c-MET Inhibitor; PI3K Inhibitor, PTEN Mutations, Homozygous Del. of PTEN or PTEN Neg. by IHC, c-Met Ampli. by FISH, INC280, BKM120, Buparlisib; Recurrent GBM
Conditions
Keywords
Glioblastoma multiforme (GBM), glioblastoma, Grade IV Astrocytoma, brain tumor, brain cancer, giant cell glioblastoma, gliosarcoma
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.
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.
Interventions
DRUGINC280
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.
DRUGBuparlisib
Buparlisib was given at the starting dose of 50mg once daily with escalation to higher strengths.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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%.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Phase II Surgical Arm: Concentrations of INC280 and Buparlisib in Tumor. | 7 days | Concentrations of INC280 and buparlisib in tumor tissue. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
Countries
Germany, Netherlands, Spain, Switzerland, United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 200 mg BID Cap+50 mg QD Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. | 5 |
| 400 mg BID Cap+50 mg QD Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. | 6 |
| 500 mg BID Cap+50 mg QD Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. | 4 |
| 500 mg BID Cap+80 mg QD Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. | 6 |
| 300 mg BID Tab +80 mg QD Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. | 7 |
| 400 mg BID Tab +80 mg QD Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. | 5 |
| 400 mg BID Tab Phase II: 400 mg INC280 (BID) tablet | 10 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Progressive disease | 5 | 5 | 4 | 5 | 6 | 4 | 10 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal of informed consent | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 6 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 10 Participants | 35 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 0 Participants | 2 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 2 Participants | 3 Participants | 7 Participants | 3 Participants | 3 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 1 | 5 / 5 | 6 / 6 | 4 / 4 | 6 / 6 | 7 / 7 | 5 / 5 | 33 / 33 | 9 / 9 | 9 / 10 |
| serious Total, serious adverse events | 1 / 1 | 3 / 5 | 2 / 6 | 3 / 4 | 3 / 6 | 3 / 7 | 4 / 5 | 18 / 33 | 2 / 9 | 3 / 10 |
Outcome results
Primary
Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1
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
Population: 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 | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Nausea | 0 Number of Patients | — |
| 200 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Personality Change | 0 Number of Patients | 1257.87 |
| 200 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Aspartate Aminotransferase Increased | 0 Number of Patients | — |
| 400 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Nausea | 0 Number of Patients | — |
| 400 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Personality Change | 1 Number of Patients | 2291.8 |
| 400 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Aspartate Aminotransferase Increased | 0 Number of Patients | — |
| 500 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Nausea | 0 Number of Patients | — |
| 500 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Personality Change | 0 Number of Patients | 2604.72 |
| 500 mg BID Cap+50 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Aspartate Aminotransferase Increased | 0 Number of Patients | — |
| 500 mg BID Cap+80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Nausea | 0 Number of Patients | — |
| 500 mg BID Cap+80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Personality Change | 0 Number of Patients | 2702.56 |
| 500 mg BID Cap+80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Aspartate Aminotransferase Increased | 0 Number of Patients | — |
| 300 mg BID Tab +80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Nausea | 1 Number of Patients | — |
| 300 mg BID Tab +80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Personality Change | 0 Number of Patients | 2702.47 |
| 300 mg BID Tab +80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Aspartate Aminotransferase Increased | 0 Number of Patients | — |
| 400 mg BID Tab+80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Personality Change | 0 Number of Patients | 5627.79 |
| 400 mg BID Tab+80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Aspartate Aminotransferase Increased | 2 Number of Patients | — |
| 400 mg BID Tab+80 mg QD | Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1 | Nausea | 0 Number of Patients | — |
Primary
Phase II: Progression Free Survival Rate (PFSR)
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
Population: 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.
Primary
Phase II Surgical Arm: Concentrations of INC280 and Buparlisib in Tumor.
Concentrations of INC280 and buparlisib in tumor tissue.
Time frame: 7 days
Population: Based on the phase I, a RP2D was not determined for the combination and the phase II combination arms were not opened.
