A Phase 2 Study of Capmatinib (INC280) in NSCLC Patients With MET Exon 14 Alterations Who Have Received Prior MET Inhibitor
Phase: PHASE2
Conditions: Malignant Non-small Cell Neoplasm of Lung Stage IV
Sponsor: Massachusetts General Hospital

DF/HCC Protocol #:16-019 
Protocol Version Date: August 6, 2019 
 1 
NCI Protocol #: 
NCT02750215 
DF/HCC Protocol #: [16-019]   
TITLE:  A Phase 2 Study of INC280 in NSCLC patients with MET exon 14 alterations or 
MET amplification who have received prior MET inhibitor. 
Coordinating Center: 
Massachusetts General Hospital 
*Principal Investigator (PI): 
Rebecca S. Heist MD MPH
Massachusetts General Hospital 
Yawkey 7B 
32 Fruit Street 
Boston MA 02114 
Ph 617 724 4000 
Fax 617 726 0453 
Email: rheist@partners.org  
Statistician: 
Study Coordinator: 
Alona Muzikansky 
Massachusetts General Hospital 
Responsible Research Nurse: 
Responsible Data Manager: 
Lisa Stober RN 
Massachusetts General Hospital 
32 Yawkey St 
Boston MA 02114 
617 724 4000 
lstober@partners.org 
NCI-Supplied Agent(s):  n/a  
Other Agent(s):  INC280, provided by Novartis 
IND #: 130130   
IND Sponsor: Rebecca Heist MD 
Protocol Type / Version # / Version Date: Amended / Version 13/ August 6, 2019 

  
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SCHEMA 
 
 
 
 
 Stage IIIB/IV NSCLC 
MET exon 14 skipping or MET 
amplification (MET:CEP7 
>1.8) 
Prior MET therapy 
INC280 PO BID, 21-day cycles 

  
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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives...................................................................................................5 
1.3 
Secondary Objectives...............................................................................................5 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Non-small cell lung cancer ......................................................................................6 
2.2 
INC280 .....................................................................................................................6 
2.3 
Rationale for this study ............................................................................................7 
2.4 
Correlative Studies Background ............................................................................10 
3. 
PARTICIPANT SELECTION ...........................................................................................10 
3.1 
Eligibility Criteria ..................................................................................................10 
3.2 
Exclusion Criteria ..................................................................................................12 
3.3 
Inclusion of Women and Minorities ......................................................................14 
4. 
REGISTRATION PROCEDURES ...................................................................................14 
4.1 
General Guidelines for DF/HCC Institutions ........................................................14 
4.2 
Registration Process for DF/HCC Institutions .......................................................15 
4.3 
General Guidelines for Other Investigative Sites ..................................................15 
4.4 
Registration Process for Other Investigative Sites.................................................15 
5. 
TREATMENT PLAN ........................................................................................................15 
5.1 
Treatment Regimen ................................................................................................15 
5.2 
Pre-Treatment Criteria ...........................................................................................15 
5.3 
Agent Administration.............................................................................................16 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................16 
Concomitant medications...................................................................................................16 
Permitted concomitant therapy ..........................................................................................17 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................20 
5.6 
Duration of Follow Up ...........................................................................................21 
5.7 
Criteria for Taking a Participant Off Study ...........................................................21 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................21 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................31 
7.1 
Adverse Events ......................................................................................................31 
7.2 
Adverse Event Characteristics ...............................................................................38 
7.3 
Expedited Adverse Event Reporting ......................................................................38 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................42 
7.5 
Expedited Reporting to Hospital Risk Management .............................................43 
7.6 
Routine Adverse Event Reporting .........................................................................43 

  
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8. 
PHARMACEUTICAL INFORMATION ..........................................................................43 
8.1 
INC280 ...................................................................................................................43 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................45 
9.1 
Biomarker Studies ..................................................................................................45 
10. 
STUDY CALENDAR .......................................................................................................46 
11. 
MEASUREMENT OF EFFECT........................................................................................48 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................48 
11.2 
Antitumor Effect – Hematologic Tumors ..............................................................55 
11.3 
Other Response Parameters ...................................................................................55 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................55 
12.1 
Data Reporting .......................................................................................................56 
12.2 
Data Safety Monitoring..........................................................................................56 
12.3 
Multicenter Guidelines...........................................................................................56 
12.4 
Collaborative Agreements Language .....................................................................56 
13. 
STATISTICAL CONSIDERATIONS...............................................................................57 
13.1 
Study Design/Endpoints.........................................................................................57 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................58 
13.3 
Stratification Factors ..............................................................................................58 
13.4 
Interim Monitoring Plan ........................................................................................58 
13.5 
Analysis of Primary Endpoints ..............................................................................58 
13.6 
Analysis of Secondary Endpoints ..........................................................................58 
13.7 
Reporting and Exclusions ......................................................................................58 
14. 
PUBLICATION PLAN .....................................................................................................58 
REFERENCES ..............................................................................................................................60 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................63 
 

  
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1. OBJECTIVES 
 
This is an open label phase II study of INC280 among patients with non-small cell lung cancer 
(NSCLC) with MET exon 14 skipping alterations (METex14) or MET amplification who have 
previously been on MET inhibitor therapy.  The primary objective is to assess the objective 
response rate to INC280 among patients with METex14 or MET amplification who have 
previously been treated with a MET inhibitor.  Secondary endpoints will include progression-
free survival (PFS), disease control rate (DCR), intracranial response rate (IRR), duration of 
response (DOR), overall survival (OS), and safety and tolerability. In addition, exploratory 
analyses will be performed on archival tumor tissue as well as on tumor biopsies and circulating 
tumor DNA to analyze potential biomarkers of response and resistance to INC280. 
  
1.1 
Study Design 
 
This is a phase II study with the primary objective of assessing objective response rate to 
INC280 among patients with non-small cell lung cancer with METex14 or MET amplification who 
have previously been on MET inhibitor therapy.  Secondary endpoints will include PFS, DCR, 
IRR, DOR, OS, and safety and tolerability. In addition, exploratory analyses will analyze 
potential biomarkers of response and resistance to INC280. 
 
1.2 
Primary Objectives 
 
Primary Objective:  To assess the objective response rate in patients with lung cancer with 
METex14 or MET amplification with prior exposure to MET inhibitor therapy, when treated with 
INC280      
 
1.3 
Secondary Objectives 
 
Secondary Objectives: 
 
1. To assess progression-free survival (PFS), disease control rate (DCR), intracranial 
response rate (IRR), and duration of response (DOR) in patients with lung cancer with 
METex14 or MET amplification with prior exposure to MET inhibitor therapy, when 
treated with INC280 
2. To assess overall survival (OS) in patients with lung cancer with METex14 or MET 
amplification with prior exposure to MET inhibitor therapy, when treated with INC280 
3. To assess safety and tolerability of INC280 among patients with lung cancer with 
METex14 or MET amplification treated with INC280. 
 
Exploratory Objectives: 
 
1. To explore potential biomarkers of response and resistance to INC280 
2. To explore co-occurrence of METex14 with MET amplification, MDM2 amplification, 
and CDK4 amplification, among others, and impact on response 
3. To generate PDX and cell line models to explore the biology underlying sensitivity and 

  
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resistance 
  
 
2. BACKGROUND 
 
2.1 
Non-small cell lung cancer 
 
Lung cancer remains the leading cause of cancer related death in the United States [1]. 
Standard therapy for Stage IV non-small cell lung cancer (NSCLC) involves platinum-based 
chemotherapy regimens as first-line therapy, and incremental improvements in chemotherapies 
for lung cancer have led to a median overall survival of over a year [2-3].  However, the most 
dramatic successes in lung cancer have been seen with genotype-guided treatment. Driver 
genetic alterations such as EGFR activating mutations, and ALK and ROS translocations, among 
others, have been identified that are targets for therapy in lung cancer [4-7].  Targeted treatment 
of these oncogenic drivers has resulted in markedly higher response rates and survival compared 
to what is typically seen with conventional therapies [8-11].  Increasingly, lung cancer is 
becoming subdivided into molecular subsets with different treatment options depending on the 
molecular diagnostics of the cancer.  Somatic mutations in MET that affect the splice sites of 
exon 14 (METex14) are emerging as a targetable alteration in lung cancer which is present in 3-
4% of NSCLC [12-23] and are further discussed below in Section 2.3. In addition, MET 
amplification is another known targetable alteration reported in 2-4% of NSCLC [24]. This study 
investigates the activity of the MET inhibitor INC280 in patients with NSCLC with METex14 or 
MET amplification who have previously received another MET inhibitor therapy. 
 
2.2 
INC280    
 
INC280 is a potent ATP competitive and reversible inhibitor of the c-MET kinase  
([IC]50 in a biochemical assay = 0.13 ± 0.05 nM). INC280 is highly specific for c-MET with a 
greater than 10,000-fold selectivity over a panel of 56 other human kinases tested. Potent 
activity has also been observed in cell-based biochemical and functional assays that measure 
c-MET-mediated signal transduction, as well as c-MET-dependent cell proliferation, 
survival, and migration. In c-MET/HGF-driven tumor models grown as xenografts in 
mice, oral dosing of INC280 demonstrated significant in vivo activity in blocking both 
c-MET phosphorylation and tumor growth. 

  
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After oral administration in humans, INC280 is rapidly absorbed. The apparent terminal 
half-life of INC280 is short to moderate, from 1.5 to 6 hours across studies. Steady state 
INC280 exposure is expected to be reached by the third day of consecutive dosing. 
Accumulation of INC280 following repeated administration is low with accumulation ratio of 
up to 3-fold. Median time to peak plasma concentrations is reached at approximately 2 hours 
(Tmax ranged from 0.5 to 8.1 h across studies). Solubility of INC280 is pH-dependent. 
Solubility of INC280 is high at pH 1.0 (>5 mg/mL) and low (~0.002 mg/mL) at pH 6.9 and 
pH 7.4. 
 
INC280 has been studied in multiple phase 1 and 2 trials, both as a single agent and in 
combination with other drugs. For detailed information please refer to the Investigator’s 
Brochure.  Of note in a phase 1 study in patients with c-MET dependent advanced solid tumors 
with an expansion part in HCC, gastric cancer, NSCLC, and PRCC and other solid tumors, 
INC280 showed preliminary signs of antitumor activity in the NSCLC expansion arm with 
three out of six patients having confirmed partial response; all patients were EGFR wildtype 
and had high MET status by immunohistochemistry or fluorescent in-situ hybridization [25].  
 
2.3 
Rationale for this study 
 
 Somatic mutations in MET that affect the splice sites of exon 14 (METex14) are a 
targetable alteration in lung cancer which is present in 3-4% of NSCLC [12-23].  These 
mutations are predominantly in the intronic segments and lead to an alternatively spliced 
transcript of MET in which deletion of the juxtamembrane domain results in the loss of the Cbl 
E3-ligase binding site [13].  The alternatively spliced MET receptor exhibits decreased 
ubiquitination and delayed downregulation, leading to prolonged activation of MET and 
MAPK/ERK pathway which is transforming [13,17].  In a retrospective study of 240 lung cancer 
cases at Massachusetts General Hospital, we found 11 cases of METex14 [19].  Similar to other 
reports, most of these occurred in the absence of other driver alterations, supporting the notion 
that this is a driver event.  Although potentially enriched among never smokers who are wildtype 
for other driver mutations, METex14 is found in smokers as well, and appears to be present 
across all lung histologies [19].  

