Clincosm LogoSign in Get a demo

Safety and Efficacy of INC280 and Buparlisib (BKM120) in Patients With Recurrent Glioblastoma

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Terminated
CT.gov ID
NCT01870726
Collaborator
(none)
43
Enrollment
13
Locations
2
Arms
35.4
Actual Duration (Months)
3.3
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study assessed the safety and the dose of the combination of INC280 and buparlisib (BKM120), as well as the anti-tumor activity of the combination, in patients with recurrent glioblastoma with PTEN mutations, homozygous deletion of PTEN or PTEN negative by IHC. In addition, the anti-tumor activity of INC280 single agent should have been assessed in patients with recurrent glioblastoma with c-Met alteration.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

This was a multi-center, open-label, phase Ib/II study. The aim of the phase Ib part was to estimate the MTD and/or to identify the recommended phase II dose (RP2D) for the combination of INC280 and buparlisib, followed by the phase II part to assess the clinical efficacy of INC280 single agent and in combination with buparlisib (BKM120), and to further assess the safety of the combination. In addition, a surgical arm should have started concurrently with the phase II part, to determine the PK/PD profile of the study drug combination in patients undergoing tumor resection for recurrent glioblastoma after 7 to 10-days treatment.

RP2D was not declared due to a lack of efficacy of the combination in the phase Ib stage, and phase II was continued with INC280 monotherapy only.

Study Design

Study Type:
Interventional
Actual Enrollment :
43 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase Ib/II, Multi-center, Open-label Study of INC280 in Combination With Buparlisib in Patients With Recurrent Glioblastoma
Actual Study Start Date :
Jan 9, 2014
Actual Primary Completion Date :
Dec 23, 2016
Actual Study Completion Date :
Dec 23, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase Ib

To estimate the safe dose of the combination INC280 and buparlisib

Drug: INC280
Phase Ib: INC280 was given at the starting dose of 200mg capsules twice daily with escalation to higher strengths. Phase II: INC280 was given at the dose of 400mg (tablets) twice daily.

Drug: Buparlisib
Buparlisib was given at the starting dose of 50mg once daily with escalation to higher strengths.
Other Names:
  • BKM120

    		•
    Experimental: Phase II

    To estimate anti-tumor efficacy of INC280 single agent and in combination with buparlisib

    Drug: INC280
    Phase Ib: INC280 was given at the starting dose of 200mg capsules twice daily with escalation to higher strengths. Phase II: INC280 was given at the dose of 400mg (tablets) twice daily.

    Outcome Measures

    Primary Outcome Measures

    1. Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 [Cycle 1, 28 days]

      A DLT is defined as an adverse event or abnormal laboratory value where the relationship to study treatment cannot be ruled out, and is not primarily related to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment (28 days) with INC280 in combination with buparlisib and meets any of the pre-defined criteria. The maximum tolerated dose was identified as INC280 300 mg BID + buparlisib 80 mg QD.

    2. Phase II: Progression Free Survival Rate (PFSR) [6 months]

      Estimated rate of patients treated during 6 months without experiencing disease progression. The Progression Free Survival Rate at 6 months was to be estimated using a Bayesian model described in the protocol. The models operating characteristics were evaluated based on the enrollment of at least 30 patients enrolled. Patients did not reach the milestone for the PFSR analysis (trial terminated); as such no analysis was performed.

    3. Phase II Surgical Arm: Concentrations of INC280 and Buparlisib in Tumor. [7 days]

      Concentrations of INC280 and buparlisib in tumor tissue.

    Secondary Outcome Measures

    1. Number of Participants With Adverse Events [throughout the duration of the trial, approximately 3 years from FPFV to LPLV]

      To characterize the safety of INC280 single agent and in combination with buparlisib including type, frequency, severity of adverse events, serious adverse events, and dose interruptions and adjustments. Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, unless otherwise specified. If CTCAE grading did not exist for an AE, the severity of mild, moderate, severe, and lifethreatening, corresponding to Grades 1 - 4, were used. CTCAE Grade 5 (death) was not used in this study but was collected as a seriousness criterion; rather, information about deaths was collected though a Death form.

    2. Pharmacokinetic Profile of INC280 - AUCtau [Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months]

      Plasma concentration profile of INC280 in combination with Buparlisib. AUCtau is the AUC from time zero to the end of dosing interval.

    3. Pharmacokinetic Profile of INC280 - Cmax [Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months]

      Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration.

    4. Pharmacokinetic Profile of INC280 - Tmax [Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months]

      Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration

    5. Pharmacokinetic Profile of INC280 - T1/2 [Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months]

      Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life

    6. Pharmacokinetic Profile of Buparlisib - AUCtau [Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months]

      Plasma concentration profile of Buparlisib in combination with INC280. AUCtau is the AUC from time zero to the end of dosing interval.

    7. Pharmacokinetic Profile of Buparlisib - Cmax [Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months]

      Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration.