Secondary
Best Overall Response (BOR)
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)
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Not Assessed | 0 Participants |
| 200 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Participants |
| 200 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 5 Participants |
| 200 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Unknown (UNK) | 0 Participants |
| 200 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 0 Participants |
| 200 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Participants |
| 400 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 5 Participants |
| 400 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Unknown (UNK) | 0 Participants |
| 400 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Participants |
| 400 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Participants |
| 400 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Not Assessed | 1 Participants |
| 400 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 0 Participants |
| 500 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 4 Participants |
| 500 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Participants |
| 500 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Not Assessed | 0 Participants |
| 500 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 0 Participants |
| 500 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Participants |
| 500 mg BID Cap+50 mg QD | Best Overall Response (BOR) | Unknown (UNK) | 0 Participants |
| 500 mg BID Cap+80 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Participants |
| 500 mg BID Cap+80 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 4 Participants |
| 500 mg BID Cap+80 mg QD | Best Overall Response (BOR) | Not Assessed | 1 Participants |
| 500 mg BID Cap+80 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Participants |
| 500 mg BID Cap+80 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 1 Participants |
| 500 mg BID Cap+80 mg QD | Best Overall Response (BOR) | Unknown (UNK) | 0 Participants |
| 300 mg BID Tab +80 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Participants |
| 300 mg BID Tab +80 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 7 Participants |
| 300 mg BID Tab +80 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Participants |
| 300 mg BID Tab +80 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 0 Participants |
| 300 mg BID Tab +80 mg QD | Best Overall Response (BOR) | Unknown (UNK) | 0 Participants |
| 300 mg BID Tab +80 mg QD | Best Overall Response (BOR) | Not Assessed | 0 Participants |
| 400 mg BID Tab+80 mg QD | Best Overall Response (BOR) | Progressive Disease (PD) | 4 Participants |
| 400 mg BID Tab+80 mg QD | Best Overall Response (BOR) | Stable Disease (SD) | 0 Participants |
| 400 mg BID Tab+80 mg QD | Best Overall Response (BOR) | Not Assessed | 1 Participants |
| 400 mg BID Tab+80 mg QD | Best Overall Response (BOR) | Unknown (UNK) | 0 Participants |
| 400 mg BID Tab+80 mg QD | Best Overall Response (BOR) | Partial Response (PR) | 0 Participants |
| 400 mg BID Tab+80 mg QD | Best Overall Response (BOR) | Complete Response (CR) | 0 Participants |
| 400 mg BID Tab | Best Overall Response (BOR) | Progressive Disease (PD) | 6 Participants |
| 400 mg BID Tab | Best Overall Response (BOR) | Complete Response (CR) | 0 Participants |
| 400 mg BID Tab | Best Overall Response (BOR) | Stable Disease (SD) | 3 Participants |
| 400 mg BID Tab | Best Overall Response (BOR) | Not Assessed | 1 Participants |
| 400 mg BID Tab | Best Overall Response (BOR) | Unknown (UNK) | 0 Participants |
| 400 mg BID Tab | Best Overall Response (BOR) | Partial Response (PR) | 0 Participants |
Secondary
Number of Participants With Adverse Events
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | SAEs | 3 Participants |
| 200 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs leading to dose adjustment/interruption | 2 Participants |
| 200 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs with grade ≥ 3 | 5 Participants |
| 200 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | Treatment-related AEs | 4 Participants |
| 200 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | Adverse events | 5 Participants |
| 200 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs requiring additional therapy | 4 Participants |
| 200 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs leading to discontinuation | 0 Participants |
| 400 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | SAEs | 2 Participants |
| 400 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs leading to discontinuation | 0 Participants |