  
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Preclinical data have shown that METex14 is a transforming event that can respond well 
to MET inhibition [13, 17].  Kong-Beltran showed prolonged phosphorylation of MET and 
MAPK with stimulation by HGF in a cell line with METex14, and increased cell proliferation, 
which was inhibited by treatment with a MET inhibitor [13].  Frampton et al showed that human 
METex14 and the homologous mouse MET exon 15 skipping alteration is transforming in cell 
lines, at least partly through activation of the MEK/ERK pathway. A mouse model of the 
homologous exon 15 deletion in MET showed sensitivity to MET inhibition with INC280 [17] 
(see Figure 1).    
Figure 1. 
 
In line with these preclinical studies, recent reports have shown promising clinical 
activity among patients with METex14 treated with MET inhibitors including crizotinib, 
cabozantinib, and INC280 [17-23].  Paik et al reported on 4 patients with METex14 who were 
treated with MET inhibitors; three with crizotinib and one with cabozantinib.  These patients all 
experienced significant regression of their tumor burden on the MET therapy [18].  Frampton et 
al reported on one patient who responded to crizotinib, and two pts who were treated on a phase 
1 study of INC280 who also demonstrated a partial response to therapy [17].  Other case reports 
have shown similar marked responses [19-23].  Table 1 shows a summary of the reported cases 
in the literature which have shown response to MET therapy.  Reported durations on therapy are 
preliminary in nature but range from approximately 3 months to 13 months. 
Table 1.  Summary of case reports of patients with METex14 and responses to MET Rx  

  
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METex14 
 
MET amplification 
Other alterations 
Drug 
Age 
Sex 
Smoking  
Hist  
Ref 
c.3028G>C 
MET amp  
 MDM2 amp and 
multiple others 
cabozantinib 
80 
F 
Never  
Adeno  
18 
c.3024_3028delAGAA 
GGTATATT 
No amp 
IHC H Score 300  
multiple 
crizotinib  
78 
M 
Former  
Adeno  
18 
c.3028+1G>T 
MET amp  
IHC n/a  
multiple 
crizotinib  
65 
M 
Former  
Adeno  
18 
c.3028G>C 
No amp 
IHC H score 300  
CDK4 amp, 
MDM2 amp 
crizotinib 
90 
F 
Never  
Adeno  
18 
c.2888-5_2944del62  
n/a 
TP53  
ZMYM3  
crizotinib  
84 
F 
Never  
Histiocytic 
sarcoma  
17 
c.3028G>C 
FISH not done 
3+IHC  
TP53 
INC280 
82 
F 
Former  
Large cell 
17 
c.3028+1G>T 
copy number 4;  
MET:CEP7 2.3 
None reported 
INC280 
66 
F 
Former   
Squamous  
17 
c.3028 G>A  
Borderline 
MET:CEP7 2.2 
Snapshot wt 
crizotinib 
73 
M 
Former 
Squamous  
19 
c.3028G>C  
n/a (presume neg, 
Foundation)  
MDM2 amp 
crizotinib 
76 
F 
Former 
Squamous  
20 
Chr7:g.116412043G>C 
No amp  
MET/CEP7 0.96 
n/a 
crizotinib 
71 
M 
Former 
Adeno  
21 
c.2887-18>2887-7del12 
n/a 
CDKN2A/B loss 
CDK4 amp 
MDM2 amp 
crizotinib  
86 
M 
Never  
Adeno  
22 
Intron 14 +3 A>G 
9 copies 
n/a 
crizotinib 
74 
F 
Former 
Sarcomatoid 
23 
 
 
In addition to MET exon 14 skipping, MET amplification is known to occur in NSCLC 
and may be targetable as well.  Among 13 patients with MET amplified NSCLC enrolled in a 
clinical trial of crizotinib, 1 had low level amplification (MET/CEP7 ratio 1.8-2.2), 6 had 
intermediate level amplification  (MET/CEP7 ratio 2.2 – 5), and 6 had high level amplification 
(MET/CEP7 ratio >5).  Partial responses were observed in 4/13 patients (33%, 95% CI 10,65), 
with none (0/1) observed in the low amplification group, 1/6 (20%) in the intermediate 
amplification group, and 3/6 (50%) in the high amplification group. [26]    
At Massachusetts General Hospital (MGH), we have been performing genotyping of 
tumors of patients with lung cancer as part of standard clinical care since 2009 [27].  Our current 
version of the SNaPshot genotyping panel tests for METex14, which previously was challenging 
to find due to their predominant location in the intronic segments of the gene.  In addition, MET 
amplification is captured on our panel as well.   Currently, all patients with lung cancer at MGH 
are tested reflexively for genetic mutations using the targeted next generation SNaPshot assay for 
point mutations and the targeted next generation translocation assay for rearrangements.   

  
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We propose a phase II study investigating the activity of INC280 in patients with 
METex14 or MET amplification who have previously received a MET inhibitor, to assess for 
activity in the setting of resistance.  Other ongoing studies are already investigating the activity 
of INC280 in the first-line setting for METex14.  The ability of ceritinib and alectinib to 
overcome resistance to crizotinib in ALK rearranged lung cancer [10, 28] points to the feasibility 
of a more potent drug being able to overcome acquired resistance.  As there will be patients who 
have previously received other MET inhibitors such as crizotinib or cabozantinib, it will be 
important to know whether INC280 has activity in the setting of prior MET inhibitor therapy. 
 
 
2.4 
Correlative Studies Background 
 
MGH has an active investigational program studying response and resistance to targeted 
therapies in lung cancer led by the Engelman lab [29-31]. Patients who respond to a targeted 
therapy and become resistant are routinely biopsied and investigations including repeat 
molecular testing as well as creation of cell line and xenograft models are utilized to interrogate 
the tumor for mechanisms of resistance.  This collaborative framework will be utilized in this 
trial to study response and resistance mechanisms from biopsy samples of patients on this study.  
To date there is a dearth of cell line and PDX models for METex14; we will attempt to generate 
such model systems for study.  In addition, MET, MDM2, and CDK4 amplification have all been 
reported to co-exist with METex14 [17-18], but the relevance to response or resistance is not 
known.  We will therefore explore the co-occurrence of these amplification events among the 
patients with METex14 enrolled in our study, and explore whether there is any preliminary 
signal of responsiveness or resistance depending on these co-alterations. 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
1. Written informed consent must be obtained prior to any screening procedures. 
2. Age ≥ 18 years 
3. Histologically or cytologically confirmed non-small cell lung cancer, advanced, recurrent, or 
metastatic 

  
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4. MET exon 14 skipping alteration or MET amplification (MET:CEP7 ratio > 1.8) by 
molecular testing (local testing is accepted for eligibility; all patients will have confirmation 
at MGH but this result is not necessary for eligibility; local molecular pathology result will 
suffice).  This testing can be from any archival or fresh sample. 
5. Must have received prior platinum containing chemotherapy for advanced/metastatic non-
small cell lung cancer, or have refused or be ineligible for such therapy. Prior 
neoadjuvant/adjuvant platinum containing chemotherapy will count has having received prior 
platinum, provided that disease recurred within 6 months of completion of 
neoadjuvant/adjuvant therapy.  
6. EGFR and ALK status must be known in all patients with adenocarcinoma histology.  
Patients with activating EGFR mutations or ALK translocations are excluded from this study, 
unless disease has progressed on all available, approved therapies targeting these alterations. 
7. At least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion 
may only be counted as a target lesion if there is clear sign of progression since the 
irradiation.  
8.  Must have received prior therapy with a MET inhibitor.  Patients must have recovered from 
all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.0). Patients with 
any grade of alopecia are allowed to enter the study. 
9. Patients must have adequate organ function including the following laboratory values at the 
screening visit: 
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support 
• Platelets ≥ 75 x 109/L 
• Hemoglobin (Hgb) > 9 g/dL 
• Serum creatinine < 1.5 x ULN or calculated creatinine clearance (using Cockcroft-Gault 
formula) > 45 mL/min for patients with creatinine levels > 1.5 x ULN 
• Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert’s syndrome, who may only 
be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN 
• Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, who 
are included if AST ≤ 5 x ULN 
• Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, who 
are only included if ALT ≤ 5 x ULN 
• Alkaline phosphatase (ALP) ≤ 5.0 x ULN 
• Asymptomatic serum amylase ≤ grade 2 and asymptomatic serum lipase < grade 2. 
Patients with grade 1 or grade 2 serum amylase or lipase at the beginning of the study 
must be confirmed to have no signs and/or symptoms suggesting pancreatitis or 
pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.) 
• Patients must have the following laboratory values within the laboratory normal limits or 
corrected to within normal limits with supplements during screening: 
• Potassium 
• Magnesium  
• Phosphorus  

  
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• Total calcium (corrected for serum albumin)  
10. ECOG performance status (PS) of 0 or 1 
11. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
 
 
3.2 
Exclusion Criteria 
 
1. Patients with known hypersensitivity to any of the excipients of INC280 (crospovidone, 
mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium stearate, 
colloidal silicon dioxide, and various coating premixes).  
2. Patients with symptomatic central nervous system (CNS) metastases who are neurologically 
unstable or have required increasing doses of steroids within the 2 weeks prior to study entry 
to manage CNS symptoms 
3. Presence or history of a malignant disease other than disease to be treated in current protocol 
that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this 
exclusion include the following: completely resected basal cell and squamous cell skin 
cancers, indolent malignancies that currently do not require treatment, and completely 
resected carcinoma in situ of any type 
4. Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically 
significant radiation pneumonitis 
5. Clinically significant, uncontrolled heart diseases. 
• Unstable angina within 6 months prior to screening 
• Myocardial infarction within 6 months prior to screening 
• History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
antihypertensive medication. Initiation or adjustment of antihypertensive medication 
(s) is allowed prior to screening 
• Ventricular arrhythmias 
• Supraventricular and nodal arrhythmias not controlled with medication 
• Other cardiac arrhythmia not controlled with medication 
• QTcF > 480 msec 
6. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting INC280 or patients who have 
not recovered from radiotherapy-related toxicities. For all other anatomic sites (including 
radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to starting INC280 
or patients who have not recovered from radiotherapy-related toxicities. Palliative 
radiotherapy for bone lesions ≤ 2 weeks prior to starting INC280 is allowed 

  
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7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 
weeks for resection of brain metastases) to starting INC280 or who have not recovered from 
side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy 
will not be counted as major surgery and patients can be enrolled in the study ≥ 1 week after 
the procedure 
8. Patients receiving treatment with medications that meet one of the following criteria and that 
cannot be discontinued at least 1 week prior to the start of treatment with INC280 and for the 
duration of the study: 
• Strong  and moderate inhibitors of CYP3A4 
• Strong inducers of CYP3A4 
• Proton pump inhibitors (PPI) 
9. Impairment of GI function or GI disease that may significantly alter the absorption of 
INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption 
syndrome) 
10. Unable or unwilling to swallow tablets as per dosing schedule 
11. Patients receiving unstable or increasing doses of corticosteroids. If patients are on 
corticosteroids for endocrine deficiencies or tumor-associated symptoms other than CNS 
related, dose must have been stabilized (or decreasing) for at least 5 days before first dose of 
INC280 
12. Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be 
discontinued at least 1 week before first dose of INC280, and for the duration of the study. 
Patients on non-enzyme-inducing anticonvulsants are eligible 
13. Previous anti-cancer and investigational agents within 2 weeks before first dose of INC280. 
If previous treatment is a small molecule TKI, last dose must be at least 7 days before first 
dose of INC280. A shorter washout period may be allowed after discussion with the Principal 
Investigator. 
14. Other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities 
that in the opinion of the investigator may increase the risk associated with study 
participation, or that may interfere with the interpretation of study results 
15. Any other condition that would, in the Investigator’s judgment, contraindicate patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow 
medication, social/ psychological issues, etc. 
16. Pregnant or nursing women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test 
17. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 30 days after stopping treatment. Highly effective contraception methods 
include: 

  
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• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the study 
the vasectomized male partner should be the sole partner for that subject 
• Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate ≤  1%), 
for example hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and 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 six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential 
18. Sexually active males unless they use a condom during intercourse while taking drug and for 
7 days after stopping treatment and should not father a child in this period. A condom is 
required to be used also by vasectomized men in order to prevent delivery of the drug via 
seminal fluid. For males with female partners of childbearing potential, couples must use 
highly effective means of contraception while taking the study drug. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 

  
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An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
 
n/a 
 
 
4.4 
Registration Process for Other Investigative Sites 
 
n/a 
 
 
5. TREATMENT PLAN 
 
 
5.1 
Treatment Regimen 
 
INC280 will be administered at 400 mg PO BID, with 21 consecutive days defined as a 
treatment cycle. Treatment will be administered on an outpatient basis.  Reported adverse events 
and potential risks are described in Section 7.  Appropriate dose modifications are described in 
Section 6.    
 
