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

| TABLE OF CONTENTS                                                                                                                      |                                                                                                                                                        |
|----------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA                                                                                                                                 |                                                                                                                                                        |
| 1.                                                                                                                                     | OBJECTIVES .                                                                                                                                           |
| 1.1                                                                                                                                    | Study Design .                                                                                                                                         |
| 1.2                                                                                                                                    | Primary Objectives                                                                                                                                     |
| 1.3                                                                                                                                    | Secondary Objectives                                                                                                                                   |
| 2.                                                                                                                                     | BACKGROUND ..........................................................................................................................................6 |
| 2.1                                                                                                                                    | Non-small cell lung cancer ..................................................................................................6                         |
| 2.2                                                                                                                                    | INC280                                                                                                                                                 |
| 2.3                                                                                                                                    | Rationale for this study ..................................................................................................................7           |
| 2.4                                                                                                                                    | Correlative Studies Background .........................................................................................10                             |
| 3.                                                                                                                                     | PARTICIPANT SELECTION                                                                                                                                  |
| 3.1                                                                                                                                    | Eligibility Criteria ....................................................................................................................10            |
| 3.2                                                                                                                                    | Exclusion Criteria ....................................................................................................................12              |
| 3.3                                                                                                                                    | Inclusion of Women and Minorities .................................................................................14                                  |
| 4.                                                                                                                                     | REGISTRATION PROCEDURES ....................................................................................................14                         |
| 4.1                                                                                                                                    | General Guidelines for DF/HCC Institutions .................................................................14                                         |
| 4.2                                                                                                                                    | Registration Process for DF/HCC Institutions                                                                                                           |
| 4.3                                                                                                                                    | General Guidelines for Other Investigative Sites ........................................................15                                            |
| 4.4                                                                                                                                    | Registration Process for Other Investigative Sites                                                                                                     |
| 5.                                                                                                                                     | TREATMENT PLAN.............................................................................................................................15          |
| 5.1                                                                                                                                    | T Treatment Regimen                                                                                                                                    |
| 5.2                                                                                                                                    | Pre-Treatment Criteria .....................................................................................................15                         |
| 5.3                                                                                                                                    | Agent Administration                                                                                                                                   |
| General Concomitant Medication and Supportive Care Guidelines                                                                          |                                                                                                                                                        |
| 5.4                                                                                                                                    |                                                                                                                                                        |
| Concomitant medications                                                                                                                |                                                                                                                                                        |
| Permitted concomitant therapy ......................................................................................................17 |                                                                                                                                                        |
| 5.5                                                                                                                                    | Criteria for Taking a Participant Off Protocol Therapy.............................................20                                                  |
| 5.6                                                                                                                                    | Duration of Follow Up                                                                                                                                  |
| 5.7                                                                                                                                    | Criteria for Taking a Participant Off Study ....................................................................21                                     |
| DOSING DELAYS/DOSE MODIFICATIONS .                                                                                                     |                                                                                                                                                        |
| 6.                                                                                                                                     |                                                                                                                                                        |
| 7.                                                                                                                                     | ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .............................31                                                                       |
| 7.1                                                                                                                                    | Adverse Events ..................................................................................................................31                    |
| 7.2                                                                                                                                    | Adverse Event Characteristics .......................................................................................38                                |
| 7.3                                                                                                                                    | Expedited Adverse Event Reporting                                                                                                                      |
| 7.4                                                                                                                                    | Expedited Reporting to the Food and Drug Administration (FDA) .......................42                                                                |
| 7.5                                                                                                                                    | Expedited Reporting to Hospital Risk Management ..................................................43                                                   |
| 7.6                                                                                                                                    | Routine Adverse Event Reporting ...............................................................................43                                      |  
| DF/HCC Protocol #:16-019                                                                                           |                                                                                                                                           |
|--------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------|
| Protocol Version Date: August 6, 2019                                                                              |                                                                                                                                           |
| 8.                                                                                                                 | PHARMACEUTICAL INFORMATION                                                                                                                |
| 8.1                                                                                                                | INC280                                                                                                                                    |
| 9.                                                                                                                 | BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .............................................45                                               |
| 9.1                                                                                                                | Biomarker Studies                                                                                                                         |
| 10.                                                                                                                | STUDY CALENDAR ...................................................................................................................46      |
| 11.                                                                                                                | MENT OF EFFECT........................................................................................................48                  |
| Antitumor Effect - Solid Tumors ................................................................................48 |                                                                                                                                           |
| 11.1                                                                                                               |                                                                                                                                           |
| 11.2                                                                                                               | Antitumor Effect - Hematologic Tumors                                                                                                     |
| 1.3                                                                                                                | O OTHER RESPONSE PARAMETERS                                                                                                               |
| 12.                                                                                                                | DATA REPORTING / REGULATORY REQUIREMENTS ................................................................55                               |
| 12.1                                                                                                               | DATA Reporting .                                                                                                                          |
| 12.2                                                                                                               | Data Safety Monitoring                                                                                                                    |
| 12.3                                                                                                               | Multicenter Guidelines                                                                                                                    |
| Collaborative Agreements Language                                                                                  |                                                                                                                                           |
| 12.4                                                                                                               |                                                                                                                                           |
| 13.                                                                                                                | STATISTICAL CONSIDERATIONS                                                                                                                |
| 13.1                                                                                                               | Study Design/Endpoints..............................................................................................................57    |
| 13.2                                                                                                               | Sample Size, Accrual Rate and Study Duration .............................................................58                              |
| 13.3                                                                                                               | Stratification Factors                                                                                                                    |
| 13.4                                                                                                               | Interim Monitoring Plan ...............................................................................................................58 |
| 13.5                                                                                                               | Analysis of Primary Endpoints ..................................................................................................58        |
| 13.6                                                                                                               | Analysis of Secondary Endpoints ............................................................................................58            |
| 13.7                                                                                                               | Reporting and Exclusions ..............................................................................................................58 |
| 14.                                                                                                                | PUBLICATION PLAN .                                                                                                                        |
| REFERENCES .                                                                                                       |                                                                                                                                           |
| APPENDIX A                                                                                                         | PERFORMANCE STATUS CRITERIA ........................................................63                                                    |
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1. objectives

This is an open label phase II study of INC280 among patients with non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations (METex14) or MET amplification who have previously been on MET inhibitor therapy. The primary objective is to assess the objective response rate to INC280 among patients with METex14 or MET amplification who have previously been treated with a MET inhibitor. Secondary endpoints will include progressionfree survival (PFS), disease control rate (DCR), intracranial response rate (IRR), duration of response (DOR), overall survival (OS), and safety and tolerability. In addition, exploratory analyses will be performed on archival tumor tissue as well as on tumor biopsies and circulating tumor DNA to analyze potential biomarkers of response and resistance to INC280.
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1.1 study design

This is a phase II study with the primary objective of assessing objective response rate to INC280 among patients with non-small cell lung cancer with METex14 or MET amplification who have previously been on MET inhibitor therapy. Secondary endpoints will include PFS, DCR, IRR, DOR, OS, and safety and tolerability. In addition, exploratory analyses will analyze potential biomarkers of response and resistance to INC280.
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1.2 primary objectives

Primary Objective: To assess the objective response rate in patients with lung cancer with METex14 or MET amplification with prior exposure to MET inhibitor therapy, when treated with INC280
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1.3 secondary objectives secondary objectives

1. To assess progression-free survival (PFS), disease control rate (DCR), intracranial response rate (IRR), and duration of response (DOR) in patients with lung cancer with METex14 or MET amplification with prior exposure to MET inhibitor therapy, when treated with INC280 2. To assess overall survival (OS) in patients with lung cancer with METex14 or MET
amplification with prior exposure to MET inhibitor therapy, when treated with INC280 3. To assess safety and tolerability of INC280 among patients with lung cancer with METex14 or MET amplification treated with INC280.
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exploratory objectives

1. To explore potential biomarkers of response and resistance to INC280 2. To explore co-occurrence of METex14 with MET amplification, *MDM2* amplification, and *CDK4* amplification, among others, and impact on response 3. To generate PDX and cell line models to explore the biology underlying sensitivity and
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2. background 2.1 non-small cell

Lung cancer remains the leading cause of cancer related death in the United States [1].  
Standard therapy for Stage IV non-small cell lung cancer (NSCLC) involves platinum-based chemotherapy regimens as first-line therapy, and incremental improvements in chemotherapies for lung cancer have led to a median overall survival of over a year [2-3]. However, the most dramatic successes in lung cancer have been seen with genotype-guided treatment. Driver genetic alterations such as *EGFR* activating mutations, and ALK and ROS translocations, among others, have been identified that are targets for therapy in lung cancer [4-7]. Targeted treatment of these oncogenic drivers has resulted in markedly higher response rates and survival compared to what is typically seen with conventional therapies [8-11]. Increasingly, lung cancer is becoming subdivided into molecular subsets with different treatment options depending on the molecular diagnostics of the cancer. Somatic mutations in MET that affect the splice sites of exon 14 (METex14) are emerging as a targetable alteration in lung cancer which is present in 34% of NSCLC [12-23] and are further discussed below in Section 2.3. In addition, MET amplification is another known targetable alteration reported in 2-4% of NSCLC [24]. This study investigates the activity of the MET inhibitor INC280 in patients with NSCLC with METex14 or MET amplification who have previously received another MET inhibitor therapy. INC280 is a potent ATP competitive and reversible inhibitor of the c-MET kinase
([IC]50 in a biochemical assay = 0.13 ± 0.05 nM). INC280 is highly specific for c-MET with a greater than 10,000-fold selectivity over a panel of 56 other human kinases tested. Potent activity has also been observed in cell-based biochemical and functional assays that measure c-MET-mediated signal transduction, as well as c-MET-dependent cell proliferation, survival, and migration. In c-MET/HGF-driven tumor models grown as xenografts in mice, oral dosing of INC280 demonstrated significant in *vivo* activity in blocking both c-MET phosphorylation and tumor growth.  
6 After oral administration in humans, INC280 is rapidly absorbed. The apparent terminal half-life of INC280 is short to moderate, from 1.5 to 6 hours across studies. Steady state INC280 exposure is expected to be reached by the third day of consecutive dosing. Accumulation of INC280 following repeated administration is low with accumulation ratio of up to 3-fold. Median time to peak plasma concentrations is reached at approximately 2 hours (Tmax ranged from 0.5 to 8.1 h across studies). Solubility of INC280 is pH-dependent. Solubility of INC280 is high at pH 1.0 (>5 mg/mL) and low (~0.002 mg/mL) at pH 6.9 and pH 7.4. INC280 has been studied in multiple phase 1 and 2 trials, both as a single agent and in combination with other drugs. For detailed information please refer to the Investigator's Brochure. Of note in a phase 1 study in patients with c-MET dependent advanced solid tumors with an expansion part in HCC, gastric cancer, NSCLC, and PRCC and other solid tumors, INC280 showed preliminary signs of antitumor activity in the NSCLC expansion arm with three out of six patients having confirmed partial response; all patients were EGFR wildtype and had high MET status by immunohistochemistry or fluorescent *in-situ* hybridization [25].
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2.3 rationale for this study

Somatic mutations in MET that affect the splice sites of exon 14 (METex14) are a targetable alteration in lung cancer which is present in 3-4% of NSCLC [12-23]. These mutations are predominantly in the intronic segments and lead to an alternatively spliced transcript of MET in which deletion of the juxtamembrane domain results in the loss of the Cbl E3-ligase binding site [13]. The alternatively spliced MET receptor exhibits decreased ubiquitination and delayed downregulation, leading to prolonged activation of MET and MAPK/ERK pathway which is transforming [13,17]. In a retrospective study of 240 lung cancer cases at Massachusetts General Hospital, we found 11 cases of METex14 [19]. Similar to other reports, most of these occurred in the absence of other driver alterations, supporting the notion that this is a driver event. Although potentially enriched among never smokers who are wildtype for other driver mutations, METex14 is found in smokers as well, and appears to be present across all lung histologies [19].  
Preclinical data have shown that METex14 is a transforming event that can respond well to MET inhibition [13, 17]. Kong-Beltran showed prolonged phosphorylation of MET and MAPK with stimulation by HGF in a cell line with METex14, and increased cell proliferation, which was inhibited by treatment with a MET inhibitor [13]. Frampton et al showed that human METex14 and the homologous mouse MET exon 15 skipping alteration is transforming in cell lines, at least partly through activation of the MEK/ERK pathway. A mouse model of the homologous exon 15 deletion in MET showed sensitivity to MET inhibition with INC280 [17] (see Figure 1).  
  
