Clinical trial NCT02019693
Conditions: Kidney Cancer
Keywords: Hereditary Papillary Renal Cell Carcinoma VEGF Pathway mTOR Inhibitor Kidney Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2014-01-24; Completion date: 2021-12-17
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Papillary Renal Cell Cancer (RCC) is the second most common histologic subtype of kidney cancer, accounting for approximately 10-15% of cases
* Type 1 papillary RCC occurs in both sporadic and hereditary forms, which are histologically identical. Non familial type 1 papillary RCC can present as both solitary renal tumors and as bilateral, multifocal disease
* There are no standard agents of proven efficacy for patients with advanced papillary

RCC.

* Patients with disease localized to the kidney are managed surgically while patients with advanced/unresectable disease are usually managed in the community with vascular endothelial growth factor (VEGF) pathway antagonists or mechanistic target of rapamycin (mTOR) inhibitors.
* Activating mutations of mesenchymal epithelial transition (MET) were identified in the germline of affected hereditary papillary renal cancer (HPRC) patients, who have a predilection for the development of bilateral, multifocal type 1 papillary RCC. Somatic MET mutations have been found in a subset of patients with non-inherited, sporadic papillary renal carcinoma
* The investigational agent Capmatinib (INC280) is a selective MET inhibitor lacking activity against the VEGF pathway
* This is a proof-of-concept study using INC280 in patients with papillary RCC to test the idea that effectively blocking the hepatocyte growth factor (HGF)/MET pathway will lead to clinical activity in patients with papillary renal cell cancer

Objectives:

Primary Objective:

-To determine the overall response rate (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) in patients with papillary renal cell carcinoma treated with single agent INC280

Eligibility:

* Diagnosis of hereditary papillary renal carcinoma (HPRC) or sporadic papillary renal cell carcinoma (RCC)

  * Patients with bilateral multifocal disease can have tumors localized to the kidney or have metastatic disease
  * Patients with sporadic papillary RCC (but without multifocal disease) should have advanced disease that is considered unresectable
* Eastern Cooperative Oncology Group (ECOG) 0-2
* Measurable disease
* Adequate organ function
* No active brain metastases
* Prior therapy

  * No more than 3 prior lines of systemic therapy
  * Prior therapy with a MET inhibitor is allowed as long as the patient has not had progressive disease while receiving the agent

Design:

* This is a phase 2 single center non-randomized trial.
* The study will be conducted using a Simon 2 stage minimax design. Initially 13 evaluable subjects will be recruited. If there are no responses to therapy, the study will be terminated. If there is at least 1 response an additional 7 evaluable subjects will be accrued.
* The two-stage minimax design is based on assuming an ineffective response rate of 5% and a targeted effective response rate of 25%. We also assume that the probability of accepting an ineffective treatment and the probability of rejecting an effective treatment are each 10%.
* Subjects will be dosed orally at a starting dose of 600 mg twice daily.
* The overall response rate (complete response + partial response) will be determined.

Detailed description:
Background:

* Papillary Renal Cell Cancer (RCC) is the second most common histologic subtype of kidney cancer, accounting for approximately 10-15% of cases
* Type 1 papillary RCC occurs in both sporadic and hereditary forms, which are histologically identical. Non familial type 1 papillary RCC can present as both solitary renal tumors and as bilateral, multifocal disease
* There are no standard agents of proven efficacy for patients with advanced papillary

RCC.

* Patients with disease localized to the kidney are managed surgically while patients with advanced/unresectable disease are usually managed in the community with vascular endothelial growth factor (VEGF) pathway antagonists or mechanistic target of rapamycin (mTOR) inhibitors.
* Activating mutations of mesenchymal epithelial transition (MET) were identified in the germline of affected HPRC patients, who have a predilection for the development of bilateral, multifocal type 1 papillary RCC. Somatic MET mutations have been found in a subset of patients with non-inherited, sporadic papillary renal carcinoma
* The investigational agent Capmatinib (INC280) is a selective MET inhibitor lacking activity against the VEGF pathway
* This is a proof-of-concept study using INC280 in patients with papillary RCC to test the idea that effectively blocking the hepatocyte growth factor (HGF)//MET pathway will lead to clinical activity in patients with papillary renal cell cancer

Objectives:

Primary Objective:

-To determine the overall response rate (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) in patients with papillary renal cell carcinoma treated with single agent INC280

Eligibility:

* Diagnosis of hereditary papillary renal carcinoma (HPRC) or sporadic papillary renal cell carcinoma (RCC)

  * Patients with bilateral multifocal disease can have tumors localized to the kidney or have metastatic disease
  * Patients with sporadic papillary RCC (but without multifocal disease) should have advanced disease that is considered unresectable
* Eastern Cooperative Oncology Group (ECOG) 0-2
* Measurable disease
* Adequate organ function
* No active brain metastases
* Prior therapy

  * No more than 3 prior lines of systemic therapy
  * Prior therapy with a MET inhibitor is allowed as long as the patient has not had progressive disease while receiving the agent

Design:

* This is a phase 2 single center non-randomized trial.
* The study will be conducted using a Simon 2 stage minimax design. Initially 13 evaluable subjects will be recruited. If there are no responses to therapy, the study will be terminated. If there is at least 1 response an additional 7 evaluable subjects will be accrued.
* The two-stage minimax design is based on assuming an ineffective response rate of 5% and a targeted effective response rate of 25%. We also assume that the probability of accepting an ineffective treatment and the probability of rejecting an effective treatment are each 10%.
* Subjects will be dosed orally at a starting dose of 400 mg twice daily.
* The overall response rate (complete response + partial response) will be determined.

Arms: arm 1: INC280 400 mg twice every day by mouth, continuously
Interventions: intervention 1: INC280
Intervention descriptions: intervention 1: Supplied by Novartis as film-coated tablet for oral use.

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
1
Abbreviated Title: INC280 in RCC
NIH Protocol #: 14-C-0037 
Version Date: February 14, 2022
NCT#: NCT02019693
Title: A Phase 2 Study of the MET Kinase Inhibitor INC280 in Papillary Renal Cell Cancer
Principal Investigator: 
Ramaprasad Srinivasan, M.D., Ph.D. 
Urology Oncology Branch, CCR, NCI
10 Center Drive, Building 10/CRC 2W-5940
Bethesda, MD 20892
Phone: 240-760-6251
Email: ramasrin@mail.nih.gov  
Investigational Agents:    
Drug Name:
INC 280
IND Number:
119133
Sponsor:
Center for Cancer Research
Manufacturer:
Supplier:
Novartis
Commercial Agents: None
 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
2
PRÉCIS
Background:

Papillary RCC is the second most common histologic subtype of kidney cancer, accounting 
for approximately 10-15% of cases

Type 1 papillary RCC occurs in both sporadic and hereditary forms, which are 
histologically identical. Non familial type 1 papillary RCC can present as both solitary 
renal tumors and as bilateral, multifocal disease

There are no standard agents of proven efficacy for patients with advanced papillary RCC.  

Patients with disease localized to the kidney are managed surgically while patients with 
advanced/unresectable disease are usually managed in the community with VEGF pathway 
antagonists or mTOR inhibitors.

Activating mutations of MET were identified in the germline of affected HPRC patients, 
who have a predilection for the development of bilateral, multifocal type 1 papillary RCC. 
Somatic MET mutations have been found in a subset of patients with non-inherited, 
sporadic papillary renal carcinoma

The investigational agent INC280 is a selective MET inhibitor lacking activity against the 
VEGF pathway

This is a proof-of-concept study using INC280 in patients with papillary RCC to test the 
idea that effectively blocking the HGF/MET pathway will lead to clinical activity in 
patients with papillary renal cell cancer
Objectives:
Primary Objective:

To determine the overall response rate (RECIST 1.1) in patients with papillary renal cell 
carcinoma treated with single agent INC280
Eligibility:

Diagnosis of hereditary papillary renal carcinoma (HPRC) or sporadic papillary renal cell 
carcinoma (RCC) 
o
Patients with bilateral multifocal disease can have tumors localized to the 
kidney or have metastatic disease
o
Patients with sporadic papillary RCC (but without multifocal disease) should 
have advanced disease that is considered unresectable

ECOG 0-2

Measurable disease

Adequate organ function

No active brain metastases

Prior therapy 
o
No more than 3 prior lines of systemic therapy
o
Prior therapy with a MET inhibitor is allowed as long as the patient has not had progressive 
disease while receiving the agent


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
3
Design:

This is a phase 2 single center non-randomized trial.

The study will be conducted using a Simon 2 stage minimax design.  Initially 13 evaluable 
subjects will be recruited.  If there are no responses to therapy, the study will be terminated.  
If there is at least 1 response an additional 7 evaluable subjects will be accrued.

The two-stage minimax design is based on assuming an ineffective response rate of 5% 
and a targeted effective response rate of 25%. We also assume that the probability of 
accepting an ineffective treatment and the probability of rejecting an effective treatment 
are each 10%.   

Subjects will be dosed orally at a starting dose of 400 mg twice daily.

The overall response rate (complete response + partial response) will be determined.
 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
4
TABLE OF CONTENTS
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................9
1 INTRODUCTION ........................................................................................................................9
1.1
Study Objectives ...............................................................................................................9
1.1.1
Primary Objective......................................................................................................9
1.1.2
Secondary Objective(s)..............................................................................................9
1.1.3
Exploratory objective.................................................................................................9
1.2
Background and Rationale................................................................................................9
1.2.1
Overview of disease pathogenesis, epidemiology and current treatments ................9
1.2.2
Overview of INC280 ...............................................................................................12
1.2.3
INC 280 Tablet Formulation ...................................................................................36
1.2.4
Study purpose/rationale ...........................................................................................46
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT.............................................................47
2.1
Eligibility Criteria ...........................................................................................................47
2.1.1
Inclusion Criteria .....................................................................................................47
2.1.2
Exclusion Criteria ....................................................................................................48
2.2
Screening Evaluation ......................................................................................................49
2.3
Registration Procedures ..................................................................................................50
2.4
Treatment Assignment Procedure...................................................................................50
2.5
Baseline Evaluation.........................................................................................................51
3 STUDY IMPLEMENTATION ..................................................................................................51
3.1
Study Design...................................................................................................................51
3.2
Drug Administration .......................................................................................................52
3.3
Dose Modifications.........................................................................................................53
3.4
Study Calendar................................................................................................................60
3.5
Follow Up Evaluations....................................................................................................64
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................64
3.6.1
Criteria for removal from protocol therapy .............................................................64
3.6.2
Off-Study Criteria....................................................................................................64
3.6.3
Off Protocol Therapy and Off Study Procedure......................................................65


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4 CONCOMITANT MEDICATIONS/MEASURES....................................................................65
4.1
Permitted Concomitant Therapy .....................................................................................65
4.2
Permitted Concomitant Therapy Requiring Caution And/Or Action .............................65
5 BIOSPECIMEN COLLECTION................................................................................................69
5.1
Correlative Studies For Research And Pharmacodynamic Assessments........................69
5.1.1
Evaluation of HGF/MET pathway modulation in tumor tissue (optional)..............69
5.1.2
Evaluation of plasma HGF and sMET modulation .................................................70
5.1.3
Evaluation of Urinary sMET modulation................................................................71
5.2
Sample Storage, Tracking And Disposition....................................................................72
6 DATA COLLECTION AND EVALUATION...........................................................................72
6.1
Data Collection ...............................................................................................................72
6.2
Response Criteria ............................................................................................................73
6.2.1
Definitions ...............................................................................................................74
6.2.2
Disease Parameters ..................................................................................................74
6.2.3
Methods for Evaluation of Measurable Disease......................................................75
6.2.4
Response Criteria.....................................................................................................77
6.2.5
Duration of Response ..............................................................................................79
6.2.6
Progression-Free Survival .......................................................................................79
6.3
Toxicity Criteria..............................................................................................................79
7 NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN..........79
7.1
Definitions.......................................................................................................................79
7.2
OHSRP Office of Compliance and Training/ IRB Reporting.........................................80
7.2.1
Expedited Reporting ...............................................................................................80
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................80
7.3
NCI Clinical Director Reporting.....................................................................................80
7.4
NIH Required Data And Safety Monitoring Plan...........................................................80
7.4.1
Principal Investigator/Research Team.....................................................................80
8 SPONSOR PROTOCOL/SAFETY REPORTING.....................................................................80
8.1
Definitions.......................................................................................................................80
8.1.1
Adverse Event..........................................................................................................80
8.1.2
Serious Adverse Event (SAE) .................................................................................81
8.1.3
Life-threatening .......................................................................................................81
8.1.4
Severity....................................................................................................................81


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8.1.5
Relationship to Study Product .................................................................................81
8.2
Assessment of Safety Events ..........................................................................................82
8.3
Reporting of Serious Adverse Events .............................................................................82
8.4
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................82
8.4.1
Reporting procedures...............................................................................................83
8.4.2
Pregnancies..............................................................................................................83
8.4.3
Ethics and Good Clinical Practice ...........................................................................83
8.4.4
Institutional Review Board/Independent Ethics Committee ...................................84
8.5
Reporting Pregnancy.......................................................................................................84
8.5.1
Maternal exposure ..................................................................................................84
8.5.2
Paternal exposure.....................................................................................................84
8.6
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................84
8.7
Sponsor Protocol Non-Adherence Reporting .................................................................85
9 CLINICAL MONITORING.......................................................................................................85
10 STATISTICAL CONSIDERATIONS......................................................................................85
10.1
Evaluation of Endpoints ..............................................................................................85
10.2
Evaluation of Secondary Endpoints ............................................................................86
10.3
Sample Size Calculation..............................................................................................86
11 COLLABORATIVE AGREEMENTS.....................................................................................86
11.1
Agreement Type..........................................................................................................86
12 HUMAN SUBJECTS PROTECTIONS ...................................................................................86
12.1
Rationale for Subject Selection ...................................................................................86
12.2
Participation of Children .............................................................................................86
12.3
Participation of Subjects Unable To Give Consent.....................................................86
12.4
Evaluation of Benefits and Risks/Discomforts ...........................................................87
12.4.1
Benefits....................................................................................................................87
12.4.2
Risks ........................................................................................................................87
12.5
Risks/Benefits Analysis...............................................................................................87
12.6
Consent Process and Documentation ..........................................................................88
12.6.1
Telephone Re-Consent Procedure ...........................................................................88
12.7
Discontinuation of Study Support ...............................................................................88
12.8
Amendments to the Protocol .......................................................................................88
12.8.1
Publication of results ...............................................................................................89


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12.8.2
Disclosure and confidentiality .................................................................................89
12.8.3
Declaration of Helsinki............................................................................................89
13 REGULATORY AND OPERATIONAL CONSIDERATIONS.............................................89
13.1
Study Discontinuation and Closure.............................................................................89
13.2
Quality Assurance and Quality Control ......................................................................90
13.3
Conflict of Interest Policy ...........................................................................................90
13.4
Confidentiality and Privacy.........................................................................................90
14 PHARMACEUTICAL INFORMATION.................................................................................91
14.1
INC280 (IND # 119133) .............................................................................................91
14.1.1
Source, packaging and labeling ...............................................................................91
14.1.2
Supply, receipt and storage......................................................................................91
14.1.3
Toxicity:...................................................................................................................92
14.1.4
Administration procedures.......................................................................................93
14.1.5
Incompatibilities ......................................................................................................94
14.1.6
Drug compliance and accountability .......................................................................94
14.1.7
Disposal and destruction..........................................................................................94
15 REFERENCES .........................................................................................................................95
16 APPENDICES ..........................................................................................................................99
16.1
Appendix A: Performance Status Criteria...................................................................99
16.2
Appendix B:  Patient’s Pill/ Side Effects Diary ........................................................100
16.3
Appendix C: Instruction Sheet for INC 280..............................................................102


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LIST OF ABBREVIATIONS  
AE 
Adverse event
ALT 
Alanine aminotransferase/serum glutamic pyruvic transaminase/SGPT
AST 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase/SGOT
AUC
Area under the plasma concentration-time curve
AUC0-24 
Area under the plasma concentration-time curve from 0 to 24 hours
b.i.d.
bis in diem/twice a day
Cmax 
Maximum (peak) concentration of drug
CNS 
Central nervous system
DLT 
Dose limiting toxicity
DMPK 
Drug metabolism and pharmacokinetics
DS&E 
Drug Safety and Epidemiology
ECG 
Electrocardiogram
EEG 
Electroencephalogram
HGF 
Hepatocyte growth factor
Hr 
Hour
i.v. 
intravenous(ly)
IC50 
Half maximal inhibitory concentration
ICH 
International Conference on Harmonization
IHC 
Immunohistochemical
IRB 
Institutional Review Board
MRI 
Magnetic resonance imaging
MTD 
Maximum tolerated dose
NOAEL 
No observable adverse event level
PK 
Pharmacokinetics
pRCC 
Papillary renal cell carcinoma
QD 
Once daily
SAE 
Serious Adverse Event
SOP 
Standard Operating Procedure
VEGFR 
Vascular endothelial growth factor receptor


Abbreviated Title: INC280 in RCC
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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
To determine the overall response rate (RECIST 1.1) in patients with papillary RCC treated with 
single agent INC280
1.1.2
Secondary Objective(s)
To assess progression-free survival, overall survival, disease control rate (partial and complete 
response plus stable disease ≥ 6 months) and duration of response 
To evaluate tolerability of INC280 in patients with papillary RCC 
Pharmacodynamic Endpoints
Evaluate modulation of the HGF/MET pathway using paired pre- and on-therapy tumor biopsies 
(when available)
Evaluate modulation of plasma HGF and sMET
1.1.3
Exploratory objective
To evaluate the impact of MET mutation (germline or somatic) or MET amplification/trisomy 7 
and/or prior MET therapy on overall response rate, PFS and other outcome measures
1.2
BACKGROUND AND RATIONALE
1.2.1
Overview of disease pathogenesis, epidemiology and current treatments
In 2012, RCC was the sixth and eighth most common malignancy among men and women, 
respectively, with an estimated new 64,770 cases and 13,570 deaths in the United States1. While 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
10
surgical treatment for localized disease can be curative, the outlook for patients with metastatic 
disease remains poor2.  With increased understanding of the molecular pathways involved in the 
pathogenesis of RCC, several new systemic agents are available for use in metastatic disease, 
largely for patients with clear cell RCC, the most common subtype.  
Papillary RCC is the second most common histologic subtype of kidney cancer, accounting for 
approximately 10-15% of cases of all tumors arising in the kidney, with a significantly higher 
incidence in African Americans3-5.  Papillary RCC can be further separated histologically into 
papillary type I and II subtypes6.  Although our understanding of the molecular underpinnings of 
papillary RCC are still evolving, emerging data suggests that there may be significant differences 
in the genetics and molecular pathways underlying different types of papillary RCC as well as 
disparate outcomes associated with these entities7-9.
Type 1 papillary tumors are characterized histologically by the presence of papillary or 
tubulo/papillary architecture with slender short papillae containing delicate fibrovascular cores 
lined by small cells with low grade basophilic nuclei and scant amphophilic cytoplasm. Type 1 
papillary RCC occurs in both sporadic and hereditary forms, which are histologically identical.  
Hereditary Papillary Renal Carcinoma (HPRC) is a hereditary cancer syndrome in which affected 
individuals are at risk for the development of bilateral, multifocal type 1 papillary renal 
carcinoma8,10.  HPRC is inherited in an autosomal, dominant fashion.  It has been estimated that 
affected patients with HPRC may develop up to 3,000 tumors per kidney (Figure 1). Activating 
mutations of MET were identified in the germline of affected HPRC patients (Figure 2) and have 
been found in tumors in a subset of patients with non-inherited, sporadic papillary renal 
carcinoma10-14. 
 
Figure 1: Multiple renal tumors in a resected kidney from an HPRC patient. Histopathologic evaluation 
reveals Type 1 papillary RCC.
The proto-oncogene MET (hepatocyte growth factor receptor) was identified as the gene for 
hereditary papillary renal carcinoma by genetic linkage analysis in families with this inherited 
renal cancer syndrome12-15. MET encodes the cell surface receptor for hepatocyte growth factor 
(HGF), and the HGF/MET pathway plays a key role in several biological processes including 
mitogenesis, morphogenesis and motogenesis16,17.  Activating mutations in the tyrosine kinase 
domain of MET have been detected in the germline of affected patients and in a subset of sporadic 
papillary kidney cancers. Nonrandom duplication of the chromosome 7 bearing the mutant MET 
allele, which was demonstrated in HPRC kidney tumors, may afford a growth advantage to these 
tumor cells, providing an important second step in HPRC tumor progression18,19 (Figure 2). 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
11
 
Figure 2: The MET proto-oncogene is located on the long arm of chromosome 7 and is mutated in patients 
with HPRC. Tumors from HPRC patients demonstrate non-random duplication of the chromosome bearing 
the mutated MET allele.
Sporadic type 1 papillary RCC accounts for approximately 5% and type 2 papillary RCC for 
approximately 10% of all kidney tumors diagnosed. While sporadic type 1 papillary RCC can 
present with solitary renal tumors, patients with bilateral multifocal tumors with no family history 
of RCC have also been described. There has been no systematic attempt at evaluating the role of 
MET activation in sporadic type 1 papillary RCC. One study identified mutations in 13% of 
patients with all subtypes of papillary RCC and no family history of renal tumors, although the 
prevalence of this genetic alteration in sporadic type I papillary RCC has not been adequately 
defined11. Furthermore, polysomy of chromosome 7, on which both MET and the gene for its 
ligand HGF are located, is seen in over two-thirds of patients with papillary RCC (both subtypes 
included in most studies), suggesting an alternative means of activation of the HGF/MET pathway 
is some papillary tumors20,21. 
Both sporadic and hereditary forms of papillary RCC have metastatic potential. Patients with 
tumors localized to the kidney are managed surgically. For patients with bilateral, multifocal 
papillary RCC, surgical management is geared toward preservation of renal function. These 
patients are usually followed radiologically until 1 or more tumors reach a size of approximately 
3 cm, at which point nephron-sparing surgical excision of these tumors is performed. Partial 
nephrectomies in these patients are not curative, but are aimed at reducing the risk of metastatic 
spread. Repeated surgical intervention may be needed because of multifocality, leading to 
compromise of renal function and other morbidity associated with multiple partial nephrectomies. 
There are no standard therapies of proven benefit for patients with metastatic papillary RCC. While 
several agents targeting the VEGF- and mTOR-pathways are approved by the US FDA for the 
treatment of metastatic RCC, their activity has been best studied in patients with clear cell RCC, 
in whom these agents appear to offer clinically meaningful improvements in progression free or 
overall survival. Papillary RCC patients with unresectable disease requiring systemic therapy 
usually receive either an mTOR inhibitor or a VEGF pathway antagonist, based on demonstration 
of modest activity in several retrospective analyses, small single arm phase 2 studies, and at least 
one subgroup analysis of a large randomized phase 3 study. In most studies, objective response 


