Malignant high-grade astrocytoma primary brain tumor grade 4
Conditions
Interventions
Treatment with INC280 single agend and in combination with BKM120 (buparlisib).
Sponsors
Novartis
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: ** 18 years of age. *Histologically confirmed diagnosis of glioblastoma after initial tumor resection with radiographic evidence of recurrent tumor per RANO criteria. *Phase I: Documented evidence of PTEN mutations, homozygous deletion of PTEN or PTEN negative (H Score 5) by FISH, all assessed centrally. Fusion transcripts or mutant c-Met (based on local data) may be eligible for single agent arm after documented agreement with Novartis. *Must have received the following treatment for glioblastoma: *Prior adjuvant treatment with radiotherapy and temozolomide; *A maximum of two prior chemotherapy/antibody regimens (including bevacizumab or other direct VEFG/VEGFR inhibitors) for recurrent disease are permitted. *Representative archival glioblastoma sample (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
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 (applicable for combination treatment arm only). *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 or CYP1A2 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 being treated with Enzyme Inducing Anti-Epileptic Drug (EIAED). If previously on an EIAED, the patient must be off of it for at least 2 weeks prior to study treatment. *Currently receiving warfarin or other coumadin-derived anticoagulants for treatment, prophylaxis or otherwise. *Currently receiving increasing or chronic treatment ( > 5 days) with corticosteroids 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 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 ULN (or > 5.0 x ULN if liver metastases are present) *Fasting plasma glucose > 120mg/dL or > 6.7 mmol/L *HbA1c > 8%. * Pregnant or nursing (lactating) women
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| -Phase Ib: Incidence of dose limiting toxicities (DLTs) -Phase II: Progression free survival rate (PFSR) -Surgical arm: Concentrations of INC280 and buparlisib in tumor | — |
Secondary
| Measure | Time frame |
|---|---|
| -Type, frequency, and severity of adverse events and serious adverse events. -Tolerability: dose interruptions, reductions and dose intensity. -Plasma concentration of INC280 and buparlisib, and PK parameters, including but not limited to Cmax, Tmax, AUCtau, and T1/2. -Overall response rate (ORR) -Overall survival (OS) | — |
Countries
Netherlands
Outcome results
None listed