparation for such an inspection.   
 
13 CHANGES IN STUDY CONDUCT 
13.1 Protocol Amendments 
Changes to the study protocol, except those intended to reduce immediate risk to study 
patients, may be made only by the Sponsor.  A protocol change intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
IRB/EC is notified within 5 days.  Any urgent safety measures taken by the investigator 
to protect the study patients against any immediately life threatening hazard must be 
reported immediately to the Sponsor. 
Any permanent change to the protocol must be handled as a protocol amendment.  The 
change and the justification will be documented in writing by the Sponsor, as an 
Administrative Letter or amended protocol.  Protocol amendments will be provided with 
a separate document describing each change and rationale.  The written Administrative 
Letter or amendment must be submitted to the IRB/EC and the investigator must await 
approval before implementing the changes.  The Sponsor will be responsible for 
submitting protocol amendments to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/EC, the investigator, and/or the Sponsor, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to 
the patient and/or has an impact on the patient's involvement as a study participant, the 
currently approved written informed consent form will require similar modification.  In 
such cases, informed consents (revised as appropriate to address protocol amendments) 
will be obtained for patients enrolled in the study before continued participation. 
13.2 Protocol Deviations 
Prospective permission to deviate from the eligibility criteria for this protocol will not be 
provided by the Sponsor.  Study specified assessments should not be omitted and the 
study treatment regimen should not deviate from protocol specifications.  Minor, 


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occasional adjustments in the clinic visit schedule may be necessary for logistical reasons 
(e.g., due to weather conditions) but must not become routine or systematically alter the 
study schedule.  The IRB/EC should be informed of any deviations that may affect a 
patient’s treatment or informed consent, especially those increasing potential risks, which 
must receive prior written approval by the IRB/EC.   
 
14 END OF TRIAL 
14.1 End of Trial in a European Union Member State  
End of Trial in a Member State of the European Union is defined as the time at which it 
is deemed that sufficient patients have been recruited and completed the study as stated in 
the regulatory application (i.e., Clinical Trial Application (CTA)) and ethics application 
in the Member State. 
14.2 End of Trial in all other Participating Countries 
End of Trial in all other participating countries is defined as the time at which all patients 
enrolled in the study have completed the last study visit and data from those visits have 
been reviewed by the investigator or designee. 
14.3 Premature Termination 
Premature termination of this study may occur at any time because of a regulatory 
authority decision, change in opinion of the IRB/EC, drug safety concerns, or at the 
discretion of the Sponsor.  In addition, the Sponsor retains the right to discontinue 
development of MGCD265 at any time.  If termination becomes necessary, the Sponsor 
will inform the appropriate regulatory authorities of the termination and the reason.  The 
Principal Investigator will inform the IRB/EC of the same.  In terminating the study, the 
Sponsor and the Principal Investigator will assure that adequate consideration is given to 
the protection of the patients’ interests. 
 
15 STUDY REPORT AND PUBLICATION POLICY 
The Sponsor is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication of study results will be governed by the applicable Clinical Research 
Agreement between the Sponsor and the Study Site and Investigator (as applicable).   
 
 


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Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib 
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Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or Carboplatin–Paclitaxel in 
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Oncology Non-Small Cell Lung Cancer Version 4, 2016. 
Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating 
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Rankin EB, Fuh KC, Taylor TE, et al. AXL is an essential factor and therapeutic target 
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Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy 
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Sequist LV, Yang JC-H, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus 
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Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-Rearranged Non–Small-Cell 
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Yano S, Yamada T, Takeuchi S, et al. Hepatocyte growth factor expression in EGFR 
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doi:10.1038/ng.2330. 
 


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APPENDIX 1. 
ECOG PERFORMANCE STATUS  
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self care.  Totally confined to bed or chair 
5 
Dead 
 
 
 