Figure 1. In line with these preclinical studies, recent reports have shown promising clinical activity among patients with METex14 treated with MET inhibitors including crizotinib, cabozantinib, and INC280 [17-23]. Paik et al reported on 4 patients with METex14 who were treated with MET inhibitors; three with crizotinib and one with cabozantinib. These patients all experienced significant regression of their tumor burden on the MET therapy [18]. Frampton et al reported on one patient who responded to crizotinib, and two pts who were treated on a phase 1 study of INC280 who also demonstrated a partial response to therapy [17]. Other case reports have shown similar marked responses [19-23]. Table 1 shows a summary of the reported cases in the literature which have shown response to MET therapy. Reported durations on therapy are preliminary in nature but range from approximately 3 months to 13 months. Table 1. Summary of case reports of patients with METex14 and responses to MET Rx  
| METex14               | MET amplification   | Other alterations               | Drug         | Age   | Sex   | Smoking   | Hist        | Ref   |
|-----------------------|---------------------|---------------------------------|--------------|-------|-------|-----------|-------------|-------|
| c.3028G>C             | MET amp             | MDM2 amp and                    | cabozantinib | 80    | F     | Never     | Adeno       | 18    |
| multiple others       |                     |                                 |              |       |       |           |             |       |
| c.3024_3028delAGAA    | No amp              | multiple                        | crizotinib   | 78    | M     | Former    | Adeno       | 18    |
| GGTATATT              | IHC H Score 300     |                                 |              |       |       |           |             |       |
| c.3028+1G>T           | MET amp             | multiple                        | crizotinib   | 65    | M     | Former    | Adeno       | 18    |
| IHC n/a               |                     |                                 |              |       |       |           |             |       |
| c.3028G>C             | No amp              | CDK4 amp,                       | crizotinib   | 90    | F     | Never     | Adeno       | 18    |
| IHC H score 300       | MDM2 amp            |                                 |              |       |       |           |             |       |
| c.2888-5_2944del62    | n/a                 | TP53                            | crizotinib   | 84    | F     | Never     | Histiocytic | 17    |
| ZMYM3                 | sarcoma             |                                 |              |       |       |           |             |       |
| c.3028G>C             | FISH not done       | TP53                            | INC280       | 82    | F     | Former    | Large cell  | 17    |
| 3+IHC                 |                     |                                 |              |       |       |           |             |       |
| c.3028+1G>T           | copy number 4;      | None reported                   | INC280       | 66    | F     | Former    | Squamous    | 17    |
| MET:CEP7 2.3          |                     |                                 |              |       |       |           |             |       |
| c.3028 G>A            | Borderline          | Snapshot wt                     | crizotinib   | 73    | M     | Former    | Squamous    | 19    |
| MET:CEP7 2.2          |                     |                                 |              |       |       |           |             |       |
| c.3028G>C             | n/a (presume neg,   | MDM2 amp                        | crizotinib   | 76    | F     | Former    | Squamous    | 20    |
| Foundation)           |                     |                                 |              |       |       |           |             |       |
| Chr7:g.116412043G>C   | No amp              | n/a                             | crizotinib   | 71    | M     | Former    | Adeno       | 21    |
| MET/CEP7 0.96         |                     |                                 |              |       |       |           |             |       |
| c.2887-18>2887-7del12 | n/a                 | CDKN2A/B loss CDK4 amp MDM2 amp | crizotinib   | 86    | M     | Never     | Adeno       | 22    |
| Intron 14 +3 A>G      | 9 copies            | n/a                             | crizotinib   | 74    | F     | Former    | Sarcomatoid | 23    |  
In addition to MET exon 14 skipping, MET amplification is known to occur in NSCLC
and may be targetable as well. Among 13 patients with MET amplified NSCLC enrolled in a clinical trial of crizotinib, 1 had low level amplification (MET/CEP7 ratio 1.8-2.2), 6 had intermediate level amplification (MET/CEP7 ratio 2.2 - 5), and 6 had high level amplification (MET/CEP7 ratio >5). Partial responses were observed in 4/13 patients (33%, 95% CI 10,65), with none (0/1) observed in the low amplification group, 1/6 (20%) in the intermediate amplification group, and 3/6 (50%) in the high amplification group. [26]
At Massachusetts General Hospital (MGH), we have been performing genotyping of tumors of patients with lung cancer as part of standard clinical care since 2009 [27]. Our current version of the SNaPshot genotyping panel tests for METex14, which previously was challenging to find due to their predominant location in the intronic segments of the gene. In addition, MET amplification is captured on our panel as well. Currently, all patients with lung cancer at MGH are tested reflexively for genetic mutations using the targeted next generation SNaPshot assay for point mutations and the targeted next generation translocation assay for rearrangements.  
We propose a phase II study investigating the activity of INC280 in patients with METex14 or MET amplification who have previously received a MET inhibitor, to assess for activity in the setting of resistance. Other ongoing studies are already investigating the activity of INC280 in the first-line setting for METex14. The ability of ceritinib and alectinib to overcome resistance to crizotinib in ALK rearranged lung cancer [10, 28] points to the feasibility of a more potent drug being able to overcome acquired resistance. As there will be patients who have previously received other MET inhibitors such as crizotinib or cabozantinib, it will be important to know whether INC280 has activity in the setting of prior MET inhibitor therapy.
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2.4 correlative studies background

MGH has an active investigational program studying response and resistance to targeted therapies in lung cancer led by the Engelman lab [29-31]. Patients who respond to a targeted therapy and become resistant are routinely biopsied and investigations including repeat molecular testing as well as creation of cell line and xenograft models are utilized to interrogate the tumor for mechanisms of resistance. This collaborative framework will be utilized in this trial to study response and resistance mechanisms from biopsy samples of patients on this study. To date there is a dearth of cell line and PDX models for METex14; we will attempt to generate such model systems for study. In addition, *MET, MDM2*, and *CDK4* amplification have all been reported to co-exist with METex14 [17-18], but the relevance to response or resistance is not known. We will therefore explore the co-occurrence of these amplification events among the patients with METex14 enrolled in our study, and explore whether there is any preliminary signal of responsiveness or resistance depending on these co-alterations.
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3. participant selection 3.1 eligibility

1. Written informed consent must be obtained prior to any screening procedures. 2. Age ≥ 18 years 3. Histologically or cytologically confirmed non-small cell lung cancer, advanced, recurrent, or metastatic
4. MET exon 14 skipping alteration or MET amplification (MET:CEP7 ratio > 1.8) by molecular testing (local testing is accepted for eligibility; all patients will have confirmation at MGH but this result is not necessary for eligibility; local molecular pathology result will suffice). This testing can be from any archival or fresh sample.  
5. Must have received prior platinum containing chemotherapy for advanced/metastatic nonsmall cell lung cancer, or have refused or be ineligible for such therapy. Prior neoadjuvant/adjuvant platinum containing chemotherapy will count has having received prior platinum, provided that disease recurred within 6 months of completion of neoadjuvant/adjuvant therapy.  
6. EGFR and ALK status must be known in all patients with adenocarcinoma histology.  
Patients with activating EGFR mutations or ALK translocations are excluded from this study, unless disease has progressed on all available, approved therapies targeting these alterations.  
7. At least one measurable lesion as defined by RECIST 1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation.  
8. Must have received prior therapy with a MET inhibitor. Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.0). Patients with any grade of alopecia are allowed to enter the study.  
9. Patients must have adequate organ function including the following laboratory values at the screening visit:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support - Platelets ≥ 75 x 109/L
- Hemoglobin (Hgb) > 9 g/dL - Serum creatinine < 1.5 x ULN or calculated creatinine clearance (using Cockcroft-Gault formula) > 45 mL/min for patients with creatinine levels > 1.5 x ULN
- Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert's syndrome, who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
- Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, who are included if AST ≤ 5 x ULN
- Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, who are only included if ALT ≤ 5 x ULN
- Alkaline phosphatase (ALP) ≤ 5.0 x ULN - Asymptomatic serum amylase ≤ grade 2 and asymptomatic serum lipase < grade 2.  
Patients with grade 1 or grade 2 serum amylase or lipase at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
- Patients must have the following laboratory values within the laboratory normal limits or corrected to within normal limits with supplements during screening:
- Potassium
- Magnesium
- Phosphorus
- Total calcium (corrected for serum albumin)
10. ECOG performance status (PS) of 0 or 1 11. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
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3.2 exclusion criteria

1. Patients with known hypersensitivity to any of the excipients of INC280 (crospovidone, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and various coating premixes).  
2. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms 3. Presence or history of a malignant disease other than disease to be treated in current protocol that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, indolent malignancies that currently do not require treatment, and completely resected carcinoma in situ of any type 4. Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis
5. Clinically significant, uncontrolled heart diseases.  
- Unstable angina within 6 months prior to screening
- Myocardial infarction within 6 months prior to screening - History of documented congestive heart failure (New York Heart Association functional classification III-IV)
- Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication. Initiation or adjustment of antihypertensive medication (s) is allowed prior to screening
- Ventricular arrhythmias
- Supraventricular and nodal arrhythmias not controlled with medication
- Other cardiac arrhythmia not controlled with medication
- QTcF > 480 msec 6. Thoracic radiotherapy to lung fields ≤ 4 weeks prior to starting INC280 or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks prior to starting INC280 or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting INC280 is allowed  
7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting INC280 or who have not recovered from side effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and patients can be enrolled in the study ≥ 1 week after the procedure 8. Patients receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with INC280 and for the duration of the study:
- Strong and moderate inhibitors of CYP3A4
- Strong inducers of CYP3A4
- Proton pump inhibitors (PPI)
9. Impairment of GI function or GI disease that may significantly alter the absorption of INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
10. Unable or unwilling to swallow tablets as per dosing schedule  
11. Patients receiving unstable or increasing doses of corticosteroids. If patients are on corticosteroids for endocrine deficiencies or tumor-associated symptoms other than CNS related, dose must have been stabilized (or decreasing) for at least 5 days before first dose of INC280 12. Patients receiving treatment with any enzyme-inducing anticonvulsant that cannot be discontinued at least 1 week before first dose of INC280, and for the duration of the study. Patients on non-enzyme-inducing anticonvulsants are eligible 13. Previous anti-cancer and investigational agents within 2 weeks before first dose of INC280.  
If previous treatment is a small molecule TKI, last dose must be at least 7 days before first dose of INC280. A shorter washout period may be allowed after discussion with the Principal Investigator.  
14. Other severe, acute, or chronic medical or psychiatric conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation, or that may interfere with the interpretation of study results 15. Any other condition that would, in the Investigator's judgment, contraindicate patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc.  
16. Pregnant or nursing women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test 17. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 30 days after stopping treatment. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the subject.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
- Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject
- Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate ≤ 1%), for example hormone vaginal ring or transdermal hormone contraception b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.  
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential 18. Sexually active males unless they use a condom during intercourse while taking drug and for 7 days after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. For males with female partners of childbearing potential, couples must use highly effective means of contraception while taking the study drug.
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3.3 inclusion of women and