| 400 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs leading to dose adjustment/interruption | 3 Participants |
| 400 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs requiring additional therapy | 5 Participants |
| 400 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | Adverse events | 6 Participants |
| 400 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | Treatment-related AEs | 4 Participants |
| 400 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs with grade ≥ 3 | 4 Participants |
| 500 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs leading to dose adjustment/interruption | 2 Participants |
| 500 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | Adverse events | 4 Participants |
| 500 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs requiring additional therapy | 3 Participants |
| 500 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs leading to discontinuation | 0 Participants |
| 500 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | AEs with grade ≥ 3 | 4 Participants |
| 500 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | SAEs | 3 Participants |
| 500 mg BID Cap+50 mg QD | Number of Participants With Adverse Events | Treatment-related AEs | 4 Participants |
| 500 mg BID Cap+80 mg QD | Number of Participants With Adverse Events | AEs with grade ≥ 3 | 2 Participants |
| 500 mg BID Cap+80 mg QD | Number of Participants With Adverse Events | AEs leading to dose adjustment/interruption | 4 Participants |
| 500 mg BID Cap+80 mg QD | Number of Participants With Adverse Events | AEs requiring additional therapy | 5 Participants |
| 500 mg BID Cap+80 mg QD | Number of Participants With Adverse Events | Adverse events | 6 Participants |
| 500 mg BID Cap+80 mg QD | Number of Participants With Adverse Events | Treatment-related AEs | 4 Participants |
| 500 mg BID Cap+80 mg QD | Number of Participants With Adverse Events | SAEs | 3 Participants |
| 500 mg BID Cap+80 mg QD | Number of Participants With Adverse Events | AEs leading to discontinuation | 0 Participants |
| 300 mg BID Tab +80 mg QD | Number of Participants With Adverse Events | AEs leading to dose adjustment/interruption | 4 Participants |
| 300 mg BID Tab +80 mg QD | Number of Participants With Adverse Events | Treatment-related AEs | 7 Participants |
| 300 mg BID Tab +80 mg QD | Number of Participants With Adverse Events | AEs leading to discontinuation | 1 Participants |
| 300 mg BID Tab +80 mg QD | Number of Participants With Adverse Events | Adverse events | 7 Participants |
| 300 mg BID Tab +80 mg QD | Number of Participants With Adverse Events | AEs with grade ≥ 3 | 5 Participants |
| 300 mg BID Tab +80 mg QD | Number of Participants With Adverse Events | AEs requiring additional therapy | 7 Participants |
| 300 mg BID Tab +80 mg QD | Number of Participants With Adverse Events | SAEs | 3 Participants |
| 400 mg BID Tab+80 mg QD | Number of Participants With Adverse Events | SAEs | 4 Participants |
| 400 mg BID Tab+80 mg QD | Number of Participants With Adverse Events | Adverse events | 5 Participants |
| 400 mg BID Tab+80 mg QD | Number of Participants With Adverse Events | AEs leading to discontinuation | 1 Participants |
| 400 mg BID Tab+80 mg QD | Number of Participants With Adverse Events | Treatment-related AEs | 5 Participants |
| 400 mg BID Tab+80 mg QD | Number of Participants With Adverse Events | AEs leading to dose adjustment/interruption | 4 Participants |
| 400 mg BID Tab+80 mg QD | Number of Participants With Adverse Events | AEs requiring additional therapy | 5 Participants |
| 400 mg BID Tab+80 mg QD | Number of Participants With Adverse Events | AEs with grade ≥ 3 | 4 Participants |
| 400 mg BID Tab | Number of Participants With Adverse Events | AEs leading to dose adjustment/interruption | 5 Participants |
| 400 mg BID Tab | Number of Participants With Adverse Events | AEs requiring additional therapy | 7 Participants |
| 400 mg BID Tab | Number of Participants With Adverse Events | AEs with grade ≥ 3 | 8 Participants |
| 400 mg BID Tab | Number of Participants With Adverse Events | SAEs | 2 Participants |
| 400 mg BID Tab | Number of Participants With Adverse Events | Adverse events | 9 Participants |
| 400 mg BID Tab | Number of Participants With Adverse Events | Treatment-related AEs | 6 Participants |
| 400 mg BID Tab | Number of Participants With Adverse Events | AEs leading to discontinuation | 0 Participants |
Secondary
Overall Survival (OS)
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)
Population: 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.
