untitled h1
untitled h2

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: | Novartis                   |
| Supplier:     |                            |  
Commercial Agents: None
untitled h1
precis 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
untitled h1
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.  
3  
| TABLE OF CONTENTS                                                                                                                                                        |                                                                                                                                                         |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS                                                                                                                                                                   |                                                                                                                                                         |
| TABLE OF CONTENTS ...............................................................................................................................4                       |                                                                                                                                                         |
| STATEMENT OF COMPLIANCE ...............................................................................................................................................9 |                                                                                                                                                         |
| 1 INTRODUCTION .                                                                                                                                                         |                                                                                                                                                         |
| 1.1                                                                                                                                                                      | Study Objectives .                                                                                                                                      |
| Primary Objective                                                                                                                                                        |                                                                                                                                                         |
| 1.1.1                                                                                                                                                                    | Secondary Objective(s)                                                                                                                                  |
| 1.1.2                                                                                                                                                                    |                                                                                                                                                         |
| 1.1.3                                                                                                                                                                    | Exploratory objective......................................................................................................................9            |
| 1.2                                                                                                                                                                      | Background and Rationale .............................................................................................................9                 |
| 1.2.1                                                                                                                                                                    | Overview of disease pathogenesis, epidemiology and current treatments ...............9                                                                  |
| Overview of INC280 ...................................................................................................................12                                 |                                                                                                                                                         |
| 1.2.2                                                                                                                                                                    |                                                                                                                                                         |
| 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                                                                                                                          |
| 2.5                                                                                                                                                                      | Baseline Evaluation                                                                                                                                     |
| 3 STUDY IMPLEMENTATION .                                                                                                                                                 |                                                                                                                                                         |
| 3.1                                                                                                                                                                      | Study Design                                                                                                                                            |
| 3.2                                                                                                                                                                      | Drug Administration                                                                                                                                     |
| Dose Modifications                                                                                                                                                       |                                                                                                                                                         |
| 3.3                                                                                                                                                                      |                                                                                                                                                         |
| 3.4                                                                                                                                                                      | Study Calendar ................................................................................................................................60       |
| 3.5                                                                                                                                                                      | Follow Up Evaluations                                                                                                                                   |
| 3.6                                                                                                                                                                      | Criteria for Removal from Protocol Therapy and Off Study Criteria................................64                                                     |
| Criteria for removal from protocol therapy ....................................................................64                                                        |                                                                                                                                                         |
| 3.6.1                                                                                                                                                                    |                                                                                                                                                         |
| 3.6.2                                                                                                                                                                    | OFF-Study Criteria                                                                                                                                      |
| Off Protocol Therapy and Off Study Procedure ................................................................65                                                          |                                                                                                                                                         |
| 3.6.3                                                                                                                                                                    | 4                                                                                                                                                       |  
| Version Date: February 14, 2022                                                                                                                    |                                                                                                                                                  |
|----------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| 4 CONCOMITANT MEDICATIONS/MEASURES ............................................................................65                                  |                                                                                                                                                  |
| Permitted Concomitant Therapy ....................................................................................................65               |                                                                                                                                                  |
| 4.1                                                                                                                                                |                                                                                                                                                  |
| 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                                                                                                         |
| 6 DATA COLLECTION AND EVALUATION .....................................................................................................72           |                                                                                                                                                  |
| 6.1                                                                                                                                                | DATA COLLECTION                                                                                                                                  |
| 6.2                                                                                                                                                | Response Criteria                                                                                                                                |
| 6.2.1                                                                                                                                              | Definitions                                                                                                                                      |
| 6.2.2                                                                                                                                              | Disease Parameters ...........................................................................................................................74 |
| 6.2.3                                                                                                                                              | Methods for Evaluation of Measurable Disease ..................................................................75                                |