Table 2. Dose and treatment schedule 
Study 
treatments 
Pharmaceutical form 
and route of 
administration 
Dose 
Frequency and/or 
Regimen 
INC280 
Tablet for oral use 
400 mg in case of single 
agent study 
Twice Daily (BID) 
 
 
5.2 
Pre-Treatment Criteria 
 

  
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All toxicities must be grade 1 or less, or tolerable grade 2, or else deemed not clinically 
significant by the treating investigator, prior to starting any cycle of therapy.  Results of day 1 
labs must be reviewed prior to start of each cycle.  Lab values on cycle 1 day 1 do not need to re-
meet eligibility criteria if they were already met, but all adverse events must be grade 1 or less or 
else deemed not clinically significant by the treating investigator. 
 
5.3 
Agent Administration 
INC280 tablet will be administered orally on a continuous twice daily (BID) dosing schedule, on 
a flat scale of 400 mg bid and not individually adjusted by weight or body surface area. A 
complete cycle of treatment is defined as a 21 day period. The investigator must instruct the 
patient to take the study drug exactly as prescribed. 
Drugs are provided in the following strengths: 50 mg, 100 mg, and 200 mg.  The tablets should 
be protected from moisture, and stored at ambient temperature (not above 25 degrees celsius or 
77 degrees farenheit). The 50 mg and 100 mg tablets should be used within six week of opening, 
and the 200 mg tablet within 4 week of opening.  
• Each dose of INC280 is to be taken with a glass of water (at least 8 ounces – approximately 
250 mL) and consumed over as short a time as possible (i.e., not slower than 1 tablet every 2 
minutes). 
• Patients should be instructed to swallow the tablets whole and not to chew them. 
• INC280 can be administered with or without food. The morning and the evening doses 
should be taken 12 (± 4) hours apart, although 12-hour interval is highly recommended. The 
morning dose should be taken the same time each morning. If a dose is not taken within 4 
hours of the planned dosing time, the missed dose should not be replaced. 
• Patients should be instructed not to make up for missed doses or partial doses (i.e., when the 
entire dose is not taken as instructed). A missed or partial dose will be defined as a case when 
the full dose is not taken within 4 hours of the scheduled twice daily dosing. If that occurs, 
then the dose (or part remaining dose) should not be taken and dosing should restart with the 
next scheduled dose. If vomiting occurs, no attempt should be made to replace the vomited 
dose before the next scheduled dose. 
• During the whole duration of treatment with INC280 alone, the patient is recommended to 
use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective 
clothing, avoid sunbathing or using a solarium). 
 
The investigator should instruct the patient to take INC280 exactly as prescribed.  
 
 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
  
Concomitant medications 
 
In general, the use of any concomitant medication/therapy deemed necessary for the care of 
the patient (e.g. such as anti-emetics, anti-diarrhea) is permitted (see section below), except when 

  
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specifically prohibited (see section below).  In selected cases after discussion with the PI 
longstanding medications may be allowed to continue with appropriate monitoring. 
 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (excluding study treatment and prior 
antineoplastic treatments), blood transfusions, surgeries and procedures (including physical 
therapy) administered within 28 days prior to the first dose administration of INC280 through 
30 days after the last dose of INC280 should be recorded.  Medications include not only 
physician prescribed medications, but also all over-the counter medications, herbal medications, 
food supplements and vitamins. 
 
The following restrictions apply during the entire duration of the study: 
• No other investigational therapy should be given to patients 
• No anticancer agents other than the study medication (INC280) should be given to patients. 
 
 
 
Permitted concomitant therapy 
 
Palliative radiation and/or palliative procedures may be allowed on study after discussion with 
the study PI.  The duration of study drug hold around the palliative radiation or procedure will be 
determined on a case by case basis after discussion with the study PI. 
 
Patients are permitted to use the following medications while taking INC280: 
• Oral or topical antibiotics 
• Medications to prevent or treat nausea, vomiting or diarrhea 
• Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelets growth factors, etc.) are 
      allowed per the investigator’s judgement and per local guidelines. 
• Treatment with bisphosphonates for pre-existing bone metastases is permitted, if clinically 
indicated, and following existing local guidelines. Treatment with bisphosphonates should 
preferably begin before the study treatment is initiated, but can also be initiated during 
therapy only if absence of radiological bone disease progression is well documented (inthis 
case, the reason for its use must be clearly documented; i.e. “pre-existing, non-progressing 
bone metastases”). 
• Oxygen therapy and blood products or transfusions 
• Nutritional support or appetite stimulants 
• Pain medication 
 
Permitted concomitant therapy requiring caution and/or action 
 
INC280 is metabolized by CYP3A4. Medications that are moderate inducers of CYP3A4 are 
not prohibited but should be administered with caution. INC280 is a time-dependent inhibitor 
of CYP1A2 and CYP3A4. Sensitive substrates for CYP3A4 and CYP1A2 should be 
administered with caution. INC280 is a weak to moderate inhibitor of CYP2C8, CYP2C9 and 
CYP2C19. Sensitive substrates of CYP2C8, CYP2C9 and CYP2C19 and substrates with a 
narrow therapeutic window should be administered with caution. Sensitive substrates for Pgp 
and OATP trasnporters should also be administered with caution. Refer to Table 4 below 

  
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for a list of the medications that require caution when concomitantly used with INC280. 
Short acting gastric acid modulators containing aluminum hydroxide and magnesium 
hydroxide, or calcium carbonate can be taken. However, it is recommended to take these 
drugs at least 3 hours before or 3 hours after administration of INC280. H2 receptor 
antagonists should be avoided. If patients are using H2 receptor antagonists during the course 
of this study, patients should not take INC280 within 2 hours of taking H2 receptor 
antagonists. In addition, the next scheduled dose of INC280 should be administered at least 8 
hours after taking H2 receptor antagonists. 
 
Table 3.    Drugs to be used with caution while on study 
Mechanism of Interaction 
Drug Name 
Moderate CYP3A4 inducer 
Bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, [talviraline], 
thioridazine 
Sensitive CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19 
substrate 
Caffeine, alosetron, duloxetine, melatonin, ramelteon, tacrine, repaglinide, 
celecoxib 
Sensitive CYP3A4 substrate 
Dronedarone, ebastine, brotizolam, midazolam, triazolam, felodipine, nisoldipine, 
brecanavir, capravirine, darunavir, atorvastatin, lovastatin, simvastatin, everolimus, 
lurasidone, perospirone, quetiapine, levomethadyl, budesonide, fluticasone, sildenafil, 
vardenafil, aprepitant, casopitant, alpha- dihydroergocryptine, aplaviroc, buspirone, 
darifenacin, eletriptan, eplerenone, lumefantrine, maraviroc, ridaforolimus, ticagrelor, 
tolvaptan, vicriviroc 
CYP2C9 substrate with NTI 
Phenytoin, warfarin 
CYP2C19 substrate with NTI 
s-Mephenytoin 
P-gp substrates 
Colchicine, digoxin, everolimus, fexofenadine, talinolol 
OATP substrates 
Atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, rosuvastatin, simvastatin 
acid, pitavastatin, pravastatin, repaglinide, valsartan, olmesartan, telmisartan 
drug- drug interactions (DDI) database, which is compiled primarily from the Indiana University School of Medicine’s 
“Clinically   Relevant”   Table   (medicine.iupui.edu/flockhart/table.html),   the   University   of   Washington’s   Drug 
Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies” 
Drugs between brackets are not marketed in US. 
Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a known 
potent inhibitor. 
NTI: narrow therapeutic index 
 
Prohibited concomitant therapy 
 
INC280 is metabolized  by  CYP3A4  in  vitro.  Strong and  moderate  inhibitors  or  strong 
inducers of CYP3A4/5 shall be discontinued 7 days prior to the start of INC280 treatment and 
are  prohibited.  All agents that  are  metabolized  mainly  by  CYP1A2  and/or CYP3A4/5 
and have a narrow therapeutic index are prohibited. 
In vitro solubility data indicated that INC280 may have decreased solubility and thus decreased 
oral absorption at pH > 4. Long-acting proton pump inhibitors are prohibited. Examples of this 
class of drugs include: omeprazole, pantoprazole, and lansoprazole. If patients are using proton 
pump inhibitors at the time of screening, these drugs must be discontinued at least 3 days prior to 
the first dose of INC280 

  
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Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies while on treatment. 
 
 
 
Table 4  List of prohibited concomitant therapy 
Mechanism of Interaction 
Drug Name 
Strong CYP3A4 inhibitor 
Antibiotics: clarithromycin, telithromycin, troleandomycin Protease 
Inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Others: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Moderate CYP3A4 inhibitor 
Antibiotics: ciprofloxacin, erythromycin 
Protease Inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir 
Antifungals: fluconazole 
Calcium Channel Blockers: diltiazem, verapamil 
Others: aprepitant, casopitant, cimetidine, dronedarone, tofisopam, grapefruit 
juice, Seville (sour) oranges, pomegranate, star fruit, schisandra 
sphenanthera 
Strong CYP3A4 inducer 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, 
rifampin, St. John's wort 
CYP1A2 substrate with NTI 
Theophylline, tizanidine 
CYP3A4 substrate with NTI 
Quinidine, [terfenadine], astemizole, cyclosporine, sirolimus, tacrolimus, 
pimozide, alfentanil, fentanyl, diergotamine, ergotamine, cisapride 
Long acting proton pump inhibitor 
Omeprazole, pantoprazole, lansoprazole, esomeprazole, rabeprazole, 
dexlansoprazole 
drug- drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies” 
Drugs between brackets are not marketed in USA. 
NTI: narrow therapeutic index 
 
Table 5 Prohibited medications causing QTc prolongation 
Class of medication 
Drug Name 
Antianginal 
Bepridil 
Antiarrhythmic 
Amiodarone, disopyramide, dofetilide, flecainide, ibutilide, procainamide, 
quinidine*, sotalol 
Antibiotic 
Azithromycin, clarithromycin*, erythromycin*, moxifloxacin, sparfloxacin 
Anticancer 
Arsenic trioxide, vavdetanib 
Antidepressant 
Citalopram 
Antihistamine 
[Astemizole]*, [terfenadine]* 
Anti-infective 
Pentamidine 
Antilipemic 
Probucol 
Antimalarial 
Chloroquine, halofantrine 
Antinausea 
[Domperidone], droperidol 

  
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Antipsychotic 
Chlorpromazine, [haloperidol]*, mesoridazine, pimozide, thioridazine 
GI stimulant 
[Cisapride] 
Opiate agonist 
[Levomethadyl], methadone 
Please note: *CYP3A substrate; drugs between brackets are not marketed in USA. 
Source: Arizona Center for Education and Research on Therapeutics (CERT), Drugs that prolong the QT interval 
and/or induce Torsades de Pointes http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and/or 
lack of clinical benefit and tolerance. In the absence of treatment delays due to adverse event(s), 
treatment may continue until one of the following criteria applies: 
 
 
• 
Disease progression (note that after discussion with the principal investigator, the 
decision can be made to continue on study past progression if the participant is having 
clinical benefit).  The following criteria must be met if the decision is made to 
continue treatment past RECIST-defined progression, and written informed consent 
must be obtained for treatment beyond RECIST-defined disease progression. 
• 
absence of clinical symptoms or signs indicating clinically significant 
disease progression;  
• 
no decline in performance status that is thought due to disease 
progression 
• 
absence of rapid disease progression or threat to vital organs or critical 
anatomical sites requiring urgent alternative medical intervention;  
• 
no significant, unacceptable or irreversible toxicities related to study 
treatment 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 

  
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A ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Rebecca Heist MD at 617 724 4000. 
 