Both men and women of all races and ethnic groups are eligible for this trial.
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4. registration procedures 4.1 general

Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not registered to the protocol before protocol therapy begins will be considered ineligible and registration will be denied. An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist. Following registration, participants may begin protocol therapy. Issues that would cause treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol therapy following registration, the participant's registration on the study must be canceled. Registration cancellations must be made in OnCore as soon as possible.
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4.2 registration process for df/hcc

DF/HCC Standard Operating Procedure for Human Subject Research Titled *Subject Protocol* Registration (SOP \#: REGIST-101) must be followed.  
4.3 General Guidelines for Other Investigative **Sites** n/a 4.4 Registration Process for Other Investigative **Sites** n/a
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5. treatment plan 5.1 treatment

INC280 will be administered at 400 mg PO BID, with 21 consecutive days defined as a treatment cycle. Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are described in Section 7. Appropriate dose modifications are described in Section 6.  
| Table 2. Dose and treatment schedule Study  Pharmaceutical form  treatments and route of  administration   | Dose                | Frequency and/or  Regimen   |                   |
|------------------------------------------------------------------------------------------------------------|---------------------|-----------------------------|-------------------|
| INC280                                                                                                     | Tablet for oral use | 400 mg in case of single    | Twice Daily (BID) |
| agent study                                                                                                |                     |                             |                   |  
All toxicities must be grade 1 or less, or tolerable grade 2, or else deemed not clinically significant by the treating investigator, prior to starting any cycle of therapy. Results of day 1 labs must be reviewed prior to start of each cycle. Lab values on cycle 1 day 1 do not need to remeet eligibility criteria if they were already met, but all adverse events must be grade 1 or less or else deemed not clinically significant by the treating investigator.
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5.3 agent administration

INC280 tablet will be administered orally on a continuous twice daily (BID) dosing schedule, on a flat scale of 400 mg bid and not individually adjusted by weight or body surface area. A complete cycle of treatment is defined as a 21 day period. The investigator must instruct the patient to take the study drug exactly as prescribed.  
Drugs are provided in the following strengths: 50 mg, 100 mg, and 200 mg. The tablets should be protected from moisture, and stored at ambient temperature (not above 25 degrees celsius or 77 degrees farenheit). The 50 mg and 100 mg tablets should be used within six week of opening, and the 200 mg tablet within 4 week of opening.  
- Each dose of INC280 is to be taken with a glass of water (at least 8 ounces - approximately 250 mL) and consumed over as short a time as possible (i.e., not slower than 1 tablet every 2 minutes).  
- Patients should be instructed to swallow the tablets whole and not to chew them.  
- INC280 can be administered with or without food. The morning and the evening doses should be taken 12 (± 4) hours apart, although 12-hour interval is highly recommended. The morning dose should be taken the same time each morning. If a dose is not taken within 4 hours of the planned dosing time, the missed dose should not be replaced.  
- Patients should be instructed not to make up for missed doses or partial doses (i.e., when the entire dose is not taken as instructed). A missed or partial dose will be defined as a case when the full dose is not taken within 4 hours of the scheduled twice daily dosing. If that occurs, then the dose (or part remaining dose) should not be taken and dosing should restart with the next scheduled dose. If vomiting occurs, no attempt should be made to replace the vomited dose before the next scheduled dose.  
- During the whole duration of treatment with INC280 alone, the patient is recommended to use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing, avoid sunbathing or using a solarium).
The investigator should instruct the patient to take INC280 exactly as prescribed.
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5.4 general concomitant medication and

In general, the use of any concomitant medication/therapy deemed necessary for the care of the patient (e.g. such as anti-emetics, anti-diarrhea) is permitted (see section below), except when specifically prohibited (see section below). In selected cases after discussion with the PI longstanding medications may be allowed to continue with appropriate monitoring.  
The patient must be told to notify the investigational site about any new medications he/she takes after the start of the study drug. All medications (excluding study treatment and prior antineoplastic treatments), blood transfusions, surgeries and procedures (including physical therapy) administered within 28 days prior to the first dose administration of INC280 through 30 days after the last dose of INC280 should be recorded. Medications include not only physician prescribed medications, but also all over-the counter medications, herbal medications, food supplements and vitamins.  
The following restrictions apply during the entire duration of the study:
- No other investigational therapy should be given to patients
- No anticancer agents other than the study medication (INC280) should be given to patients.
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permitted concomitant therapy

Palliative radiation and/or palliative procedures may be allowed on study after discussion with the study PI. The duration of study drug hold around the palliative radiation or procedure will be determined on a case by case basis after discussion with the study PI.  
Patients are permitted to use the following medications while taking INC280:
- Oral or topical antibiotics - Medications to prevent or treat nausea, vomiting or diarrhea - Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelets growth factors, etc.) are allowed per the investigator's judgement and per local guidelines.  
- Treatment with bisphosphonates for pre-existing bone metastases is permitted, if clinically indicated, and following existing local guidelines. Treatment with bisphosphonates should preferably begin before the study treatment is initiated, but can also be initiated during therapy only if absence of radiological bone disease progression is well documented (inthis case, the reason for its use must be clearly documented; i.e. "pre-existing, non-progressing bone metastases").  
- Oxygen therapy and blood products or transfusions
- Nutritional support or appetite stimulants - Pain medication
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permitted concomitant therapy requiring caution

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

INC280 is metabolized by CYP3A4 *in vitro*. Strong and moderate inhibitors or strong inducers of CYP3A4/5 shall be discontinued 7 days prior to the start of INC280 treatment and are prohibited. All agents that are metabolized mainly by CYP1A2 and/or CYP3A4/5 and have a narrow therapeutic index are prohibited. In *vitro* solubility data indicated that INC280 may have decreased solubility and thus decreased oral absorption at pH > 4. Long-acting proton pump inhibitors are prohibited. Examples of this class of drugs include: omeprazole, pantoprazole, and lansoprazole. If patients are using proton pump inhibitors at the time of screening, these drugs must be discontinued at least 3 days prior to the first dose of INC280 Patients enrolled in this study are not permitted to participate in additional parallel investigational drug or device studies while on treatment.  
| Table 4 List of prohibited concomitant therapy Mechanism of Interaction Drug Name Strong CYP3A4 inhibitor Antibiotics: clarithromycin, telithromycin, troleandomycin Protease Inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole Antivirals: boceprevir, telaprevir Others: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone Moderate CYP3A4 inhibitor Antibiotics: ciprofloxacin, erythromycin ProteaseInhibitors: amprenavir, atazanavir, darunavir, fosamprenavir Antifungals: fluconazole CalciumChannelBlockers: diltiazem, verapamil Others: aprepitant, casopitant, cimetidine, dronedarone, tofisopam, grapefruit  juice, Seville (sour) oranges, pomegranate, star fruit, schisandra  sphenanthera Strong CYP3A4 inducer Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin,  rifampin, St. John's wort CYP1A2 substrate with NTI Theophylline, tizanidine CYP3A4 substrate with NTI Quinidine, [terfenadine], astemizole, cyclosporine, sirolimus, tacrolimus,  pimozide, alfentanil, fentanyl, diergotamine, ergotamine, cisapride Long acting proton pump inhibitor Omeprazole, pantoprazole, lansoprazole, esomeprazole, rabeprazole,  dexlansoprazole drug- drug interactions (DDI) database, which is compiled primarily from the Indiana University School of  Medicine's "Clinically Relevant" Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington's  Drug Interaction Database (druginteractioninfo.org), and the FDA's "Guidance for Industry, Drug Interaction  Studies" Drugs between brackets are not marketed in USA.  NTI: narrow therapeutic index   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Table 5 Prohibited medications causing QTc prolongation Class of medication Drug Name Antianginal Bepridil Antiarrhythmic Amiodarone, disopyramide, dofetilide, flecainide, ibutilide, procainamide,  quinidine*, sotalol Antibiotic Azithromycin, clarithromycin*, erythromycin*, moxifloxacin, sparfloxacin Anticancer Arsenic trioxide, vavdetanib Antidepressant Citalopram Antihistamine [Astemizole]*, [terfenadine]* Anti-infective Pentamidine Antilipemic Probucol Antimalarial Chloroquine, halofantrine Antinausea [Domperidone], droperidol   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Antipsychotic                                                                                                                                                                                                                                                                              | Chlorpromazine, [haloperidol]*, mesoridazine, pimozide, thioridazine   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------|
| GI stimulant                                                                                                                                                                                                                                                                               | [Cisapride]                                                            |
| Opiate agonist                                                                                                                                                                                                                                                                             | [Levomethadyl], methadone                                              |
| Please note: *CYP3A substrate; drugs between brackets are not marketed in USA. Source: Arizona Center for Education and Research on Therapeutics (CERT), Drugs that prolong the QT interval and/or induce Torsades de Pointes http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm |                                                                        |
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5.5 criteria for taking a

Duration of therapy will depend on individual response, evidence of disease progression and/or lack of clinical benefit and tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue until one of the following criteria applies:  
- Disease progression (note that after discussion with the principal investigator, the decision can be made to continue on study past progression if the participant is having clinical benefit). The following criteria must be met if the decision is made to continue treatment past RECIST-defined progression, and written informed consent must be obtained for treatment beyond RECIST-defined disease progression.  
- absence of clinical symptoms or signs indicating clinically significant disease progression;
- no decline in performance status that is thought due to disease progression
- absence of rapid disease progression or threat to vital organs or critical anatomical sites requiring urgent alternative medical intervention;
- no significant, unacceptable or irreversible toxicities related to study treatment
- Intercurrent illness that prevents further administration of treatment  
- Unacceptable adverse event(s) - Participant demonstrates an inability or unwillingness to comply with the oral medication regimen and/or documentation requirements
- Participant decides to withdraw from the protocol therapy - General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The reason for removal from protocol therapy, and the date the participant was removed, must be documented in the case report form (CRF). Alternative care options will be discussed with the participant.  
A ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from protocol therapy. This form can be found on the ODQ website or obtained from the ODQ registration staff. In the event of unusual or life-threatening complications, treating investigators must immediately notify the Overall PI, Rebecca Heist MD at 617 724 4000.
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5.6 duration of follow up

Participants will be followed with periodic telephone follow up for two years after removal from protocol therapy or until death, whichever occurs first. Phone calls will be placed every three months and survival follow up obtained. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
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5.7 criteria for taking a