    8. Pharmacokinetic Profile of Buparlisib - Tmax [Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months]

      Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration

    9. Pharmacokinetic Profile of Buparlisib - T1/2 [Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months]

      Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life

    10. Best Overall Response (BOR) [throughout the duration of the trial - approximately 3 years (from FPFV to LPLV)]

      Best Overall Response (BOR) observed in the study population of INC280 Single Agent and in Combination with Buparlisib. Responses will be assessed by the investigators following the RANO criteria with MRI or CT scans scheduled every 8 weeks. Summary of the RANO response criteria: CR has no T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; PR has ≥50% decrease T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; SD has ≥50% decrease but <25% increase T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; PD has ≥25% increase in T1-Gd+ (enhancing lesion), increase T2/FLAIR (non-enhancing lesion), presence of new lesion, deterioration in clinical status.

    11. Overall Survival (OS) [throughout the duration of the trial - approximately 3 years (FPFV to LPLV)]

      Survival rate of patients from start of treatment to date of death due to any cause. Patients did not reach the milestone for the survival data analysis (terminated early); as such no analysis was done.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • ≥ 18 years of age.

    • Histologically confirmed diagnosis of glioblastoma (after initial tumor resection or biopsy) with radiographic evidence of recurrent tumor per RANO criteria.

    • Phase Ib: Documented evidence of PTEN mutations, homozygous deletion of PTEN or PTEN negative (H Score <10) by IHC confirmed by local or central assessment.

    • Phase II: Documented evidence of c-Met amplification (GCN>5) (fusion transcripts or mutant c-Met may be eligible after discussion with Novartis) or PTEN mutations, homozygous deletion of PTEN or PTEN negative (H Score <10) by central assessment.

    • Must have received the following treatment for glioblastoma:

    •Prior treatment with radiotherapy and temozolomide; Note: A maximum of two prior chemotherapy/antibody regimens (including bevacizumab or other direct VEFG/VEGFR inhibitors) for recurrent disease are permitted.

    • Representative archival tumor sample from glioblastoma (formalin-fixed paraffine embedded tissue) must be available.

    • ECOG performance status ≤ 2.

    • Able to swallow and retain oral medication.

    • Patients in the surgical arm only: patients with recurrent glioblastoma must be eligible for surgical resection as deemed by the site Investigator.

    Exclusion Criteria:

    • Prior or current treatment with a c-MET inhibitor or HGF-targeting therapy

    • Prior treatment with a PI3K and/or mTOR inhibitors for glioblastoma or for pre-existing neoplasm transformed to glioblastoma (applicable for combination treatment arm only)

    • Received radiation (including therapeutic radioisotopes such as strontium 89) therapy ≤ 3 months prior to the first dose of study treatment and have not recovered from side effects of such therapy (≤ Grade 1) prior to the first dose of study treatment, except for alopecia.

    • Receiving treatment with medications that are known strong inhibitors or inducers of CYP3A, and cannot be discontinued 7 days prior to the start of the treatment and during the course of the study.

    • Receiving treatment with medications that are known CYP3A, CYP1A2, CYP2C8, CYP2C9 or CYP2C19 substrates with narrow therapeutic index, and cannot be discontinued during the course of the study.

    • Receiving treatment with long acting proton pump inhibitors, and cannot be discontinued 3 days prior to the start of INC280 treatment and during the course of the study.

    • Currently receiving warfarin or other coumadin-derived anticoagulants for treatment, prophylaxis or otherwise.

    • Currently receiving increasing or chronic treatment ( > 5 days) with corticosteroids (e.g. dexamethasone > 4 mg/day or other corticosteroids equivalent dose) or another immunosuppressive agent.

    • History of acute or chronic pancreatitis or any risk factors that may increase the risk of pancreatitis.

    • Active cardiac disease or a history of cardiac dysfunction.

    • Impairment of gastrointestinal (GI) function or GI disease that might significantly alter the absorption of study drug

    • Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders (defined according to DSM- IV).

    • Anxiety ≥ CTCAE grade 3

    • Any of the following baseline laboratory values:

    • Hemoglobin < 9 g/dL

    • Platelet count < 75 x 109/L

    • Absolute neutrophil count (ANC) < 1.0 x 109/L

    • INR > 1.5

    • Serum lipase > normal limits for the institution

    • Asymptomatic serum amylase > grade 2

    • Potassium, magnesium, and calcium (corrected for albumin) > normal limits for the institution

    • Total bilirubin > 1.5 x ULN

    • Serum creatinine >1.5 x ULN or creatinine clearance ≤ 45 mL/min

    • Alanine aminotransferase (AST) or aspartate aminotransferase (ALT) > 3.0 x ULN (or < 5.0 x ULN if liver metastases are present)