Abbreviated Title: INC280 in RCC
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12
rates following therapy with mTOR or VEGFR-targeted TKIs were low (0-36%), with a median 
progression free survival (PFS) of less than 6 months22-28. Inhibitors of the epidermal growth factor 
receptor (EGFR) have also been evaluated in papillary RCC; in a phase 2 trial of the EGFR 
inhibitor erlotinib, the overall response rate in 52 patients with metastatic papillary RCC was 11%, 
with a 6 month PFS of only 29%29.  Several phase 2 trials evaluating the efficacy of everolimus, 
pazopanib or combined VEGF- and mTOR-pathway blockade in non clear cell RCC are currently 
underway.
The identification of oncogenic MET mutations in patients with HPRC as well as in a subset of 
patients with sporadic papillary RCC has led to considerable interest in targeting the HGF/MET 
pathway in these malignancies. Foretinib (formerly XL880), an inhibitor of Met, VEGFR2, RON 
and AXL tyrosine kinases was one of the earliest agents targeting the Met pathway available for 
clinical investigation. In a recently concluded multicenter phase 2 study, two dosing schedules of 
foretinib were evaluated in patients with papillary RCC30. A total of seventy-four patients were 
enrolled sequentially into one of two independent cohorts to receive either: A) an intermittent 
dosing regimen (240mg/d PO days 1-5 of every 14-day cycle, N=37) or B) a daily dosing regimen 
(80mg/d PO, N=37). The overall response rate in the entire cohort was 13.5%, with 10/75 patients 
experiencing a partial response. The median PFS was 9.3 months, considerably higher than that 
seen in historical controls treated with agents targeting VEGFR or mTOR pathways. The clinical 
activity of foretinib was most pronounced in patients with germline mutations in MET; in a 
preplanned subgroup analysis, 5/10 (50%) of patients with germline MET mutations experienced 
a PR, while only 5/57 (9%) of patients without this alteration had an objective response30,31. 
Patients with papillary type 1 as well as those with type 2 tumors were enrolled on this study. 
Although central pathology review of all tumors was conducted to confirm papillary histology, 
sufficient tumor was not available in several instances to render an accurate subclassification; it 
was, therefore, not possible to determine if type 1 and type 2 papillary tumors included in this trial 
exhibited differential sensitivity to foretinib. The adverse event profile associated with this agent 
was reminiscent of that seen with other inhibitors of the VEGF axis. However, a higher than 
anticipated incidence of pulmonary thromboembolism (11%) was noted, as were alterations in 
dark adaptation in several patients treated on this trial. These data suggest that Met pathway 
antagonists are worthy of further study at least in some subgroups of papillary RCC. At least one 
other Met inhibitor, tivantinib (ARQ197), is currently undergoing evaluation with or without 
erlotinib in a randomized phase 2 trial in patients with advanced papillary RCC. (NCT01688973)
1.2.2
Overview of INC280
The chemical name for INC280 is 2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2 
b][1,2,4]triazin-2-yl) benzamide dihydrochloride; dihydrochloride. INC280 is a light yellow to 
yellow powder as confirmed by visual inspection against a white background. INC280 
dihydrochloride is a nonhygroscopic solid. INC280 presents good solubility in water (4.7 mg/mL) 
at an acidic pH (2.1 mg/mL) but has poor solubility characteristics in the pH range of 7.4 to 8 
(0.002 mg/mL). INC280 drug product is provided as 50 mg, 100 mg, and 200 mg tablets. The 
formulations contain the active ingredient along with commonly used excipients that are of 
compendial grade.
INC280 possesses potent inhibitory activity against the MET kinase in vitro (IC50 = 0.13 ± 0.05 
nM). INC280 has been shown to be both ATP competitive and reversible in its mode of action. 
INC280 is also active against MET kinases from different species including murine and canine. 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
13
INC280 has been shown to be highly specific for MET with > 10,000-fold selectivity over 56 other 
human kinases.
INC280 demonstrates very potent activity in cells; cell-based biochemical assays that measure 
MET phosphorylation in response to constitutive or HGF mediated activation have yielded IC50 
values ranging from 0.2- 1.1 nM. INC280 also has been shown to inhibit MET mediated signal 
transduction with similar potency. In agreement with the biochemical assay, INC280 has shown 
potent activity, with IC50 values ranging from 0.2 – 2 nM, in functional cell assays of MET-
dependent cell proliferation, colony formation, cell survival and cell migration. Finally, the effect 
of INC280 on the activation of the EGFR family members EGFR and HER-3 by MET in relevant 
model cancer cells has also been demonstrated. To assess the effect of human serum protein 
binding on the cellular potency of INC280, a phospho-MET assay using human whole blood was 
developed. Using this assay, INC280 exhibits potent activity, with an IC50 value of 13.5 ± 3.9 nM 
and an IC90 value of 71 ± 25.1 nM.
The pharmacokinetic/pharmacodynamic relationship of INC280 was characterized in tumor-
bearing mice. These experiments probed the potential of INC280 to inhibit phosphorylation of 
MET, as assessed by phospho-MET levels in tumors using immunohistochemical or ELISA-based 
methods. In MET/HGF-driven xenograft mouse tumor models, oral dosing of INC280 
demonstrated significant in vivo activity in blocking MET phosphorylation. Oral administration 
of INC280 at a dose of 3 mg/kg suppressed > 90% MET phosphorylation for at least 7 hours in a 
mouse xenograft tumor model and this correlated with plasma INC280 levels greater than or 
equivalent to the human whole blood IC90 of 71 nM.
These studies were extended to determine the effect of INC280 on tumor cell proliferation and 
apoptosis in vivo. INC280 suppressed phosphorylation of MET nearly completely in these tumors 
and this was associated with a decrease in the percentage of cells within tumor samples staining 
positively for Ki67, a marker of proliferation and was associated with an increase in the number 
of cells staining positively for apoptosis as measured by fragmentation of DNA (TUNEL). Oral 
dosing of INC280 at dose level of 10 mg/kg and above resulted in > 90% tumor growth inhibition 
in the U-87MG glioblastoma xenograft model. Further efficacy experiments demonstrated the 
activity of INC280 as a single agent in tumor models expressing MET and its ligand HGF.
Plasma levels of INC280 correlated with both the dose administered and the extent of tumor 
growth inhibition.
Collectively, the data suggest that INC280 possesses potent in vivo biological and pharmacological 
activities, and supports its clinical development as a potentially effective oral treatment for human 
cancers.
1.2.2.1
Non-clinical experience
Nonclinical drug metabolism and pharmacokinetics (DMPK)
INC280 was absorbed rapidly in rats, dogs and monkeys. The absolute oral bioavailability 
following a single low dose was low in dogs (28%), and moderate to complete in rats and monkeys 
(>66%). Single and multiple dose toxicokinetic studies in rats and monkeys showed increase in 
plasma maximum observed concentration (Cmax) and area under the concentration-time curve 
(AUC) values of INC280 with increased dose, but the increases were not always dose-proportional.
INC280 plasma protein binding was moderate to high across species, and was 96% in humans with 
no concentration dependency. The in vitro blood-to-plasma ratio in humans was 1.5 (concentration 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
14
range of 10-1000 ng/mL). After oral dose of [14C]-INC280 in male pigmented and albino rats, 
INC280 and/or its metabolites were widely and rapidly distributed to all tissues. Melanin-
containing structures such as eye (choroid) and eye (ciliary body) appeared to show specific uptake 
and prolonged retention of drug related material. The presence of total radiolabeled components 
in those tissues was at least partly reversible. INC280 can penetrate across the blood-brain barrier.
Systemic clearance (CL) was low- to-moderate in mice, rats, dogs and monkeys. The estimated 
terminal half-life (T1/2) was short in mice, rats and dogs but long in monkeys.  Metabolism is the 
predominant mechanism of elimination of INC280 in rats and monkeys after oral administration. 
The hydroxylated metabolite M8 and the imidazo-triazinone (lactam) M16 were main metabolites 
observed in plasma and excreta of rats and monkeys. After single oral administration of 
[14C]INC280 to rats and monkeys, the majority of the radioactivity was excreted at the end of the 
observation period. The major portion of administered radioactivity was recovered in feces and 
only a minor fraction in urine. Direct renal excretion of INC280 was negligible and biliary 
excretion/intestinal secretion contributed only to a minor extent to the overall elimination of 
INC280.
1.2.2.1.1 MET kinase domain mutations causing resistance to INC280
Biochemical and cellular assays indicate that mutations of tyrosine 1230 (Y1230) and aspartic acid 
1228 (D1228) in the activation loop of the MET kinase domain strongly interfere with INC280 
activity. Based on several published co-crystal structures with chemically related compounds, 
these residues can be assumed to play a key role in binding of INC280 to MET.
More details can be found in the [Investigator's Brochure]. Y1230 and D1228 mutations also 
promote MET kinase activity and have been described in rare cases of papillary RCC. It is 
unknown if the predicted inability of some mutant forms of MET to bind INC280 will lead to 
resistance of tumors carrying these mutations.
1.2.2.2
Preclinical safety
Safety pharmacology studies with INC280 indicated that INC280 had no significant effects on 
central nervous system (CNS) and respiratory functions in rats, and no effects on cardiovascular 
function in monkeys. In vitro, INC280 inhibited human Ether-à-go-go-related gene (hERG) 
potassium current by 50% at 18.7 M.
Oral administration studies in mice, rats, and Cynomolgus monkeys were conducted in order to 
assess the potential systemic toxicity of INC280. In single dose studies, the no adverse effect level 
(NOAEL) doses were defined as 600 mg/kg both in mice and in monkeys. Repeat dose toxicity 
studies conducted in mice, rats, and Cynomolgus monkeys revealed the kidneys, pancreas, CNS, 
and potentially liver as target organs or organ systems.
In vitro genetic toxicology studies indicated that INC280 did not induce mutations or cause 
chromosome aberrations. The in vivo bone marrow micronucleus test in rats indicated that INC280 
did not induce micronuclei in the polychromatic erythrocytes of the bone marrow at doses up to 
the maximum tolerated dose (MTD).
Studies on embryofetal development in rats and rabbits indicated that INC280 is teratogenic to 
both species, and the teratogenicity is consistent with the mechanism of action by c-MET 
inhibition. INC280 should be considered potentially teratogenic to humans.
Additionally, INC280 has shown photosensitization potential in in vitro and in vivo assays.


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
15
1.2.2.3
Clinical experience
As of 28-Sep-2015, a total of 500 cancer patients and 90 non-cancer subjects have received 
INC280.
A total of 271 patients have been treated with INC280 as a single agent at different doses (198 
patients received the capsule formulation only, 66 patients received tablet formulation only, and 7 
patients switched from capsule to tablet formulation during treatment with INC280), and 229 
patients have been treated with INC280 in combination therapies: with gefitinib (143 patients of 
which 98 patients received the capsule formulation and 45 patients received the tablet 
formulation), with buparlisib (33 patients of which 21 patients received the capsule formulation 
and 12 patients received the tablet formulation), with erlotinib (23 patients of which 15 patients 
received the capsule formulation and 8 patients received the tablet formulation), with cetuximab 
(7 patients, all treated with tablet formulation),with LGX818/MEK162 (4 patients, all treated with 
capsule formulation), with EGF816 (15 patients, all treated with tablet formulation), with 
nivolumab (3 patients, all treated with tablet formulation) and with sonidegib (1 patient, treated 
with capsule formulation). In addition, 90 non-cancer subjects have received INC280 (6 subjects 
received the capsule formulation only, 60 subjects received the tablet formulation and 24 subjects 
received both capsule and tablet formulations). Fourteen clinical studies are currently ongoing with 
INC280.
A total of fourteen patients have experienced 14 DLTs: 6 in single agent studies (1 in 
[CINC280X2101T] study, 2 in [CINC280X1101] study and 3 in [CINC280X2102] study) and 8 
in combination studies (2 in combination with gefitinib ([CINC280X2202] study), 4 in 
combination with buparlisib ([CINC280X2204] study), and 2 in combination with EGF816 
([CINC280X2105C] study).
The DLTs in single agent studies were: one Grade 3 AST and ALKP increase (50 mg QD capsules) 
(in [CINC280X2101T] study); one Grade 2 malaise, Grade 2 intake difficulty and Grade 2 suicidal 
ideation (600 mg BID capsules) (due to the size and number of capsules) (in [CINC280X1101] 
study); one Grade 3 depression (400 mg BID tablets) (in [CINC280X1101] study); two Grade 3 
fatigue (200 mg BID and 450 mg BID capsules respectively) (in [CINC280X2102] study); one 
Grade 3 total bilirubin increase (250 mg BID capsules) (in [CINC280X2102] study).
The DLTs in combination with gefitinib were: one Grade 4 cough and dyspnea (600 mg BID 
capsules); and one Grade 3 dizziness (800 mg QD capsules). 
The DLTs in combination with buparlisib were: one Grade 3 personality change (400 mg BID 
capsules); one Grade 3 abdominal pain and nausea (300 mg BID tablets); one Grade 3 ALT 
increased and AST increased (400 mg BID tablets); and one Grade 3 ALT increased (400 mg BID 
tablets).
The DLTs in combination EGF816 were: one Grade 3 ALT increased (200 mg BID tablets); and 
one Grade 3 anaphylactic reaction (400 mg BID tablets).
Overall, the majority of the reported adverse events (AEs) are of mild or moderate severity.
The most frequent AEs suspected to be related to INC280 of any grade reported in the
[CINC280X2102] study, which is considered as the reference study for the safety profile of


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
16
INC280 as a single agent, were nausea (38 patients, [32.2%]), vomiting (31 patients, [26.3%]), 
fatigue (29 patients, [24.6%]), edema peripheral (27 patients, [22.9%]), and decreased appetite (22 
patients, [18.6%]), and the majority were Grade 1/2. The most frequently occurring Grade 3/4 AEs 
suspected to be related to INC280 included fatigue (6 patients, [5.1%]), lipase increased (4 patients 
[3.4%]), ALT increased (4 patients [3.4%]), AST increased (3 patients, [2.5%]), anemia, nausea, 
neutropenia, dehydration and hypophagia (each in 2 patients, [1.7%]), thrombocytopenia, 
vomiting, diarrhea, edema peripheral, blood bilirubin increased, amylase increased, lymphocyte 
count decreased, decreased appetite, hypoalbuminemia, hypophosphatemia, hyperlipasemia, 
hyperlipidemia, cerebral venous thrombosis, and rash maculopapular (each in 1 patient, [0.8%]). 
In addition, recent reports of interstitial lung disease/ pneumonitis have been reported as possibly 
related to single agent INC280 therapy.  
The MTD for INC280 capsules as single agent was not reached. The RP2D for INC280 as a single 
agent has been determined to be 600 mg BID in capsule formulation and 400 mg BID in tablet 
formulation.
Table 1-1: Summary of human study
Study
Population 
(No. of 
enrolled 
subjects
/patients)
No of 
subjects 
exposed to 
INC280
Study Title
Dose / Frequency / 
Formulation
CINCB28060-101
(Novartis code
[CINC280X2101T
])
N=45/45 
patients
45
A Phase 1, open-label, dose 
escalation study to 
determine the safety, 
tolerability, 
pharmacokinetics and 
pharmacodynamics of 
INC280 in subjects with 
advanced malignancies
Single agent study
Dose escalation arm:
INC280 QD regimen with 
capsule: 10 mg, 20 mg, 50 
mg, 70 mg, 150 mg, 200 mg, 
300 mg, 400 mg
INC280 BID regimen with 
capsule: 50 mg, 200 mg,
300 mg
[CINC280X1101]
N=44 patients
44
A Phase I study of INC280 
in Japanese patients with 
advanced solid tumors
Single agent study
Dose escalation arm:
INC280 QD regimen with 
capsule: 100 mg, 200 mg, 
400 mg, 500 mg, 600 mg, 
800 mg INC280 BID 
regimen with capsule: 400 
mg, 600 mg INC280 BID 
regimen with tablet: 200 mg 
, 400 mg


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
17
Study
Population 
(No. of 
enrolled 
subjects
/patients)
No of 
subjects 
exposed to 
INC280
Study Title
Dose / Frequency / 
Formulation
[CINC280X2102]
N=118 patients
118
A Phase I open-label dose 
escalation study with 
expansion to assess the 
safety and tolerability of 
INC280 in patients with 
cMET dependent advanced 
solid tumors
Single agent study
Dose escalation arm: 
INC280 BID regimen with 
capsule: 100 mg, 200 mg, 
250 mg, 350 mg, 450 mg, 
600 mg 
Dose expansion part: 
INC280 600 mg BID 
regimen with capsule 
Safety cohort with tablet:
INC280 400 mg BID with 
tablet
Current dose expansion arm: 
INC280 400 mg BID 
regimen with tablet
[CINC280X2201]
N=36 patients
36
A Phase II open-label, 
single arm, multicenter 
study of INC280 
administered orally in adult 
patients with advanced 
hepatocellular carcinoma
Single agent study Dose 
determining part:
INC280 300 mg BID with 
capsule
Dose expansion part:
INC280 600 mg BID with
capsule
[CINC280X2205]
N=26 patients
3
A Phase II, open-label, 
multiple arm study of single 
agents AUY922, BYL719, 
INC280, LDK378 and 
MEK162 in Chinese 
patients with advanced 
NSCLC
Single agent study
INC280 600 mg BID with 
capsule
INC280 400 mg BID with 
tablet
[CINC280A2201]
N=18 patients
18
A Phase II, multicenter, four 
cohort study of oral cMET 
inhibitor INC280 in adult 
patients with EGFR wild-
type (wt), advanced NSCLC 
who have received one or 
two prior lines of systemic 
therapy for 
advanced/metastatic disease
Single agent study
INC280 400 mg BID with 
tablet
[CINC280XUS04
T]
N=7 patients
7
A Phase II open-label 
Investigator-led study of 
INC280 in adults patients 
with papillary renal cell 
cancer
Single agent study
INC280 600 mg BID with 
capsule 
INC280 400 mg BID with 
tablet


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
18
Study
Population 
(No. of 
enrolled 
subjects
/patients)
No of 
subjects 
exposed to 
INC280
Study Title
Dose / Frequency / 
Formulation
[CINC280X2104]
N=7 patients
7
A Phase Ib, open-label, 
multicenter, dose escalation 
and expansion study, to 
evaluate the safety, 
pharmacokinetics and 
activity of INC280 in 
combination with cetuximab 
in cMET positive CRC and 
HNSCC patients who have 
progressed after anti-EGFR 
monoclonal antibody 
therapy
Combination study
First dose level: INC280150 
mg BID with  tablet plus 
cetuximab 400mg/m2 initial 
infusion followed by 
250mg/m2 infusions weekly 
Second dose level: INC280 
300 mg BID with tablet plus 
cetuximab 400mg/m2 initial 
infusion followed by 
250mg/m2 infusions weekly
[CINC280X2105
C]
N=15 patients
15
A Phase Ib/II, multicenter, 
open-label study of EGF816 
in combination with INC280 
in adult patients with EGFR 
mutated NSCLC
Combination study
Cohort 1: INC280 200 mg 
BID with tablet plus EGF816 
50 mg QD
Cohort 2: INC280 200 mg 
BID with tablet plus EGF816 
100 mg QD
Cohort 3: INC280 400 mg 
BID with tablet plus EGF816 
100 mg QD
Cohort 4: INC280 400 mg 
BID with tablet plus EGF816 
150 mg QD
[CINC280X2202]
N=143 patients
143
A Phase Ib/II, open-label, 
multicenter study of INC280 
administered orally in 
combination with gefitinib 
in adult patients with EGFR 
mutated, cMET-amplified 
NSCLC who have 
progressed after EGFR 
inhibitor treatment cancer 
who have progressed after 
EGFR inhibitor treatment
Combination study
Dose escalation arm:
INC280 QD regimen with 
capsule: 100 mg, 200 mg, 
400 mg, 800 mg in 
combination with gefitinib 
250 mg QD 
INC280 BID regimen with 
capsule: 200 mg, 400 mg, 
600 mg in combination with 
gefitinib 250 mg QD 
INC280 BID regimen with 
tablet: 200 mg in 
combination with gefitinib 
250 mg QD
Dose expansion part and 
Phase II: INC280 BID 
regimen with capsule: 400 
mg in combination with 
gefitinib 250 mg QD
INC280 BID regimen with 
tablet: 400 mg in 
combination with gefitinib 
250 mg QD


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
19
Study
Population 
(No. of 
enrolled 
subjects
/patients)
No of 
subjects 
exposed to 
INC280
Study Title
Dose / Frequency / 
Formulation
[CINC280X2204]
N=33 patients
33
A Phase Ib/II, open-label, 
multicenter study of INC280 
in combination with 
buparlisib in adult patients 
with recurrent glioblastoma
Combination study
Dose escalation arm:
INC280 BID regimen with 
capsule: 200 mg, 400 mg, 
500 mg in combination with 
buparlisib 50 mg QD, 500 
mg in combination with 
buparlisib 80 mg QD
INC280 BID regimen with 
tablet: 300 mg, 400 mg in 
combination with buparlisib 
80 mg QD
Phase II: INC280 400 mg 
BID with tablet, single agent 
only
[CINC280XUS02
T]
N=23 patients
23
A Phase Ib/II open-label 
investigator-led study of 
INC280 in combination with 
EGFR TKI erlotinib 
including dose escalation 
and expansion in adult 
patients with cMET 
expressing NSCLC
Combination study
Dose escalation INC280 mg 
BID regimen with capsule:
First dose level: INC280 100 
mg plus erlotinib 100 mg 
QD
Subsequent dose levels:
INC280 mg BID regimen 
with capsule: 100 mg, 200 
mg, 400 mg, 600 mg plus 
erlotinib 150mg QD
INC280 mg BID regimen 
with tablet: 400 mg plus 
erlotinib 150 mg QD
[CEGF816X2201]
N=17 patients
3
A Phase II, multicenter, 
open label study of EGF816 
in combination with 
Nivolumab in adult patients 
with EGFR mutated NSCLC 
and of INC280 in 
combination with 
Nivolumab in adult patients 
with cMET positive NSCLC
Combination study
INC280 400 mg BID with 
tablet in combination with 
nivolumab (3 mg/kg 
administered every 2 weeks)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
20
Study
Population 
(No. of 
enrolled 
subjects
/patients)
No of 
subjects 
exposed to 
INC280
Study Title
Dose / Frequency / 
Formulation
[CLGX818X2109
]
N=130 patients
4
A Phase II, multi-center, 
open label study of 
sequential 
LGX818/MEK162 
combination followed by a 
rational combination with 
targeted agents after 
progression, to overcome 
resistance in adult patients 
with locally advanced or 
metastatic BRAF V600 
melanoma
Combination study
Cohort 1: INC280 200 mg 
BID with capsule in 
combination with 200 mg 
LGX818 QD & 45 mg 
MEK162 BID
[CINC280XUS05I
]
N=1/1 patient
1
A Phase II open-label 
investigator-led study of 
INC280 in combination with 
LDE225 in an adult patient 
with cMET-amplified and 
12- span transmembrane 
receptor protein Patched1 
(PTCHI)- truncated 
glioblastoma
Combination study
INC280 600 mg BID with 
capsule monotherapy for 4 
months, then in combination 
with 200 mg sonidegib QD
[CINC280X2103]
N=24/24 
healthy subjects
24
A randomized, open-label, 
two sequence, two-period 
crossover study evaluating 
the relative bioavailability 
of INC280 between capsule 
and tablet following a single 
oral dose of INC280 in 
healthy subjects
Treatment A: single dose of 
INC280 600 mg given as 12 
x 50 mg with capsule
Treatment B: single dose of 
INC280 600 mg given as 3 x 
200 mg with tablet
[CINC280X2106]
N=6/6 healthy 
subjects
6
A single-center, open-label 
study to investigate the 
absorption, distribution, 
metabolism and excretion 
(ADME) of INC280 after a 
single oral dose of 600 mg 
[14C] INC280 (5.55 MBq) 
in healthy male subjects
Single dose of INC280 600 
mg with radiolabeled with 
capsule (14C)INC280
[CINC280X2107]
N=24/24 
healthy subjects
24
A randomized, single-
center, open-label, three-
period, six sequence, 
crossover study to 
investigate the effect of food 
on the pharmacokinetics of 
INC280 following a single 
oral dose of 3 x 200 mg 
film-coated tablets in 
healthy subjects
INC280 600 mg given as 3 x 
200 mg with tablet 
administered 3 times 
(fasting/low-fat meal/high-
fat meal) separated by a 7-
day washout between each 
treatment