Participants will be removed from study when any of the following criteria apply:
- Lost to follow-up
- Withdrawal of consent for data submission
- Death - Completion of required follow up The reason for taking a participant off study, and the date the participant was removed, must be documented in the case report form (CRF). A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. This form can be found on the ODQ website or obtained from the ODQ registration staff.
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6. dosing delays/dose modifications

Dose delays and modifications will be made as indicated in the following table(s). The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are permitted in order to allow the patient to continue the study treatment. All dose modifications, interruptions or discontinuations must be based on the worst preceding toxicity as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 4.0). Any changes must be recorded.
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dose reduction and re-escalation

An INC280 dose reduction will follow the dose reduction steps described in Table 6. For each patient, a maximum of 2 dose level modifications is allowed after which the patient must be discontinued from treatment with INC280. Dose re-escalation of study treatment to the previous dose level is allowed only once, and if no AE leading to dose modification is observed after at least 1 cycle (3 weeks) of study treatment at the reduced dose.  
| INC280 dose levels* Starting dose level - 0                                                                                        | Dose level - 1   | Dose level - 2**   |            |
|------------------------------------------------------------------------------------------------------------------------------------|------------------|--------------------|------------|
| INC280                                                                                                                             | 400 mg BID       | 300 mg BID         | 200 mg BID |
| *Dose reduction should be based on the worst toxicity demonstrated at the last dose. **Dose reduction below 200 mg is not allowed. |                  |                    |            |
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general guidelines for dose modifications

Unless otherwise indicated in Table 7, for grade 1 and tolerable grade 2 treatment-related toxicities, patients may continue full doses of study treatment. For intolerable grade 2 or any grade 3 treatment-related toxicities, dosing should be interrupted until at least resolution to grade 1 followed by either dose reduction or re-initiation at the same dose level, depending on the type of toxicity as described in Table 7. For any grade 4 toxicity, patients should interrupt study treatment until resolution to grade 1, followed by either dose reduction or treatment discontinuation (refer to Table 7). A patient must discontinue treatment with INC280 if, after treatment is resumed at the lowest allowed dose (200 mg BID), the toxicity recurs with the same or worse severity despite use of maximal preventive measures as per the institution guidelines for toxicity prevention and management. All interruptions or change to study drug administration must be recorded.  
Table 7 Criteria for interruption and re-initiation of INC280 treatment  
Recommended dose modifications for INC280  
Worst toxicity CTCAE 4.0 Grade a.  
(value)  
During a cycle of therapy  
HEMATOLOGICAL Neutropenia (neutrophil count decreased, ANC) Grade 1 (ANC < LLN - 1500/mm3; < LLN - 1.5 x 109/L)
Maintain dose level  
| Recommended dose modifications for INC280 Worst toxicity CTCAE 4.0 Grade a. During a cycle of therapy (value) Grade 2 (ANC < 1500 - 1000/mm3; <  Maintain dose level 1.5 - 1.0 x 109/L) Grade 3 (ANC < 1000 - 500/mm3; < 1.0  Omit dose until resolved to ≤ grade 2, then: - 0.5 x 109/L) If resolved in ≤ 7 days, resume treatment at the same dose level If resolved in > 7 days, then ↓ 1 dose level Grade 4 (ANC < 500/mm3; < 0.5 x  Omit dose until resolved to ≤ grade 2 and then ↓ 1 dose level 109/L) Febrile neutropenia (ANC < 1000/mm3  Omit dose, then: (< 1.0 x 109/L), fever > 38.3°C) If resolved in ≤ 7 days, resume treatment at ↓ 1 dose level If resolved in > 7 days, discontinue patient from study treatment Thrombocytopenia (platelet count decrease, PLT) Grade 1 (PLT < LLN - 75,000/mm3; <  Maintain dose level LLN - 75 x 109/L) Grade 2 (PLT < 75,000 - 50,000/mm3;  Maintain dose level < 75 - 50 x 109/L) Grade 3 (PLT < 50,000 - 25,000/mm3;  Omit dose until resolved to ≤ grade 1, then: < 50 - 25 x 109/L) If resolved in ≤ 7 days, then maintain dose level If resolved in > 7 days, then ↓ 1 dose level  Grade 4 (PLT < 25,000/mm3; < 25 x  Omit dose until resolved to ≤ grade 2, then ↓1 dose level109/L)   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Recommended dose modifications for INC280 Worst toxicity CTCAE 4.0 Grade a. During a cycle of therapy (value) Anemia (hemoglobin decrease) Grade 1 (Hgb < LLN - 10.0 g/dL; < LLN  Maintain dose level - 6.2 mmol/L; < LLN - 100 g/L) Grade 2 (Hgb < 10.0 - 8.0 g/dL; < 6.2 - Maintain dose level 4.9 mmol/L; < 100 - 80 g/L) Grade 3 (Hgb < 8.0 g/dL; < 4.9 mmol/L;  Omit dose until resolved to ≤ grade 2, then: < 80 g/L) If resolved in ≤ 7 days, resume treatment at the same dose level If resolved in > 7 days, then ↓ 1 dose level Grade 4 Omit dose until resolved to ≤ grade 2 and then ↓ 1 dose level If toxicity recurs, discontinue study treatment permanently RENAL Serum creatinine Grade 1 (>1 and ≤1.5 x baseline; >  Maintain dose level ULN and ≤ 1.5 x ULN) Grade 2 (>1.5 and ≤3.0 x baseline; >  Omit dose until resolved to ≤ grade 1 or baseline, then resume treatment  1.5 and ≤ 3 x ULN) at the same dose level.  Grade 3 (> 3.0 x baseline; > 3.0 and ≤  Omit dose until resolved to ≤ grade 1 or baseline, then resume treatment  6.0 x ULN) at ↓ 1 dose level. Patients will be instructed to increase their fluid intake  until resolution to ≤ Grade 1 or baseline. Grade 4 (> 6.0 x ULN) Discontinue study treatment permanently HEPATIC Total Bilirubin b.  Grade 1 (> ULN - 1.5 x ULN) Maintain dose level Grade 2 (> 1.5 - 3.0 x ULN) with ALT or  Omit dose until resolved to ≤ Grade 1, then: AST ≤ 3.0 x ULN If resolved in ≤ 7 days, then maintain dose level If resolved in > 7 days, then ↓1 dose level  Grade 3 (≥ 3.0 - 10.0 x ULN) with ALT  Omit dose until resolved to ≤ Grade 1, then: or AST ≤ 3.0 x ULN If resolved in ≤ 7 days, then ↓ 1 dose level  If resolved in > 7 days, then discontinue permanently Grade 4 (> 10.0 x ULN) Discontinue study treatment permanently   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Recommended dose modifications for INC280 Worst toxicity CTCAE 4.0 Grade a. During a cycle of therapy (value) AST or ALT Grade 1 (> ULN - 3.0 x ULN) Maintain dose level with LFTs c. monitored per protocol Grade 2 (> 3.0 - 5.0 x ULN) without  Maintain dose level with LFTs c. monitored per protocol total bilirubin elevation to > 2 x ULN Grade 3 (> 5.0 - 20.0 x ULN) without  Omit dose until resolved to ≤ grade 1 (or ≤ grade 2 if liver metastases  total bilirubin elevation to > 2 x ULN present), then If resolved in ≤ 7 days, then resume treatment at the same dose level If resolved in > 7 days, then resume treatment at ↓ 1 dose level Grade 4 (> 20.0 x ULN) without total Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level bilirubin elevation to > 2 x ULN AST or ALT, and concurrent Total Bilirubin AST and/or ALT > 3.0 x ULN and total  bilirubin > 2.0 x ULN and ALP < 2.0 x  ULN Discontinue study treatment permanently in the absence of signs of  cholestasis, hemolysis, and alternative causes of the liver injury have been  excluded (e.g., concomitant use of hepatotoxic drug(s), alcoholic hepatitis,  etc.) METABOLIC Asymptomatic amylase and/or lipase  If symptomatic elevations of any grade, discontinue INC280 elevation  Grade 1 (> ULN - 1.5 x ULN) Maintain dose level Grade 2 (> 1.5 - 2.0 x ULN) Maintain dose level Grade 3 (> 2.0 - 5.0 x ULN) Continue dosing and monitor laboratory values, if levels do not resolve to  grade 2 or baseline by 14 days after the initial report, ↓ 1 dose level Grade 4 (> 5.0 x ULN) Continue dosing and monitor laboratory values, if levels do not resolve to  grade 2 or baseline by 14 days after the initial report, ↓ 1 dose level   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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recommended dose modifications for inc280

PULMONARY
Monitor patients for pulmonary symptoms indicative of ILD/Pneumonitis. In addition, withhold INC280 for acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and during diagnostic workup for ILD/Pneumonitis to exclude alternative causes such as, but not limited to infections, lymphangitic carcinomatosis, cardiogenic edema, or pulmonary hemorrhage.  
| Interstitial lung disease/Pneumonitis Grade 1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Interrupt INC280 during diagnostic workup for ILD/Pneumonitis. Exclude  infections and other etiologies. In presence of diagnosis of ILD/Pneumonitis after diagnostic  workup, it is mandatory to permanently discontinue INC280. Only in the absence of a diagnosis of ILD/Pneumonitis may study drug  be restarted at the same dose. If it recurs after restarting of study drug,  permanently discontinue INC280.                                                                                                                                                                                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Mandatory: Interrupt INC280 dose during diagnostic workup for ILD until  improvement to ≤ Grade 1. Exclude infections and other etiologies. In presence of diagnosis of ILD/Pneumonitis after diagnostic  workup, it is mandatory to permanently discontinue INC280. Only in the absence of a diagnosis of ILD/Pneumonitis may study drug  be restarted following these guidelines: - If resolves to ≤ Grade 1 in ≤ 7 days reduce study drug by 1  dose level - If fails to resolve to ≤ Grade 1 within 7 days or recurs after  resumption of study drug at decreased dose, permanently  discontinue INC280 |
| Grade 3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Mandatory: Permanently discontinue study drug.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Mandatory: Permanently discontinue study drug.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| CARDIAC Electrocardiogram QT corrected (QTc) interval prolonged Grade 1 (QTc 450-480 ms) Maintain dose level Grade 2 (QTc 481-500 ms) Grade 3 (QTcF ≥ 501 ms on at least  Omit dose until resolved to ≤ grade 1, then: two separate ECGs) If resolved in ≤ 7 days, resume treatment at the same dose level If resolved in > 7 days, then ↓ 1 dose level Grade 4 (QTc ≥ 501 or > 60 ms change  from baseline and Torsades de pointes  or polymorphic ventricular tachycardia  or signs/symptoms of serious  arrhythmia) Discontinue study treatment permanently GASTROINTESTINAL Pancreatitis Grade 2 Maintain dose level Grade ≥ 3 Discontinue study treatment permanently Diarrhea At the first sign of abdominal cramping, loose stools, or onset of diarrhea, it  is recommended that the patient be treated according to institutional  standard of care. Grade 1 (despite maximal anti-diarrheal  Maintain dose levelmedication) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |  
| Recommended dose modifications for INC280 Worst toxicity CTCAE 4.0 Grade a. During a cycle of therapy (value) Grade 2 (despite maximal anti-diarrheal  Omit dose until resolved to ≤ grade 1, then maintain dose level. medication) If diarrhea returns as ≥ grade 2, then omit dose until resolved to ≤ grade 1,  then resume treatment at↓ 1 dose level Grade 3 or 4 (despite maximal antidiarrheal medication) Omit dose until resolved to ≤ grade 1, then resume treatment at ↓ 1 dose  level Vomiting Grade 1 (despite standard anti-emetics) Maintain dose level Grade 2 (despite standard anti-emetics) Omit dose until resolved to ≤ grade 1, then maintain dose level. If vomiting returns as ≥ grade 2, then omit dose until resolved to ≤ grade 1,  then ↓ 1 dose level. Grade 3 (despite standard anti-emetics) Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level Grade 4 (despite standard anti-emetics) Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level   |
|---|  
| Recommended dose modifications for INC280 Worst toxicity CTCAE 4.0 Grade a. During a cycle of therapy (value) Nausea Grade 1 or 2 (despite standard antiemetics) Maintain dose level Grade 3 (despite standard anti-emetics) Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash/photosensitivity Grade 1 Maintain dose level. Grade 2 Maintain dose level. Grade 3 (despite skin toxicity therapy) Omit dose until resolved to grade ≤ 1, then: If resolved in ≤ 7 days, then↓resume treatment at 1 dose level If resolved in > 7 days (despite appropriate skin toxicity therapy), then  discontinue patient from study drug treatment Grade 4 (despite skin toxicity therapy) Discontinue study treatment permanently Fatigue/ Asthenia (General disorders and administration site conditions) Grade 1 or 2 Maintain dose level Grade 3 Omit dose until resolved to ≤ grade 1, then: If resolved in ≤ 7 days, resume treatment at same dose level If resolved in > 7 days, resume treatment at↓ 1 dose level Other adverse events Grade 1 or 2 Maintain dose level,consider to initiate appropriate support medication. For any intolerable grade 2 (e.g.: limiting instrumental ADL), consider  omitting the dose until resolved to ≤ grade 1, then↓ 1 dose level.  Grade 3 Omit dose until resolved to ≤ grade 1, then↓ 1 dose level Grade 4 Discontinue study treatment permanently All dose modifications should be based on the worst preceding toxicity. a. Common Toxicity Criteria for Adverse Events (CTCAE version 4.0). b. If grade 3 or 4 hyperbilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the  etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and haptoglobin  determination), then ↓ 1 dose level* and continue treatment at the discretion of the investigator. c. LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin ≥ grade 2), alkaline phosphatase and  GGT.   |
|---|
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treatment interruption and treatment discontinuation