 
5.6 
Duration of Follow Up 
 
Participants will be followed with periodic telephone follow up for two years after removal from 
protocol therapy or until death, whichever occurs first.  Phone calls will be placed every three 
months and survival follow up obtained.  Participants removed from protocol therapy for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
• Completion of required follow up 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff.  
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
 

  
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For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. All dose modifications, 
interruptions or discontinuations must be based on the worst preceding toxicity as graded by the 
NCI Clinical Toxicity Criteria (NCI-CTCAE version 4.0). Any changes must be recorded. 
Dose reduction and re-escalation 
An INC280 dose reduction will follow the dose reduction steps described in Table 6. For each 
patient, a maximum of 2 dose level modifications is allowed after which the patient must be 
discontinued from treatment with INC280.  
Dose re-escalation of study treatment to the previous dose level is allowed only once, and if no 
AE leading to dose modification is observed after at least 1 cycle (3 weeks) of study treatment at 
the reduced dose. 
 
Table 6 Dose reduction steps for INC280   
INC280 dose levels* 
 
Starting dose level - 0 
Dose level - 1 
Dose level – 2** 
INC280 
400 mg BID 
300 mg BID 
200 mg BID 
*Dose reduction should be based on the worst toxicity demonstrated at the last dose. 
**Dose reduction below 200 mg is not allowed. 
 
General guidelines for dose modifications are presented in Table 7. 
Unless otherwise indicated in Table 7, for grade 1 and tolerable grade 2 treatment-related 
toxicities, patients may continue full doses of study treatment. For intolerable grade 2 or any 
grade 3 treatment-related toxicities, dosing should be interrupted until at least resolution to grade 
1 followed by either dose reduction or re-initiation at the same dose level, depending on the type 
of toxicity as described in Table 7. For any grade 4 toxicity, patients should interrupt study 
treatment until resolution to grade 1, followed by either dose reduction or treatment 
discontinuation (refer to Table 7).  
A patient must discontinue treatment with INC280 if, after treatment is resumed at the lowest 
allowed dose (200 mg BID), the toxicity recurs with the same or worse severity despite use of 
maximal preventive measures as per the institution guidelines for toxicity prevention and 
management. All interruptions or change to study drug administration must be recorded. 
 
Table 7 Criteria for interruption and re-initiation of INC280 treatment 
Recommended dose modifications for INC280 
Worst toxicity CTCAE 4.0 Grade a. 
(value) 
During a cycle of therapy 
HEMATOLOGICAL 
Neutropenia (neutrophil count decreased, ANC) 
Grade 1 (ANC < LLN - 1500/mm3; < 
LLN - 1.5 x 109/L) 
Maintain dose level 

  
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Recommended dose modifications for INC280 
Worst toxicity CTCAE 4.0 Grade a. 
(value) 
During a cycle of therapy 
Grade 2 (ANC < 1500 - 1000/mm3; < 
1.5 - 1.0 x 109/L) 
Maintain dose level 
Grade 3 (ANC < 1000 - 500/mm3; < 1.0 
- 0.5 x 109/L) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume treatment at the same dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (ANC < 500/mm3; < 0.5 x 
109/L) 
Omit dose until resolved to ≤ grade 2 and then ↓ 1 dose level 
Febrile neutropenia (ANC < 1000/mm3 
(< 1.0 x 109/L), fever > 38.3°C) 
Omit dose, then: 
If resolved in ≤ 7 days, resume treatment at ↓ 1 dose level 
If resolved in > 7 days, discontinue patient from study treatment 
Thrombocytopenia (platelet count decrease, PLT) 
Grade 1 (PLT < LLN - 75,000/mm3; < 
LLN - 75 x 109/L) 
Maintain dose level 
Grade 2 (PLT < 75,000 - 50,000/mm3; 
< 75 - 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50,000 - 25,000/mm3; 
< 50 - 25 x 109/L) 
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then ↓ 1 dose level  
Grade 4 (PLT < 25,000/mm3; < 25 x 
109/L) 
Omit dose until resolved to ≤ grade 2, then ↓1 dose level 

  
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Recommended dose modifications for INC280 
Worst toxicity CTCAE 4.0 Grade a. 
(value) 
During a cycle of therapy 
Anemia (hemoglobin decrease) 
 
Grade 1 (Hgb < LLN - 10.0 g/dL; < LLN 
- 6.2 mmol/L; < LLN - 100 g/L) 
Maintain dose level 
Grade 2 (Hgb < 10.0 - 8.0 g/dL; < 6.2 – 
4.9 mmol/L; < 100 - 80 g/L) 
Maintain dose level 
Grade 3 (Hgb < 8.0 g/dL; < 4.9 mmol/L; 
< 80 g/L) 
Omit dose until resolved to ≤ grade 2, then: 
If resolved in ≤ 7 days, resume treatment at the same dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 
Omit dose until resolved to ≤ grade 2 and then ↓ 1 dose level 
If toxicity recurs, discontinue study treatment permanently 
RENAL 
Serum creatinine 
Grade 1 (>1 and ≤1.5 x baseline; > 
ULN and ≤ 1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 and ≤3.0 x baseline; > 
1.5 and ≤ 3 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then resume treatment 
at the same dose level.  
Grade 3 (> 3.0 x baseline; > 3.0 and ≤ 
6.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then resume treatment 
at ↓ 1 dose level. Patients will be instructed to increase their fluid intake 
until resolution to ≤ Grade 1 or baseline. 
Grade 4 (> 6.0 x ULN) 
Discontinue study treatment permanently 
HEPATIC 
Total Bilirubin b.  
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then ↓1 dose level  
Grade 3 (≥ 3.0 - 10.0 x ULN) with ALT 
or AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then ↓ 1 dose level  
If resolved in > 7 days, then discontinue permanently 
Grade 4 (> 10.0 x ULN) 
Discontinue study treatment permanently 

  
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Recommended dose modifications for INC280 
Worst toxicity CTCAE 4.0 Grade a. 
(value) 
During a cycle of therapy 
AST or ALT 
Grade 1 (> ULN – 3.0 x ULN) 
Maintain dose level with LFTs c. monitored per protocol 
Grade 2 (> 3.0 - 5.0 x ULN) without 
total bilirubin elevation to > 2 x ULN 
Maintain dose level with LFTs c. monitored per protocol 
Grade 3 (> 5.0 - 20.0 x ULN) without 
total bilirubin elevation to > 2 x ULN 
Omit dose until resolved to ≤ grade 1 (or ≤ grade 2 if liver metastases 
present), then 
If resolved in ≤ 7 days, then resume treatment at the same dose level 
If resolved in > 7 days, then resume treatment at ↓ 1 dose level 
Grade 4 (> 20.0 x ULN) without total 
bilirubin elevation to > 2 x ULN 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level 
AST or ALT, and concurrent Total Bilirubin 
AST and/or ALT > 3.0 x ULN and total 
bilirubin > 2.0 x ULN and ALP < 2.0 x 
ULN 
Discontinue study treatment permanently in the absence of signs of 
cholestasis, hemolysis, and alternative causes of the liver injury have been 
excluded (e.g., concomitant use of hepatotoxic drug(s), alcoholic hepatitis, 
etc.) 
METABOLIC 
Asymptomatic amylase and/or lipase 
elevation  
If symptomatic elevations of any grade, discontinue INC280 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 2.0 x ULN) 
Maintain dose level 
Grade 3 (> 2.0 - 5.0 x ULN) 
Continue dosing and monitor laboratory values, if levels do not resolve to 
grade 2 or baseline by 14 days after the initial report, ↓ 1 dose level 
Grade 4 (> 5.0 x ULN) 
Continue dosing and monitor laboratory values, if levels do not resolve to 
grade 2 or baseline by 14 days after the initial report, ↓ 1 dose level 

  
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Recommended dose modifications for INC280 
Worst toxicity CTCAE 4.0 Grade a. 
(value) 
During a cycle of therapy 
PULMONARY 
 Monitor patients for pulmonary symptoms indicative of ILD/Pneumonitis. In addition, withhold INC280 for acute 
onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and during 
diagnostic workup for ILD/Pneumonitis to exclude alternative causes such as, but not limited to infections, 
lymphangitic carcinomatosis, cardiogenic edema, or pulmonary hemorrhage. 
 
Interstitial lung disease/Pneumonitis 
Grade 1  
 
 
 
 
 
 
Grade 2  
 
  
Interrupt INC280 during diagnostic workup for ILD/Pneumonitis. Exclude 
infections and other etiologies.  
In presence of diagnosis of ILD/Pneumonitis after diagnostic 
workup, it is mandatory to permanently discontinue INC280. 
Only in the absence of a diagnosis of ILD/Pneumonitis may study drug 
be restarted at the same dose. If it recurs after restarting of study drug, 
permanently discontinue INC280. 
 
Mandatory: Interrupt INC280 dose during diagnostic workup for ILD until 
improvement to ≤ Grade 1. Exclude infections and other etiologies. 
 