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
21
Study
Population 
(No. of 
enrolled 
subjects
/patients)
No of 
subjects 
exposed to 
INC280
Study Title
Dose / Frequency / 
Formulation
[CINC280A2101]
N=20/20 
healthy subjects
20
A single center, open-label, 
two-period, single-sequence 
study to assess the effect of 
rabeprazole on the 
pharmacokinetics of a single 
dose of INC280 in healthy 
subjects
Single dose of INC280 600 
mg with tablet
[CINC280A2106]
N=16
non-cancer 
subjects
16
An open-label, single-dose, 
multi-center, parallel-group, 
two-staged study to evaluate 
the pharmacokinetics of the 
oral cMET inhibitor INC280 
in non-cancer subjects with 
impaired hepatic function 
and non-cancer subjects 
with normal hepatic 
function
Single dose of INC280 200 
mg with tablet
The cut-off date for the safety data updates is 28-Sep-2015. As of the cut-off date, a total of 500 
cancer patients and 90 non-cancer subjects have received INC280. A total of 271 patients with 
solid tumors have been treated with INC280 as a single agent (198 patients received the capsule 
formulation only, 66 patients received the tablet formulation only, and 7 patients switched from 
capsule to tablet formulation during treatment with INC280), and a further 229 patients have been 
treated with INC280 in combination therapies (139 patients received the capsule formulation and 
90 patients received the tablet formulation). In addition, 90 non-cancer subjects have received 
INC280 (6 subjects received the capsule formulation only, 60 subjects received the tablet 
formulation only, and 24 subjects received both capsule and tablet formulations).
 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
22
The most common AEs summarized in Table 1-2 through Table 1-7 below. 
Table 1-2: Adverse events (greater than or equal to 5%) suspected to be related to study treatment in study
MedDRA Preferred Term
10 mg QD
(n=3)
20 mg QD
(n=4)
50 mg QD
(n=6)
70 mg QD 
(n=4)
50 
mg 
BID 
(n=3)
150 
mg
QD (n=3)
200 
mg
QD (n=4)
300 
mg
QD (n=4)
400 
mg
QD (n=6)
200 
mg
BID (n=4)
300 
mg
BID 
(n=4)
Total 
(N=45)
Subjects with any AEs, n
(%)
1 (33.3)
3 (75.0)
5 (83.3)
4 (100.0)
2 (66.7)
3 (100.0)
3 (75.0)
4 (100.0)
5 (83.3)
4 (100.0)
3 (75.0)
37 (82.2)
Nausea
0
0
3 (50.0)
2 (50.0)
0
1 (33.3)
0
0
2 (33.3)
3 (75.0)
1 (25.0)
12 (26.7)
Tremor
1 (33.3)
1 (25.0)
2 (33.3)
1 (25.0)
1 (33.3)
1 (33.3)
0
0
3 (50.0)
0
1 (25.0)
11 (24.4)
Peripheral edema
0
0
1 (16.7)
0
0
1 (33.3)
0
2 (50.0)
1 (16.7)
3 (75.0)
2 (50.0)
10 (22.2)
Fatigue
1 (33.3)
1 (25.0)
1 (16.7)
3 (75.0)
0
0
1 (25.0)
1 (25.0)
0
1 (25.0)
0
9 (20.0)
Headache
0
0
0
2 (50.0)
0
1 (33.3)
1 (25.0)
0
1 (16.7)
2 (50.0)
0
7 (15.6)
Dysgeusia
0
0
0
0
0
0
1 (25.0)
2 (50.0)
0
3 (75.0)
0
6 (13.3)
Vomiting
0
0
0
0
0
0
0
1 (25.0)
2 (33.3)
2 (50.0)
1 (25.0)
6 (13.3)
Diarrhea
0
0
1 (16.7)
0
0
1 (33.3)
1 (25.0)
0
0
0
1 (25.0)
4 (8.9)
Asthenia
0
0
1 (16.7)
0
0
0
0
0
1 (16.7)
0
1 (25.0)
3 (6.7)
Decreased appetite
0
0
0
0
0
1 (33.3)
0
0
1 (16.7)
1 (25.0)
0
3 (6.7)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
23
Table 1-3: Adverse events (greater than or equal to 5%) suspected to be related to study treatment in study [CINC280X1101]
INC280
100 mg QD Cap
200 mg QD Cap
400 mg QD Cap
500 mg QD Cap
600 mg QD Cap
800 mg QD Cap
N=3
N=4
N=3
N=4
N=4
N=4
All
Grade
All
Grade
All
Grade
All
Grade
All
Grade 3/4All gradesGrade 3/4
grades
3/4
grades
3/4
grades
3/4
grades
3/4
grades
Preferred Term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
-Total
2 (66.7)
0
2 (50.0)
0
2 (66.7)
0
3 (75.0)
1 (25.0)
4 (100)
2 (50.0)
3 (75.0)
0
Blood 
creatinine
increased
1 (33.3)
0
0
0
1 (33.3)
0
2 (75.0)
0
2 (75.0)
0
1 (25.0)
0
Nausea
0
0
1 (25.0)
0
0
0
0
0
3 (75.0)
0
1 (25.0)
0
Vomiting
0
0
2 (50.0)
0
0
0
0
0
2 (50.0)
0
1 (25.0)
0
Decreased appetite 0
0
1 (25.0)
0
0
0
0
0
3 (75.0)
0
1 (25.0)
0
Diarrhea
0
0
0
0
1 (33.3)
0
3 (75.0)
0
0
0
0
0
Fatigue
0
0
0
0
0
0
1 (25.0)
0
1 (25.0)
0
0
0
Malaise
0
0
0
0
0
0
0
0
1 (25.0)
0
0
0
Edema peripheral 0
0
0
0
0
0
0
0
1 (25.0)
0
0
0
Hypoalbuminemia 0
0
1 (25.0)
0
0
0
0
0
0
0
1 (25.0)
0
Constipation
0
0
1 (25.0)
0
0
0
0
0
0
0
1 (25.0)
0
Dry skin
1 (33.3)
0
0
0
0
0
0
0
0
0
0
0
Alanine 
aminotransferase 
increased
0
0
0
0
0
0
1 (25.0)
1 (25.0)
1 (25.0)
0
0
0
Amylase increased 0
0
0
0
0
0
0
0
0
0
0
0
Anemia
0
0
0
0
0
0
0
0
1 (25.0)
0
1 (25.0)
0


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
24
INC280
100 mg QD Cap
200 mg QD Cap
400 mg QD Cap
500 mg QD Cap
600 mg QD Cap
800 mg QD Cap
N=3
N=4
N=3
N=4
N=4
N=4
All
Grade
All
Grade
All
Grade
All
Grade
All
Grade 3/4All gradesGrade 3/4
grades
3/4
grades
3/4
grades
3/4
grades
3/4
grades
Preferred Term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Aspartate 
aminotransferase 
increased
0
0
0
0
0
0
1 (25.0)
1 (25.0)
1 (25.0)
0
0
0
Hypophosphatemia0
0
0
0
0
0
0
0
0
0
0
0
Hypotension
0
0
0
0
0
0
2 (50.0)
0
0
0
0
0
Weight decreased 0
0
1 (25.0)
0
0
0
0
0
0
0
0
0
Hypoalbuminemia 0
0
1 (25.0)
0
0
0
0
0
0
0
1 (25.0)
0
Constipation
0
0
1 (25.0)
0
0
0
0
0
0
0
1 (25.0)
0
Dry skin
1 (33.3)
0
0
0
0
0
0
0
0
0
0
0
Alanine 
aminotransferase 
increased
0
0
0
0
0
0
1 (25.0)
1 (25.0)
1 (25.0)
0
0
0
Amylase increased 0
0
0
0
0
0
0
0
0
0
0
0
Anemia
0
0
0
0
0
0
0
0
1 (25.0)
0
1 (25.0)
0
Aspartate 
aminotransferase 
increased
0
0
0
0
0
0
1 (25.0)
1 (25.0)
1 (25.0)
0
0
0
Hypophosphatemia0
0
0
0
0
0
0
0
0
0
0
0
Hypotension
0
0
0
0
0
0
2 (50.0)
0
0
0
0
0
Weight decreased 0
0
1 (25.0)
0
0
0
0
0
0
0
0
0


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
25
Table 1-4: Adverse events (greater than or equal to 5%) suspected to be related to study treatment in study [CINC280X2102]
INC280 100 mg BID 
Capsules
N=4
INC280 200 mg BID 
Capsules
N=5
INC280 250 mg BID 
Capsules
N=4
INC280 350 mg BID 
Capsules
N=3
INC280 450 mg BID 
Capsules
N=9
Preferred term
All grades n 
(%)
Grade 3/4 
n (%)
All grades n 
(%)
Grade 3/4 
n (%)
All grades n 
(%)
Grade 3/4 
n (%)
All grades n 
(%)
Grade 3/4 
n (%)
All grades 
n (%)
Grade 3/4 
n (%)
-Total
3
(75.0)
1
(25.0)
5
(100.0)
3
(60.0)
3
(75.0)
2
(50.0)
2
(66.7)
0
8
(88.9)
3
(33.3)
Nausea
1
(25.0)
0
2
(40.0)
0
0
0
0
0
4
(44.4)
0
Vomiting
2
(50.0)
0
1
(20.0)
0
1
(25.0)
0
0
0
3
(33.3)
0
Fatigue
0
0
2
(40.0)
1
(20.0)
1
(25.0)
1
(25.0)
0
0
3
(33.3)
1
(11.1)
Edema Peripheral
0
0
1
(20.0)
1
(20.0)
1
(25.0)
0
1
(33.3)
0
2
(22.2)
0
Decreased Appetite
1
(25.0)
0
2
(40.0)
0
1
(25.0)
1
(25.0)
1
(33.3)
0
3
(33.3)
0
Diarrhea
1
(25.0)
0
0
0
0
0
1
(33.3)
0
0
0
Aspartate 
Aminotransferase 
Increased
0
0
0
0
1
(25.0)
0
0
0
1
(11.1)
1
(11.1)
Asthenia
2
(50.0)
0
1
(20.0)
0
0
0
1
(33.3)
0
1
(11.1)
0
Hypoalbuminemia
0
0
2
(40.0)
1
(20.0)
0
0
1
(33.3)
0
0
0
Blood 
Creatinine 
Increased
0
0
1
(20.0)
0
0
0
1
(33.3)
0
0
0
Alanine 
Aminotransferase 
Increased
0
0
0
0
0
0
0
0
1
(11.1)
0
Lipase Increased
0
0
0
0
1
(25.0)
1
(25.0)
0
0
0
0


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
26
INC280 600 mg BID Capsules – All 
N=63
INC280 400 mg BID Capsules – All 
N=30
All patients
N-118
Preferred term
All grades n (%)
Grade 3/4 n (%)
All grades n (%)
Grade 3/4 n (%)
All grades n (%)
Grade 3/4 n (%)
-Total
54 (85.7)
17 (27.0)
23 (76.7)
3  (10.0)
98 (83.1)
29 (24.6)
Nausea
24
(38.1)
2
(3.2)
7
(23.3)
0
38
(32.2)
2
(1.7)
Vomiting
17
(27.0)
1
(1.6)
7
(23.3)
0
31
(26.3)
1
(0.8)
Fatigue
18
(28.6)
2
(3.2)
5
(16.7)
1
(3.3)
29
(24.6)
6
(5.1)
Edema Peripheral
16
(25.4)
0
6
(20.0)
0
27
(22.9)
1
(0.8)
Decreased Appetite
13
(20.6)
0
1
(3.3)
0
22
(18.6)
1
(0.8)
Diarrhea
14
(22.2)
0
3
(10.0)
1
(3.3)
19
(16.1)
1
(0.8)
Aspartate 
Aminotransferase
Increased
6
(9.5)
1
(1.6)
3
(10.0)
1
(3.3)
11
(9.3)
3
(2.5)
Asthenia
5
(7.9)
0
1
(3.3)
0
11
(9.3)
0
Hypoalbuminemia
4
(6.3)
0
3
(10.0)
0
10
(8.5)
1
(0.8)
Blood Creatinine Increased
5
(7.9)
0
2
(6.7)
0
9
(7.6)
0
Alanine Aminotransferase
4
(6.3)
3
(4.8)
3
(10.0)
1
(3.3)
8
(6.8)
4
(3.4)
Increased
Lipase Increased
6
(9.5)
3
(4.8)
0
0
7
(5.9)
4
(3.4)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
27
Table 1-5: Adverse events (greater than or equal to 5%) suspected to be study treatment related in study [CINC280X2202]
Dose of INC280 in combination with 250 mg QD gefitinib
QD 100 mg Cap N=5
QD 200 mg Cap N=7
QD 400 mg Cap N=6
QD 800 mg Cap N=7
BID 200 mg Cap N=4
All grades
Grade 3/4
All grades
Grade 3/4
All grades
Grade 3/4
All grades
Grade 3/4
All grades
Grade 3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
-Total
4 (80.0)
1 (20.0)
7 (100)
2 (28.6)
6 (100)
0
6 (85.7)
1 (14.3)
4 (100)
2 (50.0)
Nausea
1 (20.0)
0
0
0
3 (50.0)
0
5 (71.4)
0
1 (25.0)
0
Decreased Appetite
0
0
0
0
0
0
3 (42.9)
0
1 (25.0)
0
Edema Peripheral
0
0
0
0
0
0
0
0
1 (25.0)
1 (25.0)
Paronychia
1 (20.0)
0
1 (14.3)
0
1 (16.7)
0
0
0
2 (50.0)
0
Diarrhea
1 (20.0)
0
1 (14.3)
0
0
0
2 (28.6)
0
3 (75.0)
0
Rash
1 (20.0)
0
3 (42.9)
0
0
0
2 (28.6)
0
2 (50.0)
0
Vomiting
0
0
1 (14.3)
0
1 (16.7)
0
5 (71.4)
1 (14.3)
1 (25.0)
0
Amylase Increased
1 (20.0)
1 (20.0)
1 (14.3)
0
0
0
0
0
0
0
Fatigue
0
0
1 (14.3)
0
1 (16.7)
0
1 (14.3)
0
0
0
Alanine Aminotransferase
Increased
0
0
0
0
1 (16.7)
0
1 (14.3)
0
1 (25.0)
0
Blood Bilirubin Increased 0
0
0
0
0
0
0
0
0
0
Aspartate 
Aminotransferase 
Increased
0
0
0
0
1 (16.7)
0
1 (14.3)
0
0
0
Blood 
Creatinine
Increased
0
0
0
0
0
0
0
0
0
0
Lipase Increased
1 (20.0)
1 (20.0)
1 (14.3)
1 (14.3)
0
0
0
0
0
0
Dermatitis Acneiform
1 (20.0)
0
2 (28.6)
0
0
0
1 (14.3)
0
0
0
Pruritus
1 (20.0)
0
1 (14.3)
0
0
0
1 (14.3)
0
1 (25.0)
0


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
28
Dose of INC280 in combination with 250 mg QD gefitinib
BID 400 mg Cap - P1b
BID 400 mg Cap - 
P2
BID 600 mg Cap
BID 200 mg Tab
BID 400 mg Tab - 
P1b
BID 400 mg Tab - 
P2
All patients
N=12
N=52
N=5
N=7
N=8
N=30
N=143
All
Grade
All
Grade
All
Grade
All
Grade
All
Grade
All
Grade
All
Grade
grades
3/4
grades
3/4
grades
3/4
grades
3/4
grades
3/4
grades
3/4
grades
3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
-Total
11 (91.7) 3 (25.0) 43 (82.7) 7 (13.5) 4 (80.0)
1 (20.0)
6 (85.7)
3 (42.9)
6 (75.0)
1 (12.5)
23 (76.7) 9 (30.0) 120
30 (21.0)
(83.9)
Nausea
0
0
5 (9.6)
0
1 (20.0)
0
4 (57.1)
0
3 (37.5)
1 (12.5)
9 (30.0)
0
32 (22.4) 1 (0.7)
Decreased Appetite1 (8.3)
0
11 (21.2) 0
3 (60.0)
0
1 (14.3)
0
2 (25.0)
0
5 (16.7)
0
27 (18.9) 0
Edema Peripheral 4 (33.3)
0
10 (19.2) 0
2 (40.0)
0
2 (28.6)
0
1 (12.5)
0
6 (20.0)
1 (3.3)
26 (18.2) 2 (1.4)
Paronychia
3 (25.0)
0
7 (13.5)
0
0
0
2 (28.6)
0
3 (37.5)
0
6 (20.0)
1 (3.3)
26 (18.2) 1 (0.7)
Diarrhea
3 (25.0)
0
7 (13.5)
0
1 (20.0)
0
1 (14.3)
0
1 (12.5)
0
5 (16.7)
1 (3.3)
25 (17.5) 1 (0.7)
Rash
3 (25.0)
0
5 (9.6)
1 (1.9)
0
0
1 (14.3)
0
2 (25.0)
0
4 (13.3)
0
23 (16.1) 1 (0.7)
Vomiting
1 (8.3)
0
7 (13.5)
0
1 (20.0)
0
2 (28.6)
1 (14.3)
2 (25.0)
0
1 (3.3)
0
22 (15.4) 2 (1.4)
Amylase Increased 4 (33.3)
2 (16.7) 5 (9.6)
1 (1.9)
0
0
1 (14.3)
1 (14.3)
1 (12.5)
0
5 (16.7)
4 (13.3) 18 (12.6) 9 (6.3)
Fatigue
1 (8.3)
0
5 (9.6)
0
1 (20.0)
0
1 (14.3)
0
2 (25.0)
0
4 (13.3)
1 (3.3)
17 (11.9) 1 (0.7)
Alanine 
Aminotransferase 
Increased
2 (16.7)
1 (8.3)
8 (15.4)
2 (3.8)
1 (20.0)
0
0
0
0
0
0
0
14 (9.8)
3 (2.1)
Blood Bilirubin 
Increased
4 (33.3)
0
8 (15.4)
1 (1.9)
0
0
0
0
0
0
1 (3.3)
0
13 (9.1)
1 (0.7)
Aspartate 
Aminotransferase 
Increased
1 (8.3)
0
8 (15.4)
2 (3.8)
0
0
0
0
0
0
0
0
11 (7.7)
2 (1.4)
Blood Creatinine 
Increased
2 (16.7)
0
5 (9.6)
0
0
0
1 (14.3)
0
0
0
2 (6.7)
0
10 (7.0)
0


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
29
BID 400 mg Cap - P1b
BID 400 mg Cap - 
P2
BID 600 mg Cap
BID 200 mg Tab
BID 400 mg Tab - 
P1b
BID 400 mg Tab - 
P2
All patients
N=12
N=52
N=5
N=7
N=8
N=30
N=143
All
Grade
All
Grade
All
Grade
All
Grade
All
Grade
All
Grade
All
Grade
grades
3/4
grades
3/4
grades
3/4
grades
3/4
grades
3/4
grades
3/4
grades
3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Lipase Increased
2 (16.7)
2 (16.7) 3 (5.8)
0
0
0
0
0
0
0
3 (10.0)
3 (10.0) 10 (7.0)
7 (4.9)
Dermatitis 
Acneiform
1 (8.3)
0
0
0
0
0
2 (28.6)
0
0
0
2 (6.7)
0
9 (6.3)
0
Pruritus
1 (8.3)
0
2 (3.8)
0
0
0
0
0
0
0
2 (6.7)
0
9 (6.3)
0


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
30
Table 1-6: Adverse events suspected to be related to study treatment in study [CINC280X2201]
INC280 capsules BID 300 mg
N=9
BID 600 mg N=27
All patients N=36
All grades
Grade 3/4
All grades
Grade 3/4
All grades
Grade 3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
-Total
7 (77.8)
1 (11.1)
17 (63.0)
4 (14.8)
24 (66.7)
5 (13.9)
Nausea
5 (55.6)
0
9 (33.3)
1 (3.7)
14 (38.9)
1 (2.8)
Vomiting
3 (33.3)
1 (11.1)
8 (29.6)
1 (3.7)
11 (30.6)
2 (5.6)
Fatigue
1 (11.1)
0
6 (22.2)
0
7 (19.4)
0
Diarrhea
1 (11.1)
0
3 (11.1)
0
4 (11.1)
0
Blood Creatinine Increased
0
0
3 (11.1)
0
3 (8.3)
0
Decreased Appetite
1 (11.1)
0
2 (7.4)
0
3 (8.3)
0
Leukopenia
0
0
3 (11.1)
0
3 (8.3)
0
Alanine Aminotransferase Increased
0
0
2 (7.4)
1 (3.7)
2 (5.6)
1 (2.8)
Aspartate Aminotransferase Increased
0
0
2 (7.4)
1 (3.7)
2 (5.6)
1 (2.8)
Thrombocytopenia
0
0
2 (7.4)
0
2 (5.6)
0
Abdominal Pain
0
0
1 (3.7)
0
1 (2.8)
0
Amylase Increased
0
0
1 (3.7)
1 (3.7)
1 (2.8)
1 (2.8)
Blood Alkaline Phosphatase Increased
0
0
1 (3.7)
0
1 (2.8)
0
Blood Bilirubin Increased
0
0
1 (3.7)
1 (3.7)
1 (2.8)
1 (2.8)
Cholecystitis
0
0
1 (3.7)
0
1 (2.8)
0
Constipation
1 (11.1)
0
0
0
1 (2.8)
0
Dehydration
1 (11.1)
0
0
0
1 (2.8)
0
Dizziness
0
0
1 (3.7)
0
1 (2.8)
0
Dyspepsia
1 (11.1)
0
0
0
1 (2.8)
0


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
31
INC280 capsules BID 300 mg
N=9
BID 600 mg N=27
All patients N=36
All grades
Grade 3/4
All grades
Grade 3/4
All grades
Grade 3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Hypoalbuminemia
0
0
1 (3.7)
0
1 (2.8)
0
Hypocalcemia
0
0
1 (3.7)
0
1 (2.8)
0
Insomnia
0
0
1 (3.7)
0
1 (2.8)
0
International Normalized Ratio Increased
0
0
1 (3.7)
0
1 (2.8)
0
Leukocytosis
0
0
1 (3.7)
0
1 (2.8)
0
Myalgia
0
0
1 (3.7)
0
1 (2.8)
0
Neutropenia
0
0
1 (3.7)
0
1 (2.8)
0
Oral Candidiasis
1 (11.1)
0
0
0
1 (2.8)
0
Peptic Ulcer
0
0
1 (3.7)
0
1 (2.8)
0
Protein Urine
0
0
1 (3.7)
0
1 (2.8)
0