If the administration of INC280 is temporarily interrupted for reasons other than toxicity, then treatment with INC280 may be resumed at the same dose. If the treatment with INC280 is withheld due to toxicity, the dose modification guidelines in Table 6 should be followed. If the treatment with INC280 is withheld for more than 21 consecutive days (counting from the first day when a dose was interrupted), then INC280 should be permanently discontinued. When the treating physician believes that continuing treatment may still provide clinical benefit for the patient, study treatment may be resumed. Patients who discontinue the study due to a study drug related AE or an abnormal laboratory value must be followed as described below.
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follow-up and management guidelines for

All patients will be followed for safety until 30 days after the last dose of INC280. Patients whose treatment is temporarily interrupted or permanently discontinued due to an AE or abnormal laboratory value must be followed until resolution or stabilization of the event, whichever comes first, including all study assessments appropriate to monitor the event. An assessment should be performed in all cases below where toxicity monitoring is needed according to the local standard of care and physician judgment. All patients should receive best supportive care (BSC) as per standard local practice for the treatment of pre-existing medical conditions or adverse events that may arise during the study. BSC is defined as drug or non-drug therapies, nutritional support, physical therapy, or any other treatment alternative that the treating physician believes to be in the patient's best interest.  
Table 8 outlines follow up evaluations and recommended management guidelines in the event of selected toxicities.  
| Table 8                                                                                                                 | Follow-up evaluations and management guidelines for selected toxicities                                                                                                                                                                                                                                                                                                                                      |
|-------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| TOXICITY                                                                                                                | FOLLOW-UP EVALUATION                                                                                                                                                                                                                                                                                                                                                                                         |
| HEMATOLOGICAL Febrile neutropenia, Neutropenia ≥ CTCAE grade 3 Thrombocytopenia ≥ CTCAE  grade 3 Anemia ≥ CTCAE grade 3 | Test weekly (or more frequently) until ≤ CTCAE grade 2. Perform physical exam for check on bruising in case of major thrombocytopenia.                                                                                                                                                                                                                                                                       |
| RENAL Serum creatinine ≥ CTCAE                                                                                          | Test weekly (or more frequently) until ≤ CTCAE grade 1 or baseline.                                                                                                                                                                                                                                                                                                                                          |
| grade 2                                                                                                                 | Patients will be instructed to increase hydration until resolution to ≤ CTCAE  grade 1 or baseline.                                                                                                                                                                                                                                                                                                          |
| HEPATIC Total bilirubin ≥ CTCAE grade 2                                                                                 | Test weekly (or more frequently) until ≤ CTCAE grade 1 Patients with total bilirubin > 1.5 ULN (any duration) should have fractionation of  bilirubin into total/direct or indirect/direct components and any additional work-up  as clinically indicated by these results. Follow-up of hyperbilirubinemia should  proceed as per the guidelines in table 2, irrespective of the results of  fractionation. |
| AST/ALT ≥ CTCAE grade 2 and                                                                                             | Test weekly (or more frequently) until ≤ CTCAE grade 1 or ≤ CTCAE grade 2 (if                                                                                                                                                                                                                                                                                                                                |
| 3                                                                                                                       | patient is Grade 2 at baseline). In particular, test for all the following liver function tests (LFTs): albumin, ALT,  AST, total bilirubin (fractionated if total bilirubin > 1.5 x ULN), alkaline  phosphatase and GGT. Note: for patients with Gilbert Syndrome, total and direct  bilirubin must be monitored, but intensified monitoring applies to changes in  direct bilirubin only.                  |  
| Protocol Version Date: August 6, 2019    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
|------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| TOXICITY                                 | FOLLOW-UP EVALUATION                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| METABOLIC Asymptomatic amylase or lipase | Test weekly (or more frequently) until ≤ CTCAE grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| ≥ CTCAE grade 3                          | A CT scan or equivalent imaging procedure to assess the pancreas, liver, and  gallbladder is recommended within 7 days of the first occurrence of any ≥  CTCAE grade 3 result, to exclude disease progression or potential other liver or  pancreatic disease.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| CARDIAC ≥ CTCAE grade 3                  | Test weekly (or more frequently) until ≤ CTCAE grade 2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| QTcF ≥ 501 ms                            | When QTcF ≥ 501 ms (CTCAE grade 3), perform the following:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| (CTCAE grade 3)                          | - Call the study's central ECG review laboratory immediately and request an  immediate manual read of the ECG. - Perform an analysis of serum potassium, calcium, phosphorus, and  magnesium, and if below lower limit of normal, correct with supplements to within  normal limits. - Review concomitant medication usage for the potential to inhibit CYP3A4/5  (table 4) and/or to prolong the QT-interval (Table 6). - Check compliance with correct dose and administration of study treatment  Perform a repeat ECG within one hour of the first QTcF of ≥501 ms. - If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but at least once  daily until the QTcF returns to < 501 ms. Repeat ECGs 7 days and 14 days (and then every 21 days) after dose  resumption for all patients who had therapy interrupted due to QTcF ≥ 501 ms. - If QTcF of ≥ 501 ms recurs, repeat ECGs as described above. Notes: - The investigator should contact the Novartis Medical Lead or designee  regarding any questions that arise if a patient with QTcF prolongation should be  maintained on study. - If the central ECG report shows a QTcF ≥ 501 msec (not previously  documented on the site machine), contact the patient and instruct him/her to  suspend study treatment and return for a repeat ECG as soon as possible. The  central ECG reader should be called for a manual read of the repeat ECG  immediately, and the above guidance followed. |
| GASTROINTESTINAL Diarrhea                | Initiate anti-diarrhea treatment after first signs of abdominal cramping, loose  stools or overt diarrhea. Consider/Investigate potential concomitant medication, food or comorbidity  driven causes of diarrhea (including infectious causes) and remedy these  causes, if possible (e.g., discontinuation of concomitant medication, dietary  modification, treatment of comorbidity). The patient should be monitored for signs of dehydration and instructed to take  preventive measures against dehydration as soon as diarrhea occurs.  Antidiarrheal medication must be initiated at the first sign of abdominal cramping,  loose stools or overt diarrhea. Concomitant medication for the treatment of  diarrhea should follow local practice and the investigator's best judgment and  may follow "the recommended guidelines for the treatment of cancer treatmentinduced diarrhea"For example: - For uncomplicated diarrhea (grade 1 or 2 without complicating signs or  symptoms), loperamide given at a standard dose (e.g. initial administration of 4  mg, then 2 mg every 2-4 hours, maximum of 16 mg/day), along with oral  hydration and dietetic measures should be considered. Note: complicating signs  or symptoms include: moderate to severe cramping, decreased performance  status, fever, neutropenia, frank bleeding or dehydration. - For complicated diarrhea (all grade 3 or 4, grade 1-2 with complicating signs or  symptoms), management should involve intravenous (IV) fluids, and consider  treatment with octreotide (at starting dose of 100 to 150 µg sub-cutaneous tid or  25 to 50 µg IV) and antibiotics (e.g. fluoroquinolone) should be given.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
| TOXICITY            | FOLLOW-UP EVALUATION                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
|---------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Nausea and Vomiting | The investigator should consider/investigate potential concomitant medication,  food or comorbidity driven causes of nausea and/or vomiting and remedy these  causes if possible (e.g. discontinuation of concomitant medication, dietary  modification, treatment of comorbidity). Individualized supportive and anti-emetic treatment should be initiated, as  appropriate, at the first signs and/or symptoms of these AEs. In patients with  vomiting, the patient should be monitored for signs of dehydration and instructed  to take preventive measures against dehydration. Concomitant medication for the treatment of nausea and/or vomiting should  follow local practice and the investigator's best judgment. |
| NERVOUS SYSTEM DISORDERS Any Neurological Toxicity ≥ Grade 2 Neurological assessments must be repeated at least twice a week until resolution  to < CTCAE grade 1. Unscheduled MRI and gadolinium enhanced T1 imaging  may also be conducted to evaluate patients for intramyelinic edema like lesions,  brain metastases and other unanticipated CNS occurrences. An EEG may be  performed to monitor for physiological changes in brain activity. SKIN TOXICITY (rash and photosensitivity) Prevention/Prophylaxis Avoid unnecessary exposure to sunlight Apply broad-spectrum sunscreen with SPF≥15 at least twice daily CTCAE grade 1 Use alcohol-free emollient cream (e.g. glycerine and cetomacrogol cream) for  management of itching related to dry skin Consider to initiate institute appropriate skin toxicity therapy (such as  antihistamines, topical antibiotics and/or corticosteroids and short course lowdose systemic corticosteroids) CTCAE grade 2 Initiate/intensify appropriate skin toxicity therapy (such as antihistamines, topical  antibiotics and/or corticosteroids and short course low-dose systemic  corticosteroids). ≥ CTCAE grade 3 Intensify appropriate skin toxicity therapy and monitor weekly or more frequently  until resolved to grade ≤ 2                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
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7. adverse events list and