    • Fasting plasma glucose > 120mg/dL or > 6.7 mmol/L

    • HbA1c > 8%.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Dana Farber Cancer Institute SC Boston Massachusetts United States 02215
    2 Columbia University Medical Center- New York Presbyterian Dept of Oncology New York New York United States 10032
    3 Memorial Sloan Kettering Cancer Center Neurology New York New York United States 90033
    4 Duke University Medical Center Duke - Baker Durham North Carolina United States 27710
    5 University of Texas MD Anderson Cancer Center SC-3 Houston Texas United States 77030
    6 Novartis Investigative Site Bonn Germany 53105
    7 Novartis Investigative Site Heidelberg Germany 69120
    8 Novartis Investigative Site Tübingen Germany 72076
    9 ErasmusMC Cancer Institute - Neurooncology, RM G3-55 Rotterdam Netherlands 3075EA
    10 University Medical Center Utrecht, Rm Q05.4.300, P.O. Box 85500 Utrecht Netherlands 3508 GA
    11 Novartis Investigative Site Barcelona Catalunya Spain 08035
    12 Novartis Investigative Site Madrid Spain 28041
    13 Novartis Investigative Site St. Gallen Switzerland 9007

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01870726
    Other Study ID Numbers:
    • CINC280X2204
    • 2013-000699-14
    First Posted:
    Jun 6, 2013
    Last Update Posted:
    May 30, 2018
    Last Verified:
    May 1, 2018
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Glioblastoma multiforme (GBM), glioblastoma, Grade IV Astrocytoma, brain tumor, brain cancer, giant cell glioblastoma, gliosarcoma
    Additional relevant MeSH terms:
    Glioblastoma
    Recurrence

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail A total of 43 patients enrolled in this trial, 33 patients in the Phase Ib part of the study (patients were assigned to 6 dose combinations of INC280 with buparlisib) and 10 patients in the Phase II part of the study.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD 400 mg BID Tab
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase II: 400 mg INC280 (BID) tablet
    Period Title: Overall Study
    STARTED 5 6 4 6 7 5 10
    COMPLETED 0 0 0 0 0 0 0
    NOT COMPLETED 5 6 4 6 7 5 10

    Baseline Characteristics

    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD 400 mg BID Tab Total
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase II: 400 mg INC280 (BID) tablet Total of all reporting groups
    Overall Participants 5 6 4 6 7 5 10 43
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    2
    40%
    6
    100%
    4
    100%
    5
    83.3%
    4
    57.1%
    4
    80%
    10
    100%
    35
    81.4%
    >=65 years
    3
    60%
    0
    0%
    0
    0%
    1
    16.7%
    3
    42.9%
    1
    20%
    0
    0%
    8
    18.6%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    2
    33.3%
    2
    50%
    3
    50%
    0
    0%
    2
    40%
    7
    70%
    16
    37.2%
    Male
    5
    100%
    4
    66.7%
    2
    50%
    3
    50%
    7
    100%
    3
    60%
    3
    30%
    27
    62.8%

    Outcome Measures

    1. Primary Outcome
    Title Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1
    Description A DLT is defined as an adverse event or abnormal laboratory value where the relationship to study treatment cannot be ruled out, and is not primarily related to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment (28 days) with INC280 in combination with buparlisib and meets any of the pre-defined criteria. The maximum tolerated dose was identified as INC280 300 mg BID + buparlisib 80 mg QD.
    Time Frame Cycle 1, 28 days

    Outcome Measure Data

    Analysis Population Description
    Dose determining set (DDS) consisted of all patients from the SAS who either met the minimum exposure criterion and had sufficient safety evaluations during Cycle 1, or discontinued earlier due to DLT during Cycle 1.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 4 5 4 6 7 4
    Personality Change
    0
    (1257.87)
    1
    (2291.80)
    0
    (2604.72)
    0
    (2702.56)
    0
    (2702.47)
    0
    (5627.79)
    Nausea
    0
    0
    0
    0
    1
    0
    Aspartate Aminotransferase Increased
    0
    0
    0
    0
    0
    2
    2. Primary Outcome
    Title Phase II: Progression Free Survival Rate (PFSR)
    Description Estimated rate of patients treated during 6 months without experiencing disease progression. The Progression Free Survival Rate at 6 months was to be estimated using a Bayesian model described in the protocol. The models operating characteristics were evaluated based on the enrollment of at least 30 patients enrolled. Patients did not reach the milestone for the PFSR analysis (trial terminated); as such no analysis was performed.
    Time Frame 6 months

    Outcome Measure Data

    Analysis Population Description
    Based on the phase I, a RP2D was not determined for the combination arm (Phase II combination arms were not opened). Patients did not reach the milestone needed for the PFSR analysis (at minimum the Bayesian model requires 30 patients) due to early termination, as such no analysis for PFSR was performed.
    Arm/Group Title BID Tab+Buparlisib
    Arm/Group Description Phase II: INC280 (BID) as a single agent and in combination with buparlisib
    Measure Participants 0
    3. Primary Outcome
    Title Phase II Surgical Arm: Concentrations of INC280 and Buparlisib in Tumor.
    Description Concentrations of INC280 and buparlisib in tumor tissue.
    Time Frame 7 days