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
32
Table 1-7: Adverse events (greater than or equal to 5%) suspected to be related to study treatment in study [CINC280X2204]
All patients
INC280 200 mg
BID Cap +
Buparlisib 50
mg QD
N=5
INC280 400 mg
BID Cap +
Buparlisib 50
mg QD
N=6
INC280 500 mg
BID Cap +
Buparlisib 50
mg QD
N=4
INC280 500 mg
BID Cap +
Buparlisib 80
mg QD
N=6
INC280 300 mg
BID Cap +
Buparlisib 80
mg QD
N=7
INC280 400 mg
BID Cap +
Buparlisib 80
mg QD
N=5
N=33
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
-Total
4 (80.0) 1
4 (66.7) 2
4 (100)
2
4 (66.7) 0
7 (100)
4
5 (100)
3
28 (84.8)12
(20.0)
(33.3)
(50.0)
(57.1)
(60.0)
(36.4)
Fatigue
2 (40.0) 0
2 (33.3) 0
0
0
2 (33.3) 0
2 (28.6) 1
2
0
10 (30.3)1 (3.0)
(14.3)
(40.0)
Alanine 
Aminotransferase
Increased
1 (20.0) 0
1 (16.7) 1
1
1
0
0
2 (28.6) 1
4
3
9 (27.3) 6
(16.7)
(25.0)
(25.0)
(14.3)
(80.0)
(60.0)
(18.2)
Nausea
1 (20.0) 0
1 (16.7) 0
1
0
1 (16.7) 0
3 (42.9) 1
2
0
9 (27.3) 1 (3.0)
(25.0)
(14.3)
(40.0)
Aspartate Aminotransferase
1 (20.0) 0
1 (16.7) 1
1
1
0
0
2 (28.6) 1
3
3
8 (24.2) 6
Increased
(16.7)
(25.0)
(25.0)
(14.3)
(60.0)
(60.0)
(18.2)
Depression
1 (20.0) 0
0
0
1
0
0
0
3 (42.9) 0
2
0
7 (21.2) 0
(25.0)
(40.0)
Hyperglycemia
2 (40.0) 0
0
0
2
0
1 (16.7) 0
2 (28.6) 0
0
0
7 (21.2) 0
(50.0)
Blood Bilirubin Increased
1 (20.0) 0
0
0
2
0
0
0
1 (14.3) 0
1
0
5 (15.2) 0
(50.0)
(20.0)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
33
All patients
INC280 200 mg
BID Cap +
Buparlisib 50
mg QD
N=5
INC280 400 mg
BID Cap +
Buparlisib 50
mg QD
N=6
INC280 500 mg
BID Cap +
Buparlisib 50
mg QD
N=4
INC280 500 mg
BID Cap +
Buparlisib 80
mg QD
N=6
INC280 300 mg
BID Cap +
Buparlisib 80
mg QD
N=7
INC280 400 mg
BID Cap +
Buparlisib 80
mg QD
N=5
N=33
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Blood Creatinine Increased
2 (40.0) 0
0
0
1
0
0
0
0
0
2
0
5 (15.2) 0
(25.0)
(40.0)
Diarrhea
1 (20.0) 0
1 (16.7) 0
0
0
1 (16.7) 0
2 (28.6) 0
0
0
5 (15.2) 0
Insulin C-Peptide Increased
2 (40.0) 0
0
0
1
0
0
0
2 (28.6) 0
0
0
5 (15.2) 0
(25.0)
Anxiety
1 (20.0) 0
0
0
0
0
0
0
2 (28.6) 1
1
0
4 (12.1) 1 (3.0)
(14.3)
(20.0)
Dyspepsia
0
0
0
0
0
0
1 (16.7) 0
1 (14.3) 0
1
0
3 (9.1)
0
(20.0)
Glomerular Filtration Rate
2 (40.0) 0
0
0
1
0
0
0
0
0
0
0
3 (9.1)
0
Decreased
(25.0)
Hypophosphatemia
0
0
0
0
1
0
0
0
2 (28.6) 1
0
0
3 (9.1)
1 (3.0)
(25.0)
(14.3)
Lipase Increased
1 (20.0) 0
0
0
1
1
0
0
0
0
1
0
3 (9.1)
1 (3.0)
(25.0)
(25.0)
(20.0)
Platelet Count Decreased
0
0
0
0
0
0
0
0
1 (14.3) 0
2
0
3 (9.1)
0
(40.0)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
34
All patients
INC280 200 mg
BID Cap +
Buparlisib 50
mg QD
N=5
INC280 400 mg
BID Cap +
Buparlisib 50
mg QD
N=6
INC280 500 mg
BID Cap +
Buparlisib 50
mg QD
N=4
INC280 500 mg
BID Cap +
Buparlisib 80
mg QD
N=6
INC280 300 mg
BID Cap +
Buparlisib 80
mg QD
N=7
INC280 400 mg
BID Cap +
Buparlisib 80
mg QD
N=5
N=33
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Vomiting
1 (20.0) 0
0
0
0
0
0
0
1 (14.3) 0
1
0
3 (9.1)
0
(20.0)
Amylase Increased
1 (20.0) 0
0
0
1
0
0
0
0
0
0
0
2 (6.1)
0
(25.0)
Constipation
0
0
1 (16.7) 0
1
0
0
0
0
0
0
0
2 (6.1)
0
(25.0)
Cough
1 (20.0) 0
0
0
0
0
0
0
0
0
1
0
2 (6.1)
0
(20.0)
Decreased Appetite
0
0
1 (16.7) 0
1
0
0
0
0
0
0
0
2 (6.1)
0
(25.0)
Leukopenia
1 (20.0) 0
1 (16.7) 0
0
0
0
0
0
0
0
0
2 (6.1)
0
Pruritus
1 (20.0) 0
0
0
0
0
0
0
0
0
1
0
2 (6.1)
0
(20.0)
Rash
0
0
0
0
0
0
0
0
0
0
2
0
2 (6.1)
0
(40.0)
Rash Maculopapular
0
0
0
0
0
0
0
0
1 (14.3) 0
1
0
2 (6.1)
0
(20.0)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
35
All patients
INC280 200 mg
BID Cap +
Buparlisib 50
mg QD
N=5
INC280 400 mg
BID Cap +
Buparlisib 50
mg QD
N=6
INC280 500 mg
BID Cap +
Buparlisib 50
mg QD
N=4
INC280 500 mg
BID Cap +
Buparlisib 80
mg QD
N=6
INC280 300 mg
BID Cap +
Buparlisib 80
mg QD
N=7
INC280 400 mg
BID Cap +
Buparlisib 80
mg QD
N=5
N=33
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
All 
grades
Grade 
3/4
Preferred term
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Somnolence
1 (20.0) 0
0
0
0
0
0
0
1 (14.3) 0
0
0
2 (6.1)
0
Stomatitis
0
0
0
0
0
0
1 (16.7) 0
0
0
1
0
2 (6.1)
0
(20.0)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
36
1.2.2.4
Pharmacokinetics
As of 28-Sep-2015, INC280 single agent steady state PK data are evaluable in four studies with 
tablet and/or capsule formulations ([CINC280X2101T], [CINC280X1101], [CINC280X2102] and 
[CINC280X2201]).  The mean plasma exposures (Cmax and AUC) of INC280 capsules were 
increased with dose following QD administration up to 600 mg/day in studies [CINC280X2101T] 
and [CINC280X1101], no further increase in the mean exposure was observed at 800 mg QD in 
[CINC280X1101]). Following twice daily dosing the mean plasma exposures (Cmax and AUC) 
of INC280 capsules increased with dose up to 600 mg twice per day (1200 mg/day).  INC280 
tablet provided higher exposures than the capsule at the same doses tested, with generally lower 
inter-subject variability. The mean plasma exposures of INC280 tablet appeared to increase dose 
proportionally from 200 to 400 mg twice per day ([CINC280X1101] and [CINC280X2102]). In 
the study [CINC280X2102], compared with the INC280 capsule at 600 mg BID (RP2D, N=21), 
the INC280 tablet at 400 mg BID (N=4) provided comparable mean AUC0-12h,ss (1.03-fold) and 
slightly higher Cmax,ss (1.22-fold) in the limited subjects tested. The apparent terminal half-life 
T1/2 of INC280 estimated from [CINC280X1101] QD treatment is 4.4 h, ranging, from 2.8 to 9.0 
across the cohorts. Steady state INC280 exposure is expected to be reached by the third day of 
consecutive dosing. Accumulation of INC280 tablet following repeated administration at 400 mg 
BID is low with an accumulation ratio of up to 2-fold in [CINC280X1101] and [CINC280X2102]; 
however, some subjects had higher accumulation ratios up to 10-fold in [CINC280X1101].
1.2.2.5
Dose Rationale
INC280 600 mg bid is the highest safe dose being evaluated based on the clinical experience from 
ongoing studies. INC280 exposure increases by dose up to 600 mg bid. At this dose level, INC280 
is expected to achieve target inhibition. In preclinical S114 xenograft model, plasma concentration 
of 71 nM was associated with 90% inhibition of p-MET. To predict the drug exposure of INC280 
and its tumor growth inhibition effect, a PK/PD-tumor growth model has been built based on the 
data from preclinical xenograft models. The model suggested that average INC280 drug exposure 
at total daily doses of 400 mg (400 mg qd or 200 mg bid) and above will lead to tumor shrinkage 
in MET addicted tumors. BID dosing regimen is potentially more appropriate in fast growing 
tumors than a QD regimen (Georgieva et al, 2012). Concentration leading to tumor stasis (Cstasis) 
calculated from the GTL-16 xenograft model was close to five folds of in vivo IC90 for p-c-MET 
inhibition. Observed mean Ctrough concentration on Day 15 at 600 bid was about 2648 nM 
(preliminary PK result from ongoing study INC280X2102), equaling to 37 folds of in vivo IC90 
and 7 folds of Cstasis. Therefore, minimal average steady state concentration of INC280 600 mg 
bid in tumor patients could well above Cstasis. Allowing for interpatient PK variability, given at 
600 mg bid, more than 90% patient population could achieve concentration above Cstasis 
throughout the dosing interval. Novartis plans to use 600mg BID as the RP2D for all their single 
agent studies.
Taken together, the clinical safety and PK data as well as PKPD information from preclinical 
xenograft models suggest that 600 mg bid is a reasonable dose for this phase II study.
1.2.3
INC 280 Tablet Formulation
The Recommended Phase 2 Dose (RP2D) for INC280 single agent therapy has been determined 
in study CINC280X2102. CINC280X2102 study is a Phase I dose-escalation study conducted by 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
37
Novartis with expansion in patients with solid tumors and MET dysregulation. The dose of INC280 
at 600 mg BID was selected as the RP2D (in capsules) based on safety, PD parameters, and PK 
profiles as outlined above.
INC280 was originally formulated as hard gelatin capsules (HGC) at 10 mg and 50 mg strengths. 
Consequently, a large number of capsules are required to be taken by the patients e.g., twelve 50 
mg size 0 capsules twice a day for a 600 mg BID dosing (RP2D), amounting to a total of 24 
capsules per day. For technical reasons capsules with strengths higher than 50 mg cannot be 
manufactured. To improve convenience for patients and consequently patient compliance, INC280 
film coated tablets (FCT) at 50 mg, 100 mg, and 200 mg strengths were developed. A relative 
bioavailability study (CINC280X2103) compared the tablet and the capsule formulations in 
healthy volunteers (N=24). The study results showed that the tablet formulation provided higher 
systemic exposure with geometric mean ratios (tablet vs. capsule) of 2.4 and 3 for AUC and Cmax, 
respectively.
The tablet formulation was subsequently tested in patients first at 200 mg BID (N=3) and then at 
400 mg BID (N=3) as a single agent (study CINC280X1101), and at 200 mg BID (N=7) in 
combination with gefitinib (study CINC280X2202). Based on the tablet PK and safety data from 
these studies, the dosage of 400 mg BID tablets was then introduced initially with a tablet safety 
cohort in study CINC280X2102 (Protocol Amendment #5; IND 116,691/S-0026/12-Feb-2014).
The INC280 tablet formulation at 400 mg BID showed good tolerability, comparable/favorable 
safety profile and exposure within the range of exposure of the capsule formulation at 600 mg BID 
with a 41% increase in mean steady state Cmax. Prior to the Dose Determination Meeting on 23-
Oct-2014, no DLT has been observed with the tablet formulation. The preliminary PK data also 
suggest that 400 mg tablet BID may achieve and maintain the drug concentration needed for tumor 
inhibition throughout the treatment (e.g., unbound Ctrough greater than IC50 and IC90 for the 
inhibition of proliferation of the S114 cell line in vitro; Investigator’s Brochure edition 5.1). As 
the exposure of the 600 mg capsule BID was reached by the 400 mg tablet BID, and the targeted 
unbound Ctrough was achieved and maintained throughout the treatment with the 400 mg tablet 
BID dose, further dose escalations were deemed unnecessary and 400 mg BID was declared the 
tablet RP2D for single agent INC280 in study CINC280X2102. During the Dose Determination 
Meeting on 23-Oct-2014, all study investigators agreed to 400 mg BID as the RP2D for the tablet 
formulation in study CINC280X2102. With no DLTs being observed, an expansion cohort with 
INC280 tablets at 400 mg BID was opened, as well as allowing patients to switch from 600 mg 
BID capsules to 400 mg BID tablets n study CINC280X2102. 
Based on the clinical safety and pharmacokinetic data with INC280 tablet and as supported by the 
risk assessment (EWOC) within the BLRM derived from current single-agent dose-DLT data and 
predicted interaction, Novartis considers 400 mg BID is the RP2D for the INC280 single agent 
tablet formulation.
INC280 single agent at the dose of 400 mg BID in tablet formulation has been administered to 
patients enrolled in study CINC280X1101 and study CINC280X2102. Study CINC280X1101 is a 
Phase I, open-label, multi-center dose-escalation study with an expansion part of INC280 
conducted in Japanese patients with MET-dependent advanced solid tumors. Study 
CINC280X2102 is a global Phase I, open-label, multi-center, dose-escalation study with a dose 
expansion part of INC280 in patients with MET-dependent advanced solid tumors.


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
38
As of a data cut-off date of 31-Dec-2014, a total of twenty-four patients have been treated with 
INC280 single agent at 400 mg BID in tablet formulation: six patients in study CINC280X1101 
and eighteen patients in study CINC280X2102 (five of these patients received 400 mg BID 
INC280 tablets after switching from 600 mg BID INC280 capsules).
As of 31-Dec-2014, no DLTs have been observed for patients treated with the INC280 tablet 
formulation. Safety data from these patients are outlined in Table 1-4, Table 1-5 and Table 1-6. As 
per preliminary safety data, fatigue grade 3 and hypophosphatemia grade 3 suspected to be related 
to investigational treatment have been observed in patients treated with 400 mg BID tablet in the 
CINC280X2102 study and hypophosphatemia grade 3 and hyponatremia grade 3 suspected to be 
related to INC280 have been reported in patients treated at 400 mg BID in tablet in the Japanese 
study CINC280X1101. The PK and safety profiles of INC280 tablet formulation (at 400 mg BID) 
continues to be further evaluated in the ongoing INC280 studies.
PK data from studies CINC280X1101 and CINC280X2202 are summarized in Table 1-11 and 
Table 1-12, and Figure 3 and include preliminary PK data with the tablet formulation at 400mg 
PO BID tablets (Table 1-12). 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
39
Table 1-8: Patients (N=6) treated at 400 mg BID INC280 tablets in study CINC280X1101 as of 31-Dec-2014
Patient 
ID
Treatment 
start
Treatment 
end
Treatment 
duration 
days 
(number 
of cycles*)
Dose 
interruption
G1/2 AEs suspected to be related 
to study drug
G3/4 AEs
suspected to be related to study drug
SAE
Treatment 
d/c (reason 
for 
EOT/ 
study 
completion)
1001_022 13-Nov-
2014
9-Dec- 
2014
27 days
(0.96
cycles)
yes
peripheral edema G1, decreased 
appetite G1, nausea G1, vomiting 
G1
hypophosphatemia G3 started on 
C1D22 and lasted 2 days; study drug 
temporarily interrupted; 
hypophosphatemia started after drug 
d/c (11-Dec-2014) and lasted 12 days
worsening of 
tumor pain G3 
not suspected 
to be related to 
study drug, 
started on 
C2D9 and 
lasted 7 days; 
no action 
taken on the 
study drug;
yes (PD)
1001_023 18-Nov-
2014
20-Nov-
2014
3 days (0.1 
cycles)
yes
increased serum creatinine G2
no
no
yes (PD)
1002_022 15-Jul-
2014
5-Sep- 
2014
53 days
(1.89
cycles)
no
increased serum creatinine G1, 
pruritus G1, peripheral edema G1, 
hypoalbuminemia G2
no
no
yes (PD)
1002_023 29-Jul-
2014
6-Nov- 
2014
101 days
(3.6 
cycles)
no
increased serum creatinine G1, 
vomiting G1, malaise G1, erythema 
multiforme G1, weight loss G1, 
peripheral edema G1; anemia G2, 
hypoalbuminemia G2, increased 
lipase G2
no
no
yes (PD)
1002_024 19-Aug-
2014
ongoing
134 days
(4.8 
cycles)
no
increased AST G1, increased ALT 
G1, peripheral edema G1, vomiting 
G1, 
maculopapular 
rash 
G1, 
gastroesophageal reflux G1
no
no
N/A 
(ongoing)
1002_025 22-Dec-
2014
ongoing
10 days
(0.3 
cycles)
yes
nausea G1, vomiting G1, diarrhea 
G1
hyponatremia G3 started on C1D8 and 
lasted 2 days; study drug temporarily 
interrupted; AE resolved
no
N/A 
(ongoing)
* Cycle duration = 28 days; AEs = adverse events; SAE = serious adverse event; d/c = discontinuation; EOT = End of Trial; PD = disease progression; N/A = not applicable


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
40
Table 1-9: Patients (N=13) treated at 400 mg BID INC280 tablets in study CINC280X2102 as of 31-Dec-2014
Patient ID
Treatment 
start
Treatment 
end
Treatment 
duration 
days 
(number of 
cycles*)
Dose 
interruption
G1/2 AEs suspected to be 
related to study drug
G3/4 AEs
suspected 
to 
be 
related to study 
drug
SAE
Treatment d/c 
(reason 
for 
EOT/ 
study 
completion)
1351_31001
19-Aug-
2014
1-Sep- 2014 14 days
(0.5 cycles)
no
no
no
death 
on 
15-Sep- 
2014 due to PD
yes (PD)
1201_31002
22-Aug-
2014
17-Oct-
2014
57 days (2 
cycles)
no
dizziness 
G1, 
oral 
mucositis G1, fatigue G1, 
constipation G1, hearing 
impairing G1
no
no
yes (PD)
1452_31003
26-Aug-
2014
ongoing
127 days
(4.5 cycles)
no
diarrhea G1, nausea G1, 
hypoalbuminemia, 
G1, 
peripheral 
edema 
G1, 
hypoalbuminemia 
G2, 
peripheral edema G2
no
no
N/A (ongoing)
1501_31005
21-Aug-
2014
11-Dec-
2014
113 days (4 
cycles)
no
peripheral edema G1
no
no
yes (PD)
1351_31007
28-Aug-
2014
22-Oct-
2014
56 days (2 
cycles)
yes
epigastralgia G1, vomiting 
G1, 
nausea 
G1, 
AST 
increase G1, ALT increase 
G1, 
gastroesophageal 
reflux G1, odynophagia 
G1, 
cholestasis 
G1, 
anxious 
depressive 
syndrome 
G1; 
hypoalbuminemia 
G2, 
asthenia G2
no
no
yes (PD)
1301_22031
14-Nov-
2014
15-Dec-
2014
32 days
(1.1 cycles)
no
nausea G1, vomiting G1, 
AST increase G1, ALT 
increase G2, nausea G2, 
fatigue G2
fatigue G3, started on 
C2D3, ongoing 30 
days after treatment 
discontinuation; 
no 
action taken on study 
drug
malaise G2 suspected 
to be related with 
study drug, started on 
C2D4, lasted 4 days
yes (PD)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
41
1600_22032
4-Nov- 2014 ongoing
58 days (2 
cycles)
no
lipase increase G1, loss of 
appetite G1, AST increase 
G1, lymphopenia G1
no
no
N/A (ongoing)
1501_22033
11-Dec-
2014
ongoing
21 days
(0.7 cycles)
yes
no
no
no
N/A (ongoing)
1600_22034
17-Nov-
2014
ongoing
45 days
(1.6 cycles)
no
leukopenia G1, peripheral 
edema G1; lymphopenia 
G2
hypophosphatemia 
G3, started on C1D8, 
lasted 14 days, no 
action taken on study 
drug C1D4
no
N/A (ongoing)
1501_23016
6-Nov- 2014
ongoing
56 days
(1.9 cycles)
no
fatigue G1, peripheral edema 
G1
no
no
N/A (ongoing)
1152_24026
27-Oct-
2014
16-Nov-
2014
21 days
(0.8 cycles)
no
vomiting G1
no
no
yes (PD)
1501_24027
21-Nov-
2014
30-Nov-
2014
10 days
(0.4 cycles)
no
Fatigue 
G2, 
nausea 
G2, 
vomiting G2
no
no
yes (withdrawn 
consent)
* Cycle duration = 28 days; AEs = adverse events; SAE = serious adverse event; d/c = discontinuation; EOT = End of Trial; PD = disease progression; N/A = not applicable


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
42
Table 1-10: Patients (N=5) who switched from 600 mg BID INC280 capsules to 400 mg BID INC280 tablets in study CINC280X2102 as of 31-
Dec-2014
Patient ID
Treatment 
start 
with 
capsule
Date 
of 
switch 
to 
tablet
Treatment durationa 
days  capsule
+ tablet (number of 
cyclesb)
Treatment 
durationa
days 
tablet 
only
(number 
of 
cyclesb)
Dose 
interruption
G1/2 AEs suspected to be 
related to study drug
G3/4 AEs
suspected to 
be related to 
study drug
SAE
1600_21017
15-May-
2014
28-Oct-
2014
231 days (8.3 cycles)
65 days (2.3 
cycles)
no
cough G1, pruritus G1, 
dyspnea G1, fatigue G1, 
thrombocytopenia, 
G1, 
peripheral 
edema 
G1, 
pruritus G2, fatigue G2
no
no
1600_22016
6-Jun- 2014
24-Oct-
2014
209 days (7.5 cycles)
69 days (2.4 
cycles)
no
ALT 
increase 
G1, 
hypophosphatemia 
G1, 
hypocalcemia, 
G1, 
peripheral 
edema 
G1; 
peripheral edema G2
no
pulmonary haemorrhage 
G2, not suspected to be 
related to study drug, 
started on 13-Dec- 2014 
and lasted 4 days
1151_22024
30-Jul-
2014
19-Nov-
2014
155 days (5.5 cycles)
43 days (1.5 
cycles)
no
edema G1, vomiting G1, 
nausea G1; lipase increase 
G2
no
pneumonia 
G2, 
not 
suspected to be related to 
study drug; started on 
C1D12, lasted 11 days
1201_22027
15-Sep-
2014
27-Oct-
2014
108 days (3.9 cycles)
66 days (2.3 
cycles)
no
fatigue G1, weight loss G1, 
anorexia G1, nausea G1, 
vomiting G1, odynophagia 
G1, insomnia G1; fatigue 
G2, vomiting G2
no
no
1600_24023
26-Jun-
2014
13-Nov-
2014
189 days (6.8 cycles)
49 days (1.7 
cycles)
no
nausea G1, edema G1, 
lipase 
increase 
G1, 
leukopenia G1; edema G2, 
leukopenia G2
no
no
a all patients are ongoing at the time of data cut-off date (31-Dec-2014); b Cycle duration = 28 days; AEs = adverse events; SAE = serious adverse event;


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
43
Table 1-11: Summary of PK parameters after INC280 administration as a single agent (mean ([SD]) on Cycle 1, Day 15 (as of Sept 28, 2015)
Study
Regimen 
Tmax (range) 
(h) a
                 Cmax,ss (ng/mL) AUC0-t,ss 
(h*ng/mL) b
[CINC280X2101T]
(n = 3)
10 mg QD 
2.0 (0.5; 2. 0)
                  38 (15)
214 (77)
(n = 3)
20 mg QD 
2.0 (1.0; 2. 0)
                   63 (12.5)
393 (53)
(n = 5)
mg QD 
2.0 (1.0; 5. 0)
                   240 (115)
1184 (395)
(n = 4)
70 mg QD 
1.1 (1.0; 1. 1)
                   394 (241)
1720 (742)
(n = 3)
150 mg QD 
2.0 (1.0; 2. 0)
                   1159 (656)
5444 (2318)
(n = 4)
200 mg QD
1.5 (1.0; 2. 0)
                   895 (381)
5114 (1897)
(n = 4)
300 mg QD 
2.0 (1.0; 2. 0)
                   866 (213)
4248 (1262)
(n = 5)
400 mg QD 
2.0 (1.0; 4. 0)
                   1712 (1250)
9445 (8207)
(n = 3)
50 mg BID 
1.1 (1.0; 4. 1)
                   181 (92)
957 (292)
(n = 4)
200 mg BID 
1.0 (1.0; 1. 1)
                   2070 (1081)
7754 (2598)
(n = 4)
300 mg BID 
1.6 (1.1; 4. 0)
                   4124 (1105)
15713 (3411)
[CINC280X1101]
(n = 3)
100 mg QD 
4.0 (1.0; 4. 1)
395 (53.1)
2770 (1040)
(n = 3)
200 mg QD 
1.0 (1.0; 2. 0)
2160 (760)
9910 (1960)
(n = 3)
400 mg QD 
2.0 (2.0; 2. 1)
5060 (4010)
26400 (18400)
(n = 3)
500 mg QD 
2.0 (1.0; 2. 0)
7960 (952)
43700 (7680)
(n = 4)
600 mg QD 
1.5 (1.0; 2. 0)
7180 (897)
39000 (7140)
(n = 4)
800 mg QD 
3.0 (2.0; 4. 1)
6450 (3550)
39400 (7700)
(n = 3)
400 mg BID 
4.0 (2.0; 4. 0)
1980 (1740)
11000 (8750)
(n = 2)
600 mg BID
2.0 (2.0; 2. 0)
16500 (2190)
62500 (645)
(n = 3)
200 mg BID (tablet)
1.0 (1.0; 2. 0)
3140 (1620)
12000 (6150)
(n = 12)
400 mg BID (tablet)
1.0 (0.45; 2.0)
7110 (4440)
29300 (20100)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
44
Study
Regimen 
Tmax (range) 
(h) a
                 Cmax,ss (ng/mL) AUC0-t,ss 
(h*ng/mL) b
[CINC280X2102]
(n = 4)
100 mg BID                  
2.9 (1.9; 4. 0)
660 (550)
2910 (2090)h
(n = 5)
200 mg BID                 
1.9 (1.9; 8. 0)
2500 (856)
9700 (4040)c
(n = 3)
250 mg BID                  
1.0 (0.5; 2. 0)
1580 (1010)
6140d
(n = 3)
350 mg BID                  
3.9 (1.0; 4. 0)
4410 (3800)
25500d
(n = 7)
450 mg BID                  
2.0 (1.8; 7. 9)
3200 (1280)
19600d
(n = 45)
600 mg BID                  
2.0 (0.0; 8. 4)
4790 (3440)
24700 (13500)e
(n = 8)
400 mg BID (tablet)      
1.6 (0.5; 4. 3)
5860 (2780)
25500 (14400)g
[CINC280X2201]
(n = 8)
300 mg QD                  
2.0 (1.0; 2.0)f
3060 (1703)f
10276 (6208)g
n: number of subjects with non-missing values and evaluable PK
a median value
b AUC0-12h for BID regimen and AUC0-24h for QD regimen
c n=3
d n=1
e n=21
f n=6
g n=4
h AUC0-8h