| 6.2.4                                                                                                                                              | Response Criteria                                                                                                                                |
| 6.2.5                                                                                                                                              | D Duration of Response                                                                                                                           |
| 6.2.6                                                                                                                                              | Progression-Free Survival ..........................................................................................................79           |
| 6.3                                                                                                                                                | Toxicity Criteria                                                                                                                                |
| 7 NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN..........79                                                                           |                                                                                                                                                  |
| 7.1                                                                                                                                                | Definitions                                                                                                                                      |
| 7.2                                                                                                                                                | OHSRP Office of Compliance and Training/ IRB Reporting..............................................80                                           |
| Expedited Reporting  .................................................................................................................80           |                                                                                                                                                  |
| 7.2.1                                                                                                                                              |                                                                                                                                                  |
| 7.2.2                                                                                                                                              | IRB Requirements for PI Reporting at Continuing Review .........................................80                                               |
| 7.3                                                                                                                                                | NCI Clinical Director Reporting                                                                                                                  |
| 7.4                                                                                                                                                | NIH Required Data And Safety Monitoring Plan                                                                                                     |
| Principal Investigator/Research Team                                                                                                               |                                                                                                                                                  |
| 7.4.1                                                                                                                                              |                                                                                                                                                  |
| 8 SPONSOR PROTOCOL/SAFETY REPORTING                                                                                                                |                                                                                                                                                  |
| 8.1                                                                                                                                                | DEFINITIONS                                                                                                                                      |
| 8.1.1                                                                                                                                              | Adverse Event.........................................................................................................................80         |
| 8.1.2                                                                                                                                              | Serious Adverse Event (SAE) .................................................................................................81                  |
| 8.1.3                                                                                                                                              | Life-threatening ........................................................................................................................81      |
| 8.1.4                                                                                                                                              | SEVERITY                                                                                                                                         |
| S                                                                                                                                                  |                                                                                                                                                  |  
| Version Date: February 14, 2022                                                                                                                          |                                                                                                                                             |
|----------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|
| Relationship to Study Product ...................................................................................................81                      |                                                                                                                                             |
| 8.1.5                                                                                                                                                    |                                                                                                                                             |
| Assessment of Safety Events .............................................................................................................82              |                                                                                                                                             |
| 8.2                                                                                                                                                      | Reporting of Serious Adverse Events .............................................................................................82         |
| 8.3                                                                                                                                                      |                                                                                                                                             |
| 8.4                                                                                                                                                      | Safety Reporting Criteria to the Pharmaceutical Collaborators                                                                               |
| Reporting procedures                                                                                                                                     |                                                                                                                                             |
| 8.4.1                                                                                                                                                    | Pregnancies                                                                                                                                 |
| 8.4.2                                                                                                                                                    |                                                                                                                                             |
| 8.4.3                                                                                                                                                    | Ethics and Good Clinical Practice ..........................................................................................83              |
| Institutional Review Board/Independent Ethics Committee ........................................84                                                       |                                                                                                                                             |
| 8.4.4                                                                                                                                                    |                                                                                                                                             |
| Reporting Pregnancy                                                                                                                                      |                                                                                                                                             |
| 8.5                                                                                                                                                      |                                                                                                                                             |
| 8.5.1                                                                                                                                                    | Maternal exposure ...................................................................................................................84     |
| 8.5.2                                                                                                                                                    | Paternal exposure                                                                                                                           |
| Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND..................84                                                                   |                                                                                                                                             |
| 8.6                                                                                                                                                      | Sponsor Protocol Non-Adherence Reporting .............................................................................85                    |
| 8.7                                                                                                                                                      |                                                                                                                                             |
| 9 CLINICAL MONITORING ................................................................................................................................85 |                                                                                                                                             |
| 10 STATISTICAL CONSIDERATIONS                                                                                                                            |                                                                                                                                             |