    Outcome Measure Data

    Analysis Population Description
    Based on the phase I, a RP2D was not determined for the combination and the phase II combination arms were not opened.
    Arm/Group Title BID + QD
    Arm/Group Description The combination of INC280 (BID) and Buparlisib (QD).
    Measure Participants 0
    4. Secondary Outcome
    Title Number of Participants With Adverse Events
    Description To characterize the safety of INC280 single agent and in combination with buparlisib including type, frequency, severity of adverse events, serious adverse events, and dose interruptions and adjustments. Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, unless otherwise specified. If CTCAE grading did not exist for an AE, the severity of mild, moderate, severe, and lifethreatening, corresponding to Grades 1 - 4, were used. CTCAE Grade 5 (death) was not used in this study but was collected as a seriousness criterion; rather, information about deaths was collected though a Death form.
    Time Frame throughout the duration of the trial, approximately 3 years from FPFV to LPLV

    Outcome Measure Data

    Analysis Population Description
    Safety Analysis Set (SAS): The SAS comprised all patients who received at least one full or partial dose of study treatment. Patients were analyzed according to the treatment actually received. The SAS was used for all safety analyses.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab + 80 mg QD 400 mg BID Tab + 80 mg QD 400 mg BID Tab
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: the combination of 400 mg INC280 (BID) tablet and 80 mg Buparlisib (QD) once daily Phase II: 400 mg INC280 (BID) tablet
    Measure Participants 5 6 4 6 7 5 9
    Adverse events
    5
    100%
    6
    100%
    4
    100%
    6
    100%
    7
    100%
    5
    100%
    9
    90%
    Treatment-related AEs
    4
    80%
    4
    66.7%
    4
    100%
    4
    66.7%
    7
    100%
    5
    100%
    6
    60%
    AEs with grade ≥ 3
    5
    100%
    4
    66.7%
    4
    100%
    2
    33.3%
    5
    71.4%
    4
    80%
    8
    80%
    SAEs
    3
    60%
    2
    33.3%
    3
    75%
    3
    50%
    3
    42.9%
    4
    80%
    2
    20%
    AEs leading to discontinuation
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    1
    20%
    0
    0%
    AEs leading to dose adjustment/interruption
    2
    40%
    3
    50%
    2
    50%
    4
    66.7%
    4
    57.1%
    4
    80%
    5
    50%
    AEs requiring additional therapy
    4
    80%
    5
    83.3%
    3
    75%
    5
    83.3%
    7
    100%
    5
    100%
    7
    70%
    5. Secondary Outcome
    Title Pharmacokinetic Profile of INC280 - AUCtau
    Description Plasma concentration profile of INC280 in combination with Buparlisib. AUCtau is the AUC from time zero to the end of dosing interval.
    Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 5 5 4 6 4 5
    Cycle 1 Day 1
    2435.6
    (1257.87)
    3005.9
    (2291.80)
    4789.7
    (2604.72)
    5071.7
    (2702.56)
    5732.2
    (2702.47)
    11127.7
    (5627.79)
    Cycle 1 Day 15
    5749.3
    11261.7
    10581.0
    2779.4
    12801.3
    16590.6
    Cycle 2 Day 1
    4894.6
    2655.6
    23498.3
    10554.3
    9593.5
    13051.1
    6. Secondary Outcome
    Title Pharmacokinetic Profile of INC280 - Cmax
    Description Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration.
    Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 5 5 4 6 4 5
    Cycle 1 Day 1
    618.0
    (509.47)
    880.0
    (481.70)
    960.5
    (898.05)
    860.0
    (1081.12)
    1990.0
    (778.91)
    3635.0
    (1499.76)
    Cycle 1 Day 15
    1560.0
    2005.0
    3480.0
    545.5
    3610.0
    4850.0
    Cycle 2 Day 1
    1200.0
    2142.5
    5010.0
    2254.5
    3080.0
    3220.0
    7. Secondary Outcome
    Title Pharmacokinetic Profile of INC280 - Tmax
    Description Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration
    Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 5 5 4 6 4 5
    Cycle 1 Day 1
    1.1
    (509.47)
    2.0
    (481.70)
    1.5
    (898.05)
    1.3
    (1081.12)
    1.6
    (778.91)
    2.0
    (1499.76)
    Cycle 1 Day 15
    1.9
    2.0
    2.0
    2.6
    1.0
    1.5
    Cycle 2 Day 1
    2.0
    2.0
    1.5
    2.1
    1.5
    1.0
    8. Secondary Outcome
    Title Pharmacokinetic Profile of INC280 - T1/2
    Description Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life
    Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 5 5 4 6 4 5
    Cycle 1 Day 15
    13.4
    20.8
    26.0
    7.3
    13.1
    8.0
    Cycle 2 Day 1
    9.9
    17.4
    26.3
    8.7
    6.3
    4.3
    9. Secondary Outcome
    Title Pharmacokinetic Profile of Buparlisib - AUCtau
    Description Plasma concentration profile of Buparlisib in combination with INC280. AUCtau is the AUC from time zero to the end of dosing interval.
    Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 5 5 4 6 4 5
    Cycle 1 Day 1
    3072.0
    (1257.87)
    1865.0
    (2291.80)
    3328.2
    (2604.72)
    3825.8
    (2702.56)
    4425.3
    (2702.47)
    3658.8
    (5627.79)
    Cycle 1 Day 15
    8728.5
    4591.9
    6108.4
    10844.6
    10366.5
    8535.1
    Cycle 2 Day 1
    7930.8
    3776.7
    6976.0
    5903.0
    7857.2
    7344.3
    10. Secondary Outcome
    Title Pharmacokinetic Profile of Buparlisib - Cmax
    Description Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration.
    Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 5 5 4 6 4 5
    Cycle 1 Day 1
    484.0
    (509.47)
    351.0
    (481.70)
    399.0
    (898.05)
    522.0
    (1081.12)
    508.0
    (778.91)
    475.0
    (1499.76)
    Cycle 1 Day 15
    664.0
    459.0
    542.0
    785.0
    814.0
    788.5
    Cycle 2 Day 1
    560.0
    377.5
    611.0
    529.5
    735.0
    600.0
    11. Secondary Outcome
    Title Pharmacokinetic Profile of Buparlisib - Tmax
    Description Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration
    Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 5 5 4 6 4 5
    Cycle 1 Day 1
    1.0
    (509.47)
    1.0
    (481.70)
    1.0
    (898.05)
    0.6
    (1081.12)
    1.2
    (778.91)
    1.0
    (1499.76)
    Cycle 1 Day 15
    0.9
    2.0
    1.0
    1.6
    1.0
    1.3
    Cycle 2 Day 1
    1.0
    1.5
    1.0
    1.8
    1.0
    1.0
    12. Secondary Outcome
    Title Pharmacokinetic Profile of Buparlisib - T1/2
    Description Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life
    Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
    Measure Participants 5 5 4 6 4 5
    Cycle 1 Day 15
    37.3
    31.1
    21.8
    30.9
    38.0
    22.8
    Cycle 2 Day 1
    34.0
    21.3
    27.0
    17.2
    20.1
    12.0
    13. Secondary Outcome
    Title Best Overall Response (BOR)
    Description Best Overall Response (BOR) observed in the study population of INC280 Single Agent and in Combination with Buparlisib. Responses will be assessed by the investigators following the RANO criteria with MRI or CT scans scheduled every 8 weeks. Summary of the RANO response criteria: CR has no T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; PR has ≥50% decrease T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; SD has ≥50% decrease but <25% increase T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; PD has ≥25% increase in T1-Gd+ (enhancing lesion), increase T2/FLAIR (non-enhancing lesion), presence of new lesion, deterioration in clinical status.
    Time Frame throughout the duration of the trial - approximately 3 years (from FPFV to LPLV)