In presence of diagnosis of ILD/Pneumonitis after diagnostic 
workup, it is mandatory to permanently discontinue INC280. 
Only in the absence of a diagnosis of ILD/Pneumonitis may study drug 
be restarted following these guidelines: 
• 
If resolves to ≤ Grade 1 in ≤ 7 days reduce study drug by 1 
dose level 
• 
If fails to resolve to ≤ Grade 1 within 7 days or recurs after 
resumption of study drug at decreased dose, permanently 
discontinue INC280 
Grade 3  
Mandatory: Permanently discontinue study drug. 
Grade 4  
Mandatory: Permanently discontinue study drug. 
CARDIAC 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTc 450-480 ms) 
Grade 2 (QTc 481-500 ms) 
Maintain dose level 
Grade 3 (QTcF ≥ 501 ms on at least 
two separate ECGs) 
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, resume treatment at the same dose level 
If resolved in > 7 days, then ↓ 1 dose level 
Grade 4 (QTc ≥ 501 or > 60 ms change 
from baseline and Torsades de pointes 
or polymorphic ventricular tachycardia 
or signs/symptoms of serious 
arrhythmia) 
Discontinue study treatment permanently 
GASTROINTESTINAL 
Pancreatitis 
 
Grade 2 
Maintain dose level 
Grade ≥ 3 
Discontinue study treatment permanently 
Diarrhea 
At the first sign of abdominal cramping, loose stools, or onset of diarrhea, it 
is recommended that the patient be treated according to institutional 
standard of care. 
Grade 1 (despite maximal anti-diarrheal 
medication) 
Maintain dose level 

  
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Recommended dose modifications for INC280 
Worst toxicity CTCAE 4.0 Grade a. 
(value) 
During a cycle of therapy 
Grade 2 (despite maximal anti-diarrheal 
medication) 
Omit dose until resolved to ≤ grade 1, then maintain dose level. 
If diarrhea returns as ≥ grade 2, then omit dose until resolved to ≤ grade 1, 
then resume treatment at↓ 1 dose level 
Grade 3 or 4 (despite maximal anti-
diarrheal medication) 
Omit dose until resolved to ≤ grade 1, then resume treatment at ↓ 1 dose 
level 
Vomiting 
 
Grade 1 (despite standard anti-emetics) 
Maintain dose level 
Grade 2 (despite standard anti-emetics) 
Omit dose until resolved to ≤ grade 1, then maintain dose level. 
If vomiting returns as ≥ grade 2, then omit dose until resolved to ≤ grade 1, 
then ↓ 1 dose level. 
Grade 3 (despite standard anti-emetics) 
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level 
Grade 4 (despite standard anti-emetics) 
Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level 

  
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28 
Recommended dose modifications for INC280 
Worst toxicity CTCAE 4.0 Grade a. 
(value) 
During a cycle of therapy 
Nausea 
 
Grade 1 or 2 (despite standard anti-
emetics) 
Maintain dose level 
Grade 3 (despite standard anti-emetics) 
Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash/photosensitivity 
Grade 1 
Maintain dose level. 
Grade 2 
Maintain dose level. 
Grade 3 (despite skin toxicity therapy) 
Omit dose until resolved to grade ≤ 1, then: 
If resolved in ≤ 7 days, then↓resume treatment at 1 dose level 
If resolved in > 7 days (despite appropriate skin toxicity therapy), then 
discontinue patient from study drug treatment 
Grade 4 (despite skin toxicity therapy) 
Discontinue study treatment permanently 
Fatigue/ Asthenia (General disorders and administration site conditions) 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ grade 1, then: 
If resolved in ≤ 7 days, resume treatment at same dose level 
If resolved in > 7 days, resume treatment at↓ 1 dose level 
Other adverse events 
Grade 1 or 2 
Maintain dose level,consider to initiate appropriate support medication. 
For any intolerable grade 2 (e.g.: limiting instrumental ADL), consider 
omitting the dose until resolved to ≤ grade 1, then↓ 1 dose level.  
Grade 3 
Omit dose until resolved to ≤ grade 1, then↓ 1 dose level 
Grade 4 
Discontinue study treatment permanently 
All dose modifications should be based on the worst preceding toxicity. 
a. Common Toxicity Criteria for Adverse Events (CTCAE version 4.0). 
b. If grade 3 or 4 hyperbilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin 
determination), then ↓ 1 dose level* and continue treatment at the discretion of the investigator. 
c.  LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin ≥ grade 2), alkaline phosphatase and 
GGT. 
Treatment interruption and treatment discontinuation 
If the administration of INC280 is temporarily interrupted for reasons other than toxicity, then 
treatment with INC280 may be resumed at the same dose. If the treatment with INC280 is 
withheld due to toxicity, the dose modification guidelines in Table 6 should be followed.  
If the treatment with INC280 is withheld for more than 21 consecutive days (counting from the 
first day when a dose was interrupted), then INC280 should be permanently discontinued. When 
the treating physician believes that continuing treatment may still provide clinical benefit for the 
patient, study treatment may be resumed.  
Patients who discontinue the study due to a study drug related AE or an abnormal laboratory 
value must be followed as described below. 
Follow-up and management guidelines for toxicities 
All patients will be followed for safety until 30 days after the last dose of INC280. Patients 

  
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29 
whose treatment is temporarily interrupted or permanently discontinued due to an AE or 
abnormal laboratory value must be followed until resolution or stabilization of the event, 
whichever comes first, including all study assessments appropriate to monitor the event. 
An assessment should be performed in all cases below where toxicity monitoring is needed 
according to the local standard of care and physician judgment. 
All patients should receive best supportive care (BSC) as per standard local practice for the 
treatment of pre-existing medical conditions or adverse events that may arise during the study. 
BSC is defined as drug or non-drug therapies, nutritional support, physical therapy, or any other 
treatment alternative that the treating physician believes to be in the patient’s best interest. 
 
Table 8 outlines follow up evaluations and recommended management guidelines in the event of 
selected toxicities. 
 
Table 8 
Follow-up evaluations and management guidelines for selected toxicities 
TOXICITY 
FOLLOW-UP EVALUATION 
HEMATOLOGICAL 
Febrile neutropenia, 
Neutropenia ≥ CTCAE grade 3 
Thrombocytopenia ≥ CTCAE 
grade 3 
Anemia ≥ CTCAE grade 3 
Test weekly (or more frequently) until ≤ CTCAE grade 2. 
Perform physical exam for check on bruising in case of major thrombocytopenia. 
RENAL 
Serum creatinine ≥ CTCAE 
grade 2 
Test weekly (or more frequently) until ≤ CTCAE grade 1 or baseline.  
Patients will be instructed to increase hydration until resolution to ≤ CTCAE 
grade 1 or baseline. 
HEPATIC 
Total bilirubin ≥ CTCAE grade 2 
Test weekly (or more frequently) until ≤ CTCAE grade 1 
Patients with total bilirubin > 1.5 ULN (any duration) should have fractionation of 
bilirubin into total/direct or indirect/direct components and any additional work-up 
as clinically indicated by these results. Follow-up of hyperbilirubinemia should 
proceed as per the guidelines in table 2, irrespective of the results of 
fractionation. 
AST/ALT ≥ CTCAE grade 2 and 
3 
Test weekly (or more frequently) until ≤ CTCAE grade 1 or ≤ CTCAE grade 2 (if 
patient is Grade 2 at baseline). 
In particular, test for all the following liver function tests (LFTs): albumin, ALT, 
AST, total bilirubin (fractionated if total bilirubin > 1.5 x ULN), alkaline 
phosphatase and GGT. Note: for patients with Gilbert Syndrome, total and direct 
bilirubin must be monitored, but intensified monitoring applies to changes in 
direct bilirubin only. 

  
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30 
TOXICITY 
FOLLOW-UP EVALUATION 
METABOLIC 
 
Asymptomatic amylase or lipase 
≥ CTCAE grade 3 
Test weekly (or more frequently) until ≤ CTCAE grade 2  
A CT scan or equivalent imaging procedure to assess the pancreas, liver, and 
gallbladder is recommended within 7 days of the first occurrence of any ≥ 
CTCAE grade 3 result, to exclude disease progression or potential other liver or 
pancreatic disease. 
CARDIAC 
≥ CTCAE grade 3 
Test weekly (or more frequently) until ≤ CTCAE grade 2. 
QTcF ≥ 501 ms 
(CTCAE grade 3) 
When QTcF ≥ 501 ms (CTCAE grade 3), perform the following: 
● Call the study’s central ECG review laboratory immediately and request an 
immediate manual read of the ECG. 
● Perform an analysis of serum potassium, calcium, phosphorus, and 
magnesium, and if below lower limit of normal, correct with supplements to within 
normal limits. 
● Review concomitant medication usage for the potential to inhibit CYP3A4/5 
(table 4) and/or to prolong the QT-interval (Table 6). 
● Check compliance with correct dose and administration of study treatment  
Perform a repeat ECG within one hour of the first QTcF of ≥501 ms. 
● If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but at least once 
daily until the QTcF returns to < 501 ms. 
Repeat ECGs 7 days and 14 days (and then every 21 days) after dose 
resumption for all patients who had therapy interrupted due to QTcF ≥ 501 ms. 
● If QTcF of ≥ 501 ms recurs, repeat ECGs as described above. 
Notes: 
● The investigator should contact the Novartis Medical Lead or designee 
regarding any questions that arise if a patient with QTcF prolongation should be 
maintained on study. 
● If the central ECG report shows a QTcF ≥ 501 msec (not previously 
documented on the site machine), contact the patient and instruct him/her to 
suspend study treatment and return for a repeat ECG as soon as possible. The 
central ECG reader should be called for a manual read of the repeat ECG 
immediately, and the above guidance followed. 
GASTROINTESTINAL 
Diarrhea 
Initiate anti-diarrhea treatment after first signs of abdominal cramping, loose 
stools or overt diarrhea. 
Consider/Investigate potential concomitant medication, food or comorbidity 
driven causes of diarrhea (including infectious causes) and remedy these 
causes, if possible (e.g., discontinuation of concomitant medication, dietary 
modification, treatment of comorbidity). 
The patient should be monitored for signs of dehydration and instructed to take 
preventive measures against dehydration as soon as diarrhea occurs. 
Antidiarrheal medication must be initiated at the first sign of abdominal cramping, 
loose stools or overt diarrhea. Concomitant medication for the treatment of 
diarrhea should follow local practice and the investigator’s best judgment and 
may follow “the recommended guidelines for the treatment of cancer treatment-
induced diarrhea”For example: 
● For uncomplicated diarrhea (grade 1 or 2 without complicating signs or 
symptoms), loperamide given at a standard dose (e.g. initial administration of 4 
mg, then 2 mg every 2-4 hours, maximum of 16 mg/day), along with oral 
hydration and dietetic measures should be considered. Note: complicating signs 
or symptoms include: moderate to severe cramping, decreased performance 
status, fever, neutropenia, frank bleeding or dehydration. 
● For complicated diarrhea (all grade 3 or 4, grade 1-2 with complicating signs or 
symptoms), management should involve intravenous (IV) fluids, and consider 
treatment with octreotide (at starting dose of 100 to 150 µg sub-cutaneous tid or 
25 to 50 µg IV) and antibiotics (e.g. fluoroquinolone) should be given. 

  
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31 
TOXICITY 
FOLLOW-UP EVALUATION 
Nausea and Vomiting 
The investigator should consider/investigate potential concomitant medication, 
food or comorbidity driven causes of nausea and/or vomiting and remedy these 
causes if possible (e.g. discontinuation of concomitant medication, dietary 
modification, treatment of comorbidity). 
Individualized supportive and anti-emetic treatment should be initiated, as 
appropriate, at the first signs and/or symptoms of these AEs. In patients with 
vomiting, the patient should be monitored for signs of dehydration and instructed 
to take preventive measures against dehydration. 
Concomitant medication for the treatment of nausea and/or vomiting should 
follow local practice and the investigator’s best judgment. 
NERVOUS SYSTEM DISORDERS 
Any Neurological Toxicity 
 
≥ Grade 2 
Neurological assessments must be repeated at least twice a week until resolution 
to < CTCAE grade 1. Unscheduled MRI and gadolinium enhanced T1 imaging 
may also be conducted to evaluate patients for intramyelinic edema like lesions, 
brain metastases and other unanticipated CNS occurrences. An EEG may be 
performed to monitor for physiological changes in brain activity. 
SKIN TOXICITY (rash and photosensitivity) 
Prevention/Prophylaxis 
Avoid unnecessary exposure to sunlight 
Apply broad-spectrum sunscreen with SPF≥15 at least twice daily 
CTCAE grade 1 
Use alcohol-free emollient cream (e.g. glycerine and cetomacrogol cream) for 
management of itching related to dry skin 
Consider to initiate institute appropriate skin toxicity therapy (such as 
antihistamines, topical antibiotics and/or corticosteroids and short course low-
dose systemic corticosteroids) 
CTCAE grade 2 
Initiate/intensify appropriate skin toxicity therapy (such as antihistamines, topical 
antibiotics and/or corticosteroids and short course low-dose systemic 
corticosteroids). 
≥ CTCAE grade 3 
Intensify appropriate skin toxicity therapy and monitor weekly or more frequently 
until resolved to grade ≤ 2 
 
 
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
7.1 
Adverse Events 
 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
For a detailed discussion of toxicities seen to date please see the Investigator’s Brochure.  
 