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
45
Table 1-12: Summary of PK parameters after INC280 administration (400mg BID Tablet formulation) as a single agent (mean ([SD]) on Cycle 1, 
Day1 and C1D 15 (as of Dec 31, 2014)
Study
Dose 
(mg)
Formula
tion
C1D1 (Mean (CV%)) 
 
C1D15 (Mean (CV%)) 
 
N
Tmax 
(h)
Cmax (ng/mL)
AUC0-12 (ng*h/mL)
N
Tmax 
(h)
Cmax (ng/mL)
AUC0-12 (ng*h/mL)
X2102
400
Tablet
4
2.0
5385 (44)
20214 (26)
4
1.5
7425 (30)
30988 (35)
X2202
400
Tablet
NA NA
NA
NA
5
1
6600 (29)
27800 (21)


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
46
Figure 3: Summary of AUC)-12 of single agent INC 280 capsules and tablets (preliminary)
1.2.4
Study purpose/rationale
While several treatment options are available for patients with metastatic clear-cell RCC, systemic 
therapies for patients with unresectable papillary RCC are limited. Multikinase inhibitors 
recommended for advanced clear-cell RCC generally do not target the MET receptor, and appear 
to have limited activity in papillary RCC 9. Similarly, the role of mTOR inhibitors, another class 
of agents with activity in RCC, remains poorly defined in papillary RCC.  A recently concluded 
clinical trial sought to determine the efficacy of foretinib, a kinase inhibitor of both MET and 
VEGF receptors, in patients with papillary kidney cancer (both hereditary and sporadic).  Results 
from this study have suggested efficacy of this agent in patients with papillary RCC31,32.  However, 
it would be difficult to determine if activity associated with this agent is attributable to its VEGF 
pathway or MET inhibitory properties. Furthermore, most of the adverse events reported with this 
agent appear to be related to VEGF pathway inhibition, dictating tolerability and drug dosing, and 
potentially compromising the ability to optimally target the MET pathway with this and similar 
agents.
We propose to conduct a phase 2, proof-of-concept study using a selective MET antagonist lacking 
activity against the VEGF pathway in patients with papillary RCC to test the hypothesis that 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
47
effective pharmacologic blockade of the HGF/MET pathway will translate to clinical activity in 
patients with papillary renal cell cancer. In addition to advancing research in an area of unmet need 
in a rare patient population, this trial would offer critical scientific insight into the role of the MET 
pathway in papillary RCC.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Patients must have histologically or cytologically confirmed papillary RCC.
a.
Patients with bilateral multifocal disease can have tumors localized to the kidney or 
have metastatic disease
b. Patients with sporadic papillary RCC (but without multifocal disease) should have 
advanced disease that is considered unresectable
2.1.1.2
Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions).  Nodal lesions must be ≥ 15mm 
by CT scan or MRI.  Non nodal lesions must be >10 mm with CT scan or MRI.  See 
Section 6.2 for the evaluation of measurable disease.
2.1.1.3
Patients must have normal organ and marrow function as defined below:

Hemoglobin > 9 g/dL (SI Units: 90 g/L) 

Platelet count ≥ 75 x 109/L

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support

Total bilirubin ≤ 2 x upper limit of normal (ULN)

AST/SGOT and/or ALT/SGPT ≤ 2.5 x upper limit of normal (ULN)

Serum creatinine ≤ 1.5 x ULN 

Asymptomatic serum amylase ≤ 2 x ULN; patients with > ULN but ≤ 2 x ULN serum 
amylase at study start must be confirmed to have no signs and/or symptoms 
suggestion pancreatitis or pancreatic injury (e.g. elevated P-amylase, abnormal 
imaging findings of pancreas, etc.) 

Serum lipase ≤ ULN

Fasting serum triglyceride level ≤500 mg/dL
2.1.1.4
Patients may have had no more than 3 prior lines of systemic therapy.  Prior therapy 
with a MET inhibitor is allowed as long as the patient has not had progressive disease 
while receiving the agent
2.1.1.5
Patient must be able to swallow and retain oral medication
2.1.1.6
Age >18 years. 
2.1.1.7
ECOG performance status 0 - 2 (see Appendix A).
2.1.1.8
Patients must provide written informed consent prior to any study procedures.
2.1.1.9
Patients must be willing and able to comply with scheduled visits, treatment plan and 
laboratory tests


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
48
2.1.2
Exclusion Criteria
2.1.2.1
Patients who are receiving any other investigational agents for treatment of their 
kidney cancer.
2.1.2.2
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to INC280. Excipients in the current formulation include 
microcrystalline cellulose, mannitol, sodium starch glycolate, magnesium stearate 
and colloidal silicon dioxide
2.1.2.3
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection requiring intravenous antibiotics, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations   
that would limit compliance with study requirements or potentially affect the 
interpretation of study data.
2.1.2.4
Subjects with significant or uncontrolled cardiovascular disease (e.g., uncontrolled 
hypertension, peripheral vascular disease, congestive heart failure, cardiac 
arrhythmia, or acute coronary syndrome) within 6 months prior to starting study 
treatment or heart attack within 12 months prior to starting study treatment
2.1.2.5
Patients receiving any medications that are known to be strong inducers or inhibitors 
of CYP3A4, or sensitive substrates of CYP3A4, CYP1A2, CYP2C9, CYP2C9, 
CYP2C19 or P-gp with a narrow therapeutic index. Lists including medications and 
substances known or with the potential to interact with the relevant CYP isoenzymes 
and P-gp transporter are provided in Table 4-1.
2.1.2.6
Symptomatic CNS metastases that are neurologically unstable or requiring > 5 
mg/day of dexamethasone (or equivalent) to control CNS disease.
Note: Patients with controlled CNS metastases are allowed. Radiotherapy or surgery for 
CNS metastases must have been completed >2 weeks prior to study entry. Patients must 
be neurologically stable, having no new neurologic deficits on clinical examination, and 
no new findings on CNS imaging. Steroid use for management of CNS metastases must 
be at a stable dose for two weeks preceding study entry.
2.1.2.7
Patients with ≥ Grade 2 neuropathy.
2.1.2.8
Treatment with proton pump inhibitors within 3 days prior to study entry. If 
continued use of GI prophylaxis is required, the patient will be switched to an 
appropriate H2 antagonist with appropriate counsel and caution as detailed in Section 
4.2.
2.1.2.9
Currently receiving any prohibited medications including vitamins and herbal 
supplements found in section 4. 
2.1.2.10 Major surgery within 4 weeks prior to initiating treatment, excluding the placement 
of vascular access.
2.1.2.11 The subject has not recovered to baseline, CTCAE ≤ Grade 1 from toxicity due to 
all prior therapies for RCC or to a level permitted under other sections of the 
eligibility criteria except alopecia and other non-clinically significant AEs.


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
49
2.1.2.12 Any other condition that would, in the Investigator’s judgment, contraindicate 
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.
2.1.2.13 Pregnant or nursing (lactating) 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 (> 30 mIU/mL).  Laboratory values >5 mIU/mL, but 
<30 mIU/mL should be repeated in 48 hours.
2.1.2.14 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 3 month days after stopping study drug. Highly effective 
contraception methods include:

Total abstinence or

Male or female sterilization or

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
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
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.
2.1.2.15 Sexually active males must use a condom during intercourse while taking the drug 
and for 3 months after stopping study drug 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.
2.1.2.16 HIV-positive patients on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with INC280.  
2.1.2.17 Prior invasive malignancy of other histology currently requiring treatment. 
2.2
SCREENING EVALUATION
Screening evaluations must be performed within the timeframes indicated below.  Screening 
procedures may be performed on an NIH screening protocol or the Urology Branch 89-C-0086 
and/or 97-C-0149. Imaging studies may also be performed at an outside institution for expedience.  
If procedures are performed on this treatment protocol, the screening examination must start with 
the Informed Consent procedure. The investigator is obliged to give the patient thorough 
information about the study and the study related assessments, and the patient should be given 
ample time to consider his or her participation. The investigator must not start any study related 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
50
procedure before ICF is signed and dated by both patient (and impartial witness, if applicable) and 
investigator.
To be performed within 4 weeks prior to subject receiving study drug

History and physical evaluation

Performance status

Bone scan (performed on all patients with known or suspected metastatic disease)

Brain MRI or Brain CT (studies are to be performed with contrast unless renal 
impairment or allergy prohibits the use of contrast)

FDG-PET in patients with known or suspected metastatic disease
To be performed within 2 weeks prior to subject receiving the study drug

CBC with differential

Serum β hCG (in female patients of childbearing potential)

Total and direct bilirubin, acute care panel, albumin, AST/SGOT, ALT/SGPT, 
serum creatinine, calcium, magnesium, LDH, amylase, lipase, lipid panel T3, free 
thyroxine, TSH PT, PTT, Creatine Kinase, Uric Acid, Total Protein, Urinalysis, 
Urine Creatinine.

CT chest/abdomen/pelvis or CT chest plus MRI abdomen for organ confined 
disease; MRI of the pelvis only if indicated.
For baseline evaluations, please see section 2.4. 
2.3
REGISTRATION PROCEDURES
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent. A registration Eligibility Checklist from the web site () must 
be completed and sent via encrypted email to:  NCI Central Registration Office  
ncicentralregistration-l@mail.nih.gov.  After confirmation of eligibility at Central Registration 
Office, CRO staff will call pharmacy to advise them of the acceptance of the patient on the protocol 
prior to the release of any investigational agents.  Verification of Registration will be forwarded 
electronically via e-mail to the research team. A recorder is available during non-working hours. 
2.4
TREATMENT ASSIGNMENT PROCEDURE
Cohort
Number
Name
Description
1
Single cohort
Patients with hereditary papillary renal carcinoma 
(HPRC) or sporadic papillary renal cell carcinoma (RCC)
Arm
Number
Name
Description
1
Single arm
INC280 400 mg twice every day by mouth, continuously
Patients enrolled to cohort 1 will be directly assigned to arm 1.


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
51
2.5
BASELINE EVALUATION
Baseline procedures need not be repeated if they have been performed within the appropriate 
screening timeframe (See section 2.2).

Serum β hCG (in female patients of childbearing potential)

CBC with differential

Total and direct bilirubin, AST/SGOT, ALT/SGPT, acute care panel, albumin, calcium, 
magnesium, LDH, amylase, lipase, lipid panel, T3, free thyroxine, TSH

Ocular Monitoring (as needed):
o
Dilated Eye Examination
o
Electroretinogram and Dark Adaptation Testing 
o
Optical Coherence Tomography 
o
Humphrey Visual Field 30-2 Sita Fast 
o
Optos color and fundus autofluorescence photos

CT chest/abdomen/pelvis or CT chest and MRI abdomen for organ confined disease; MRI 
of the pelvis only if indicated.

Bone scan (if metastases are suspected)

Brain MRI or Brain CT

ECG

FDG-PET in patients with known or suspected metastatic disease

Biopsies (optional) and blood for correlative studies (see section 5)

Obtain archival tumor tissue when available (tissue block and/or up to 30 unstained slides) 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is an open-label single arm phase 2 study.  Up to 20 evaluable patients with bilateral 
multifocal papillary RCC (metastatic or localized to the kidney) or patients with advanced 
papillary RCC will be enrolled on study to be treated with 400 mg of INC280 taken orally twice 
per day until disease progression or unacceptable toxicity.  Treatment may also be discontinued 
permanently if the manufacturer (Novartis) is unable to provide the agent for ongoing use (in 
accordance with the terms outlined in the clinical M-CRADA under which this trial will be 
conducted). Each treatment cycle will consist of 28 days and drug dosing will be continuous (i.e., 
there will be no break between cycles in the absence of toxicity). Patients will be assessed for 
overall response rate with restaging studies performed approximately every 8 weeks for the first 
32 weeks and approximately every 12 weeks thereafter while on study.  Patients will also be 
assessed for progression free survival, duration of response, safety and pharmacodynamic 
endpoints.  Patients will be counseled on evaluation for the presence of germline MET mutations 
when clinically indicated (bilateral multifocal disease and/or family history suggestive of HPRC).  
These patients will be counseled by the PI or qualified genetic counselor on the risks of genetic 
testing and the implications should the subject be found to have a germline alteration; patients who 
agree to pursue germline testing at the Clinical Center will typically be enrolled on another IRB 
approved protocol designed for this purpose, such as 89-C-0086.  When feasible, patients without 
germline mutations will have their tumors evaluated for the presence of: a) Somatic MET 
mutations by full length sequencing, b) Polysomy 7/ amplification of the MET and/or HGF locus 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
52
by CGH. These data will be used in an exploratory analysis to determine if alterations in MET 
impact response to therapy.  Please see section 8.5, the statistical section, for further details.
Patients will also undergo optional biopsies of accessible tumors before initiation of therapy and 
following 2 cycles of therapy. These paired tumor samples will be used to assess target modulation 
(of MET and related pathways).
3.2
DRUG ADMINISTRATION
Patients should be instructed to take the study drug as per protocol and instructed to complete the 
medication diary found in Appendix B.  All dosages prescribed and dispensed to the patient and 
any dose change or interruption must be recorded appropriately.
Table 3-1: Treatment and Treatment Schedule
Study 
treatments
Pharmaceutical form and route of 
administration
Dose
Frequency 
and/or regimen
INC280
Tablet for oral use
400 mg
twice every day, 
continuously
The orally administered film coated tablet formulation is provided in two strengths of 100mg and 
200mg.  The 100 mg strength is formulated as a light red ovaloid, curved tablet with beveled edges, 
without score, imprinted with ‘OU’ on one side and ‘NVR’ on the back side. The 200 mg strength 
is formulated as a dark brown, ovaloid, curved tablet, without score, imprinted with ‘NVR’ on 
both sides. The 200 mg strength can also be formulated as a yellow ovaloid, curved tablet with 
beveled edges, without score, imprinted with ‘LO’ on one side and ‘NVR’ on the back side.
INC280 will be dosed on a flat scale and not individually adjusted by weight or body surface area. 
Patients will self-administer the study medication with at least 8 ounces of water and consume at 
least 8 ounces of water 2 hours after drug intake as directed by the study doctor. The patients 
should be instructed to avoid grapefruit juice or Seville orange juice for seven (7) days prior to the 
first dose of study drug.  
Patients should be instructed to take their dose twice a day at approximately the same time each 
day. Doses should be at least eight (8) hours apart. Patients should fast 2 hours before and for two 
hours following drug ingestion. During the fasting period, patients can freely drink water. The 
patient will also be permitted to drink the following clear liquids during the fasting period if 
necessary: ginger ale, apple juice, cranberry juice. If a planned dose is missed, it can be taken 
within four hours of the planned time. The patient should resume their normal dosing time the 
following day. If a dose is not taken within 4 hours of the planned dosing time, the missed dose 
should not be replaced.
If vomiting occurs, no attempt should be made to replace the vomited dose. If a patient vomits 
within 4 hours of INC280 dosing, this should be recorded appropriately.
Please see section 14.1.6 for drug accountability and compliance instructions.


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
53
3.3
DOSE MODIFICATIONS
All dose modifications should be based on the worst preceding toxicity. Dose modifications will 
be made only for those AEs thought to be related to INC280. 
For each patient, once a dose reduction has occurred, the dose level may not be re-escalated during 
subsequent treatment cycles with INC280. Dose modifications will follow the scheme outlined in 
Table 3-3.  No more than 2 dose reductions will be allowed per patient.
When study drug is interrupted or permanently discontinued due to an AE or abnormal laboratory 
value, the patients must be followed at least once a week for 4 weeks, and subsequently in 4-week 
intervals, until resolution or stabilization of the event, whichever comes first. If a patient requires 
a dose delay of > 14 days from the intended day of the scheduled dose due to adverse events related 
to INC280, then the patient must be permanently discontinued from study therapy. However, the 
patient will be followed up for toxicity as previously described. All patients will be followed for 
adverse events and serious adverse events for 30 days following the last dose of study drug.
Patients who discontinue from the study for a study-related AE or an abnormal laboratory value 
must be followed as described in Table 3-4. 
The investigator must notify the Novartis immediately of any unexpected CTCAE grade ≥ 3 
adverse events or laboratory abnormalities. The criteria for interruption and re-initiation of INC280 
can be found in Table 3-3.
Table 3-2: INC Dose level table
Dose level
Dose
1
400 mg twice per day
-1
300 mg twice per day
-2
200 mg twice per day


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
54
Table 3-3: Criteria for interruption and re-initiation of INC280 treatment
Recommended dose modifications for INC280**
Worst toxicity
CTCAE grade* (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing.
Hematologic
        Neutropenia (ANC)
Grade 1 
(LLN - 1500/mm3 or LLN – 
1.5x10e9/L)
Maintain dose level
Grade 2 
(<1500 - 1000/mm3 or <1.5 - 
1.0x10e9/L)
Maintain dose level
Grade 3
(< 1000 - 500/mm3 or < 1.0 – 
0.5x10e9/L)
Discontinue INC280:
If depression lasts for ≤ 7 days (until ANC recovers to >1500): 
Resume treatment at same dose level.
If depression lasts for >7 days (until ANC to recovers to 
>1500): Resume treatment at ↓1 dose level.
Grade 4 
(< 500/mm3 or < 0.5x10e9/L)
Discontinue INC280
       Thrombocytopenia (PLT)
Grade 1 or 2
(PLT < LLN - 50,000/mm3)
Maintain dose level
Grade 3 
(<50 – 25x10e9/L)
Discontinue dose until resolved to ≤ Grade 1 or baseline, then:
If not associated hemorrhage/bleeding: Resume treatment at same 
dose level.
If associated with hemorrhage/bleeding: Resume treatment at ↓ 1 
dose level.
Grade 4 
(<25x10e9/L)
Discontinue dose until resolved to ≤ Grade 1 or baseline, then 
resume treatment at ↓ 1 dose level.


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
55
Recommended dose modifications for INC280**
Worst toxicity
CTCAE grade* (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing.
         Febrile Neutropenia
Febrile neutropenia 
(ANC < 1.0 x 109/L or 1000/mm3 
and a single temperature of >38.3°C 
(101 °F) or a sustained temperature 
of >=38 °C (100.4 ° F) for more than 
one hour.)
Discontinue dose until fever resolved and ANC is at ≤ Grade 1 or 
baseline, then resume treatment at ↓1 dose level.
Renal
         Serum creatinine
(< ULN - 2.0 x ULN)
Maintain dose level
(>2.0 -6.0 x ULN)
Discontinue dose until resolved to ≤ 2.0 ULN or baseline, 
then resume treatment at ↓1 dose level. Patients will be 
instructed to increase their fluid intake until resolution to ≤ 
2.0 x ULN or baseline.
Grade 4 (> 6.0 x ULN)
Discontinue INC280


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56
Recommended dose modifications for INC280**
Worst toxicity
CTCAE grade* (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing.
Hepatic
             Bilirubin
Grade 1
(> ULN - 1.5 x ULN)
Maintain dose level
Grade 2* 
(> 1.5 - 3.0 x ULN)
Discontinue dose until resolved to ≤ Grade 1 or baseline, then 
resume at the same dose level
Grade 3* 
(> 3.0 - 10.0 x ULN)
Discontinue dose until resolved to ≤ Grade 1 or baseline, then 
resume at ↓ 1 dose level
Grade 4* 
(> 10.0 x ULN)
Discontinue INC280
            AST or ALT
Grade 1 or 2 
(> ULN - 5.0 x ULN)
Maintain dose level
Grade 3* 
(> 5.0 – 20.0 x ULN)
Discontinue INC280:

If elevation lasts for ≤ 7 days: Resume treatment same dose 
level

If elevations lasts for >7 days: Resume treatment at ↓ 1 dose 
level
Grade 4 *
(> 20.0 x ULN)
Discontinue INC280 
* Discontinue INC280 if > Grade 3ALT accompanied by > Grade 2 Bilirubin


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Recommended dose modifications for INC280**
Worst toxicity
CTCAE grade* (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing.
Pancreas
Asymptomatic 
Grade 1 or 2 amylase or lipase 
(>ULN – 2.0x ULN)

Maintain dose level
Grade 3 amylase or lipase (> 2.0 - 
> 5.0 x ULN)
Grade 4 amylase or lipase

Continue dosing and monitor laboratory values. If levels do 
not resolve to grade 2 or less by 14 days after the initial report, 
discontinue INC280. If levels return to grade 1 or less within 
14 days, resume at ↓ 1 dose level

Discontinue INC280
Symptomatic 
Amylase or lipase elevations of 
any grade

Discontinue INC280
Neurologic
Any Neurological Toxicity
Grade 2 or greater
Discontinue INC280.
Neurological assessments must be repeated as clinically indicated 
until resolution to < CTCAE grade 1 or until stabilization.
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.
Cardiac (General) 
Grade 1 
Maintain dose level
Grade 2 
Discontinue dose until resolved to ≤ Grade 1 or baseline, then 
resume at ↓1 dose level
Grade 3 or 4
Discontinue INC280


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Recommended dose modifications for INC280**
Worst toxicity
CTCAE grade* (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing.
Other adverse events+**
Grade 1 or 2
Maintain dose level
Grade 3
Discontinue dose until resolved to ≤ Grade 1, then ↓1 dose level
Grade 4
Discontinue INC280
All dose modifications should be based on the worst preceding toxicity.
*Common Toxicity Criteria for Adverse Events (CTCAE Version 4.0).
** If the investigator deems that a recommended dose reduction or the recommendation to maintain the 
same dose level is not in the best interest of the patient, this decision may be discussed with Novartis 
on a case-by-case basis.
+ Dose modifications for diarrhea, nausea and constipation will only be made for grade 3-4 toxicities 
that persist despite optimal medical intervention. No dose reductions are necessary for electrolyte 
abnormalities that can be corrected within 72 hours
Table 3-4: Follow up evaluations for selected toxicities
Toxicity
Follow-up evaluation
Hematology
If febrile neutropenia of any duration occurs, the patient must be followed until 
resolution.
If ≥ CTCAE grade 3 hematologic toxicity occurs, the parameter must be repeated 
at least twice a week until resolution to ≤ CTCAE grade 1 and then at least weekly 
until either initiation of retreatment or until stabilization.
Renal
If serum creatinine ≥ CTCAE grade 3 has been demonstrated, this parameter must 
be repeated at least twice a week until resolution to ≤ CTCAE grade 1 or baseline, 
and then at least weekly until either initiation of re-treatment or until stabilization.  
Patients will be instructed to increase hydration until resolution to ≤ CTCAE grade 
1 or baseline.
Hepatic
If total bilirubin ≥ 3 x ULN or ≥ CTCAE grade 3 AST or ALT has been 
demonstrated, these parameters must be repeated at least twice a week until 
resolution to baseline, and then at least weekly until either initiation of re-
treatment or until stabilization.  
Patients with total bilirubin > 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.