    Outcome Measure Data

    Analysis Population Description
    FAS
    Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD 400 mg BID Tab
    Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase II: 400 mg INC280 (BID) tablet
    Measure Participants 5 6 4 6 7 5 10
    Complete Response (CR)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Partial Response (PR)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Stable Disease (SD)
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    3
    30%
    Progressive Disease (PD)
    5
    100%
    5
    83.3%
    4
    100%
    4
    66.7%
    7
    100%
    4
    80%
    6
    60%
    Unknown (UNK)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Not Assessed
    0
    0%
    1
    16.7%
    0
    0%
    1
    16.7%
    0
    0%
    1
    20%
    1
    10%
    14. Secondary Outcome
    Title Overall Survival (OS)
    Description Survival rate of patients from start of treatment to date of death due to any cause. Patients did not reach the milestone for the survival data analysis (terminated early); as such no analysis was done.
    Time Frame throughout the duration of the trial - approximately 3 years (FPFV to LPLV)

    Outcome Measure Data

    Analysis Population Description
    Based on the phase I, a RP2D was not determined for the combination arm (Phase II combination arms were not opened). Patients did not reach the milestone needed for the OS analysis (at minimum the Bayesian model requires 30 patients) due to early termination, as such no analysis for OS was done.
    Arm/Group Title All Patients
    Arm/Group Description The combination of INC280 (BID) and Buparlisib (QD).
    Measure Participants 0