In brief, a total of 622 patients have been treated with INC280 as a single agent at different 
doses, and 487 patients have been treated with INC280 in combination therapies: 
with gefitinib (161 patients), with buparlisib (43 patients), with erlotinib (55 patients), with 

  
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32 
cetuximab (13 patients),  with LGX818/MEK162 (12 patients), with EGF816 (130 patients), 
with nivolumab (18 patients), with sonidegib (one patient), with PDR001 (20 patients), and 
with bevacizumab (34 patients). Twenty-one clinical trials are currently ongoing with 
INC280. 
 
A total of nineteen patients have experienced 25 DLTs: one Grade 3 AST and ALKP 
increase (50 mg QD), one Grade 2 suicidal ideation (600 mg BID), one Grade 3 depression 
(400 mg BID), two Grade 3 fatigue (200 mg BID and 450 mg BID respectively), one 
Grade 3 ALT increased, AST increased, and rash (400 mg BID, in combination with 
erlotinib), one Grade 3 rash pustular (400 mg BID, in combination with erlotinib), one Grade 
3 total bilirubin increase (250 mg BID), one Grade 4 cough and dyspnea (600 mg BID, 
combination with gefitinib), one Grade 3 dizziness (800 mg QD, combination with 
gefitinib), one Grade 3 personality change (400 mg BID, in combination with buparlisib), 
one Grade 3 nausea (300 mg BID, in combination with buparlisib), two Grade 3 ALT 
increased and AST increased (400 mg BID, in combination with buparlisib), one Grade 3 ALT 
increased (INC280 200mg with 50 mg QD EGF816), one Grade 3 anaphylactic reaction 
(INC280 400mg with 100mg QD EGF816), one Grade 3 rash maculo-papular and Grade 1 
pyrexia (INC280 400 mg BID with 150 mg QD EGF816), one Grade 3 rash maculopapular 
and dermatitis allergic (INC280 400mg BID with 150 mg QD EGF816), and one Grade 3 
diarrhea (400mg BID, in combination with PDR001).   
 
The majority of the reported AEs were mild or moderate (CTCAE Grade 1 or 2). CTCAE 
Grade 3/4AEs suspected to be related to INC280 included- ALT increased, AST increased, 
GGT increased, neutrophil count decreased, white blood cell count decreased, 
hypophosphatemia, hyponatremia, depression, colitis ulcerative and lung infection (each in 
one patient [2.3%]) (in [CINC280X1101]); AST increased, hypophosphatemia, and 
peripheral edema (each in one patient [2.2%])(in [CINC280X2101]); edema peripheral and 
lipase increased (each in nine patients [4.1%]), nausea, ALT increased (7 patients [3.2%]), AST 
increased,  hypophosphatemia, nausea, and vomiting (each in three patients [1.4%])(in 
[CINC280A2201]); fatigue (three patients [7.9%]), =ALT increased, hypophagia (two patients 
[5.3%]), decreased appetite, amylase increased, AST increased, blood bilirubin increased, 
edema peripheral, hypoalbuminemia, anemia, lipase increased, and neutropenia (each in one 
patient [2.6%]) (in [CINC280X2102]); ALT increased (4 patients [4.3%], nausea, fatigue, 
lipase increased, hypophosphatemia (each in three patients [3.2%]), peripheral edema, rash 
maculo-papular, amylase increased, AST increased, asthenia, dehydration (each in two patients 
[2.2%]) (in Dose Expansion Group, [CINC280X2102]); vomiting (2 patients [13.2%]), nausea, 
ALT increased, AST increased, amylase increased and blood bilirubin increased (each 
in one patient [2.6%] (in combination with erlotinib, [CINC280X2201]); ALT increased, 
edema peripheral, amylase increased, gamma-glutamyl transferase increased, interstitial lung 
disease, and neutropenia (each in one patient [6.3%]) (in [CINC280X2205]); fatigue and amylase 
increased (each in two patients [15.4%]), ALT increased and lipase increased (each in one 
patient [7.7%]) (in combination with cetuximab, [CINC280X2104]); rash maculopapular (17 
patients, [14.9%]), ALT increased and amylase increased (each in 8 patients [4.4%]), fatigue (4 
patients [3.5%]), asthenia, AST increased, and vomiting (each in 3 patients [2.6%]) (in 
combination with EGF816, [CINC280X2105C]); nausea (2 patients [10%]), edema peripheral, 
ALT increased, diarrhea, stomatitis, hypotension, platelet count decreased, acute myocardial 
infarction, unstable angina, blood bilirubin increased, dehydration, and neutropenia (each in one 

  
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33 
patient [5%]) (in combination with PDR001, [CINC280X2108]); amylase increased and lipase 
increased (each in 10 patients [6.2%]),  edema peripheral (6 patients [3.7%]), vomiting and 
fatigue (each in four patients [2.5%]), ALT increased (3 patients [2.1%]),rash, pulmonary 
embolism, hyponatremia, asthenia, AST increased, dizziness (each in 2 patients [1.2%]), and, 
with single incidences of paronychia, vomiting, blood bilirubin increased, and hemoptysis 
[0.6%] (in combination with gefitinib, [CINC280X2202]); hyperlipasaemia (2 patients [5.4%]), 
asthenia, blood alkaline phosphatase increased, lipase increased (each in one patient [2.7%]) (in 
DDI-study, [CINC280A2103]); and vomiting (2 patients [6.3%]), anemia, abdominal pain, ALT 
increased, AST increased, asthenia, blood albumin decreased, lipase increased, lymphocyte 
count decreased, malaise, quality of life decreased and vitamin k decreased (each in one patient 
[3.1%]) (in DDI-study, [CINC280A2105]). 
 
 
 
 
 
 
 
 
 
Adverse Drug Reactions considered to be expected for reporting purposes 
System 
Organ Class 
Adverse 
Reaction 
Nature1 
Serio
us2  
AE frequency 
regardless of 
causality from 
single agent study- 
CINC280A2201 
 
AE frequency, 
suspected to be 
INC280 related from 
single agent study- 
CINC280A2201 
Number 
of 
observed 
suspected 
SARs5 and 
frequency 
CINC2
80A22
01 
(N=220
)3 
n (%) 
Categor
y 
CINC28
0A2201 
(N=220)
4 
n (%) 
Categor
y 
N =1109 
cancer 
patients6 
Gastrointesti
nal disorders 
Vomiting 
Hospitalizati
on and 
antiemetic 
were 
required in 
most of 
serious cases 
Yes 
59 
(26.8) 
Very 
common 
40 
(18.2) 
Very 
common 
12 (1.0) 
Nausea 
Nausea often 
associated 
with 
vomiting, 
Hospitalizati
on and 
antiemetic 
were 
required in 
most of 
serious 
cases. 
Yes 
94 
(42.7)    
Very 
common 
69 
(31.4) 
Very 
common 
8 (0.7) 

  
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System 
Organ Class 
Adverse 
Reaction 
Nature1 
Serio
us2  
AE frequency 
regardless of 
causality from 
single agent study- 
CINC280A2201 
 
AE frequency, 
suspected to be 
INC280 related from 
single agent study- 
CINC280A2201 
Number 
of 
observed 
suspected 
SARs5 and 
frequency 
CINC2
80A22
01 
(N=220
)3 
n (%) 
Categor
y 
CINC28
0A2201 
(N=220)
4 
n (%) 
Categor
y 
N =1109 
cancer 
patients6 
Diarrhea 
Diarrhea 
associated 
with 
vomiting and 
nausea; 
Interruption 
of study 
medication; 
Hospitalizati
on was 
required in 
most of 
serious 
cases.  
Yes  
35 
(15.9) 
Very 
common 
22 
(10.0) 
Very 
common 
9 (0.8) 
Abdomin
al pain; 
Abdomin
al pain 
upper   
Hospitalizati
on and study 
medication 
dose 
adjustment 
or 
interruption 
/discontinuat
ion was 
required in 
most serious 
cases 
Yes  
27 
(12.3 )    
Very 
common 
12 (5.5) 
Commo
n 
5 (0.4) 
General 
disorders and 
administratio
n site 
conditions 
Fatigue 
Hospitalizati
on and study 
medication 
dose 
adjustment 
or 
interruption 
/discontinuat
ion was 
required in 
most serious 
cases 
Yes 
52 
(23.6)    
Very 
common 
34 
(15.5)     
Very 
common 
5 (0.4) 

  
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System 
Organ Class 
Adverse 
Reaction 
Nature1 
Serio
us2  
AE frequency 
regardless of 
causality from 
single agent study- 
CINC280A2201 
 
AE frequency, 
suspected to be 
INC280 related from 
single agent study- 
CINC280A2201 
Number 
of 
observed 
suspected 
SARs5 and 
frequency 
CINC2
80A22
01 
(N=220
)3 
n (%) 
Categor
y 
CINC28
0A2201 
(N=220)
4 
n (%) 
Categor
y 
N =1109 
cancer 
patients6 
Edema 
peripheral 
Hospitalizati
on and study 
medication 
dose 
adjustment 
or 
interruption. 
Treatment 
with 
diuretics. 
Yes 
98 
(44.5)    
Very 
common 
77 
(35.0)     
Very 
common 
4 (0.3) 
Asthenia 
Hospitalizati
on and study 
medication 
dose 
adjustment 
or 
interruption 
/discontinuat
ion was 
required in 
most serious 
cases 
Yes 
27 
(12.3)    
Very 
common 
12  (5.5) 
Commo
n 
4 (0.3) 
Investigation
s 
 
Alanine 
aminotran
sferase 
increased 
Hospitalizati
on and study 
medication 
interruption 
was required 
in some of 
the serious 
cases  
Yes 
18 (8.2)   Commo
n 
12  (5.5)   Commo
n 
9 (0.8) 
Aspartate 
aminotran
sferase 
increased 
Hospitalizati
on and study 
medication 
interruption 
was required 
in some of 
the serious 
cases 
Yes 
15 (6.8)   Commo
n 
11  (5.0) 
Commo
n 
5 (0.4) 
Gamma-
glutamylt
ransferase 
increased 
n/a 
No 
12 (5.5)   Commo
n 
3  (1.4) 
Commo
n 
n/a 

  
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36 
System 
Organ Class 
Adverse 
Reaction 
Nature1 
Serio
us2  
AE frequency 
regardless of 
causality from 
single agent study- 
CINC280A2201 
 