Secondary
Pharmacokinetic Profile of Buparlisib - AUCtau
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
Population: Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 15 | 8728.5 hr*ng/ml | — |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 1 | 3072.0 hr*ng/ml | Full Range 1257.87 |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 2 Day 1 | 7930.8 hr*ng/ml | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 15 | 4591.9 hr*ng/ml | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 1 | 1865.0 hr*ng/ml | Full Range 2291.8 |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 2 Day 1 | 3776.7 hr*ng/ml | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 15 | 6108.4 hr*ng/ml | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 1 | 3328.2 hr*ng/ml | Full Range 2604.72 |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 2 Day 1 | 6976.0 hr*ng/ml | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 15 | 10844.6 hr*ng/ml | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 1 | 3825.8 hr*ng/ml | Full Range 2702.56 |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 2 Day 1 | 5903.0 hr*ng/ml | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 15 | 10366.5 hr*ng/ml | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 1 | 4425.3 hr*ng/ml | Full Range 2702.47 |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 2 Day 1 | 7857.2 hr*ng/ml | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 1 | 3658.8 hr*ng/ml | Full Range 5627.79 |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 2 Day 1 | 7344.3 hr*ng/ml | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - AUCtau | Cycle 1 Day 15 | 8535.1 hr*ng/ml | — |
Secondary
Pharmacokinetic Profile of Buparlisib - Cmax
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
Population: Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 15 | 664.0 ng/ml | — |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 1 | 484.0 ng/ml | Full Range 509.47 |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 2 Day 1 | 560.0 ng/ml | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 15 | 459.0 ng/ml | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 1 | 351.0 ng/ml | Full Range 481.7 |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 2 Day 1 | 377.5 ng/ml | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 15 | 542.0 ng/ml | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 1 | 399.0 ng/ml | Full Range 898.05 |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 2 Day 1 | 611.0 ng/ml | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 2 Day 1 | 529.5 ng/ml | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 1 | 522.0 ng/ml | Full Range 1081.12 |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 15 | 785.0 ng/ml | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 1 | 508.0 ng/ml | Full Range 778.91 |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 15 | 814.0 ng/ml | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 2 Day 1 | 735.0 ng/ml | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 15 | 788.5 ng/ml | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 1 Day 1 | 475.0 ng/ml | Full Range 1499.76 |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - Cmax | Cycle 2 Day 1 | 600.0 ng/ml | — |
Secondary
Pharmacokinetic Profile of Buparlisib - T1/2
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
Population: Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 1 Day 15 | 37.3 hr |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 2 Day 1 | 34.0 hr |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 1 Day 15 | 31.1 hr |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 2 Day 1 | 21.3 hr |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 1 Day 15 | 21.8 hr |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 2 Day 1 | 27.0 hr |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 2 Day 1 | 17.2 hr |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 1 Day 15 | 30.9 hr |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 1 Day 15 | 38.0 hr |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 2 Day 1 | 20.1 hr |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 1 Day 15 | 22.8 hr |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - T1/2 | Cycle 2 Day 1 | 12.0 hr |
Secondary
Pharmacokinetic Profile of Buparlisib - Tmax
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
Population: Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 15 | 0.9 hr | — |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 1 | 1.0 hr | Full Range 509.47 |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 2 Day 1 | 1.0 hr | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 15 | 2.0 hr | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 1 | 1.0 hr | Full Range 481.7 |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 2 Day 1 | 1.5 hr | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 15 | 1.0 hr | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 1 | 1.0 hr | Full Range 898.05 |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 2 Day 1 | 1.0 hr | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 15 | 1.6 hr | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 1 | 0.6 hr | Full Range 1081.12 |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 2 Day 1 | 1.8 hr | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 15 | 1.0 hr | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 1 | 1.2 hr | Full Range 778.91 |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 2 Day 1 | 1.0 hr | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 1 | 1.0 hr | Full Range 1499.76 |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 2 Day 1 | 1.0 hr | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of Buparlisib - Tmax | Cycle 1 Day 15 | 1.3 hr | — |
Secondary
Pharmacokinetic Profile of INC280 - AUCtau