| Evaluation of Endpoints ...............................................................................................................85                |                                                                                                                                             |
| 10.1                                                                                                                                                     |                                                                                                                                             |
| 10.2                                                                                                                                                     | Evaluation of Secondary Endpoints ........................................................................................86                |
| 10.3                                                                                                                                                     | Sample Size Calculation                                                                                                                     |
| 1 COLLABORATIVE AGREEMENTS .......................................................................................................86                     |                                                                                                                                             |
| 1.1                                                                                                                                                      | A A REEMENT TYPE                                                                                                                            |
| 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                                                                                            |
| 12.4                                                                                                                                                     | Evaluation of Benefits and Risks/Discomforts ..................................................................87                           |
| 12.4.1                                                                                                                                                   | Benefits .                                                                                                                                  |
| 12.4.2                                                                                                                                                   | Risks                                                                                                                                       |
| 12.5                                                                                                                                                     | Risks/Benefits Analysis                                                                                                                     |
| 12.6                                                                                                                                                     | Consent Process and Documentation ......................................................................................88                  |
| 12.6.1                                                                                                                                                   | Telephone Re-Consent Procedure ...........................................................................................88                |
| Discontinuation of Study Support .................................................................................................88                     |                                                                                                                                             |
| 12.7                                                                                                                                                     |                                                                                                                                             |
| 12.8                                                                                                                                                     | Amendments to the Protocol ...........................................................................................................88    |
| 12.8.1                                                                                                                                                   | Publication of results ..................................................................................................................89 |
| 6                                                                                                                                                        |                                                                                                                                             |  
| Version Date: February 14, 2022                                                                                                   |                                                                                                                                               |
|-----------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|
| 12.8.2                                                                                                                            | Disclosure and confidentiality ................................................................................................89             |
| 12.8.3                                                                                                                            | Declaration of Helsinki                                                                                                                       |
| 13 REGULATORY AND OPERATIONAL CONSIDERATIONS .....................................................89                              |                                                                                                                                               |
| 13.1                                                                                                                              | Study Discontinuation and Closure                                                                                                             |
| 13.2                                                                                                                              | Quality Assurance and Quality Control ...............................................................................90                       |
| 13.3                                                                                                                              | Conflict of Interest Policy ......................................................................................................90          |
| 13.4                                                                                                                              | Confidentiality and Privacy .                                                                                                                 |
| 14 PHARMACEUTICAL INFORMATION                                                                                                     |                                                                                                                                               |
| INC280 (IND # 119133) .........................................................................................................91 |                                                                                                                                               |
| 14.1                                                                                                                              |                                                                                                                                               |
| 14.1.1                                                                                                                            | Source, packaging and labeling ............................................................................................91                 |
| 14.1.2                                                                                                                            | Supply, receipt and storage                                                                                                                   |
| 14.1.3                                                                                                                            | Toxicity:..................................................................................................................................92 |
| 14.1.4                                                                                                                            | Administration procedures                                                                                                                     |
| 14.1.5                                                                                                                            | Incompatibilities .....................................................................................................................94     |
| Drug compliance and accountability ................................................................................94             |                                                                                                                                               |
| 14.1.6                                                                                                                            | Disposal and destruction                                                                                                                      |
| 14.1.7                                                                                                                            |                                                                                                                                               |
| 15 REFERENCES                                                                                                                     |                                                                                                                                               |
| 16 APPENDICES                                                                                                                     |                                                                                                                                               |
| Appendix A: Performance Status Criteria.............................................................................9             |                                                                                                                                               |
| 16.1                                                                                                                              |                                                                                                                                               |
| 16.2                                                                                                                              | Appendix B:  Patient's Pill/ Side Effects Diary .............................................................100                              |
| 16.3                                                                                                                              | Appendix C: Instruction Sheet for INC 280.....................................................................102                             |  
| Version Date: February 14, 2022  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   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
untitled h1
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.
untitled h1
1 introduction 1.1 study objectives

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
untitled h1
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 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.  
  
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).  