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Toxicity
Follow-up evaluation
Pancreatic
If serum amylase or serum lipase ≥ CTCAE grade 3, follow until resolution to 
grade 2 or less
Neurologic
If any neurological abnormality or toxicity ≥ Grade 2 has been demonstrated, 
neurological assessments must be repeated as clinically indicated until resolution 
to ≤ CTCAE grade 1 or stabilization.
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 also be performed to monitor 
for physiological changes in brain activity.
Ocular
If patient reports dark adaptation changes, ocular monitoring will be as follows:

Dilated Eye Examination 

Electroretinogram and Dark Adaptation Testing 

Humphrey Visual Field 30-2 Sita Fast 

Optos color and fundus autofluorescence photos if clinically indicated 
Cardiac
Monitor toxicity until resolution to grade 1 or baseline. If applicable, monitor 
ECGs twice weekly until normalization or stabilization.
Non-
laboratory
Patients who experience non-laboratory DLTs must be evaluated at least once a 
week following demonstration of the toxicity until resolution of the toxicity to 
allow for re-treatment, until stabilization of the toxicity, or until study completion.


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3.4
STUDY CALENDAR
1 cycle = 28 days
Evaluations below may be performed within ± 5days of indicated time in order to accommodate patient schedules, holidays and weather 
emergencies. Imaging studies and optional tumor biopsies may be performed within ± 5days of indicated time.
While on study therapy, beginning of the cycle assessments (those occurring at week 1) will be performed at the NIH Clinical Center. 
Mid cycle assessments (occurring during week 3) may be performed at any CLIA certified laboratory (or CLIA equivalent if other than 
USA) if this is the patient’s preference.
Cycle 1
Subsequent Cycles
Procedure
Screenin
g/
Baseline
Wk 1
Wk 
2
Wk 
3
Wk 
4
Wk 1
Wk 
2
Wk 
3
Wk 
4 
Restage
Post 
Therapy 
Follow-
up5
Informed consent
X
History and PE
X
X
X
Vital signs
X
X
X
Performance status
X
X
CBC with differential
X
X2
X
X
X
PT/ PTT
X
Serum β hCG1
X
X2
X
Total 
and 
direct 
bilirubin, 
AST/SGOT, 
ALT/SGPT, 
acute 
care panel, phosphorus
X
X2
X
X2
X
X


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Cycle 1
Subsequent Cycles
Procedure
Screenin
g/
Baseline
Wk 1
Wk 
2
Wk 
3
Wk 
4
Wk 1
Wk 
2
Wk 
3
Wk 
4 
Restage
Post 
Therapy 
Follow-
up5
albumin, 
calcium, 
magnesium, 
LDH, amylase, lipase, creatine 
kinase, uric acid, total protein
X
X2
X
X2
X
Lipid Panel
X
X
X
TSH, T3, Free T4
X
X
Urinalysis/ Urine Creatinine
X
X
Ocular Monitoring
Dilated Eye Examination
X7
X
Electroretinogram 
and 
Dark 
Adaptation Testing
X7
X
Optical Coherence Tomography
X7
X
Humphrey Visual Field 30-2 Sita 
Fast
X7
X
Optos 
color 
and 
fundus 
autofluorescence photos
X7
X


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Cycle 1
Subsequent Cycles
Procedure
Screenin
g/
Baseline
Wk 1
Wk 
2
Wk 
3
Wk 
4
Wk 1
Wk 
2
Wk 
3
Wk 
4 
Restage
Post 
Therapy 
Follow-
up5
ECG
X
X
X
X
Archival 
tissue 
for 
diagnostic 
evaluation
X
INC280
Continuous dosing 
Fresh tumor biopsy for biomarker 
assessment
X
X 6
Correlative 
Research 
Studies/Pharmacodynamics 
X
X
CT abdomen or MRI abdomen; CT 
chest if indicated; CT or MRI pelvis 
if indicated
 ± bone scan 
X
Every 8 weeks for first 32 weeks; every 12 weeks 
thereafter. Restaging bone scans are performed only in 
patients with evidence of bone metastases at baseline.
Brain CT or brain MRI
X
If negative at baseline, will not repeat unless patient 
becomes symptomatic.  If positive then patients will be 
assessed as above, every 8 weeks for the first 32 weeks; 
every 12 weeks thereafter.


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Cycle 1
Subsequent Cycles
Procedure
Screenin
g/
Baseline
Wk 1
Wk 
2
Wk 
3
Wk 
4
Wk 1
Wk 
2
Wk 
3
Wk 
4 
Restage
Post 
Therapy 
Follow-
up5
PET
X
May be performed at restaging to clarify if residual 
disease or equivocal new foci on conventional imaging 
represent tumor
Adverse Events
Continuous (up to 30 days post therapy discontinuation)
Concomitant Medications
Continuous
1 In women of childbearing potential only
2Performed prior to dosing
3 In cycle 3 only
4 Odd numbered cycles only.  See section 5.1 for collection of blood and urine specimens.
5 See section 3.5 for details
6 First restage only
7As needed 


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3.5
FOLLOW UP EVALUATIONS
After subjects have stopped taking the study medication for any of the reasons listed in section 
3.6.1, they will be seen at NIH, if feasible, for a safety visit within 4-5 weeks of drug 
discontinuation.  The safety assessments may be performed by a local physician and laboratory if 
patients unable to return to the NIH Clinical Center at this time. If patients are unable to comply 
with the follow-up visit, this will be documented in the patient chart.
The following assessments will be performed at follow up.

History and Physical Examination

CBC with differential, acute care panel, phosphorus, AST, ALT, Total and Direct 
Bilirubin

Ocular Monitoring:
o
Dilated Eye Examination
o
Electroretinogram and Dark Adaptation Testing 
o
Optical Coherence Tomography 
o
Humphrey Visual Field 30-2 Sita Fast 
o
Optos color and fundus autofluorescence photos
After the safety visit, if there are no unresolved grade 3 or higher AEs, we may, when feasible 
contact the patient annually by telephone to find out how they are doing and to determine survival 
status.  If there are unresolved, unexpected grade 3 – 4 AEs, patients will be followed either at the 
NIH clinical center or by their local physician.  In the latter case, we will obtain the physician’s 
record of AEs.
Any scans performed outside of the NIH will also be obtained when possible.  
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.6.1
Criteria for removal from protocol therapy

Completion of protocol therapy

Progressive disease

Participant requests to be withdrawn from active therapy

Unacceptable Toxicity as defined in section 3.3

Investigator discretion

Positive pregnancy test
3.6.2
Off-Study Criteria

Completed study follow-up period

Patient lost to follow-up

Investigator discretion

Participant requests to be withdrawn from study

Death
Every attempt will be made to complete the follow up evaluation prior to study removal.


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3.6.3
Off Protocol Therapy and Off Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
PERMITTED CONCOMITANT THERAPY
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 (other than study drug) and significant non-drug 
therapies (including blood transfusions) administered during the study should be recorded.
4.2
PERMITTED CONCOMITANT THERAPY REQUIRING CAUTION AND/OR ACTION 
Medications that are weak inducers or inhibitors of CYP3A4 are not prohibited but should be 
administered with caution. 
Short acting gastric acid modulators containing aluminum hydroxide and magnesium hydroxide, 
(e.g., Maalox®) or calcium carbonate (e.g., TUMS®) can be taken. However, it is recommended 
to take these drugs at least 4 hours before or 4 hours after administration of INC280. H2 receptor 
antagonists should be avoided when possible. If patients are using H2 receptor antagonists during 
the course of this study, patients should take INC280 at least 2 hours before H2 antagonists. Next 
scheduled dose of INC280 should be taken at least 8 hours after the previous H2 antagonist 
administration.
Guidance on concomitant medications with CYP3A4/5 interactions and gastric acid pH 
modulators interactions:
In general, the use of any concomitant medication / therapies deemed necessary for the care of the 
patient is permitted. However, caution is advised on the use of concomitant medications that are 
metabolized by CYP3A4/5. Prior to starting study treatment, investigators should carefully review 
the study subject’s current medications for drugs metabolized by these isoenzymes.
Drugs known to interact with CYP3A4 should be used with caution because of the inherent risk 
of either reduced activity or enhanced toxicity of the respective concomitant medication and/or 
INC280. Based on in vitro metabolism studies, INC280 is predominantly metabolized by CYP3A4 
and to a less extent by aldehyde oxidase. Therefore, strong CYP3A4 inhibitors or inducers or 
sensitive CYP3A4 substrates with narrow therapeutic index should be prohibited during the course 
of this study. A list of those medications can be found in Table 4-1. Sensitive CYP3A4/5 substrates 
can be cautiously used and are listed in Table 4-2. Further, INC280 is a moderate inhibitor of 
CYP2C8, weak inhibitor of CYP1A2, CYP2C9 and CYP2C19 and a time dependent inhibitor of 
CYP1A2. The concomitant use of sensitive CYP1A2, CYP2C9, CYP2C9 and CYP2C19 
substrates with a narrow therapeutic index is prohibited in this study and listed in Table 4-1. These 
lists are not exhaustive and additional drug interaction information can be found at the University 
of 
Washington 
Drug 
Metabolism 
and 
Transport 
Drug 
Interaction 
Database 
at 
http://druginteractioninfo.org/.


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In vitro solubility data indicated that INC280 may have decreased solubility and oral absorption at 
pH >4. Long-acting proton pump inhibitors are prohibited. Examples of this class of drugs can be 
found in Table 4-3.
INC280 also shows inhibition to P-gp transporter in vitro. Moderate P-gP inhibitors (which result 
in substrate AUC≥ 2-fold increase and < 5-fold increase) and P-gP substrates are detailed in Table 
4-4. All patients must be carefully monitored for potential toxicity due to an individual 
concomitant medication. During the study, sensitive P-gp substrates with narrow therapeutic index 
are prohibited.  These are listed in Table 4-1.  
Table 4-1: Prohibited medications that are strong CYP3A4/5 inhibitors or inducers or sensitive substrates 
of CYP3A4, 2C8, 2C9, 2C19 and P-gp transporter with narrow therapeutic index
Strong CYP3A4/5 inhibitors
Strong CYP3A4/5 
inducers
Sensitive 
CYP3A4 
substrates with narrow 
TI
Sensitive 
CYP2C9 
substrates 
with 
narrow TI
Macrolide 
antibiotics: 
clarithromycin and telithromycin
Carbamazepine
Alfentanil
warfarin
Anti-fungal: 
Itraconazole, 
ketoconazole, 
voriconazole, 
posaconazole
Efavirenz  
Cyclosporine
Anti-virals: lopinavir, indinavir, 
nelfinavir, ritonavir, saquinavir
Modafinil 
Diergotamine, ergotamine
Conivaptan
Nevirapine
Fentanyl
Mibefradil
Phenobarbital
Pimozide
Nefazodone
Phenytoin 
Quinidine
Troleandomycin
Rifampin
Sirolimus
Tacrolimus
Grapefruit juice
St John's wort
Note: 
the 
following 
medications 
are 
not 
available 
in 
US: 
Astemizole, 
Cisapride, 
Terfenadine
phenytoin

Sensitive 
CYP2C19 
Substrates with narrow TI

Sensitive 
CYP2C8 
substrates with 
narrow TI

Sensitive 
CYP1A2 
substrates 
with 
narrow TI

Sensitive 
P-gp 
substrates 
with 
narrow TI
Methytoin
Paclitaxel
Theophylline
Tizanidine
Methadone
Digoxin
Source:
1. FDA guidance drug interaction studies: study design, data analysis, and implication for dosing and labeling, 
2006.
2. Oncology Clinical Pharmacology internal memo: drug-drug Interactions (DDI) database, 2010


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67
Table 4-2: List of co-medications with known CYP3A4/5 interaction
Drug name
Class
Note
Alfentanil
Analgesic
Alprazolam
Benzodiazepines
Astemizole
Antihistamine/allergic rhinitis
Increased exposure of this 
medication may result in QTc 
prolongation
Brecanavir
Budesonide
Anti-inflammatory corticosteroid
Buspirone
Antibiotics
Chlorpheniramine
Anti-histamine
Diazepam
Benzodiazepine
Ebastine
Anti-histamine
Eletriptan
5-HT agonist/anti-migraine
Everolimus
Immune modulators
Erythromycin
Antibiotics
Increased exposure of this 
medication may result in QTc 
prolongation
Felodipine
Calcium channel blockers
Imatinib
Anti-leukemia
Lovastatin
HMG CoA reductase inhibitors
Midazolam
Benzodiazepine/sedatives
Nisoldipine
Calcium channel blockers
Sildenafil
PDE5 agonist/ erectile dysfunction
Simvastatin
HMG CoA reductase inhibitors
Triazolam
Benzodiazepine
Prohibited medications are marked in Bold
Source:
1. FDA guidance drug interaction studies: study design, data analysis, and implication for dosing and 
labeling, 
2006.
2. Oncology Clinical Pharmacology internal memo: drug-drug Interactions (DDI) database, 2010


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Table 4-3: List of OTC co-medications that are proton pump inhibitors
Proton pump inhibitors (brand name)
Esomeprazole (Nexium)
Lansoprazole (Prevacid)
Omeprazole (Prilosec)
Pantoprazole (Protonix)
Rabeprazole (Aciphex)
Dexlansoprzole (Dexilant)
Source: MicroMedex 2.0
Table 4-4: List of co-medications that are P-gp inhibitors, substrates or inducers
P-gp inhibitors
P-gp substrates 
P-gp inducers
elacridar (GF120918)
Digoxin 
Prednisone
indinavir
Fexofenadine 
Corticosteroids
quinidine
Indinavir 
Liponavir
valspodar (PSC833)
Vincristine 
Tipranavir
Colchicine 
Tenofovir
Talinolol  
Avasimib
Topotecan 
Etravirine
Paclitaxel
Milk thistle 
Mefloquine
Source: 
FDA 
guidance 
drug 
interaction 
studies: 
http://fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractions
Labeling/ucm080499.htm


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5
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH AND PHARMACODYNAMIC ASSESSMENTS
In light of the central role of oncogenic HGF/Met signaling in HPRC and evidence of pathway 
involvement in sporadic type I papillary RCC as described in section 1.2.1, a multilevel 
pharmacodynamic interrogation of the HGF/Met signaling pathway is proposed for this clinical 
trial.  The following measurements are proposed at baseline and at later times coinciding with 
scheduled clinical evaluation: [1] tumor Met protein; [2] tumor phospho-Met; [3] plasma HGF; 
[4] plasma soluble Met ectodomain (sMet); [5] urinary sMet.  The rationale and general protocol 
for each of these measurements is as follows.
5.1.1
Evaluation of HGF/MET pathway modulation in tumor tissue (optional)
Tumor Met: The abundance of Met protein has been linked to malignancy in several prevalent 
human cancers; increased MET gene expression is a direct consequence of pathway activation16,33.  
In recent clinical trials of rilotumumab for advanced gastroesophageal cancer and onartuzumab for 
advanced non-small cell lung cancer, both agents showed superior efficacy in patients with higher 
tumor Met protein content34,35.  Met protein abundance as measured in a semi-quantitative manner 
by immunohistochemistry (IHC) staining has become accepted as a proxy of HGF/Met pathway 
activation, primarily because of the functional link described above, the correlative link established 
from prior studies, and the availability of suitable antibodies and fixed tumor tissue used for initial 
pathological diagnosis.  However, this method does not provide precise or absolute values, only 
those relative to neighboring tissue processed at the same time.  We plan to measure tumor Met 
content using a highly quantitative two-site immunoassay with external reference standards that 
allows direct comparisons of tumor Met level across individuals or groups as well as historically; 
tissue for these measurements must be flash-frozen and stored in an ultra-low temperature freezer 
prior to analysis.  Because the tissue sample is mechanically disrupted and extracted with detergent 
for analysis, the method does not provide histological information.
Tumor phospho-Met: The abundance of phospho-Met, (more precisely, phosphotyrosyl 1235-Met) 
is directly related to the level of Met kinase activity and downstream signaling36.  Although this is 
considered the gold standard marker of Met signaling, the limited availability of monoclonal 
antibodies with high affinity and target selectivity and lability of Met tyrosyl phosphorylation 
placed this measurement out of reach of most clinical laboratories.  Recently we have overcome 
this limitation through the use of newly generated monoclonal antibodies, the development of 
tissue procurement procedures that minimize loss of the labile phosphate group, and analysis using 
the same two-site immunoassay platform as used to measure Met protein content.  Phospho-Met 
measurement can be corrected for total Met content to provide the stoichiometry of Met 
phosphorylation; external reference standards are available.
5.1.1.1
Collection of specimen(s)
Tumor biopsies (renal primary or metastases) may be obtained from patients who have easily 
accessible lesions. Core or excisional biopsy of an easily accessible sentinel lesion (such as 
cutaneous/subcutaneous lesions, percutaneously accessible hepatic or renal lesions, lymph nodes 
etc.) may be performed at study entry and again at approximately at 8 weeks following initiation 
of therapy. It is preferred that at least four (if feasible) core biopsies of 16 - 18 gauge diameter and 
at least 1cm in length are obtained.  Some biopsies may be performed with CT- or Ultrasound 


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guidance. Biopsies that are to be used solely for research purposes will be obtained only if they 
can be performed with minimal risk of complications from the procedure and only after the 
procedure has been explained to the patient and informed consent obtained. The biopsies will be 
performed by members of the interventional radiology, dermatology or surgical staff. 
5.1.1.2
Handling of Specimen(s)
A portion of the biopsies will be frozen in liquid nitrogen immediately and transferred to the UOB 
laboratory (Contact for receiving and processing specimen: Cathy Vocke, Ph.D. - Tel: 301-496-
6353). Prior to freezing and depending on tissue availability, a small portion of the biopsy 
specimen may be transferred under sterile conditions to the UOB laboratory to be used to establish 
a tumor cell line.
In addition, attempts will be made to obtain any available archived tumor tissue on all patients to 
help evaluate MET mutation status (by direct targeted sequencing of MET), evidence of 
MET/HGF amplification (using comparative genomic hybridization or quantitative PCR).
5.1.1.3
Sites Performing the Study
UOB Laboratory, Center for Cancer Research, NCI and the Molecular Genetics Section, Center 
for Cancer Research, NCI
5.1.2
Evaluation of plasma HGF and sMET modulation
Plasma HGF: Plasma levels of HGF have been shown to have diagnostic and prognostic value for 
a variety of human cancers37, providing a strong rationale to measure baseline plasma HGF and to 
correlate this with tumor burden (sum of the longest diameters) upon entering the trial.  High 
plasma HGF levels may result from production by the tumor and/or the tumor microenvironment 
through local feedback mechanisms, suggesting that decreases in plasma HGF while on drug may 
indicate target inhibition and potentially reduction in tumor burden.  Periodic measurement of 
plasma HGF over the course of the study will be correlated with tumor burden as measured by 
RECIST 
criteria. 
 
Plasma 
HGF 
measurement 
is 
performed 
using 
the 
same 
electrochemiluminescent two-site immunoassay platform as Met and phospho-Met content.  The 
measurement is high quantitative and the use of external reference standards allow lateral and 
longitudinal comparisons among individuals or groups.
Plasma sMet: Prior studies using human tumor-derived cell lines and human xenograft tumor 
models suggested that sMet values in plasma and urine correlated with level of malignancy and 
with overall tumor burden38. Subsequent studies using plasma and urine samples obtained from 
patients seen in the UOB and through several collaborations confirmed these findings39.  
Accumulating indirect evidence links malignancy, increased proteolytic activity, and proteolytic 
activation of HGF at the target cell surface with increased sMet production.  There is also evidence 
that the Met TK domain is activated as a consequence of ectodomain cleavage, and the degradation 
of this active TK fragment that rapidly ensues in normal cells may be disrupted in certain cancers, 
contributing to oncogenesis (manuscript in preparation).  In a phase II study of the Met/VEGFR 
inhibitor foretinib, median plasma sMet increased from baseline and correlated with drug plasma 
PK and median tumor burden40.  Further studies are needed to determine whether changes in 
plasma sMet over the course of treatment can indicate changes in tumor burden in individual 
patients. Plasma sMet measurement is performed using the same electrochemiluminescent two-
site immunoassay platform as Met and phospho-Met content.  The measurement is high 


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quantitative and the use of external reference standards allow lateral and longitudinal comparisons 
among individuals or groups.
5.1.2.1
Collection of Specimen(s)
Approximately 10mL of plasma will be collected in the presence citrate or EDTA as anticoagulant 
at baseline and every restaging.
5.1.2.2
Handling of Specimen(s)
Plasma samples will be transferred to the UOB laboratory (Contact for receiving and processing 
specimen: Cathy Vocke, Ph.D. - Tel: 301-496-6353; Donald P Bottaro, Ph.D.- Tel: 301-496-6353). 
Samples will be frozen in aliquots and stored in the UOB laboratory until required for study.
5.1.2.3
Site Performing the Study
UOB Laboratory, Center for Cancer Research, NCI
5.1.3
Evaluation of Urinary sMET modulation
Preclinical studies revealed the presence of sMet in urine samples from healthy volunteers and 
showed that urinary sMet correlated directly with tumor burden in mouse xenografts38.  We 
hypothesized that GU malignancies where the HGF/Met signaling pathway contribute to disease 
progression, and with exposure to the urinary tract, would show increased urinary sMet levels.  
Indeed, we found significant differences in median urinary sMet between the normal men and men 
with metastic prostate cancer41.  In a more recent analysis of 180 individuals with urothelial 
carcinoma of the bladder (BCa), we found that urinary sMet levels accurately differentiated 
patients with BCa from those without, patients with muscle-invasive BCa from those with non-
muscle-invasive BCa, and that median urinary sMet increased significantly with BCa grade 
(manuscript in preparation).  We hypothesize that patients with papillary RCC will show elevated 
urinary sMet levels and that changes in this level may indicate changes in tumor burden, and 
propose the analysis of baseline urinary sMet and periodic measurements that coincide with 
scheduled clinical evaluations. Urinary sMet is measured using the electrochemiluminescent two-
site immunoassay platform using external reference standards and requires normalization to 
urinary creatinine measured in the same sample.
5.1.3.1
Collection of Specimen(s)
Approximately 10-20 cc of urine will be collected at baseline and every restaging.
5.1.3.2
Handling of Specimen(s)
Urine samples will be transferred to the UOB laboratory (Contact for receiving and processing 
specimen: Cathy Vocke, Ph.D. - Tel: 301-496-6353; Donald P Bottaro, Ph.D.- Tel: 301-496-6353). 
Samples will be frozen in aliquots and stored in the UOB laboratory until required for study.
5.1.3.3
Site Performing the Study
UOB Laboratory, Center for Cancer Research, NCI


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5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION
Research samples will be collected with a view to performing the studies listed above.  Samples 
will be ordered and tracked through a Clinical Trial Data Management System.  Should a CRIS 
screen not be available, the CRIS downtime procedures will be followed.  Samples will not be sent 
outside NIH without appropriate approvals and/or agreements.
Each patient research sample will be assigned a unique patient identifier and relevant sample 
characteristics (such as timing of sample collection, treatment cycle and day identifiers) will be 
recorded. The location of all samples will be carefully tracked in the secure UOB database.  All 
stored samples will be coded and no identifying patient information will be on placed on sample 
containers. Stored samples will be kept in freezers / refrigerators or secure containers located in 
the Urologic Oncology Branch research laboratories or in the laboratories of collaborators.
Samples will be stored until requested by an authorized researcher(s).  All researchers are required 
to use the samples for research purposes associated with this trial (as per the IRB approved 
protocol). Subjects will be given the option of consenting to future use of their research samples 
per the informed consent process with their option declared in the consent document.  Samples 
from those patients who consent to this will be stored permanently. However, these samples will 
be used only for research studies on active IRB approved protocols covered by a valid informed 
consent document. Samples will be destroyed at the completion of the study from those subjects 
who decline future use of their samples. Once primary research objectives for the protocol are 
achieved, intramural researchers can request access to remaining samples provided they have an 
IRB approved protocol and patient consent. Any unused samples must be returned to the UOB 
laboratories as appropriate. If a patient withdraws consent the participant’s data will be excluded 
from future distributions, but data that have already been distributed for approved research use will 
not be able to be retrieved.  The PI will record any loss or unanticipated destruction of samples as 
a deviation. Reporting will be per the requirements of section 7.2. 
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant  data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts. Primary and final analyzed data will have 
identifiers so that research data can be attributed to an individual human subject participant.
Quality assurance complete records must be maintained on each patient treated on the protocol.  
These records should include primary documentation (e.g.: laboratory report slips, scan reports, 
pathology reports, physician notes, etc.) which confirm that:

The patient met all eligibility criteria

Signed informed consent was obtained prior to treatment

Treatment was given according to protocol (dated notes about doses given, 
complications, and clinical outcomes)

Toxicity was assessed according to protocol (laboratory report slips, etc.)