AE frequency, 
suspected to be 
INC280 related from 
single agent study- 
CINC280A2201 
Number 
of 
observed 
suspected 
SARs5 and 
frequency 
CINC2
80A22
01 
(N=220
)3 
n (%) 
Categor
y 
CINC28
0A2201 
(N=220)
4 
n (%) 
Categor
y 
N =1109 
cancer 
patients6 
Blood 
bilirubin 
increased 
Hospitalizati
on and study 
medication 
interruption 
was required 
in some of 
the serious 
cases 
Yes  
7 (3.2)    Commo
n 
6  (2.7)  
Commo
n 
2 (0.2) 
Amylase 
increased 
n/a 
No 
12 (5.5)   Commo
n 
11  (5.0) 
Commo
n 
n/a 
Lipase 
increased 
n/a 
No  
14 (6.4)   Commo
n 
13  (5.9) 
Commo
n 
n/a 
Blood 
creatinine 
increase 
Hospitalizati
on, study 
medication 
interruption 
and 
treatment 
with fluids 
and 
electrolytes  
Yes 
54 
(24.5) 
Very 
common 
39 
(17.7) 
Very 
common 
2 (0.2) 
Metabolism 
and nutrition 
disorders 
Decrease
d appetite 
Hospitalizati
on and study 
medication 
dose 
adjustment 
or 
interruption 
/discontinuat
ion was 
required in 
most serious 
cases 
Yes 
46 
(20.9)    
Very 
common 
31 
(14.1) 
Very 
common 
3 (0.3) 
Hyponatr
emia 
Hospitalizati
on and study 
medication 
dose 
adjustment 
or 
interruption 
/discontinuat
ion was 
required in 
most serious 
cases 
Yes 
7 (3.2)    Commo
n 
1  (0.5)    
Uncom
mon 
3 (0.3) 

  
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37 
System 
Organ Class 
Adverse 
Reaction 
Nature1 
Serio
us2  
AE frequency 
regardless of 
causality from 
single agent study- 
CINC280A2201 
 
AE frequency, 
suspected to be 
INC280 related from 
single agent study- 
CINC280A2201 
Number 
of 
observed 
suspected 
SARs5 and 
frequency 
CINC2
80A22
01 
(N=220
)3 
n (%) 
Categor
y 
CINC28
0A2201 
(N=220)
4 
n (%) 
Categor
y 
N =1109 
cancer 
patients6 
Nervous 
system 
disorders 
Dizziness 
n/a 
No 
17 (7.7)   Commo
n 
8  (3.6) 
Commo
n 
n/a 
Renal and 
urinary 
disorders 
Renal 
impairme
nt; Acute 
kidney 
injury 
Hospitalizati
on, study 
medication 
interruption 
and 
treatment 
with fluids 
and 
electrolytes 
Yes 
4 (1.9) 
Commo
n 
2  (0.9) 
Uncom
mon 
2 (0.2) 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Pneumoni
tis / 
interstitial 
lung 
disease  
Hospitalizati
on, study 
medication 
interruption 
and steroid 
treatment is  
required 
Yes 
7 (3.2) 
Commo
n  
2  (0.9) 
Uncom
mon 
10 (0.9) 
n/a: not applicable 
1 Additional description of serious ADRs  
2 For the purpose of individual case safety reporting in clinical trials, serious forms of adverse reactions 
indicated as non-serious in this table will always be considered unexpected.  
3 Frequency is calculated based on all events regardless of grades and causality assessment in study 
CINC280A2201 clinical trial database (N=220) with the data cut-off of 09-Aug-2017.  The category is 
based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon 
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) 
4 Frequency is calculated based on all events (all grades) which are assessed as suspected by the 
investigators in study CINC280A2201 clinical trial database (N=220) with the data cut-off of 09-Aug-
2017.  The category is based on the following convention: very common (≥1/10); common (≥1/100 to 
<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) 
5 Number of subjects who have experienced the suspected SAR and frequency of suspected SAR as of 
the cut-off date of 28-Sep-2017 
6 As of the cut-off date of 28-Sep-2017, a total of 1109 cancer patients received INC280. 
 
 
 
 
 
 
 
 
 

  
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38 
 
7.2 
Adverse Event Characteristics 
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
Serious Adverse Events 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• Abnormal lab values that do not require treatment 
•  treatment planned before signing informed consent for a pre-existing condition that did not 
worsen  
• emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• respite care 
 

  
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Expected Adverse Events 
 
Adverse events can be 'Expected' or 'Unexpected’. Expected adverse events are those that have 
been previously identified as resulting from administration of the agent. For the purposes of this 
study, an adverse event is considered expected when it appears in the Investigator’s Brochure  
Unexpected Adverse Events 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the Investigator’s Brochure.   
Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment.  
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
 
 
7.3 
Procedures for AE and SAE Recording and Reporting 
 
Reporting or participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded 
in the participant’s medical record and on the appropriate study-specific case report forms. Each 
recorded AE or SAE will be described by its duration (i.e., start and end dates), intensity 
treatment required, grade, suspected relationship to the investigational product (causality), 
outcome and actions taken with investigational product. 
 
The descriptions and grading scales found in the CTEP NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. The CTCAE version 4.0 
is located on the CTEP website at: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All appropriate treatment areas should have access to a copy of the CTEP Active Version of 
CTCAE. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
• YES 

  
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There is a plausible temporal relationship between the onset of the AE and administration of the 
investigational product, and the AE cannot be readily explained by the patient’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response 
to the investigational product; and/or the AE abates or resolves upon discontinuation of the 
investigational product or dose reduction and, if applicable, reappears upon re-challenge. 
• NO 
Evidence exists that the AE has an etiology other than the investigational product (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
medication); and/or the AE has no plausible temporal relationship to administration of the 
investigational product (e.g., cancer diagnosed 2 days after first dose of study drug).  
 
Each participating investigator is required to abide by the reporting requirements set by the 
DF/HCC. The study must be conducted in compliance with FDA regulations, local safety 
reporting requirements, and reporting requirements of the principal investigator. Specific 
reporting requirements are detailed below. 
 
Reporting to Novartis  
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has provided the main informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739). 
 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the 
case report form documentation at the study site. 
 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not, and whether the patient continued or 
withdrew from study participation. 

  
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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. 
 
Pregnancies 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment of 
the possible relationship to the study treatment and pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form. 
 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
Women of childbearing potential should be advised to use highly effective contraception 
methods while they are receiving study treatment and up to 7 days after INC280 treatment has 
been stopped. If a pregnancy occurs while on study treatment, the newborn will be followed for 
at least 3 months. 
Serious Adverse Event Reporting 
Reporting to the Institutional Review Board 
 
All serious adverse events that occur, during treatment, or within 28 days of the last dose of 
treatment must be reported to the DFCI Office for Human Research Studies (OHRS).  This 
includes events meeting the criteria outlined in Section 6.2.2, as well as the following: 
 
• Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at least possibly 
related/associated with the intervention. 
 

  
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• All Grade 4 (life-threatening or disabling) events that are unexpected or not specifically 
listed in the protocol as not requiring reporting. 
 
• All Grade 5 (fatal) events while the participant is enrolled and actively participating in 
the trial OR when the event occurs within 28 days of the last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  
 
Participating investigators must report each serious adverse event within 24 hours of learning of 
the occurrence. In the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after learning of it and document 
the time of his or her first awareness of the adverse event.   
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation. 
 
Events that occur after consent but before study enrollment/registration and receiving study 
treatment do not need to be reported.   
 
7.4 
Expedited Adverse Event Reporting  
 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
 
7.4.1 
DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
 

  
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7.6 
Expedited Reporting to Hospital Risk Management 
 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.7 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
 
8.1 
INC280 
 
8.1.1 
Description 
 
The chemical name of INC280 drug substance is 2-fluoro-N-methyl-4-(7-(quinolin-6-
ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride monohydrate. INC280 
has a molecular formula of C23H21Cl2FN6O2 and a molecular weight of 503.35 (salt form on 
monohydrate basis). 
 
INC280 dihydrochloride monohydrate is a slightly hygroscopic light yellow to yellow powder. 
The solubility of INC280 dihydrochloride at 25°C is approximately 3.47 mg/mL in water; 
0.08 mg/mL in pH 6.8 and 0.72 mg/mL in pH 3.0 buffer. 
 
8.1.2 
Form 
 
INC280 is presently formulated as an orally administered capsule dosage form or as a 
film-coated tablet.  The tablet form will be used in this study.  Drug request order forms are 
sent directly to Novartis. 
 
 
The orally administered  film-coated tablets contain the active drug INC280, along with the 
following 
commonly 
used 
excipients: 
colloidal 
silicon 
dioxide, 
crospovidone, 
magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, 
and various coating premixes.  
 
 
8.1.3 
Storage and Stability 
 
The stability data of clinical batches for INC280 film-coated tablets shows acceptable 
physical and chemical stability under designated storage conditions. Refer to the clinical 

  
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label for storage condition requirements. 
 
8.1.4 
Compatibility 
 
 
INC280 will be administered as a single agent in this study. 
 
8.1.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
  
 
8.1.6 
Availability 
 
INC280 will be provided by Novartis for this study. 
  
 
8.1.7 
Preparation 
 
INC280 is presently formulated as an orally administered capsule dosage form or as a 
film-coated tablet.  The tablet form will be used in this study. 
 
8.1.8 
Administration 
 
INC280 tablet will be administered orally on a continuous twice daily (BID) dosing schedule, on 
a flat scale of mg/day and not individually adjusted by weight or body surface area. A complete 
cycle of treatment is defined as 21 days of twice daily treatment with INC280. The investigator 
must instruct the patient to take the study drug exactly as prescribed.  Patients will record their 
daily dosing in a drug diary. 
• Each dose of INC280 is to be taken with a glass of water (at least 8 ounces – approximately 
250 mL) and consumed over as short a time as possible (i.e., not slower than 1 tablet every 2 
minutes). 
• Patients should be instructed to swallow the tablets whole and not to chew them. 
• INC280 can be administered with or without food. The morning and the evening doses 
should be taken 12 (± 4) hours apart, although 12-hour interval is highly recommended. The 
morning dose should be taken the same time each morning. If a dose is not taken within 4 
hours of the planned dosing time, the missed dose should not be replaced. 
• Patients should be instructed not to make up for missed doses or partial doses (i.e., when the 
entire dose is not taken as instructed). A missed or partial dose will be defined as a case when 
the full dose is not taken within 4 hours of the scheduled twice daily dosing. If that occurs, 
then the dose (or part remaining dose) should not be taken and dosing should restart with the 

  
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next scheduled dose. If vomiting occurs, no attempt should be made to replace the vomited 
dose before the next scheduled dose. 
During the whole duration of treatment with INC280 alone, the patient is recommended 
to use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, 
protective clothing, avoid sunbathing or using a solarium). 
  
8.1.9 
Ordering 
 
INC280 will be provided by Novartis. 
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
 
            Drug will be returned and destroyed per DF/HCC SOP pharmacy policy (INV-100 and               
INV-102) 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Biomarker Studies 
 
Archival tumor tissue will be collected at baseline for all patients where this is available. At 
least 10 unstained slides will be obtained from the archival tissue if possible.  An optional biopsy 
at study entry may be used to provide this tissue.  Tumors will be tested for biomarkers that may 
predict response, including baseline mutational status as assessed by a next generation 
sequencing panel, as well as MET, CDK4, and MDM2 amplification, among others.  Circulating 
tumor DNA will be collected at study entry and during study and assessed for mutational status 
as well.  Biomarker testing will be done at MGH in collaboration with Dr. Engelman’s lab. 
 
Optional tumor biopsy at time of progression 
 
Patients will be asked to undergo an optional biopsy at time of progression for correlative 
studies investigating mechanisms of resistance to INC280.  For any patient undergoing an 
optional biopsy, tumor will be collected and assessed for mutational testing and for development 

  
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into cell lines or patient-derived xenograft models for further study.  This will be done at MGH 
in collaboration with Dr. Engelman’s lab. 
 
