Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Recurrence

Glioblastoma

Brain Neoplasms

Astrocytoma

Gliosarcoma

Disease Attributes

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

To estimate the safe dose of the combination INC280 and buparlisib

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

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.

INC280

Buparlisib was given at the starting dose of 50mg once daily with escalation to higher strengths.

Buparlisib

Novartis Pharmaceuticals

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.

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.

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

A Phase Ib/II, Multi-center, Open-label Study of INC280 in Combination With Buparlisib in Patients With Recurrent Glioblastoma

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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.

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.

Concentrations of INC280 and buparlisib in tumor tissue.

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.

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

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

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

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

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

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.

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.

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.

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.

INC280 200 mg BID Tab

Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.

200 mg BID Cap+50 mg QD

Phase Ib: The combination of 400mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.

400 mg BID Cap + 50 mg QD

Phase Ib: The combination of 500mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.

500 mg BID Cap+50 mg QD

Phase Ib: The combination of 500mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib.

500 mg BID Cap+80 mg QD

Phase Ib: The combination of 300mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib.

300 mg BID Tab+ 80 mg QD

Phase Ib: The combination of 400mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib.

400 mg BID Tab+80 mg QD

Phase Ib: All Patients with the combination of INC280 (BID) and Buparlisib (QD) once daily.

All Patients (Phase Ib)

Phase II: 400mg INC280 (BID) tablet in Phase II.

400 mg BID Tab

Phase II: All patients treated with INC280 (BID) tablet once daily in the Phase II.

All Patients (Phase II)

Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.

400 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.

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.

300 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.

400 mg BID Tab +80 mg QD

Total

Age, Categorical

Sex: Female, Male

Full Analysis Set (FAS): The FAS comprised all patients who received at least one full or partial dose of study treatment. Patients were classified according to the planned treatment.

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.

Study Director

Personality Change

Nausea

Aspartate Aminotransferase Increased

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.

Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1

Phase II: INC280 (BID) as a single agent and in combination with buparlisib

BID Tab+Buparlisib

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.

Phase II: Progression Free Survival Rate (PFSR)

The combination of INC280 (BID) and Buparlisib (QD).

BID + QD

Based on the phase I, a RP2D was not determined for the combination and the phase II combination arms were not opened.

Phase II Surgical Arm: Concentrations of INC280 and Buparlisib in Tumor.

Adverse events

Treatment-related AEs

AEs with grade ≥ 3

SAEs

AEs leading to discontinuation

AEs leading to dose adjustment/interruption

AEs requiring additional therapy

300 mg BID Tab + 80 mg QD

Phase Ib: the combination of 400 mg INC280 (BID) tablet and 80 mg Buparlisib (QD) once daily

400 mg BID Tab + 80 mg QD

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.

Number of Participants With Adverse Events

Cycle 1 Day 1

Cycle 1 Day 15

Cycle 2 Day 1

Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.

Pharmacokinetic Profile of INC280 - AUCtau

Pharmacokinetic Profile of INC280 - Cmax

Pharmacokinetic Profile of INC280 - Tmax

Pharmacokinetic Profile of INC280 - T1/2

Pharmacokinetic Profile of Buparlisib - AUCtau

Pharmacokinetic Profile of Buparlisib - Cmax

Pharmacokinetic Profile of Buparlisib - Tmax

Pharmacokinetic Profile of Buparlisib - T1/2

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Unknown (UNK)

Not Assessed

Best Overall Response (BOR)

All Patients

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.

Overall Survival (OS)

Phase Ib: The combination of 500 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.

Spots Global Cancer Trial Database for glioblastoma multiforme (gbm), glioblastoma, grade iv astrocytoma, brain tumor, brain cancer, giant cell glioblastoma, gliosarcoma