  
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 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)
untitled h1
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. 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 METdependent 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 tumorbearing 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.
untitled h1
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 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. Melanincontaining 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.
untitled h1
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.
untitled h1
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 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.  
| Population                                      |                                                                                                                                                                                               |                                                                                                                                                                                                                               |                                                                             |                                 |
|-------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------|---------------------------------|
| Study                                           | (No. of  enrolled  subjects /patients)                                                                                                                                                        | No of  subjects  exposed to  INC280                                                                                                                                                                                           | Study Title                                                                 | Dose / Frequency /  Formulation |
| CINCB28060-101 (Novartis code [CINC280X2101T ]) | 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 |                                 |
| N=45/45                                         | 45                                                                                                                                                                                            | A Phase 1, open-label, dose                                                                                                                                                                                                   |                                                                             |                                 |
| patients                                        | 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: 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 |                                                                             |                                 |  
Table 1-1: Summary of human study  
| Version Date: February 14, 2022  Population  Study (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 wildtype (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                                                                               | N=7 patients                                                                            | 7                                                                                  | A Phase II open-label                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                           |
| T]                                                                                          | 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 |                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                           |  
| Version Date: February 14, 2022  Population  Study (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                                                                               | N=15 patients                                                                                                                                                                                                                                                                                                                                                                       | 15            | A Phase Ib/II, multicenter,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| C]                                                                                          | 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 |  
| Version Date: February 14, 2022  Population  Study (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                                                                               | N=23 patients                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | 23            | A Phase Ib/II open-label                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| T]                                                                                          | 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)                                                                                                                                           |  
| Version Date: February 14, 2022  Population  Study (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                                                                                                                                                                                                                                                                                                                    | 24                                                                                                                                                       | A randomized, open-label,         |
| healthy subjects                                                                            | 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                                                                                                                                                                                                                                                                                                              | 6                                                                                                                                                        | A single-center, open-label       |
| subjects                                                                                    | 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                                                                                                                                                                                                                                                                                                                    | 24                                                                                                                                                       | A randomized, singlecenter, open-label, threeperiod, six sequence,                                   |
| healthy subjects                                                                            | 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/highfat meal) separated by a 7- day washout between each  treatment                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                          |                                   |  
| Version Date: February 14, 2022  Population  Study (No. of  enrolled  subjects /patients)   | No of  subjects  exposed to  INC280                                                                                                                                                         | Study Title   | Dose / Frequency /  Formulation                                                                                                                                                                                                                                                                             |
|---------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| [CINC280A2101]                                                                              | N=20/20                                                                                                                                                                                     | 20            | A single center, open-label,                                                                                                                                                                                                                                                                                |
| healthy subjects                                                                            | 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).  
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  
| 10 mg QD  20 mg QD  50 mg QD  70 mg QD  50        | mg       |          |           |            |           |          |           |          |           |          |           |           |
|---------------------------------------------------|----------|----------|-----------|------------|-----------|----------|-----------|----------|-----------|----------|-----------|-----------|
| MedDRA Preferred Term (n=3)                       | (n=4)    | (n=6)    | (n=4)     | BID  (n=3) | 150       | mg  200  | mg  300   | mg  400  | mg  200   | mg  300  | mg        |           |
| QD (n=3) QD (n=4) QD (n=4) QD (n=6) BID (n=4) BID | Total    |          |           |            |           |          |           |          |           |          |           |           |