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APPENDIX 2. 
ABBREVIATED PRESENTATION OF RECIST VERSION 1.1 
GUIDELINES  
A modification to RECIST 1.1 has been made to account for the possibility of temporary 
changes resulting from the potentially beneficial treatment response of tumor necrosis 
and cavitation.   
Categorizing Lesions at Baseline 
Measurable Lesions 
• Accurately measured in at least one dimension. 
• When assessed by CT or MRI, longest diameter at least 10 mm or greater (slice 
thickness 5-8 mm), measured in the axial plane.  If the slice thickness is greater than 
5 mm (including any inter-slice gap), the longest diameter must be at least twice the 
slice thickness. 
• Malignant lymph nodes with a short axis (defined as the largest measurement 
perpendicular to the longest diameter of the lesion) 15 mm or greater when assessed 
by CT or MRI. 
The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other lesions.   
Non-Measurable Disease 
• Lesions too small to be considered measurable (including nodes with short axis 
between 10 and 14.9 mm) or truly non-measurable disease such as pleural or 
pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, and abdominal masses identified by 
physical exam that are not measurable by reproducible imaging techniques. 
• Bone disease is non-measurable with the exception of soft tissue components that can 
be evaluated by CT or MRI and meet the definition of measurability at baseline.   
• Previously irradiated lesions (or those subjected to other local treatment) are 
non-measurable unless they have progressed since completion of treatment. 
Normal Lesions 
• Non-malignant simple cysts should not be recorded either as target or non-target 
disease.  Cystic lesions thought to represent cystic metastases can be measurable 
lesions, if they meet the specific definition above.   
• Lymph nodes with short axis < 10 mm are considered normal and should not be 
followed as disease. 
 
 


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Tumor Assessments 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  All required scans must be done within the window 
of time specified in the Schedule of Assessments prior to treatment.  If the baseline 
assessment is inadequate, subsequent statuses generally should be indeterminate.   
The determination of whether lesions are measurable is performed only at baseline.  
“Measurable” at baseline means eligible for selection as target lesions, and thus for 
quantitative assessment throughout the trial.  Once selected as a target lesion, a lesion 
remains target throughout the trial. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in 
the case of pathological lymph nodes for which the short axis should be recorded.  The 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions at baseline will be the basis for comparison to look for partial response at 
later assessments.   
• If 2 target lesions coalesce the longest diameter measurement of the coalesced mass is 
used.  If a large target lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be recorded.  If 
a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be 
recorded. 
• When nodal lesions decrease to < 10 mm (normal), the actual measurement should 
still be recorded. 
Non-Target Lesions 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
qualitative evaluations of status will be recorded.  Multiple non-target lesions in one 
organ may be recorded as a single item on the CRF (e.g., ‘multiple liver metastases’). 
Objective Response Status at Each Evaluation 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast.  If not, subsequent objective statuses may be indeterminate.   
 
 


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Target Disease 
• Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
< 10 mm).  All target lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed.   
• Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions 
must be assessed.  Stable can follow PR only in the rare case that the sum increases 
by less than 20% from the nadir, but enough that a previously documented 30% 
decrease no longer holds.   
• Progressive Disease (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy) with a minimum absolute increase of 5 mm.   
• Indeterminate: Progression has not been documented, and  
o one or more target lesions have not been assessed,  
o or assessment methods used were inconsistent with those used at baseline and 
impaired assessment, 
o or one or more target lesions cannot be measured accurately (e.g., poorly visible 
unless due to being too small to measure), 
o or one or more target lesions were excised or irradiated and have not reappeared 
or increased.   
Non-Target Disease 
• CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (< 10 mm short axis). 
• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.   
• PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.   
• Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline. 
 
 


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New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the 
etiology.  If repeat assessments confirm the lesion, then progression should be recorded 
on the date of the initial assessment.  A lesion identified in an area not previously 
scanned will be considered a new lesion. 
Lesion Changes That May Be Transient 
Potential exists for individual tumor lesions to develop necrosis, to cavitate, have a flair 
response to treatment or become otherwise difficult to evaluate for a period of time as the 
result of beneficial study treatment impact.  For example, tumor necrosis, cavitation or 
flair may result in increase in overall size of individual lesions or unclear tumor margins 
prior to recovery to smaller lesions, development of scar tissue, or complete resolution.  
The true tumor measurements of lesions should be recorded but the conclusion of 
progressive disease may be suspended until continued assessment clarifies the nature of 
the tumor change.  If repeat assessments indicate progression of disease, then PD should 
be recorded on the date of the first assessment giving the impression of progression.  If 
repeat assessments indicate that the change was a process of transition, then NE (not 
evaluable) should be recorded during the period of transition, and PR or CR may be 
recorded for subsequent evaluations.  The CRF will collect information on the 
observations during the period of transition to support the assessment conclusions.   
Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate.  If no disease is identified, objective status is CR. 
Best Objective Response 
Target 
Lesions 
Non-Target 
Lesions 
New Lesion 
Point in Time 
Response 
Best Response 
CR 
CR 
No 
CR 
CR and PR require 
confirmation at least 
4 weeks after first 
observation 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
SD requires an on-study 
assessment after at least 
6weeks on treatment. 
Unconfirmed PR or CR are 
reported as SD. 
PD 
Any 
Yes or No 
PD 
 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 


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Subjective Progression 
Patients requiring discontinuation of treatment due to worsening health status attributable 
to advancement of the malignancy under study but without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of 
Health Status.