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
Response was assessed according to protocol (CT and/or MRI scan, lab reports, 
date noted on clinical assessment, as appropriate)
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other means, 
will be collected and recorded and followed as appropriate. Study drug (or therapy) includes the 
drug (or therapy) under evaluation, and any reference or placebo drug (or therapy) given during 
any phase of the trial.
Medical conditions/diseases present before starting study treatment are only considered adverse 
events if they worsen after starting study treatment (any procedures specified in the protocol). 
Adverse events occurring before starting study treatment but after signing the informed consent 
form are recorded. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms or require therapy and are recorded. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for 30 days after removal from study treatment or until off-
study, whichever comes first.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.
6.2
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for response every 8 weeks for the 
first 32 weeks and approximately every 12 weeks thereafter while on study.  Response evaluation 
will consist of CT CAP or MRI scan and a bone scan if bone disease is suspected or present.  In 
addition to a baseline scan, confirmatory scans should also be obtained (≥4) weeks following initial 
documentation of objective response.  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)42 and Prostate Cancer Clinical Trials Working Group criteria (PCWG2)43.  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.
6.2.1
Definitions
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with INC280.
Evaluable for objective response: Only those patients 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 response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.)


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Evaluable Non-Target Disease Response:  Patients 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. 
6.2.2
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, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as 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 patient, 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. 


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6.2.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm 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 slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for 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.
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.  
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date 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 at CT, MRI may be used instead of 
CT in selected instances.


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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 patient 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 published43-45.  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 cancer46.
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.
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional 
follow-up CT scans are needed to determine if there is truly progression occurring at that 
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the 
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is 
not progressing on the basis of the anatomic images, this is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring.  
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication.  However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
6.2.4
Response Criteria
6.2.4.1
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.


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Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
6.2.4.2
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).
6.2.4.3
Metastatic bone lesions
Disease progression is considered if a minimum of two new lesions is observed on bone scan. New 
lesions seen by the end of cycle 2 or before cycle 3 (after the first staging bone scan) may represent 
disease that was not detected on the pre-study scan, and a confirmatory scan will be required in 
next scheduled staging bone scan unless clinically not indicated. If confirmed, progression should 
be dated by the initial time when the lesions are first detected. If new lesions are seen after cycle 
2, but no additional lesions are seen on confirmatory scans, the scans from after cycle 2 would 
serve as the baseline scan to evaluate for disease progression). 42Furthermore, new bony lesions 
on bone scan or CT/MRI will not be considered an indication of disease progression if these lesions 
were present on the baseline FDG-PET scan. 
6.2.4.4
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 response assignment will depend on the 
achievement of both measurement and confirmation criteria.
For Patients with Measurable Disease (i.e., Target Disease)


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78
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
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 wks. 
from baseline**
PD
Any
Yes 
or 
No
PD
Any
PD***
Yes 
or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
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:
Patients 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 Patients 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


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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
6.2.5
Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
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.
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. 
6.2.6
Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
6.3
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  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#ctc_40). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING/ IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 


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7.3
NCI CLINICAL DIRECTOR REPORTING
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in section 
7.2.1 will be submitted within the appropriate timelines.
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 


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condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions

A congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 


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82
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement. 
8.5
REPORTING PREGNANCY
All 
required 
pregnancy 
reports/follow-up 
to 
OSRO 
will 
be 
submitted 
to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions can 
be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
8.5.1
Maternal exposure
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known.
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented.
8.5.2
Paternal exposure
Male participants should refrain from fathering a child or donating sperm during the study and for 
28 days after the last dose of Pomalidomide.


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Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 28 days after the last dose 
should, if possible, be followed up and documented.
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 
reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.7
SPONSOR PROTOCOL NON-ADHERENCE REPORTING
Protocol non-adherence is defined as any noncompliance with the clinical trial protocol, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol non-adherence identified by the 
Staff or the site Monitor on the OSRO Site Protocol Non-Adherence Log.  The protocol-specific, 
cumulative non-adherence log should be maintained in the site essential documents file and 
submitted to OSRO via OSROMonitoring@mail.NIH.gov on the first business day of each 
month over the duration of the study. In addition, any non-adherence to the protocol should be 
documented in the participant’s source records and reported to the local IRB per their guidelines. 
OSRO required protocol non-adherence reporting is consistent with E6(R2) GCP: Integrated 
Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; 
and ICH E3 16.2.2 Protocol deviations.
9
CLINICAL MONITORING
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on:

Informed consent process

Eligibility confirmation

Drug administration and accountability

Adverse events monitoring

Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.


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This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.
10 STATISTICAL CONSIDERATIONS  
10.1 EVALUATION OF ENDPOINTS
The primary endpoint will be efficacy (RECIST response rate). The study will use a Simon two-
stage minimax design. Thirteen patients will be accrued in the first stage. If there are no responses 
(either CR or PR) in 13 evaluable patients, accrual to the trial will be terminated, and the treatment 
will be considered ineffective. If at least one patient responds among the 13 patients then 7 
additional evaluable patients will be accrued. If 3 or more patients of 20 respond then the treatment 
will be considered worthy of future investigation.  If fewer than 3 patients respond, the treatment 
will not be considered worthy of additional investigation. 
The two-stage minimax design is based on assuming an ineffective response rate of 5% and a 
targeted effective response rate of 25%. We also assume that the probability of accepting an 
ineffective treatment and the probability of rejecting an effective treatment are each 10%.   With 
this design, we have a 51% chance of stopping accrual at the end of the first stage if the response 
rate is 5%.
10.2 EVALUATION OF SECONDARY ENDPOINTS
Secondary objectives are listed in Section 1.1.2. The follow-up times for biomarker endpoints are 
given in Section 3.4. Analyses will focus on comparing changes in these biomarkers on treatment 
from the pre-study measurement.  Longitudinal changes in continuous biomarkers (eg.  plasma 
HGF) or imaging outcomes will be analyzed using Wilcoxon signed-rank tests (which compares 
measurements at a single post-treatment time point with measurements at the pre-treatment time 
point) as well as with linear mixed models (which incorporates all follow-up times when 
evaluating change). Evaluation of time to progression and progression free survival will be based 
on restaging studies performed as outlined and along with overall survival will be summarized 
using Kaplan-Meier curves. Disease control rate will be presented as the proportion of patients 
with stable disease ≥ 6 months, partial response or complete response.
10.3 SAMPLE SIZE CALCULATION
The accrual ceiling of this study will be set at 22 to allow for the replacement of patients that are 
inevaluable. At an accrual rate of 1-2 patients per month, it expected that the trial will complete 
accrual within 12-24 months. 
11 COLLABORATIVE AGREEMENTS 
11.1 AGREEMENT TYPE
This investigational agent for this study, INC280 is being provided to the NIH under a 
Collaborative Agreement Clinical Materials-Cooperative Research and Development Agreement 
(CRADA) with Novartis; #02869. 


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12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
Patients of all races, genders and ethnic origins will be eligible.  Eligibility assessment will be 
based solely on the patient’s medical status.  Recruitment of patients onto this study will be through 
standard CCR mechanisms.  No special recruitment efforts will be conducted.
12.2 PARTICIPATION OF CHILDREN
This protocol will exclude children below 18 years of age since there are no safety data available 
in this group of patients.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.5), all subjects ≥ age 18 will be offered the opportunity to fill in 
their wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment 
of whether an individual has the capacity to provide consent; assistance in identifying and 
assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint 
a surrogate.  For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not 
have a legal guardian or durable power of attorney, will be followed. 
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.4.1 Benefits
The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, which 
may or may not have a favorable impact on symptoms and/or outcome.
12.4.2 Risks
12.4.2.1 Study Agent
The primary risks of participation in this study include the possible occurrence of any of a range 
of side effects from the study agent INC280 which are listed in the section 14.1.3, the investigator 
brochure and in the consent document.  Frequent monitoring for adverse effects and exclusion of 
subjects at risk for these adverse effects will help to minimize the risks associated with 
administration.
12.4.2.2 Optional biopsies
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent. If patients suffer any physical injury as a result of the biopsies, 
immediate medical treatment is available at the NCI’s Clinical Center in Bethesda, Maryland.  


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Although no compensation is available, any injury will be fully evaluated and treated in keeping 
with the benefits or care to which patients are entitled under applicable regulations.
Some biopsies may be performed with CT guidance.  If that is the case, then this research study 
involves exposure to radiation from up to 2 CT scans with combined effective dose of 1.60 rem.  
This is below the guideline of 5.0 rem per year allowed for research subjects by the NIH Radiation 
Safety Committee.
12.5 RISKS/BENEFITS ANALYSIS
There are currently no standard therapeutic options for patients with metastatic renal cell 
carcinoma associated with HPRC or for patients with advanced sporadic papillary RCC, who have 
a poor prognosis with most dying from metastatic disease and its sequelae. Patients participating 
in this trial (including patients unable to give consent) may derive a benefit from the treatment 
administered.  Although the possible toxicities from the proposed therapy may be potentially 
serious, given the nature of the underlying disease, they are acceptable.  Additionally, we do not 
anticipate toxicities significantly more severe than those observed with other, approved agents.  
For these reasons, the risk/benefit ratio of this protocol is favorable; therefore, this protocol 
involves greater than minimal risk to patients, but presents the potential for direct benefit to 
individual subjects.
12.6 CONSENT PROCESS AND DOCUMENTATION
The investigator must explain to each subject the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved and any discomfort it 
may entail. Each subject must be informed that participation in the study is voluntary and that 
he/she may withdraw from the study at any time and that withdrawal of consent will not affect 
his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient could 
not read or sign the documents. No patient can enter the study before his/her informed consent has 
been obtained.
The informed consent form is considered to be part of the protocol and must be submitted by the 
investigator with it for IRB approval. 
Fertile men and women of child-bearing potential should be informed that taking the study 
medication may involve unknown risks to the fetus if pregnancy were to occur during the study 
and agree that in order to participate in the study they must adhere to the contraception requirement 
for the duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
If there is an optional biopsy for research in the protocol, then the patient will consent at the time 
of the procedure.  If the patient refuses the optional biopsy at that time, the refusal will be 
documented in the medical record and in the research record. 


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12.6.1 Telephone Consent Procedure 
Consent on this study may be obtained via telephone according to the following procedure: The 
informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. The original informed consent document will 
be sent back to the consenting investigator who will sign and date the consent form with the date 
the consent was obtained via telephone.  A fully executed copy will be returned via mail for the 
subject’s records.  The informed consent process will be documented in the medical records.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be contacted, 
as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 


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The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by the 
clinical site(s) and by NCI CCR research staff will be secured and password protected. At the end 
of the study, all study databases will be archived at the NCI CCR.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 


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objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
14 PHARMACEUTICAL INFORMATION  
14.1 INC280 (IND # 119133)
(For complete information, please see the Investigator Brochure for INC280)
14.1.1 Source, packaging and labeling
INC280 tablets will be supplied by Novartis as film-coated tablet for oral use, packaged in either 
bottles or blisters, and will be administered on a flat scale and not individually adjusted by weight 
or body surface area. 
Medication will be labeled for Clinical Trial use and will include storage conditions for the drug 
and the medication number but no information about the patient.
Table 14-1: Packaging and labeling
Study drugs
Packaging
Labeling 
(and 
dosing 
frequency)
INC280
Tablets in bottles or blisters (100 
mg and 200 mg)
Labeled as “INC280”
14.1.2 Supply, receipt and storage
Study drug must be received by a designated person at the study site, handled and stored safely 
and properly and kept in a secured location to which only the investigator and designated assistants 
have access. Refer to the clinical label for storage condition requirements.  Upon receipt, INC280 
should be stored according to the instructions specified on the drug labels. Study medication will 
be dispensed by an authorized person at the investigator’s site. 
Patients will be provided with adequate supply of INC280 for self-administration at home until at 
least their next scheduled study visit.  
14.1.3 Toxicity: 
14.1.3.1 Animal Studies
Kidney toxicity was observed in the 28-day monkey study where mild-to-moderate deposits of 
amphophilic, crystalline-like material surrounded by multinucleated giant cells within the renal 
interstitium and/or tubular lumen were present in the 75 and 150 mg/kg/day, but not in the 30 
mg/kg/day groups.
The findings in pancreas were observed in rats and monkeys in the 28-day studies, including 
pancreatic acinar cell vacuolation and/or apoptosis without inflammation. In monkeys, a dose of 
30 mg/kg/day was identified as a NOAEL because of the low grade and reversible pancreatic 
findings present at that dose. In rats, the mid-dose groups (60 mg/kg/day in males and 30 
mg/kg/day in females) also showed reversible low-grade pancreatic changes. Reversibility has 
been clearly demonstrated in both species.
Clinical signs indicative of CNS toxicity (seizures, tremors, lethargy, staggered gait, imbalance, 
splayed limbs), and histopathological findings of white matter vacuolation in thalamus were 


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observed only in rats of high-dose groups (60 mg/kg/day for females, and 120 mg/kg/day for 
males) in 28-day toxicity study. No signs of CNS toxicity were observed in Cynomolgus monkeys 
studies. Additionally, results from the 13-week rat toxicity study reproduced the CNS effects and 
histopathological findings in the brain and also demonstrated that the CNS effects and brain lesions 
were reversible.
Changes in serum chemistry liver enzymes (ALT, AST, and/or SDH) were observed in several 
different studies in rats and monkeys. These changes were restricted to highly variable, minimal-
to-mild elevations lacking a clear dose response. The significance of elevations of liver enzymes 
remains undetermined because of the high degree of individual variability, and the absence of any 
histological correlate within the liver.
14.1.3.2 Human Studies
In a study of 45 patients in a first in human study of INC280, one DLT, CTCAE Grade 3 AST and 
alkaline phosphatase increase was reported for a patient at the dose level of 50mg. 
Forty-four (97.8%) out of 45 patients experienced adverse events (AEs) any grades and regardless 
of causality. The most common adverse events (≥15%) were peripheral edema (44.4%), nausea 
(35.6%), fatigue (33.3%), tremor (28.9%), vomiting (24.4%), abdominal pain (22.2%), headache 
(20.0%), cough (17.8%), abdominal tenderness, constipation, diarrhea, dizziness and 
musculoskeletal pain (15.6%, respectively).
The most frequent AEs suspected to be related to INC280 any CTCAE grade, were nausea 
(26.7%), tremor (24.4%), fatigue (20.0%), peripheral edema (15.6%), and headache (15.6%). Two 
patients (4.4%) experienced CTCAE Grade 3 or Grade 4 AEs suspected to be treatment related, 
which were AST (50mg QD) and hypophosphataemia (150mg QD).
Expected Adverse Events are listed in the table below.
MedDRA system organ class
Preferred Term
Blood and Lymphatic
System Disorders
Anemia, 
Neutropenia
Ear and Labyrinth Disorders
Deafness
Gastrointestinal disorders
Vomiting 
Nausea
Diarrhea
Abdominal pain
Pancreatitis
General disorders and
administration site
conditions
Fatigue, 
Edema peripheral
Asthenia
Cellulitis 
Pruritus
Urticaria


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MedDRA system organ class
Preferred Term
Infections and infestations
Lung infection
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased 
Gamma-glutamyltransferase increased 
Amylase increased 
Blood bilirubin increased 
Lipase increased
Amalyse increased
Creatine Increased
Metabolism and nutrition
disorders
Decreased appetite 
Hyponatremia
Dehydration
Hypophagia 
Hypophosphatemia
Nervous system disorders
Dizziness
Respiratory, thoracic and mediastinal disorders
Dyspnea, cough
Eleven serious adverse events (SAEs) have been reported in 9 (20%) out of 45 patients. They were 
deep venous thrombosis, electrocardiogram QT prolonged, failure to thrive (all at 10 mg QD), 
clavicle fracture (20mg QD), ascites, humerus fracture (both at 200mg QD), constipation, 
pneumonia, staphylococcal sepsis, hepatic encephalopathy (all at 400mg QD), diarrhea (50mg 
BID). All SAEs were reported as not related to INC280.
14.1.4 Administration procedures 
See section 3.2
14.1.5 Incompatibilities 
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.
Please see section 4 on concomitant medications for managing drug interactions.


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14.1.6 Drug compliance and accountability
Clinical drug supply must be accounted for and patients will be asked to return all unused study 
drug and packaging on a regular basis, usually at the time of scheduled clinic visits and at the end 
of the study or at the time of study drug discontinuation.  
Drug accountability and subject compliance will be assessed with drug dispensing and return 
records as described below. 
All oral self-administered investigational agents will be properly accounted for, handled, and 
disposed in accordance with existing federal regulations and principles of Good Clinical Practice.  
CRR 
SOPs 
on 
self-administered 
investigational 
agents 
may 
be 
found 
here:  
https://ccrod.cancer.gov/confluence/display/CCRCRO/Documenting+Drug+Accountability+for+
Oral+Investigational+Agents 
The investigator will maintain accurate records of receipt of all INC280, including dates of receipt.  
In addition, accurate records will be kept regarding when and how much study treatment is 
dispensed and used by each subject in the study. Reasons for deviation from the expected 
dispensing regimen must also be recorded.
At the conclusion of the study, and, as appropriate during the course of the study, the Investigator 
will return all used and unused study drug, packaging, drug labels, and a copy of the completed 
drug accountability ledger to Novartis. 
14.1.7 Disposal and destruction 
The drug supply will be destroyed at a Novartis facility, Drug Supply group or third party, as 
appropriate. Study drug destruction at the investigational site will only be permitted if authorized 
by Novartis in a prior agreement and if permitted by local regulations.
 


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doi:10.1517/14728222.2012.680957 (2012).
17
Peruzzi, B. & Bottaro, D. P. Targeting the c-Met signaling pathway in cancer. Clinical 
cancer research : an official journal of the American Association for Cancer Research 12, 
3657-3660, doi:10.1158/1078-0432.CCR-06-0818 (2006).
18
Fischer, J. et al. Duplication and overexpression of the mutant allele of the MET proto-
oncogene in multiple hereditary papillary renal cell tumours. Oncogene 17, 733-739, 
doi:10.1038/sj.onc.1201983 (1998).
19
Zhuang, Z. et al. Trisomy 7-harbouring non-random duplication of the mutant MET allele 
in hereditary papillary renal carcinomas. Nature genetics 20, 66-69, doi:10.1038/1727 
(1998).
20
Balint, I., Szponar, A., Jauch, A. & Kovacs, G. Trisomy 7 and 17 mark papillary renal cell 
tumours irrespectively of variation of the phenotype. Journal of clinical pathology 62, 892-
895, doi:10.1136/jcp.2009.066423 (2009).
21
Kovacs, G., Fuzesi, L., Emanual, A. & Kung, H. F. Cytogenetics of papillary renal cell 
tumors. Genes, chromosomes & cancer 3, 249-255 (1991).
22
Tannir, N. M. et al. A phase 2 trial of sunitinib in patients with advanced non-clear cell 
renal cell carcinoma. European urology 62, 1013-1019, doi:10.1016/j.eururo.2012.06.043 
(2012).
23
Molina, A. M. et al. Phase II trial of sunitinib in patients with metastatic non-clear cell 
renal cell carcinoma. Investigational new drugs 30, 335-340, doi:10.1007/s10637-010-
9491-6 (2012).
24
Lee, J. L. et al. Multicenter phase II study of sunitinib in patients with non-clear cell renal 
cell carcinoma. Ann Oncol 23, 2108-2114, doi:10.1093/annonc/mdr586 (2012).
25
Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. 
The New England journal of medicine 356, 2271-2281, doi:10.1056/NEJMoa066838 
(2007).
26
Dutcher, J. P. et al. Effect of temsirolimus versus interferon-alpha on outcome of patients 
with advanced renal cell carcinoma of different tumor histologies. Medical oncology 26, 
202-209, doi:10.1007/s12032-009-9177-0 (2009).
27
Choueiri, T. K. et al. Efficacy of sunitinib and sorafenib in metastatic papillary and 
chromophobe renal cell carcinoma. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 26, 127-131, doi:10.1200/JCO.2007.13.3223 
(2008).
28
A, R., S, O. & DR, F. First-line sunitinib in type I and papillary renal cell carcinoma 
(PRCC): SUPAP, a phase II study of the French Genito-Urinary Group (GETUG) and the 
Group of Early Phase trials (GEP). Ann Oncol 23, Abstr 797PD (2012).


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
95
29
Gordon, M. S. et al. Phase II study of erlotinib in patients with locally advanced or 
metastatic papillary histology renal cell cancer: SWOG S0317. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 27, 5788-5793, 
doi:10.1200/JCO.2008.18.8821 (2009).
30
Choueiri, T. K. et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor 
foretinib in patients with papillary renal cell carcinoma. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 31, 181-186, 
doi:10.1200/JCO.2012.43.3383 (2013).
31
Srinivasan, R. et al. in ASCO Genitourinary Cancers Symposium.
32
Choueiri, T. et al. in ASCO Genitourinary Cancers Symposium.
33
Dharmawardana, P. G., Giubellino, A. & Bottaro, D. P. Hereditary papillary renal 
carcinoma type I. Current molecular medicine 4, 855-868 (2004).
34
Zhu, M. et al. Exposure-response (E-R) analysis of rilotumumab (R, AMG 102) plus 
epirubicin/cisplatin/capecitabine (ECX) in patients (pts) with locally advanced or 
metastatic gastric or esophagogastric junction (G/EGJ) cancer. Journal of clinical oncology 
: official journal of the American Society of Clinical Oncology 30, suppl abstract 2535 
(2012).
35
Spigel, D. R. et al. The MetLUNG study: A randomized, double-blind, phase III study of 
onartuzumab (MetMAb) plus erlotinib versus placebo plus erlotinib in patients with 
advanced, MET-positive non-small cell lung cancer (NSCLC). Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 30, suppl abstract 
TPS7616 (2012).
36
Bottaro, D. P. et al. Identification of the hepatocyte growth factor receptor as the c-met 
proto-oncogene product. Science 251, 802-804 (1991).
37
Rubin, J. S. & Bottaro, D. P. Nature UCSD Signaling Gateway: Molecule Pages. A 
comprehensive 
review 
of 
HGF 
biology, 
2011., 
<http://www.signaling-
gateway.org/molecule/query?afcsid=A004032> (
38
Athauda, G. et al. c-Met ectodomain shedding rate correlates with malignant potential. 
Clinical cancer research : an official journal of the American Association for Cancer 
Research 12, 4154-4162, doi:10.1158/1078-0432.CCR-06-0250 (2006).
39
Bottaro, D. P., Athauda, G., Giubellino, A. & Burgess, T. US Provisional Patent 
Application No. 60/734,993 (November 8, 2005) and US Provisional Patent Application 
No. 60/780,626 (March 9, 2006): Methods for Diagnosing and Monitoring the Progression 
of Cancer.
40
Cecchi, F. et al. Shed MET (sMET), VEGFA, and sVEGFR2 are markers of foretinib 
treatment in metastatic gastric cancer patients Mol Cancer Ther 8, Abstract B210, doi: 
10.1158/1535-7163.TARG-09-B210 (2009).
41
Russo, A. L. et al. Urine analysis and protein networking identify met as a marker of 
metastatic prostate cancer. Clinical cancer research : an official journal of the American 
Association for Cancer Research 15, 4292-4298, doi:10.1158/1078-0432.CCR-09-0599 
(2009).