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
Population: Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 15 | 5749.3 hr*ng/ml | — |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 1 | 2435.6 hr*ng/ml | Full Range 1257.87 |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 2 Day 1 | 4894.6 hr*ng/ml | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 15 | 11261.7 hr*ng/ml | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 1 | 3005.9 hr*ng/ml | Full Range 2291.8 |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 2 Day 1 | 2655.6 hr*ng/ml | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 15 | 10581.0 hr*ng/ml | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 1 | 4789.7 hr*ng/ml | Full Range 2604.72 |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 2 Day 1 | 23498.3 hr*ng/ml | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 15 | 2779.4 hr*ng/ml | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 1 | 5071.7 hr*ng/ml | Full Range 2702.56 |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 2 Day 1 | 10554.3 hr*ng/ml | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 15 | 12801.3 hr*ng/ml | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 1 | 5732.2 hr*ng/ml | Full Range 2702.47 |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 2 Day 1 | 9593.5 hr*ng/ml | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 1 | 11127.7 hr*ng/ml | Full Range 5627.79 |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 2 Day 1 | 13051.1 hr*ng/ml | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - AUCtau | Cycle 1 Day 15 | 16590.6 hr*ng/ml | — |
Secondary
Pharmacokinetic Profile of INC280 - Cmax
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
Population: Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 15 | 1560.0 ng/ml | — |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 1 | 618.0 ng/ml | Full Range 509.47 |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 2 Day 1 | 1200.0 ng/ml | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 15 | 2005.0 ng/ml | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 1 | 880.0 ng/ml | Full Range 481.7 |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 2 Day 1 | 2142.5 ng/ml | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 15 | 3480.0 ng/ml | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 1 | 960.5 ng/ml | Full Range 898.05 |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 2 Day 1 | 5010.0 ng/ml | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 15 | 545.5 ng/ml | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 1 | 860.0 ng/ml | Full Range 1081.12 |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 2 Day 1 | 2254.5 ng/ml | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 15 | 3610.0 ng/ml | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 1 | 1990.0 ng/ml | Full Range 778.91 |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 2 Day 1 | 3080.0 ng/ml | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 1 | 3635.0 ng/ml | Full Range 1499.76 |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 2 Day 1 | 3220.0 ng/ml | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - Cmax | Cycle 1 Day 15 | 4850.0 ng/ml | — |
Secondary
Pharmacokinetic Profile of INC280 - T1/2
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
Population: Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 2 Day 1 | 9.9 hr |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 1 Day 15 | 13.4 hr |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 1 Day 15 | 20.8 hr |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 2 Day 1 | 17.4 hr |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 2 Day 1 | 26.3 hr |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 1 Day 15 | 26.0 hr |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 1 Day 15 | 7.3 hr |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 2 Day 1 | 8.7 hr |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 1 Day 15 | 13.1 hr |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 2 Day 1 | 6.3 hr |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 2 Day 1 | 4.3 hr |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - T1/2 | Cycle 1 Day 15 | 8.0 hr |
Secondary
Pharmacokinetic Profile of INC280 - Tmax
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
Population: Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 15 | 1.9 hr | — |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 1 | 1.1 hr | Full Range 509.47 |
| 200 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 2 Day 1 | 2.0 hr | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 15 | 2.0 hr | — |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 1 | 2.0 hr | Full Range 481.7 |
| 400 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 2 Day 1 | 2.0 hr | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 15 | 2.0 hr | — |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 1 | 1.5 hr | Full Range 898.05 |
| 500 mg BID Cap+50 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 2 Day 1 | 1.5 hr | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 15 | 2.6 hr | — |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 1 | 1.3 hr | Full Range 1081.12 |
| 500 mg BID Cap+80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 2 Day 1 | 2.1 hr | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 15 | 1.0 hr | — |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 1 | 1.6 hr | Full Range 778.91 |
| 300 mg BID Tab +80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 2 Day 1 | 1.5 hr | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 1 | 2.0 hr | Full Range 1499.76 |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 2 Day 1 | 1.0 hr | — |
| 400 mg BID Tab+80 mg QD | Pharmacokinetic Profile of INC280 - Tmax | Cycle 1 Day 15 | 1.5 hr | — |