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited reporting in addition to routine reporting.  
For a detailed discussion of toxicities seen to date please see the Investigator's Brochure. In brief, a total of 622 patients have been treated with INC280 as a single agent at different doses, and 487 patients have been treated with INC280 in combination therapies: with gefitinib (161 patients), with buparlisib (43 patients), with erlotinib (55 patients), with cetuximab (13 patients), with LGX818/MEK162 (12 patients), with EGF816 (130 patients), with nivolumab (18 patients), with sonidegib (one patient), with PDR001 (20 patients), and with bevacizumab (34 patients). Twenty-one clinical trials are currently ongoing with INC280.  
A total of nineteen patients have experienced 25 DLTs: one Grade 3 AST and ALKP increase (50 mg QD), one Grade 2 suicidal ideation (600 mg BID), one Grade 3 depression (400 mg BID), two Grade 3 fatigue (200 mg BID and 450 mg BID respectively), one Grade 3 ALT increased, AST increased, and rash (400 mg BID, in combination with erlotinib), one Grade 3 rash pustular (400 mg BID, in combination with erlotinib), one Grade 3 total bilirubin increase (250 mg BID), one Grade 4 cough and dyspnea (600 mg BID, combination with gefitinib), one Grade 3 dizziness (800 mg QD, combination with gefitinib), one Grade 3 personality change (400 mg BID, in combination with buparlisib),
one Grade 3 nausea (300 mg BID, in combination with buparlisib), two Grade 3 ALT
increased and AST increased (400 mg BID, in combination with buparlisib), one Grade 3 ALT increased (INC280 200mg with 50 mg QD EGF816), one Grade 3 anaphylactic reaction (INC280 400mg with 100mg QD EGF816), one Grade 3 rash maculo-papular and Grade 1 pyrexia (INC280 400 mg BID with 150 mg QD EGF816), one Grade 3 rash maculopapular and dermatitis allergic (INC280 400mg BID with 150 mg QD EGF816), and one Grade 3 diarrhea (400mg BID, in combination with PDR001). The majority of the reported AEs were mild or moderate (CTCAE Grade 1 or 2). CTCAE Grade 3/4AEs suspected to be related to INC280 included- ALT increased, AST increased, GGT increased, neutrophil count decreased, white blood cell count decreased, hypophosphatemia, hyponatremia, depression, colitis ulcerative and lung infection (each in one patient [2.3%]) (in [CINC280X1101]); AST increased, hypophosphatemia, and peripheral edema (each in one patient [2.2%])(in [CINC280X2101]); edema peripheral and lipase increased (each in nine patients [4.1%]), nausea, ALT increased (7 patients [3.2%]), AST increased, hypophosphatemia, nausea, and vomiting (each in three patients [1.4%])(in [CINC280A2201]); fatigue (three patients [7.9%]), =ALT increased, hypophagia (two patients [5.3%]), decreased appetite, amylase increased, AST increased, blood bilirubin increased, edema peripheral, hypoalbuminemia, anemia, lipase increased, and neutropenia (each in one patient [2.6%]) (in [CINC280X2102]); ALT increased (4 patients [4.3%], nausea, fatigue, lipase increased, hypophosphatemia (each in three patients [3.2%]), peripheral edema, rash maculo-papular, amylase increased, AST increased, asthenia, dehydration (each in two patients [2.2%]) (in Dose Expansion Group, [CINC280X2102]); vomiting (2 patients [13.2%]), nausea, ALT increased, AST increased, amylase increased and blood bilirubin increased (each in one patient [2.6%] (in combination with erlotinib, [CINC280X2201]); ALT increased, edema peripheral, amylase increased, gamma-glutamyl transferase increased, interstitial lung disease, and neutropenia (each in one patient [6.3%]) (in [CINC280X2205]); fatigue and amylase increased (each in two patients [15.4%]), ALT increased and lipase increased (each in one patient [7.7%]) (in combination with cetuximab, [CINC280X2104]); rash maculopapular (17 patients, [14.9%]), ALT increased and amylase increased (each in 8 patients [4.4%]), fatigue (4 patients [3.5%]), asthenia, AST increased, and vomiting (each in 3 patients [2.6%]) (in combination with EGF816, [CINC280X2105C]); nausea (2 patients [10%]), edema peripheral, ALT increased, diarrhea, stomatitis, hypotension, platelet count decreased, acute myocardial infarction, unstable angina, blood bilirubin increased, dehydration, and neutropenia (each in one patient [5%]) (in combination with PDR001, [CINC280X2108]); amylase increased and lipase increased (each in 10 patients [6.2%]), edema peripheral (6 patients [3.7%]), vomiting and fatigue (each in four patients [2.5%]), ALT increased (3 patients [2.1%]),rash, pulmonary embolism, hyponatremia, asthenia, AST increased, dizziness (each in 2 patients [1.2%]), and, with single incidences of paronychia, vomiting, blood bilirubin increased, and hemoptysis [0.6%] (in combination with gefitinib, [CINC280X2202]); hyperlipasaemia (2 patients [5.4%]), asthenia, blood alkaline phosphatase increased, lipase increased (each in one patient [2.7%]) (in DDI-study, [CINC280A2103]); and vomiting (2 patients [6.3%]), anemia, abdominal pain, ALT increased, AST increased, asthenia, blood albumin decreased, lipase increased, lymphocyte count decreased, malaise, quality of life decreased and vitamin k decreased (each in one patient [3.1%]) (in DDI-study, [CINC280A2105]).  
| Adverse Drug Reactions considered to be expected for reporting purposes System  Adverse  Nature1 Serio AE frequency  Organ Class Reaction us2 regardless of  causality from  single agent studyCINC280A2201 Number  of  observed  suspected  SARs5 and  frequency CINC2 80A22 01  (N=220 ) 3 n (%) AE frequency,  suspected to be  INC280 related from  single agent studyCINC280A2201 Categor CINC28 y 0A2201  (N=220) 4 n (%) Categor N =1109  y cancer  patients6 Gastrointesti Vomiting Hospitalizati nal disorders on and  antiemetic  were  required in  most of  serious cases Yes 59  Very  40  Very  12 (1.0) (26.8) common (18.2) common Nausea Nausea often  associated  with  vomiting,  Hospitalizati on and  antiemetic  were  required in  most of  serious  cases. Yes 94  Very  69  Very  8 (0.7)(42.7)  common (31.4) common   |
|---|  
| Protocol Version Date: August 6, 2019                    |                                                                                                                                                     |                                                                                                                                     |         |                                                       |          |       |         |         |
|----------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|---------|-------------------------------------------------------|----------|-------|---------|---------|
| System                                                   | Adverse                                                                                                                                             | Nature1                                                                                                                             | Serio   | AE frequency                                          |          |       |         |         |
| Organ Class                                              | Reaction                                                                                                                                            | us2                                                                                                                                 | regardless of  causality from  single agent studyCINC280A2201         | Number  of  observed  suspected  SARs5 and  frequency |          |       |         |         |
| CINC2 80A22 01  (N=220 ) 3 n (%)                         | AE frequency,  suspected to be  INC280 related from  single agent studyCINC280A2201                                                                                                                                                     |                                                                                                                                     |         |                                                       |          |       |         |         |
| Categor                                                  | CINC28                                                                                                                                              |                                                                                                                                     |         |                                                       |          |       |         |         |
| y                                                        | 0A2201  (N=220) 4 n (%)                                                                                                                             | Categor                                                                                                                             | N =1109 |                                                       |          |       |         |         |
| y                                                        | cancer  patients6                                                                                                                                   |                                                                                                                                     |         |                                                       |          |       |         |         |
| Diarrhea                                                 | Diarrhea  associated  with  vomiting and  nausea;  Interruption  of study  medication;  Hospitalizati on was  required in  most of  serious  cases. | Yes                                                                                                                                 | 35      | Very                                                  | 22       | Very  | 9 (0.8) |         |
| (15.9)                                                   | common                                                                                                                                              | (10.0)                                                                                                                              | common  |                                                       |          |       |         |         |
| Abdomin al pain;  Abdomin al pain  upper                 | Hospitalizati on and study  medication  dose  adjustment  or  interruption  /discontinuat ion was  required in  most serious  cases                 | Yes                                                                                                                                 | 27      | Very                                                  | 12 (5.5) | Commo | 5 (0.4) |         |
| (12.3 )                                                  | common                                                                                                                                              | n                                                                                                                                   |         |                                                       |          |       |         |         |
| General  disorders and  administratio n site  conditions | Fatigue                                                                                                                                             | Hospitalizati on and study  medication  dose  adjustment  or  interruption  /discontinuat ion was  required in  most serious  cases | Yes     | 52                                                    | Very     | 34    | Very    | 5 (0.4) |
| (23.6)                                                   | common                                                                                                                                              | (15.5)                                                                                                                              | common  |                                                       |          |       |         |         |  
| Protocol Version Date: August 6, 2019   |                                                                                                                                     |                                                                                                    |          |                                                       |          |          |         |         |
|-----------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|----------|-------------------------------------------------------|----------|----------|---------|---------|
| System                                  | Adverse                                                                                                                             | Nature1                                                                                            | Serio    | AE frequency                                          |          |          |         |         |
| Organ Class                             | Reaction                                                                                                                            | us2                                                                                                | regardless of  causality from  single agent studyCINC280A2201          | Number  of  observed  suspected  SARs5 and  frequency |          |          |         |         |
| CINC2 80A22 01  (N=220 ) 3 n (%)        | AE frequency,  suspected to be  INC280 related from  single agent studyCINC280A2201                                                                                                                                     |                                                                                                    |          |                                                       |          |          |         |         |
| Categor                                 | CINC28                                                                                                                              |                                                                                                    |          |                                                       |          |          |         |         |
| y                                       | 0A2201  (N=220) 4 n (%)                                                                                                             | Categor                                                                                            | N =1109  |                                                       |          |          |         |         |
| y                                       | cancer  patients6                                                                                                                   |                                                                                                    |          |                                                       |          |          |         |         |
| Edema                                   | Hospitalizati                                                                                                                       |                                                                                                    |          |                                                       |          |          |         |         |
| peripheral                              | on and study  medication  dose  adjustment  or  interruption.  Treatment  with  diuretics.                                          | Yes                                                                                                | 98       | Very                                                  | 77       | Very     | 4 (0.3) |         |
| (44.5)                                  | common                                                                                                                              | (35.0)                                                                                             | common   |                                                       |          |          |         |         |
| Asthenia                                | Hospitalizati on and study  medication  dose  adjustment  or  interruption  /discontinuat ion was  required in  most serious  cases | Yes                                                                                                | 27       | Very                                                  | 12 (5.5) | Commo    | 4 (0.3) |         |
| (12.3)                                  | common                                                                                                                              | n                                                                                                  |          |                                                       |          |          |         |         |
| Investigation                           | Alanine                                                                                                                             |                                                                                                    |          |                                                       |          |          |         |         |
| s                                       | aminotran sferase  increased                                                                                                        | Hospitalizati on and study  medication  interruption  was required  in some of  the serious  cases | Yes      | 18 (8.2)                                              | Commo    | 12 (5.5) | Commo   | 9 (0.8) |
| n                                       | n                                                                                                                                   |                                                                                                    |          |                                                       |          |          |         |         |
| Aspartate  aminotran sferase  increased | Hospitalizati on and study  medication  interruption  was required  in some of  the serious  cases                                  | Yes                                                                                                | 15 (6.8) | Commo                                                 | 11 (5.0) | Commo    | 5 (0.4) |         |
| n                                       | n                                                                                                                                   |                                                                                                    |          |                                                       |          |          |         |         |
| Gammaglutamylt ransferase  increased                                         | n/a                                                                                                                                 | No                                                                                                 | 12 (5.5) | Commo                                                 | 3 (1.4)  | Commo    | n/a     |         |
| n                                       | n                                                                                                                                   |                                                                                                    |          |                                                       |          |          |         |         |  
| Protocol Version Date: August 6, 2019   |                                                                                                                       |               |          |                                                       |          |       |         |
|-----------------------------------------|-----------------------------------------------------------------------------------------------------------------------|---------------|----------|-------------------------------------------------------|----------|-------|---------|
| System                                  | Adverse                                                                                                               | Nature1       | Serio    | AE frequency                                          |          |       |         |
| Organ Class                             | Reaction                                                                                                              | us2           | regardless of  causality from  single agent studyCINC280A2201          | Number  of  observed  suspected  SARs5 and  frequency |          |       |         |
| CINC2 80A22 01  (N=220 ) 3 n (%)        | AE frequency,  suspected to be  INC280 related from  single agent studyCINC280A2201                                                                                                                       |               |          |                                                       |          |       |         |
| Categor                                 | CINC28                                                                                                                |               |          |                                                       |          |       |         |
| y                                       | 0A2201  (N=220) 4 n (%)                                                                                               | Categor       | N =1109  |                                                       |          |       |         |
| y                                       | cancer  patients6                                                                                                     |               |          |                                                       |          |       |         |
| Blood  bilirubin  increased             | Hospitalizati on and study  medication  interruption  was required  in some of  the serious  cases                    | Yes           | 7 (3.2)  | Commo                                                 | 6 (2.7)  | Commo | 2 (0.2) |
| n                                       | n                                                                                                                     |               |          |                                                       |          |       |         |
| Amylase                                 | n/a                                                                                                                   | No            | 12 (5.5) | Commo                                                 | 11 (5.0) | Commo | n/a     |
| increased                               | n                                                                                                                     | n             |          |                                                       |          |       |         |
| Lipase                                  | n/a                                                                                                                   | No            | 14 (6.4) | Commo                                                 | 13 (5.9) | Commo | n/a     |
| increased                               | n                                                                                                                     | n             |          |                                                       |          |       |         |
| Blood  creatinine  increase             | Hospitalizati on, study  medication  interruption  and  treatment  with fluids  and  electrolytes                     | Yes           | 54       | Very                                                  | 39       | Very  | 2 (0.2) |
| (24.5)                                  | common                                                                                                                | (17.7)        | common   |                                                       |          |       |         |
| Metabolism  and nutrition disorders     | Decrease                                                                                                              | Hospitalizati |          |                                                       |          |       |         |
| d appetite                              | on and study  medication  dose  adjustment  or  interruption  /discontinuat ion was  required in  most serious  cases | Yes           | 46       | Very                                                  | 31       | Very  | 3 (0.3) |
| (20.9)                                  | common                                                                                                                | (14.1)        | common   |                                                       |          |       |         |
| Hyponatr                                | Hospitalizati                                                                                                         |               |          |                                                       |          |       |         |
| emia                                    | on and study  medication  dose  adjustment  or  interruption  /discontinuat ion was  required in  most serious  cases | Yes           | 7 (3.2)  | Commo                                                 | 1 (0.5)  | Uncom | 3 (0.3) |
| n                                       | mon                                                                                                                   |               |          |                                                       |          |       |         |  
| System                                                       | Adverse                                    | Nature1                                                                                           | Serio   | AE frequency                                          |       |         |       |          |
|--------------------------------------------------------------|--------------------------------------------|---------------------------------------------------------------------------------------------------|---------|-------------------------------------------------------|-------|---------|-------|----------|
| Organ Class                                                  | Reaction                                   | us2                                                                                               | regardless of  causality from  single agent studyCINC280A2201         | Number  of  observed  suspected  SARs5 and  frequency |       |         |       |          |
| CINC2 80A22 01  (N=220 ) 3 n (%)                             | AE frequency,  suspected to be  INC280 related from  single agent studyCINC280A2201                                            |                                                                                                   |         |                                                       |       |         |       |          |
| Categor                                                      | CINC28                                     |                                                                                                   |         |                                                       |       |         |       |          |
| y                                                            | 0A2201  (N=220) 4 n (%)                    | Categor                                                                                           | N =1109 |                                                       |       |         |       |          |
| y                                                            | cancer  patients6                          |                                                                                                   |         |                                                       |       |         |       |          |
| Nervous  system  disorders                                   | Dizziness                                  | n/a                                                                                               | No      | 17 (7.7)                                              | Commo | 8 (3.6) | Commo | n/a      |
| n                                                            | n                                          |                                                                                                   |         |                                                       |       |         |       |          |
| Renal and  urinary  disorders                                | Renal  impairme nt; Acute  kidney  injury  | Hospitalizati on, study  medication  interruption  and  treatment  with fluids  and  electrolytes | Yes     | 4 (1.9)                                               | Commo | 2 (0.9) | Uncom | 2 (0.2)  |
| n                                                            | mon                                        |                                                                                                   |         |                                                       |       |         |       |          |
| Respiratory,  thoracic and  mediastinal  disorders           | Pneumoni tis /  interstitial  lung disease | Hospitalizati on, study  medication  interruption  and steroid  treatment is  required            | Yes     | 7 (3.2)                                               | Commo | 2 (0.9) | Uncom | 10 (0.9) |
| n                                                            | mon                                        |                                                                                                   |         |                                                       |       |         |       |          |
| n/a: not applicable 1 Additional description of serious ADRs |                                            |                                                                                                   |         |                                                       |       |         |       |          |  
n/a: not applicable 1 Additional description of serious ADRs 2 For the purpose of individual case safety reporting in clinical trials, serious forms of adverse reactions indicated as non-serious in this table will always be considered unexpected. 3 Frequency is calculated based on all events regardless of grades and causality assessment in study CINC280A2201 clinical trial database (N=220) with the data cut-off of 09-Aug-2017. The category is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) 4 Frequency is calculated based on all events (all grades) which are assessed as suspected by the investigators in study CINC280A2201 clinical trial database (N=220) with the data cut-off of 09-Aug2017. The category is based on the following convention: very common (≥1/10); common (≥1/100 to
<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) 5 Number of subjects who have experienced the suspected SAR and frequency of suspected SAR as of the cut-off date of 28-Sep-2017 6 As of the cut-off date of 28-Sep-2017, a total of 1109 cancer patients received INC280.
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7.2 adverse event characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
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serious adverse events