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
96
42
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 45, 228-247, doi:10.1016/j.ejca.2008.10.026 (2009).
43
Scher, H. I. et al. Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer 
Clinical Trials Working Group. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 26, 1148-1159, doi:10.1200/JCO.2007.12.4487 
(2008).
44
Rustin, G. J. et al. Re: New guidelines to evaluate the response to treatment in solid tumors 
(ovarian cancer). J Natl Cancer Inst 96, 487-488, doi:10.1093/jnci/djh081 (2004).
45
Bubley, G. J. et al. Eligibility and response guidelines for phase II clinical trials in 
androgen-independent prostate cancer: recommendations from the Prostate-Specific 
Antigen Working Group. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 17, 3461-3467, doi:10.1200/JCO.1999.17.11.3461 (1999).
46
Vergote, I. et al. Re: new guidelines to evaluate the response to treatment in solid tumors 
[ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst 92, 1534-1535, 
doi:10.1093/jnci/92.18.1534 (2000).


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
97
16 APPENDICES
16.1 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, 
no 
complaints, 
no 
evidence of disease.
0
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; some 
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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
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.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very 
sick, 
hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, 
fatal 
processes 
progressing rapidly.
5
Dead.
0
Dead.


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
98
16.2 APPENDIX B:  PATIENT’S PILL/ SIDE EFFECTS DIARY
Today’s date ________________________________
Cycle__________ Week_________
Dose_________
Patient Name_____________________________  Patient Study ID ___________________________________
(initials acceptable)
INSTRUCTIONS TO THE PATIENT:
1.
Complete one form for each  1 week period (1 cycle = 4 weeks)
2.
You will take your medication in the morning and evening.  You should not eat anything 2 hours prior to or after 
the medication; drink a full glass of water with the medication and 2 hours after you take the medication. If you miss 
the intended time to take your INC 280 by 4 hours or more, do not take that dose.
3.
Record the date, the number of pills you took, and when you took them. Also record that you have fasted.  
4.
If you have any comments or notice any side effects, please record them in the Comments column.
3.
Please bring your pill bottle and this form to your physician when you go for your next appointment.
Date
Day #
# 
of 
pills 
taken
Time
Taken
Fasted 
Before
Fasted
After
SIDE EFFECTS/COMMENTS
Init
#1  
#1  
# 2 
# 2  
# 3 
#3  
# 4 
# 4 
# 5 
# 5 
# 6 
# 6 
#7 
# 7 


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
99
Patient’s 
Signature: 
_____________________________________________ 
 
Date: 
______________________________________
Physician’s Office will complete this section:
1.
Date patient started protocol treatment________________   Date patient was removed from study 
_____________________
2.
Patient’s planned daily dose________________________    Total number of pills taken this  
week_____________________
Physician/Nurse/Data 
Manager’s 
Signature 
______________________________________________________________________


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
100
16.3 APPENDIX C: INSTRUCTION SHEET FOR INC 280
You have been prescribed the medication INC 280. INC 280 is believed to work by blocking MET, 
a protein in your body which if altered can promote tumor formation and spread. You should take 
the INC 280 the same time twice a day, at least 8 hours apart. You should fast for 2 hours before 
and 2 hours after taking INC 280. You should take a full glass of water (8 OZ) with INC 280 and 
another full glass of water 2 hours after taking INC 280. If necessary, you can take ginger ale, 
apple juice, or cranberry juice in addition to water during the fasting period. Document the time 
you take the medication on your diary. If you forget to take your medication at the usual time, you 
can take it within 4 hours, then resume your usual schedule the next day.  If you vomit a dose of 
INC280, do NOT take another. Bring your medication and your diary with you to every doctor’s 
visit.  ALWAYS check with your medical team before beginning any new medication.
There are few important points to remember:
•
NO grapefruit juice or Seville orange juice while on INC 280. Avoid for 7 days prior to the 
first dose
•
NO herbal supplements or teas while on INC 280 until you speak with your medical team.
•
If you are of reproductive age, you MUST use birth control.
•
Report any unplanned surgery or wounds IMMEDIATELY to your medical team so your 
INC 280 can be adjusted accordingly.
•
You MUST wear sunscreen (SPF> 45) when outside.
•
If you develop a skin rash, notify your medical team immediately so we can begin 
medication to prevent the rash from worsening.
•
You cannot take long acting proton pump inhibitors while on INC 280 because they will 
affect the absorption of the medication. Examples of these would be Prilosec (omeprasole); 
Protonix (pantoprazol); Prevacid (lansoprazol). 
Medications to Treat Common Side Effects: When you begin INC 280, the medical team will give 
you medications for nausea, diarrhea, and constipation. Please notify the medical team if any of 
these are occurring, document in your diary, and begin the appropriate medication listed below. 
Please be sure to have a working thermometer at home so you can check your temperature when 
instructed to do so.
For Nausea:
•
Prochlorperazine / Ondansetron: Take as directed.
For Diarrhea:
•
Loperamide 2mg tablets to be taken for diarrhea, as directed.
•
Diet: BRAT diet – bananas, rice, applesauce, toast – can be helpful
For Constipation: 
•
Docusate 100mg – take 1-2 initially for constipation, then 1 a day as needed


Abbreviated Title: INC280 in RCC
Version Date: February 14, 2022 
101
If questions or problems during the week please contact:
Erin Purcell RN research nurse; 240-858-3933 OR erin.purcell@nih.gov. 
After 5pm or on weekends call the NIH page operator: 301-496-1211 and ask to speak with 
Urologic Oncology fellow. In case of an emergency, go to your nearest hospital emergency 
department.

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
14-C-0037 
PRINCIPAL INVESTIGATOR: 
Ramaprasad Srinivasan, M.D., Ph.D. 
STUDY TITLE:  
A Phase 2 Study of the MET Kinase Inhibitor INC280 in Papillary Renal Cell Cancer 
 
Continuing Review Approved by the IRB on 05/26/21 
Amendment Approved by the IRB on 04/29/20 (I) 
 
                          Date Posted to Web: 06/02/21 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
INC280 is a medicine which has not been approved by the US Food and Drug Administration.  It 
is not currently “on the market” (available for you to buy) in any country.  Preliminary results 
from a first in human study however have shown that INC280 is generally tolerated with few 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 2 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
serious side effects.  INC280 has been shown in laboratory studies to block a certain protein 
called MET that is important to the growth and multiplication of cells.  This protein has been 
shown to be highly activated in certain cancers, including some forms of papillary renal cell 
carcinoma.  The purpose of this study is to measure what effect if any, treatment with INC280, 
has on the tumors of patients with papillary renal cell carcinoma.  We will also try to determine 
how long patients using INC280 survive without cancer, how long patients survive overall and 
determine the types of side effects they have from using INC280. 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have been diagnosed with papillary 
renal cell carcinoma, either hereditary or sporadic (not inherited). 
How many people will take part in this study?  
Approximately 20 people will be enrolled in this study. 
Description of Research Study 
Before you begin the study 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  However, there are some extra exams, tests and procedures that you 
will need to have if you take part in this study. If you have had some of them recently, they may 
not need to be repeated.   
These tests include: 
• History and physical evaluation including vital signs 
• Tests to check your blood counts and blood chemistries 
• Urine tests 
• Serum pregnancy test (if you are female and can have children) 
• CT scan of chest/abdomen/pelvis or MRI 
• Brain MRI or brain CT 
• Bone scan (if it is suspected that your tumor has spread to your bones) 
• FDG-PET if your cancer is known or suspected to have spread outside the kidneys 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 3 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
During the study 
If you meet the “entry criteria” of the study, you will have your blood pressure and heart rate 
measured, an ECG will be performed and you will be asked again about any medications you 
have been taking.  You may also need to have some of the tests that were done at screening 
repeated depending on how much time has passed.  Your study team will let you know if any of 
the above tests need to be repeated. In addition, your study doctor may also discuss enrolling you 
in another study, in order to determine if your cancer is associated with any genetic changes. 
INC280 is provided free of charge by Novartis Pharmaceuticals for a time span of one year 
or so long as you remain on study (if more than one year).  
You will take INC280 (2 tablets) twice a day by mouth and will continue taking INC280 until 
your disease gets worse or you experience intolerable side effects. You will return to your 
doctor’s office at regular intervals so that your condition can be monitored. The Study Doctor 
will ask you how you are feeling. It is very important that you take the medicine given to you 
just as the doctor tells you to.  
You will take the study medication at about the same time each day for the entire time you are 
participating in the study. For seven (7) days prior to your first dose, and while you are taking 
INC280, you should not drink grapefruit juice or Seville orange juice. INC280 should be taken at 
least 8 hours apart. The morning dose may be taken 2 hours after a light breakfast, and a 2 hour 
fast must occur following this dose. For the evening dose, you must not have eaten anything 2 
hours before or 2 hours after taking the evening dose. Each dose should be taken with at least 8 
ounces of water and you should drink at least another 8 ounces of water within 2 hours after 
taking the medication.  If necessary, you may have some ginger ale, apple juice or cranberry 
juice. Do not miss any tablets; however, if you do forget to take a dose, do not replace if you are 
more than 4 hours past the planed dosing time. Resume your normal schedule the next day. 
Tell the study staff about any medications you are taking during the study. This includes 
prescriptions drugs, over-the-counter medicines, vitamins, nutritional supplements or herbal 
remedies. This is very important. Some over-the-counter and prescription medications can 
reduce the effectiveness or increase the side effects of INC280. Likewise, INC280 can increase 
the side effects or lessen the effectiveness of some medications. 
You must tell your doctor, or his/her delegate, if you are taking aluminium hydroxide and 
magnesium hydroxide, (e.g., Maalox®) or calcium carbonate (e.g., TUMS®). If you need to take 
one of these medications, you must do so 4 hours before or after you have taken the study drug. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 4 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Medications such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), ranitidine 
(Zantac) should be avoided when possible.  If you need to take one of these medications, you 
have to take it at least 2 hours after the study drug.  The next scheduled dose of the study drug 
should be taken at least 8 hours after you have taken the medication. Proton pump inhibitors such 
as Prevacid, Nexium, Protonix and Prilosec should not be used when you are on this study. 
A variety of other medications can result in harmful interactions with INC280. Since it is not 
possible to list all of them here, your research team will carefully go over all the medications you 
are taking to ensure that you do not take medications that could result in potential harm. Please 
do not take any new medications during the study without consulting your research team at the 
NIH. 
In order to monitor your progress during the study, we will divide the time you are on the study 
into cycles.  One cycle = 4 weeks or 28 days. 
You will need the following tests and procedures that are part of regular cancer care. 
• History and physical evaluation will be done during week 1 of each cycle 
• Serum pregnancy test (if you are female and can have children) will be done during 
week 1 of each cycle 
• Vital signs will be taken during weeks 1 and 3 of the first cycle, and during week 1 
of the following cycles. 
• Tests to check your blood counts and blood chemistries will be performed during 
week 1 and week 3 of each cycle 
• CT or MRI of the abdomen if tumors are only in the kidney; CT of the chest if 
indicated; CT or MRI of the pelvis if indicated; and a bone scan if disease in the 
bone. These tests will be performed during week 1 of every other cycle until cycle 8 
(week 32).  After that they will be performed during week 1 of every third cycle. 
• Urine tests will be performed on the same schedule as CT or MRI scans 
• FDG-PET if your cancer is known or suspected to have spread outside the kidney 
You will need the following tests or procedures that are not usually part of regular cancer care to 
help us monitor your safety 
• Record when you take your medication and any symptoms that you experience in a 
diary provided by the study team 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 5 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• An electrocardiogram (ECG), a test for your heart will be performed during week 1 
and week 3 of cycle 1, then during week 1 of the following cycles 
• A series of eye examinations ~ 4 -5 hours in total will be performed at the 
beginning of the study, as needed, before you have taken any drug. Additional eye 
examinations may also be performed if you complain of any symptoms.  
You will also need the following tests for research to see how the drug is affecting your body and 
other research studies. 
• Tumor biopsy (optional) will be collected at the beginning of the study before you 
have taken any study drug and then at approximately 8 weeks (the end of cycle 2). 
The tumor samples we obtain will be used to look for special markers that may be 
helpful in the study of kidney cancer and in understanding the effect of the study 
drugs on the tumor.  We may also use the samples to grow tumor cell lines (cells 
which keep dividing and growing in the laboratory, sometimes for years allowing us 
to continually study those cells).  Results of research done on your specimens and 
data will not be available to you or your doctor.  A separate consent form will be 
provided to you at the time of the biopsy for you to grant permission to that 
procedure if you agree to the biopsy.   
• ~ 2 teaspoons of blood will be collected at the beginning of the study and every 
restaging after while you are taking INC280 so that we can measure the level of 
certain proteins, that may help to determine how much tumor you have in your body 
and to determine if these protein levels are changing when you are receiving 
treatment 
• ~2 -4 teaspoons of urine will be collected at the beginning of the study and every 
restaging after while you are taking INC280 so that we can measure the level of 
certain protein(s), that may help to determine how much tumor you have in your 
body and to determine if these protein levels are changing when you are receiving 
treatment 
• At the beginning of the study, we would like to obtain your previously collected 
tumor tissue if it is available.  We would like to test your tissue for genes that may 
be linked to cancer. 
When you are finished taking the drugs (treatment) 
We would like to see you again within 4 to 5 weeks after you have finished taking the study drug 
in order to perform the following tests: 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 6 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Medical history physical examination 
• Tests to check your blood counts and blood chemistries 
• Eye examinations 
After you have completed this visit, we would also like to contact you by telephone 
approximately once per year to find out how you are doing. 
Birth Control 
The risks to an unborn human fetus or a nursing child from INC280 are not known.  Animal 
studies have shown that the offspring of female rabbits treated with INC280 had defects in the 
muscles of their legs and of the tongue. Therefore, it must be considered that INC280 could 
cause similar or other defects during a human pregnancy. Therefore, it is important that you do 
not become or attempt to become pregnant or father a child while you are taking INC280 and for 
at least three months after your last dose of the drug. 
Women who are pregnant or nursing a child may not participate in this study. You must confirm 
that, to the best of your knowledge, you are not now pregnant, and that you do not intend to 
become pregnant during the study. If there is any possibility that you may become pregnant 
during the study, the Study Doctor will discuss appropriate birth control measures with you. If 
you suspect that you have become pregnant during the study, you must notify the Study Doctor 
immediately, and you have to stop study treatment immediately. You will not be able to continue 
in the study if you become pregnant. Although you will not be able to receive medical care 
related to your pregnancy at the NIH Clinical Center, your study doctors will ask you and the 
doctor(s) managing your pregnancy to provide relevant medical information until delivery to 
monitor you and your child’s safety. 
As a male participant in the study you must agree to use a condom during intercourse and not to 
father a child during the study and for the period of 3 months following stopping of study 
treatment. In addition, it is advised that your female partner uses a highly effective form of birth 
control method (contraception) if she is sexually active and may become pregnant. In case you 
father a child while in this study you will be asked to report the pregnancy to the study doctor. 
Your study doctor will seek your partner’s permission to obtain relevant medical information 
relating to this pregnancy until delivery to monitor the mother’s and child’s safety.   
Effective forms of birth control include:  
• abstinence  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 7 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study? 
Risks are possible side effects of study medicine or another medicine, those of taking blood, 
those associated with scans or other tests/procedures associated with the study, and those of 
taking a piece of tumor during the biopsies.  Although blood samples will be taken throughout 
the trial, the Study Doctor may decide that you may need to have additional blood tests for your 
safety to follow up on any side effects. 
Risks of INC280 
The early results from INC280 single agent human studies have reported common side effects 
possibly related to INC280 (in at least 10% of patients) such as nausea (feeling like vomiting), 
vomiting, peripheral edema (swelling in arms and legs), decreased appetite, fatigue, headache, 
tremor, diarrhea, malaise (feeling of general discomfort), distortion of the sense of taste and 
decrease in blood chemistry parameter (albumin). Very common side effects related to INC280 
(in at least 52% of patients) include blood creatinine increase. This could be an indication of 
kidney damage or kidney failure. Other side effects that have been seen in patients taking 
INC280 include pancreatitis (inflammation of the pancreas),  cellulitis (inflammation of tissue), 
pruritus (itching of the skin), urticaria (a rash on the skin that will be itchy and possibly cause 
swelling), amylase increase lipase increase (molecules that help digest and are produced in your 
pancreas increase), abdominal pain (stomach pain), arthralgia (joint pain), constipation, 
dizziness, heartburn or GI reflux, musculoskeletal pain, pain in extremity (arm or leg), changes 
in the  levels of phosphorus, and potassium in the blood, low blood pressure, eye redness, 
sensitivity to light, neuropathy (damage to nerves that can lead to numbness, tingling or impaired 
muscle function), altered gait, rash, dry skin, changes in skin color, fever, urinary tract infection, 
hyponatremia (decreased sodium levels), abnormalities in liver enzymes that may indicate 
inflammation of or damage to the liver, allergic reaction, decreased white blood cells, and 
elevated triglycerides. One case of cough that got worse and notable shortness of breath leading 
to death has been reported by one patient with lung cancer, possibly related to INC280 in a trial 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 8 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
of INC280 combined with another anticancer medication. In addition, reports of inflammation of 
the lung tissue have occurred in patients receiving INC280, which may cause coughing and 
difficulty breathing. 
 
In preclinical experiments, INC280 absorbs light in the UVA-range (sunlight), and caused skin 
sensitization to sunlight in animals; it may be advisable not to sunbathe intensively or use a 
solarium intensively whilst taking INC280. 
In some ongoing clinical studies, an uncommon side effect of temporary hearing impairment has 
been observed in some patients treated with either INC280 single agent or combined with other 
anticancer medication. The majority of the events were mild to moderate in severity. 
It is important to report any side effects to the treatment team promptly so interventions can be 
initiated. This will help avoid stopping the drug due to side effects or hospitalizations. 
Blood sampling risks 
Taking blood may cause some discomfort, bleeding or bruising where the needle enters the body, 
and in rare cases, it may result in fainting.  There is a small risk of infection.  Some people have 
not felt well when having their blood taken.  Some people have felt dizzy while having their 
blood drawn or after.  Let the nurse know if you would prefer to lie down while you have your 
blood drawn. 
Biopsy risks 
The biopsy will be performed by physicians specially trained in the necessary procedures. We 
will only ask you to undergo the biopsies if we feel that the tumor can be easily accessed and 
there are no major risks associated with the procedure.  
 
The biopsy procedure usually causes only brief discomfort at the site from which the biopsy is 
taken.  Rarely, infection or bleeding may occur at the needle site. 
 
The biopsy may be done under CT guidance.  If that is the case, then this research study involves 
exposure to radiation from up to 2 CT scans.  This radiation exposure is not required for your 
medical care and is for research purposes only. The amount of radiation you will receive in this 
study is 1.6 rem which is below the guideline of 5 rem (or 0.5 rem in children) per year allowed 
for research subjects by the NIH Radiation Safety Committee.  The average person in the United 
States receives a radiation exposure of 0.3 rem per year from natural sources, such as the sun, 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 9 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
outer space, and the earth's air and soil.  If you would like more information about radiation, 
please ask the investigator for a copy of the pamphlet, An Introduction to Radiation for NIH 
Research Subjects. 
 
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer.  
 
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.  
 
If you are pregnant you will not be permitted to participate in this research study. If you are 
breast feeding and the protocol involves injection of radioactive material, you will not be 
permitted to participate.  It is best to avoid radiation exposure to unborn or nursing infants since 
they are more sensitive to radiation than adults.  
 
Eye examination risks 
 Dilating drops or anesthetic drops may sting. They can cause an allergic reaction, or if 
contaminated, can cause an infection, but neither of these problems is very likely to 
occur. Dilating drops can also cause a sudden increase of pressure (acute glaucoma) in 
eyes that are already predisposed to develop this condition. There is little risk of 
glaucoma being triggered in this way, but if it is, treatment is available. You will be 
tested at each eye examination to determine whether there is an increased risk of 
developing glaucoma. 
 Taking photographs of the retina (located at the back of your eye) will involve a bright 
flash. This brief flash may cause temporary discomfort but does not damage the eye. 
 In rare instances, the cornea (the transparent covering of the colored part of your eye) 
may be scratched during measurement of intraocular pressure or use of a contact lens 
during one of the exams. A corneal abrasion of this sort may be painful, but it heals 
quickly with no lasting effects. 
 Testing to determine how well you adapt to darkness may cause fatigue or loss of 
motivation or attention due to the length of the procedure (~ 2 – 3 hours) 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 10 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Other risks 
The side effects that may occur when INC280 is taken with other medicines or alcohol are 
unknown. Combining INC280 with other medicines and/or alcohol might result in serious 
reactions. Some over-the-counter and prescription medications can reduce the effectiveness or 
increase the side effects of INC280. INC280 can also increase the side effects or lessen the 
effectiveness of some over-the counter or prescription medications. Throughout the study, you 
should always discuss the use of alcohol or any medicines (over-the-counter, health food 
supplements, prescription, illegal) with the study doctor before taking INC280. In addition, some 
fruit and fruit juice/products (grapefruit and Seville orange juice) should be avoided while taking 
INC280, because they can possibly increase the side effects of INC280. 
Since INC280 is a new drug that is still in the early stages of being studied, problems or side 
effects that are not now known, including serious or life-threatening side effects or death, could 
also occur. You will be given any new information that may affect your willingness to start or 
continue in the study. 
Side Effects Diary 
You will be asked to keep a diary of any side effects, when they occurred, how long they lasted, 
and what if anything helped to relieve the side effect. This diary will be reviewed by the study 
team during each visit. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will cause your tumors to shrink.  
We do not know if you will receive personal, medical benefit from taking part in this study.    
These potential benefits could include shrinking or decreasing the growth of your tumor or 
lessening of your symptoms, such as pain, that are caused by the cancer.  Because there is not 
much information about the drug’s effect on your cancer, we do not know if you will benefit 
from taking part in this study, although the knowledge gained from this study may help others in 
the future who have cancer.   
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 11 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study. Some studies suggest 
that medications used in the more common (clear cell) form of kidney cancer such as 
sunitinib and temsirolimus may be beneficial in some patients with papillary kidney 
cancer and your oncologist may offer you treatment with one or more of these agents. 
• Taking part in another study 
• Continued observation or surgery, if appropriate 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 12 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
 
In the event that you are injured as a result of taking part in this study, Novartis will not pay any 
money to you or your medical bills. 
Will your medical information be kept private? 
For purposes of this study, NCI and Dr. Srinivasan will use medical information collected or 
created as part of the study, such as medical records and test results, which identifies you by 
name or in another way. Your consent to participate in the study means you agree that NCI and 
Dr. Srinivasan may obtain your medical information that they request for study purposes from 
your physicians and your other health care providers. You are also agreeing that NCI and Dr. 
Srinivasan may use and share this information with the parties described below. In addition, you 
agree that, during the study, you may not have access to some of your medical information 
obtained or created as part of this study. You will be allowed to access this information once the 
study is finished. 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• Governmental agencies in other countries where the study drug may be considered for 
approval 
• National Institutes of Health Intramural Review Board 
• Qualified representatives from Novartis, the pharmaceutical company who supplies 
INC280, or its authorized representatives. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 13 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your tumor grows during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
• if the company who makes the drug can no longer supply INC280 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Novartis or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed.  Unless and 
until you do withdraw your consent to participate in this study, it will remain valid and effective. 
Certificate of Confidentiality 
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 14 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using a drug developed 
by Novartis through a joint study with your researchers and the company.  The company also 
provides financial support for this study.  
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:     14-C-0037 
CONTINUATION: page 15 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  14-C-0037 
CONTINUATION: page 16 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action.   
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Ramaprasad Srinivasan, M.D., Ph.D.  Building 10, Room 2W-5940, 
Telephone:  240-760-6251. You may also call the Clinical Center Patient Representative at 301-
496-2626. If you have any questions about the use of your specimens or data for future research 
studies, you may also contact the Office of the Clinical Director, Telephone:  240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again.


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  14-C-0037 
CONTINUATION: page 17 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM MAY 26, 2021 THROUGH MAY 24, 2022.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name