| (n=4)                                             | (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)   |  
| 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  1 (33.3) | 0             | 0             | 0             | 1 (33.3)      | 0        | 2 (75.0) | 0        | 2 (75.0)                     | 0        | 1 (25.0) | 0     |
| increased 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     |  
Table 1-3: Adverse events (greater than or equal to 5%) suspected to be related to study treatment in study [CINC280X1101]  
| Version Date: February 14, 2022          | 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        |       |  
| 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  All grades n  Grade 3/4  All grades n  Grade 3/4  All grades n  Grade 3/4  All grades  Grade 3/4  (%) n (%) (%) n (%) (%) n (%) (%) n (%) n (%) 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  0                                                                                                                                                                  | 0                                 | 1                                 | (20.0) | 0      | 0       | 0  | 1      | (33.3) | 0      | 0      | 0      |        |        |        |        |        |    |        |
| Increased 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      |        |        |        |        |        |    |        |  
Table 1-4: Adverse events (greater than or equal to 5%) suspected to be related to study treatment in study [CINC280X2102]  
| INC280 600 mg BID Capsules - All   | INC280 400 mg BID Capsules - All  All patients   |                 |                  |                 |                  |                 |       |        |        |        |       |       |
|------------------------------------|--------------------------------------------------|-----------------|------------------|-----------------|------------------|-----------------|-------|--------|--------|--------|-------|-------|
| N=63                               | N=30                                             | 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  6                              | (9.5)           | 1                | (1.6)           | 3                | (10.0)          | 1     | (3.3)  | 11     | (9.3)  | 3     | (2.5) |
| Increased 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)  |       |       |  
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  0                              | 0                 | 0                 | 0                 | 1 (16.7)           | 0         | 1 (14.3)   | 0         | 1 (25.0)   | 0         |          |
| Increased 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  0     | 0                 | 0                 | 0                  | 0         | 0          | 0         | 0          | 0         | 0        |
| Increased 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        |  
| Dose of INC280 in combination with 250 mg QD gefitinib   |                                                |                |                                                  |          |          |          |                        |           |          |                            |                   |          |                   |         |
|----------------------------------------------------------|------------------------------------------------|----------------|--------------------------------------------------|----------|----------|----------|------------------------|-----------|----------|----------------------------|-------------------|----------|-------------------|---------|
| BID 400 mg Cap - P1b                                     | BID 400 mg Cap -  BID 600 mg Cap               | BID 200 mg Tab | BID 400 mg Tab -  BID 400 mg Tab -  All patients |          |          |          |                        |           |          |                            |                   |          |                   |         |
| P2                                                       | P1b                                            | P2             |                                                  |          |          |          |                        |           |          |                            |                   |          |                   |         |
| 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                                          | 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) |
| Increased 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  2 (16.7)                               | 0                                              | 5 (9.6)        | 0                                                | 0        | 0        | 1 (14.3) | 0                      | 0         | 0        | 2 (6.7)                    | 0                 | 10 (7.0) | 0                 |         |
| Increased                                                |                                                |                |                                                  |          |          |          |                        |           |          |                            |                   |          |                   |         |  
| BID 400 mg Cap - P1b   | BID 400 mg Cap -  BID 600 mg Cap   | BID 200 mg Tab   | BID 400 mg Tab -  BID 400 mg Tab -  All patients   |        |       |        |          |        |       |          |                   |         |         |       |
|------------------------|------------------------------------|------------------|----------------------------------------------------|--------|-------|--------|----------|--------|-------|----------|-------------------|---------|---------|-------|
| P2                     | P1b                                | P2               |                                                    |        |       |        |          |        |       |          |                   |         |         |       |
| 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             | 1 (8.3)                            | 0                | 0                                                  | 0      | 0     | 0      | 2 (28.6) | 0      | 0     | 0        | 2 (6.7)           | 0       | 9 (6.3) | 0     |
| Acneiform Pruritus     | 1 (8.3)                            | 0                | 2 (3.8)                                            | 0      | 0     | 0      | 0        | 0      | 0     | 0        | 2 (6.7)           | 0       | 9 (6.3) | 0     |  
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        |
| 30                                   |                   |                     |           |            |           |          |  
| 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     |  
Table 1-7: Adverse events (greater than or equal to 5%) suspected to be related to study treatment in study [CINC280X2204]  
| 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                                               | 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                                            | 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  1 (20.0) 0                      | 1 (16.7) 1                                        | 1                                                 | 1                                                 | 0                                                 | 0          | 2 (28.6) 1 | 4          | 3                 | 9 (27.3) 6   |            |        |       |       |
| Increased                                         | (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)                                            |                                                   |                                                   |                                                   |                                                   |            |            |            |                   |              |            |        |       |       |  
All patients 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                                               | 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 (%) |
| 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)                                            |                                                   |                                                   |                                                   |                                                   |                                                   |            |            |            |            |        |                  |            |         |       |  
| 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                                             | 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 (%) |
| 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)                                          |                                                 |                                                 |                                                 |                                                 |                                                 |            |       |            |            |        |         |         |         |       |  
| 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                                             | 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 (%) |
| 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)                                          |                                                 |                                                 |                                                 |                                                 |                                                 |            |            |            |       |        |         |         |       |       |
untitled h1
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].