A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that:
- Results in death
- Is life-threatening. Life-threatening means that the person was at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction which hypothetically might have caused death had it occurred in a more severe form.  
- Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour hospitalization or prolonged a hospitalization beyond the expected length of stay). Hospitalization admissions and/or surgical operations scheduled to occur during the study period, but planned prior to study entry are not considered SAEs if the illness or disease existed before the person was enrolled in the trial, provided that it did not deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than planned).  
- Results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of a person's ability to conduct normal life functions.  
- Is a congenital anomaly or birth defect; or - Is an important medical event when, based upon appropriate medical judgment, it may jeopardize the participant and require medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.  
Events **not** considered to be serious adverse events are hospitalizations for:
- routine treatment or monitoring of the studied indication, not associated with any deterioration in condition, or for elective procedures
- Abnormal lab values that do not require treatment
- treatment planned before signing informed consent for a pre-existing condition that did not worsen
- emergency outpatient treatment for an event not fulfilling the serious criteria outlined above and not resulting in inpatient admission
- respite care
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expected adverse events

Adverse events can be 'Expected' or 'Unexpected'. Expected adverse events are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is considered expected when it appears in the Investigator's Brochure
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unexpected adverse events

For the purposes of this study, an adverse event is considered unexpected when it varies in nature, intensity or frequency from information provided in the Investigator's Brochure.  
Attribution Attribution is the relationship between an adverse event or serious adverse event and the study treatment. Attribution will be assigned as follows:  
- Definite - The AE is clearly related to the study treatment. - Probable - The AE is likely related to the study treatment. - Possible - The AE may be related to the study treatment. - Unlikely - The AE is doubtfully related to the study treatment.  
- Unrelated - The AE is clearly NOT related to the study treatment.
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7.3 procedures for ae and

Reporting or participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation time points during the study. All AEs and SAEs whether reported by the participant, discovered during questioning, directly observed, or detected by physical examination, laboratory test or other means, will be recorded in the participant's medical record and on the appropriate study-specific case report forms. Each recorded AE or SAE will be described by its duration (i.e., start and end dates), intensity treatment required, grade, suspected relationship to the investigational product (causality), outcome and actions taken with investigational product. The descriptions and grading scales found in the CTEP NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. The CTCAE version 4.0 is located on the CTEP website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All appropriate treatment areas should have access to a copy of the CTEP Active Version of CTCAE. To ensure consistency of AE and SAE causality assessments, investigators should apply the following general guideline:
- YES
There is a plausible temporal relationship between the onset of the AE and administration of the investigational product, and the AE cannot be readily explained by the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to the investigational product; and/or the AE abates or resolves upon discontinuation of the investigational product or dose reduction and, if applicable, reappears upon re-challenge.  
- NO
Evidence exists that the AE has an etiology other than the investigational product (e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to administration of the investigational product (e.g., cancer diagnosed 2 days after first dose of study drug). Each participating investigator is required to abide by the reporting requirements set by the DF/HCC. The study must be conducted in compliance with FDA regulations, local safety reporting requirements, and reporting requirements of the principal investigator. Specific reporting requirements are detailed below.
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reporting to novartis

To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has provided the main informed consent and until at least 30 days after the patient has stopped study treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after this 30 days period should only be reported to Novartis if the investigator suspects a causal relationship to the study treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event. Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable sections of the form must be completed in order to provide a clinically thorough report. The investigator must assess and record the relationship of each SAE to each specific study treatment (if there is more than one study treatment), complete the SAE Report Form in English, and send the completed, signed form by fax within 24 hours to the oncology Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739). The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report form documentation at the study site. Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report. Each re-occurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not, and whether the patient continued or withdrew from study participation. If the SAE is not previously documented in the Investigator's Brochure or Package Insert (new occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require further information from the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification (IN), to inform all investigators involved in any study with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries.
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pregnancies