    Adverse Events

    Time Frame Treatment Emergent Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit, approximately 3 years.
    Adverse Event Reporting Description Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Arm/Group Title INC280 200 mg BID Tab 200 mg BID Cap+50 mg QD 400 mg BID Cap + 50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab+ 80 mg QD 400 mg BID Tab+80 mg QD All Patients (Phase Ib) 400 mg BID Tab All Patients (Phase II)
    Arm/Group Description Phase II: 200mg INC280 (BID) tablet in Phase II. A patient never received the intended PhII dose as planned (400 mg BID) but is resented as a separate group for safety. Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: All Patients with the combination of INC280 (BID) and Buparlisib (QD) once daily. Phase II: 400mg INC280 (BID) tablet in Phase II. Phase II: All patients treated with INC280 (BID) tablet once daily in the Phase II.
    All Cause Mortality
    INC280 200 mg BID Tab 200 mg BID Cap+50 mg QD 400 mg BID Cap + 50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab+ 80 mg QD 400 mg BID Tab+80 mg QD All Patients (Phase Ib) 400 mg BID Tab All Patients (Phase II)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    INC280 200 mg BID Tab 200 mg BID Cap+50 mg QD 400 mg BID Cap + 50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab+ 80 mg QD 400 mg BID Tab+80 mg QD All Patients (Phase Ib) 400 mg BID Tab All Patients (Phase II)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/1 (100%) 3/5 (60%) 2/6 (33.3%) 3/4 (75%) 3/6 (50%) 3/7 (42.9%) 4/5 (80%) 18/33 (54.5%) 2/9 (22.2%) 3/10 (30%)
    Gastrointestinal disorders
    ABDOMINAL PAIN 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    DIARRHOEA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    GASTRIC ULCER 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    NAUSEA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    General disorders
    PYREXIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Infections and infestations
    FEBRILE INFECTION 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    INFLUENZA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PERITONITIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    PNEUMOCYSTIS JIROVECII PNEUMONIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PNEUMONIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    URINARY TRACT INFECTION 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Injury, poisoning and procedural complications
    FALL 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 3/5 (60%) 4/33 (12.1%) 0/9 (0%) 0/10 (0%)
    ASPARTATE AMINOTRANSFERASE INCREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 3/5 (60%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    Metabolism and nutrition disorders
    HYPONATRAEMIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Nervous system disorders
    APHASIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    ATAXIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 1/5 (20%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    BRAIN OEDEMA 1/1 (100%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 0/9 (0%) 1/10 (10%)
    HAEMORRHAGE INTRACRANIAL 0/1 (0%) 2/5 (40%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    HEMIPARESIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    LETHARGY 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    NEUROLOGICAL DECOMPENSATION 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PARAPARESIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PARTIAL SEIZURES 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    SEIZURE 0/1 (0%) 0/5 (0%) 0/6 (0%) 2/4 (50%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    Psychiatric disorders
    APATHY 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Skin and subcutaneous tissue disorders
    DERMATITIS ALLERGIC 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    RASH 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Vascular disorders
    EMBOLISM 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HYPERTENSION 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Other (Not Including Serious) Adverse Events
    INC280 200 mg BID Tab 200 mg BID Cap+50 mg QD 400 mg BID Cap + 50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab+ 80 mg QD 400 mg BID Tab+80 mg QD All Patients (Phase Ib) 400 mg BID Tab All Patients (Phase II)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/1 (0%) 5/5 (100%) 6/6 (100%) 4/4 (100%) 6/6 (100%) 7/7 (100%) 5/5 (100%) 33/33 (100%) 9/9 (100%) 9/10 (90%)
    Blood and lymphatic system disorders
    ANAEMIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    LEUKOPENIA 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    NEUTROPENIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    THROMBOCYTOPENIA 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    Cardiac disorders
    LEFT VENTRICULAR DYSFUNCTION 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    SINUS BRADYCARDIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Eye disorders
    DIPLOPIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    VISION BLURRED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    Gastrointestinal disorders
    ABDOMINAL PAIN 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 1/5 (20%) 2/33 (6.1%) 1/9 (11.1%) 1/10 (10%)
    ABDOMINAL PAIN UPPER 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    CONSTIPATION 0/1 (0%) 2/5 (40%) 1/6 (16.7%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 5/33 (15.2%) 3/9 (33.3%) 3/10 (30%)
    DIARRHOEA 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 1/4 (25%) 1/6 (16.7%) 2/7 (28.6%) 1/5 (20%) 7/33 (21.2%) 1/9 (11.1%) 1/10 (10%)
    DYSPEPSIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 2/6 (33.3%) 2/7 (28.6%) 1/5 (20%) 6/33 (18.2%) 1/9 (11.1%) 1/10 (10%)
    DYSPHAGIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 1/7 (14.3%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    GASTROOESOPHAGEAL REFLUX DISEASE 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    HAEMORRHOIDS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    NAUSEA 0/1 (0%) 1/5 (20%) 2/6 (33.3%) 1/4 (25%) 1/6 (16.7%) 3/7 (42.9%) 2/5 (40%) 10/33 (30.3%) 2/9 (22.2%) 2/10 (20%)