 
Sample Type 
Proposed Studies 
   
Archival FFPE 
tumor tissue or 
optional tumor 
biopsy at study 
entry 
Baseline mutational status 
 
MET, CDK4, MDM2 
amplification, among others 
 
Cell lines and PDX models, if 
optional fresh biopsy 
  
Optional tumor 
biopsy at 
progression  
Mutational status at 
progression 
 
MET, CDK4, MDM2 
amplification, among others 
 
Cell lines and PDX models 
  
 
10. STUDY CALENDAR 
 
Screening evaluations are to be conducted < 4 weeks prior to start of protocol therapy.  Scans 
must be done <4 weeks prior to the start of therapy.   
 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 
 
Follow-up data will be collected every 3 months until participant withdrawal, death, or removal 
from study. 

  
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+/- 3 day window around visits 
 
Visit Name 
Screen 
Cycle 1 
(21days) 
Cycle 2 -18 
(Up to 
Month 13) 
Cycles > 
18 
(Months > 
13) 
EOT 
Follow up 
phone calls 
Day of cycle 
-28 to -1 
C1 
D1 
C1 
D8 
Day 1 
Day 1 of 
Every 
Other 
Cycle 
 
Every 
three 
months 
from end 
of 
treatment 
Obtain study informed 
consent 
x 
 
 
 
 
 
 
Collection of archival 
tumor tissue (paraffin 
blocks/slides) a 
x 
 
 
 
 
 
 
Confirm METex14 
(locally confirmed by 
investigator) 
x 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
Relevant medical and 
oncologic history b  
x 
 
 
 
 
 
 
Physical examination  
x 
x 
x 
x 
x 
x 
 
Vital signs  
x 
x 
x 
x 
x 
x 
 
Performance status 
x 
x 
x 
x 
x 
x 
 
ECG 
x 
x 
 
x 
x 
x 
 
Pregnancy test (serum test)  x 
  
 
  
 
  
 
Hematologyc 
x 
x 
x 
x 
x 
x 
 
Chemistryd 
x 
x 
x 
x 
x 
x 
 
Tumor evaluation by 
RECIST (CT/MRI)e 
x 
 
Every two cycles 
 
INC280 PO BID 
 
x 
x 
x 
x 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
 
Optional tumor biopsy   
x 
 
 
 
 
x 
 
Circulating tumor DNA 
x 
 
Every two cycles 
 
Survival follow up 
 
 
 
 
 
 
x 
a Collection of archival tumor tissue is highly encouraged but not mandatory for study entry if archival tissue is not available 
bRelevant medical and oncologic history should include prior cancer treatment history 
cHematology includes: a complete blood count (CBC) consisting of red blood cells (RBCs), hemoglobin, a complete white blood 
cell count with differential (total neutrophils (bands and segs), lymphocytes, monocytes, eosinophils, and basophils), and platelet 
count  
d Chemistry includes: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
and fractionated (e.g., direct and/or indirect) bilirubin, calcium, creatinine, glucose, magnesium, phosphate (inorganic 
phosphorus), potassium, protein (total), sodium, urea or blood urea nitrogen (BUN), amylase, lipase. 
eTumor evaluations, repeating the type of scan which was originally performed at screening, will be performed every two cycles 
and evaluated by RECIST by TIMC.  At the discretion of the treating investigator, non-scheduled scans can be performed if 
clinically indicated. 
 

  
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11. MEASUREMENT OF EFFECT 
 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every two cycles.   
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
  
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.    
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 

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

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

  
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51 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
MIBG (meta-iodobenzylguanidine).The following is recommended, to assure high 
quality images are obtained.  
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds.  
Images from the head to the distal lower extremities should be obtained.  
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A 
large field of view dual head gamma camera with low energy collimators is preferred.  
 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 

  
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as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances.  
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
11.1.4 Response Criteria 
 
 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 

  
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20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 

  
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response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 

  
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Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
11.1.7 Response Review 
N/a 
 
11.2 
Antitumor Effect – Hematologic Tumors 
 
N/a 
 
11.3 
Other Response Parameters 
 
N/a 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 

  
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12.1 
Data Reporting 
 
12.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
12.3 
Multicenter Guidelines 
 
 
n/a 
 
 
12.4 
Collaborative Agreements Language 
 
 
n/a 
 
 
 
 

  
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13. STATISTICAL CONSIDERATIONS 
 
  
 
13.1 
Study Design/Endpoints 
 
This is an open label Phase II study enrolling patients with MET exon 14 skipping or 
MET amplification who have previously been treated with a MET inhibitor.   
The primary endpoint is response rate (RR) as measured by RECIST 1.1 criteria.   
Secondary endpoints are: 
Progression-Free Survival (PFS):  PFS will be defined as the time from the start of study 
drug to the date of first documented progression or death. 
Disease control rate (DCR): Disease control rate will be defined as the sum of complete 
response, partial response, and stable disease at 12 weeks by RECIST 1.1. 
Intracranial response rate (IRR): Intracranial response rate will be calculated based on 
response assessments in the brain for patients with measurable CNS disease at baseline by 
RECIST v 1.1 criteria. 
Duration of response (DOR): Duration of response will be calculated from the time of first 
assessment of CR or PR until the first occurrence of progressive disease or death.  
Overall survival (OS): Overall survival will be defined as the time from the start of study 
drug to the date of death due to any cause.  OS time for patients who are alive at the end of hte 
study or are lost to follow up will be censored at the time of last contact. OS will be estimated 
using the Kaplan-Meier method. 
Safety and tolerability: Toxicity will be assessed using the CTCAE v4.0 criteria. 
 
 
Exploratory studies will assess biomarkers of response and resistance as well as attempt to 
establish cell lines and PDX models from optional tumor biopsies. 
 All patients who begin study drug on protocol will be considered evaluable.  Any patient 
who does not begin study drug on protocol will be considered not evaluable and will be 
 replaced. 
 

  
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13.2 
Sample Size, Accrual Rate and Study Duration 
 
The planned sample size is n = 20.  Patients who never begin protocol therapy after 
signing consent or who are not evaluable will be replaced.  With n =20 patients, the study will 
have an 80% power to detect an improvement in the overall response rate of 21.3% from the null 
of 10% using a one-sided binomial test with alpha of 0.05; i.e. a comparison of response rate of 
10% versus 31.3%.   
 
 
13.3 
Stratification Factors 
 
No stratification planned 
 
13.4 
Interim Monitoring Plan 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual from this study. 
 
13.5 
Analysis of Primary Endpoints 
 
As described in section 13.1. 
 
13.6 
Analysis of Secondary Endpoints 
 
As described in section 13.1. 
 
  
 
13.7 
Reporting and Exclusions 
 
 
13.7.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
All participants will be evaluable for response from the time of their first treatment.  
Participants who never start protocol therapy will be considered inevaluable.   
 
14. PUBLICATION PLAN 
 

  
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The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  

  
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2013; 2895-2902. 
 
[4]  Lynch TJ, Bell, DW, Sordella R, et al.  Activating mutations in the epidermal growth factor 
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[5]  Paez JG, Janne PA, Lee LC, et al.  EGFR mutations in lung cancer: correlation with clinical 
response to gefitinib therapy. Science 2004;304:1497-500. 
 
[6]  Pao W, Miller V, Zakowski M, et al.  EGF receptor gene mutations are common in lung 
cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and 
erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-11. 
 
[7]  Soda M, Choi YL, Enomoto M, et al.  Identification of the transforming EML4-ALK fusion 
gene in non small-cell lung cancer. Nature 2007;448:561-6. 
 
[8]  Mok TS, Wu YL, Thongprasert S, et al.  Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med 2009;361:947-57. 
 
[9]  Kwak EL, Bang YJ, Camidge DR, et al.  Anaplastic lymphoma kinase inhibition in non-
small cell lung  Anaplastic lymphoma kinase inhibition in non-small cell lung cancer. N Engl J 
Med 2010;363:1693-703. 
 
[10]  Shaw AT, Kim DW, Mehra R, et al.  Ceritinib in ALK-rearranged non-small-cell lung 
cancer. N Engl J Med 2014;370:1189-97. 
 
[11]  Shaw AT, Ou SH, Bang YJ, et al.  Crizotinib in ROS1-rearranged non-small-cell lung 
cancer. N Engl J Med 2014;371:1963-71 
 
[12] Ma PC, Jagadeewaran R, Jagadeesh S, et al.  Functional expression and mutations of c-met 
and its therapeutic inhibition with SU11274 and small interering RNA in non-small cell lung 
cancer. Cancer Res 2005; 65 (4): 1479-88. 
 
[13] Kong-Beltran M, Seshagiri S, Zha J, et al. Somatic mutations lead to an oncogenic deletion 
of met in lung cancer.  Cancer Res 2006; 66 (1): 283-9. 

  
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[14] Onozato R, Kosaka T, Kuwano H, et al. Activation of MET by gene amplification or by 
splice mutations deleting the juxtamembrane domain in primary resected lung cancers. JTO 
2009; 4: 5-11. 
 
[15] Seo JS, Ju YS, Lee WC, Shin JY, Lee JK, Bleazard T, et al. The transcriptional landscape 
and mutational profile of lung adenocarcinoma. Genome Res 2012;22:2109-19. 
 
[16] Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung 
adenocarcinoma. Nature 2014;511:543-50. 
 
[17] Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via diverse exon 14 
splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET 
inhibitors.  Cancer Disovery 2015; epub ahead of print. 
 
[18] Paik PK, Drilon A, Yu H, et al. Response to MET inhibitors in patients with stage IV lung 
adenocarcinomas harboring MET mutations causing exon 14 skipping.  Cancer Discovery 2015; 
epub ahead of print. 
 
[19] Heist RS. Shim L, Dardaei L, et al.  Oncogenic drivers in lung cancer: report of novel 
transforming fusions including targetable MET exon 14 skipping alterations, manuscript 
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[20] Mendenhall MA and Goldman JW.  JTO 2015; 10 (5): e33-34. 
 
[21] Waqar SN, Morgensztern D and Sehn J. MET mutation associated with responsiveness to 
crizotinib.  JTO 2015; 10(5): e29-31. 
 
[22] Jenkins RW, Oxnard GR, Elkin S, et al. Response to crizotinib in a patient with lung 
adenocarcinoma harboring a MET splice site mutation.  Clin Lun Cancer 2015; epub ahead of 
print. 
 
[23] Liu X, Jia Y, Stooper MB et al. Next generation sequencing of pulmonary sarcomatoid 
carcinoma reveals high frequency of actionable met gene mutations. JCO 2015 epub ahead of 
print. 
 
[24] Solomon, B. 2015. MET Amplification in Non-Small Cell Lung Cancer. My Cancer 
Genome https://www.mycancergenome.org/content/disease/lung-cancer/met/59/  
 
[25]  Bang YJ, Su WC, Nam DH, et al (2014) Phase I study of the safety and efficacy of 
INC280 in patients with advanced MET-dependent solid tumors. J Clin Oncol 32:5s (suppl; 
abstr 2520. 
 
[26] Camidge DR, Ou SI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with c-
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[27] Sequist LV, Heist RS, Shaw AT, et al.  Implementing multiplexed genotyping of non-small 
cell lung cancers in routine clinical practice.  Ann Oncol 2011; 22 (12): 2616-24. 
 
[28] Gandhi L, Shaw AT, Gadgeel SM, et al.  A phase II, open-label, multicenter study of the 
ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canadian 
population who had progressed on crizotinib.  J Clin Oncol 33, 2015 (suppl; abstr 8019) 
 
[29] Sequist LV, Waltman BA, Dias-Santagata D, et al.  Genotypic and histologic evoluation of 
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[30] Awad MM, Engelman JA, Shaw AT.  Acquired resistance to crizotinib from a mutation in 
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ALK-rearranged lung cancers.  STM 2012; 8 (4): 120ra17. 
 
 

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