To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). Pregnancy follow-up should be recorded on the same form and should include an assessment of the possible relationship to the study treatment and pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. Pregnancy outcomes must be collected for the female partners of any males who took study treatment in this study. Consent to report information regarding these pregnancy outcomes should be obtained from the mother. Women of childbearing potential should be advised to use highly effective contraception methods while they are receiving study treatment and up to 7 days after INC280 treatment has been stopped. If a pregnancy occurs while on study treatment, the newborn will be followed for at least 3 months.  
Serious Adverse Event Reporting Reporting to the Institutional Review Board All serious adverse events that occur, during treatment, or within 28 days of the last dose of treatment must be reported to the DFCI Office for Human Research Studies (OHRS). This includes events meeting the criteria outlined in Section 6.2.2, as well as the following:  
- Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at least possibly related/associated with the intervention.
- All Grade 4 (life-threatening or disabling) events that are unexpected or not specifically listed in the protocol as not requiring reporting.  
- All Grade 5 (fatal) events while the participant is enrolled and actively participating in the trial OR when the event occurs within 28 days of the last study intervention. Note: If the participant is in long term follow up, report the death at the time of continuing review.  
Participating investigators must report each serious adverse event within 24 hours of learning of the occurrence. In the event that the participating investigator does not become aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), the participating investigator is to report the event within 24 hours after learning of it and document the time of his or her first awareness of the adverse event. Within the following 24-48 hours, the participating investigator must provide follow-up information on the serious adverse event. Follow-up information should describe whether the event has resolved or continues, if and how the event was treated, and whether the participant will continue or discontinue study participation. Events that occur after consent but before study enrollment/registration and receiving study treatment do not need to be reported. 7.4 **Expedited Adverse Event Reporting**
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- for expedited reporting purposes

- AEs for the agent(s) that are listed above should be reported only if the adverse event varies in nature, intensity or frequency from the expected toxicity information which is provided.  
7.4.1 DF/HCC Expedited Reporting Guidelines Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.
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7.5 expedited reporting to the

The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the FDA's criteria for expedited reporting following the reporting requirements and timelines set by the FDA.
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7.6 expedited reporting to hospital

Participating investigators will report to their local Risk Management office any participant safety reports or sentinel events that require reporting according to institutional policy.
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7.7 routine adverse event reporting

All Adverse Events **must** be reported in routine study data submissions to the Overall PI on the toxicity case report forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also **be reported in routine study data submissions.**
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8. pharmaceutical information

A list of the adverse events and potential risks associated with the investigational agent administered in this study can be found in Section 7.1.
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8.1 inc280 8.1.1 description

The chemical name of INC280 drug substance is 2-fluoro-N-methyl-4-(7-(quinolin-6ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide dihydrochloride monohydrate. INC280 has a molecular formula of C23H21Cl2FN6O2 and a molecular weight of 503.35 (salt form on monohydrate basis). INC280 dihydrochloride monohydrate is a slightly hygroscopic light yellow to yellow powder. The solubility of INC280 dihydrochloride at 25°C is approximately 3.47 mg/mL in water; 0.08 mg/mL in pH 6.8 and 0.72 mg/mL in pH 3.0 buffer.
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8.1.2 form

INC280 is presently formulated as an orally administered capsule dosage form or as a film-coated tablet. The tablet form will be used in this study. Drug request order forms are sent directly to Novartis. The orally administered film-coated tablets contain the active drug INC280, along with the following commonly used excipients: colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, and various coating premixes.
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8.1.3 storage and stability

The stability data of clinical batches for INC280 film-coated tablets shows acceptable physical and chemical stability under designated storage conditions. Refer to the clinical label for storage condition requirements.
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8.1.4 compatibility

INC280 will be administered as a single agent in this study.
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8.1.5 handling

Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent in a self-contained and protective environment.
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8.1.7 preparation

INC280 is presently formulated as an orally administered capsule dosage form or as a film-coated tablet. The tablet form will be used in this study.
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8.1.8 administration

INC280 tablet will be administered orally on a continuous twice daily (BID) dosing schedule, on a flat scale of mg/day and not individually adjusted by weight or body surface area. A complete cycle of treatment is defined as 21 days of twice daily treatment with INC280. The investigator must instruct the patient to take the study drug exactly as prescribed. Patients will record their daily dosing in a drug diary.  
- Each dose of INC280 is to be taken with a glass of water (at least 8 ounces - approximately 250 mL) and consumed over as short a time as possible (i.e., not slower than 1 tablet every 2 minutes).  
- Patients should be instructed to swallow the tablets whole and not to chew them. - INC280 can be administered with or without food. The morning and the evening doses should be taken 12 (± 4) hours apart, although 12-hour interval is highly recommended. The morning dose should be taken the same time each morning. If a dose is not taken within 4 hours of the planned dosing time, the missed dose should not be replaced.  
- Patients should be instructed not to make up for missed doses or partial doses (i.e., when the entire dose is not taken as instructed). A missed or partial dose will be defined as a case when the full dose is not taken within 4 hours of the scheduled twice daily dosing. If that occurs, then the dose (or part remaining dose) should not be taken and dosing should restart with the  
next scheduled dose. If vomiting occurs, no attempt should be made to replace the vomited dose before the next scheduled dose.  
During the whole duration of treatment with INC280 alone, the patient is recommended to use precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing, avoid sunbathing or using a solarium).
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8.1.10 accountability

The investigator, or a responsible party designated by the investigator, should maintain a careful record of the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) or another comparable drug accountability form. (See the NCI Investigator's Handbook for Procedures for Drug Accountability and Storage.)
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8.1.11 destruction and return

Drug will be returned and destroyed per DF/HCC SOP pharmacy policy (INV-100 and INV-102)
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9. biomarker correlative and special

Archival tumor tissue will be collected at baseline for all patients where this is available. At least 10 unstained slides will be obtained from the archival tissue if possible. An optional biopsy at study entry may be used to provide this tissue. Tumors will be tested for biomarkers that may predict response, including baseline mutational status as assessed by a next generation sequencing panel, as well as *MET, CDK4*, and *MDM2* amplification, among others. Circulating tumor DNA will be collected at study entry and during study and assessed for mutational status as well. Biomarker testing will be done at MGH in collaboration with Dr. Engelman's lab.
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optional tumor biopsy at time

Patients will be asked to undergo an optional biopsy at time of progression for correlative studies investigating mechanisms of resistance to INC280. For any patient undergoing an optional biopsy, tumor will be collected and assessed for mutational testing and for development into cell lines or patient-derived xenograft models for further study. This will be done at MGH in collaboration with Dr. Engelman's lab.  
| Sample Type                                                            | Proposed Studies                                                                                                             |
|------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|
| Archival FFPE  tumor tissue or  optional tumor  biopsy at study  entry | Baseline mutational status MET, CDK4, MDM2  amplification, among others Cell lines and PDX models, if  optional fresh biopsy |
| Optional tumor  biopsy at  progression                                 | Mutational status at  progression MET, CDK4, MDM2  amplification, among others Cell lines and PDX models                     |
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10. study calendar

Screening evaluations are to be conducted < 4 weeks prior to start of protocol therapy. Scans must be done <4 weeks prior to the start of therapy. Assessments must be performed prior to administration of any study agent. Study assessments and agents should be administered within + 3 days of the protocol-specified date, unless otherwise noted. Follow-up data will be collected every 3 months until participant withdrawal, death, or removal from study.  
| +/- 3 day window around visits                                                                                                                                                                                         |                  |                     |                              |          |                                                                      |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|---------------------|------------------------------|----------|----------------------------------------------------------------------|----|
| Cycle 1                                                                                                                                                                                                                | Cycle 2 -18      |                     |                              |          |                                                                      |    |
| (21days)                                                                                                                                                                                                               | (Up to           |                     |                              |          |                                                                      |    |
| Visit Name                                                                                                                                                                                                             | Screen           | Month 13)           | Cycles >  18  (Months >  13) | EOT      | Follow up  phone calls Every  three  months  from end  of  treatment |    |
| Obtain study informed  consent                                                                                                                                                                                         | x                |                     |                              |          |                                                                      |    |
| Collection of archival  tumor tissue (paraffin                                                                                                                                                                         | x                |                     |                              |          |                                                                      |    |
| blocks/slides) a                                                                                                                                                                                                       | C1               | C1                  | Day 1                        | Day 1 of |                                                                      |    |
| D1                                                                                                                                                                                                                     | D8               | Every  Other  Cycle |                              |          |                                                                      |    |
| Day of cycle                                                                                                                                                                                                           | -28 to -1        |                     |                              |          |                                                                      |    |
| Confirm METex14  (locally confirmed by                                                                                                                                                                                 | x                |                     |                              |          |                                                                      |    |
| investigator) Inclusion/exclusion  criteria                                                                                                                                                                            | x                |                     |                              |          |                                                                      |    |
| Relevant medical and  oncologic history b                                                                                                                                                                              | x                |                     |                              |          |                                                                      |    |
| Physical examination                                                                                                                                                                                                   | x                | x                   | x                            | x        | x                                                                    | x  |
| Vital signs                                                                                                                                                                                                            | x                | x                   | x                            | x        | x                                                                    | x  |
| Performance status                                                                                                                                                                                                     | x                | x                   | x                            | x        | x                                                                    | x  |
| ECG                                                                                                                                                                                                                    | x                | x                   | x                            | x        | x                                                                    |    |
| Pregnancy test (serum test)                                                                                                                                                                                            | x                |                     |                              |          |                                                                      |    |
| Hematologyc                                                                                                                                                                                                            | x                | x                   | x                            | x        | x                                                                    | x  |
| Chemistryd                                                                                                                                                                                                             | x                | x                   | x                            | x        | x                                                                    | x  |
| Tumor evaluation by                                                                                                                                                                                                    | Every two cycles |                     |                              |          |                                                                      |    |
| RECIST (CT/MRI)e                                                                                                                                                                                                       | x                |                     |                              |          |                                                                      |    |
| INC280 PO BID                                                                                                                                                                                                          | x                | x                   | x                            | x        |                                                                      |    |
| Adverse events                                                                                                                                                                                                         | x                | x                   | x                            | x        | x                                                                    |    |
| Optional tumor biopsy                                                                                                                                                                                                  | x                | x                   |                              |          |                                                                      |    |
| Circulating tumor DNA                                                                                                                                                                                                  | x                | Every two cycles    |                              |          |                                                                      |    |
| Survival follow up                                                                                                                                                                                                     | x                |                     |                              |          |                                                                      |    |
| a Collection of archival tumor tissue is highly encouraged but not mandatory for study entry if archival tissue is not available bRelevant medical and oncologic history should include prior cancer treatment history |                  |                     |                              |          |                                                                      |    |  
INC280 PO BID x x x x Adverse events x x x x x Optional tumor biopsy x x Circulating tumor DNA x Every two cycles Survival follow up x a Collection of archival tumor tissue is highly encouraged but not mandatory for study entry if archival tissue is not available bRelevant medical and oncologic history should include prior cancer treatment history cHematology includes: a complete blood count (CBC) consisting of red blood cells (RBCs), hemoglobin, a complete white blood cell count with differential (total neutrophils (bands and segs), lymphocytes, monocytes, eosinophils, and basophils), and platelet count d Chemistry includes: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and fractionated (e.g., direct and/or indirect) bilirubin, calcium, creatinine, glucose, magnesium, phosphate (inorganic phosphorus), potassium, protein (total), sodium, urea or blood urea nitrogen (BUN), amylase, lipase.  
eTumor evaluations, repeating the type of scan which was originally performed at screening, will be performed every two cycles and evaluated by RECIST by TIMC. At the discretion of the treating investigator, non-scheduled scans can be performed if clinically indicated.
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11. measurement of effect 11.1

For the purposes of this study, participants should be re-evaluated for response every two cycles. Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [*Eur J Ca* 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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11.1.1 definitions

Evaluable for Target Disease response. Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for target disease response. These participants will have their response classified according to the definitions stated below. (Note: Participants who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response. Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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11.1.2 disease parameters

Measurable disease. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same participant, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target** lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow up.