    RECTAL ULCER HAEMORRHAGE 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    STOMATITIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 1/5 (20%) 2/33 (6.1%) 1/9 (11.1%) 1/10 (10%)
    VOMITING 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 2/5 (40%) 5/33 (15.2%) 1/9 (11.1%) 1/10 (10%)
    General disorders
    ASTHENIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 2/33 (6.1%) 1/9 (11.1%) 1/10 (10%)
    CHILLS 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    FATIGUE 0/1 (0%) 2/5 (40%) 3/6 (50%) 1/4 (25%) 2/6 (33.3%) 2/7 (28.6%) 2/5 (40%) 12/33 (36.4%) 3/9 (33.3%) 3/10 (30%)
    GAIT DISTURBANCE 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    GENERAL PHYSICAL HEALTH DETERIORATION 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    OEDEMA PERIPHERAL 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 1/6 (16.7%) 0/7 (0%) 2/5 (40%) 4/33 (12.1%) 1/9 (11.1%) 1/10 (10%)
    PYREXIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Hepatobiliary disorders
    HEPATIC STEATOSIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HYPERBILIRUBINAEMIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Infections and infestations
    ORAL HERPES 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    ORCHITIS 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Injury, poisoning and procedural complications
    CONTUSION 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    FALL 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 2/5 (40%) 3/33 (9.1%) 2/9 (22.2%) 2/10 (20%)
    LACERATION 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 1/4 (25%) 0/6 (0%) 2/7 (28.6%) 4/5 (80%) 9/33 (27.3%) 0/9 (0%) 0/10 (0%)
    AMYLASE INCREASED 0/1 (0%) 1/5 (20%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 2/33 (6.1%) 2/9 (22.2%) 2/10 (20%)
    ASPARTATE AMINOTRANSFERASE INCREASED 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 1/4 (25%) 0/6 (0%) 2/7 (28.6%) 3/5 (60%) 8/33 (24.2%) 0/9 (0%) 0/10 (0%)
    BLOOD ALBUMIN DECREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    BLOOD BILIRUBIN INCREASED 0/1 (0%) 1/5 (20%) 0/6 (0%) 2/4 (50%) 0/6 (0%) 1/7 (14.3%) 1/5 (20%) 5/33 (15.2%) 1/9 (11.1%) 1/10 (10%)
    BLOOD CREATININE INCREASED 0/1 (0%) 2/5 (40%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 2/5 (40%) 5/33 (15.2%) 1/9 (11.1%) 1/10 (10%)
    BLOOD GLUCOSE INCREASED 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    BLOOD POTASSIUM INCREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    BLOOD TRIGLYCERIDES INCREASED 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    GLOMERULAR FILTRATION RATE DECREASED 0/1 (0%) 2/5 (40%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 4/33 (12.1%) 0/9 (0%) 0/10 (0%)
    INSULIN C-PEPTIDE INCREASED 0/1 (0%) 2/5 (40%) 1/6 (16.7%) 1/4 (25%) 0/6 (0%) 2/7 (28.6%) 0/5 (0%) 6/33 (18.2%) 0/9 (0%) 0/10 (0%)
    LIPASE INCREASED 0/1 (0%) 1/5 (20%) 0/6 (0%) 1/4 (25%) 1/6 (16.7%) 0/7 (0%) 1/5 (20%) 4/33 (12.1%) 3/9 (33.3%) 3/10 (30%)
    LYMPHOCYTE COUNT DECREASED 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 2/7 (28.6%) 0/5 (0%) 3/33 (9.1%) 1/9 (11.1%) 1/10 (10%)
    NEUTROPHIL COUNT DECREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PLATELET COUNT DECREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 2/5 (40%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    PROTEIN TOTAL DECREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PROTHROMBIN TIME PROLONGED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    WEIGHT DECREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    WEIGHT INCREASED 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    Metabolism and nutrition disorders
    DECREASED APPETITE 0/1 (0%) 2/5 (40%) 1/6 (16.7%) 1/4 (25%) 1/6 (16.7%) 1/7 (14.3%) 0/5 (0%) 6/33 (18.2%) 0/9 (0%) 0/10 (0%)
    HYPERGLYCAEMIA 0/1 (0%) 2/5 (40%) 0/6 (0%) 2/4 (50%) 1/6 (16.7%) 2/7 (28.6%) 0/5 (0%) 7/33 (21.2%) 1/9 (11.1%) 1/10 (10%)
    HYPERURICAEMIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HYPOALBUMINAEMIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HYPOGLYCAEMIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HYPOKALAEMIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HYPONATRAEMIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HYPOPHOSPHATAEMIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 2/7 (28.6%) 0/5 (0%) 4/33 (12.1%) 0/9 (0%) 0/10 (0%)
    Musculoskeletal and connective tissue disorders
    BACK PAIN 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    MUSCLE SPASMS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    MUSCULAR WEAKNESS 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 1/5 (20%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    MUSCULOSKELETAL PAIN 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    MYALGIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 2/7 (28.6%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    PAIN IN EXTREMITY 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    Nervous system disorders
    AMNESIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    APHASIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 2/7 (28.6%) 1/5 (20%) 4/33 (12.1%) 0/9 (0%) 0/10 (0%)
    ATAXIA 0/1 (0%) 2/5 (40%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    BRAIN OEDEMA 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    COGNITIVE DISORDER 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    DISTURBANCE IN ATTENTION 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 1/4 (25%) 1/6 (16.7%) 1/7 (14.3%) 2/5 (40%) 7/33 (21.2%) 0/9 (0%) 0/10 (0%)
    DIZZINESS 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 2/33 (6.1%) 1/9 (11.1%) 1/10 (10%)
    DYSARTHRIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 1/5 (20%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    DYSKINESIA 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    DYSMETRIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    EPILEPSY 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    FACIAL PARALYSIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    FACIAL PARESIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HEADACHE 0/1 (0%) 2/5 (40%) 0/6 (0%) 1/4 (25%) 2/6 (33.3%) 2/7 (28.6%) 2/5 (40%) 9/33 (27.3%) 4/9 (44.4%) 4/10 (40%)
    HEMIANOPIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    HEMIANOPIA HOMONYMOUS 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    HEMIPARESIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 2/4 (50%) 1/6 (16.7%) 1/7 (14.3%) 1/5 (20%) 5/33 (15.2%) 1/9 (11.1%) 1/10 (10%)
    HEMIPLEGIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    LETHARGY 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    MEMORY IMPAIRMENT 0/1 (0%) 0/5 (0%) 2/6 (33.3%) 1/4 (25%) 0/6 (0%) 2/7 (28.6%) 2/5 (40%) 7/33 (21.2%) 0/9 (0%) 0/10 (0%)
    NEUROLOGIC NEGLECT SYNDROME 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    NEUROLOGICAL SYMPTOM 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    PARAESTHESIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PARALYSIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PARAPARESIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    PARESIS 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    PERIPHERAL MOTOR NEUROPATHY 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    PERIPHERAL SENSORY NEUROPATHY 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 2/33 (6.1%) 1/9 (11.1%) 1/10 (10%)
    PYRAMIDAL TRACT SYNDROME 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    RESTLESS LEGS SYNDROME 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    SEIZURE 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 1/4 (25%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 3/33 (9.1%) 1/9 (11.1%) 1/10 (10%)
    SOMNOLENCE 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 1/4 (25%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 4/33 (12.1%) 1/9 (11.1%) 1/10 (10%)
    TREMOR 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    VITH NERVE PARALYSIS 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Psychiatric disorders
    AGITATION 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    ANXIETY 0/1 (0%) 2/5 (40%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 2/7 (28.6%) 1/5 (20%) 6/33 (18.2%) 1/9 (11.1%) 1/10 (10%)
    APATHY 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    BRADYPHRENIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    CONFUSIONAL STATE 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    DEPRESSED MOOD 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    DEPRESSION 0/1 (0%) 2/5 (40%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 3/7 (42.9%) 2/5 (40%) 8/33 (24.2%) 1/9 (11.1%) 1/10 (10%)
    DISORIENTATION 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    INSOMNIA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 1/7 (14.3%) 0/5 (0%) 3/33 (9.1%) 1/9 (11.1%) 1/10 (10%)
    IRRITABILITY 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    MOOD ALTERED 0/1 (0%) 1/5 (20%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    PERSONALITY CHANGE 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    SLEEP DISORDER 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Renal and urinary disorders
    ACUTE KIDNEY INJURY 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    CHRONIC KIDNEY DISEASE 0/1 (0%) 0/5 (0%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    CYSTITIS NONINFECTIVE 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HAEMATURIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    MICTURITION URGENCY 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    URINARY INCONTINENCE 0/1 (0%) 1/5 (20%) 0/6 (0%) 1/4 (25%) 0/6 (0%) 1/7 (14.3%) 1/5 (20%) 4/33 (12.1%) 0/9 (0%) 0/10 (0%)
    URINARY RETENTION 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    Reproductive system and breast disorders
    TESTICULAR PAIN 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Respiratory, thoracic and mediastinal disorders
    BRONCHOSPASM 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    COUGH 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 1/5 (20%) 3/33 (9.1%) 2/9 (22.2%) 2/10 (20%)
    HICCUPS 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    OROPHARYNGEAL PAIN 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    PRODUCTIVE COUGH 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    RHINORRHOEA 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Skin and subcutaneous tissue disorders
    ALOPECIA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    DERMATITIS ACNEIFORM 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    DRY SKIN 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 2/5 (40%) 2/33 (6.1%) 1/9 (11.1%) 1/10 (10%)
    PRURITUS 0/1 (0%) 1/5 (20%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 1/5 (20%) 3/33 (9.1%) 0/9 (0%) 0/10 (0%)
    RASH 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 1/9 (11.1%) 1/10 (10%)
    RASH MACULAR 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    RASH MACULO-PAPULAR 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 1/5 (20%) 2/33 (6.1%) 0/9 (0%) 0/10 (0%)
    SKIN ATROPHY 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    Vascular disorders
    EMBOLISM 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 1/6 (16.7%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HAEMATOMA 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 1/5 (20%) 1/33 (3%) 0/9 (0%) 0/10 (0%)
    HOT FLUSH 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 0/33 (0%) 1/9 (11.1%) 1/10 (10%)
    HYPERTENSION 0/1 (0%) 0/5 (0%) 0/6 (0%) 0/4 (0%) 0/6 (0%) 1/7 (14.3%) 1/5 (20%) 2/33 (6.1%) 1/9 (11.1%) 1/10 (10%)
    HYPOTENSION 0/1 (0%) 0/5 (0%) 1/6 (16.7%) 0/4 (0%) 0/6 (0%) 0/7 (0%) 0/5 (0%) 1/33 (3%) 0/9 (0%) 0/10 (0%)

    Limitations/Caveats

    At the end of Phase Ib, it was decided not to enroll patients in the two Phase II arms evaluating INC280 with buparlisib. The phase II INC280 single agent arm was halted before it reached target enrollment.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862-778-8300
    Email Novartis.email@novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01870726
    Other Study ID Numbers:
    • CINC280X2204
    • 2013-000699-14
    First Posted:
    Jun 6, 2013
    Last Update Posted:
    May 30, 2018
    Last Verified:
    May 1, 2018