A Phase Ib/II, open-label, multicenter study of INC280 in combination with buparlisib in adult patients with recurrent glioblastoma
- Conditions
- Malignant high-grade astrocytomaprimary brain tumor grade 410027656
- Registration Number
- NL-OMON45098
- Lead Sponsor
- ovartis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 10
** 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 < 10) by IHC confirmed by local documentation (phase Ib only) or central assessment
*Phase II: Documented evidence of PTEN mutations, homozynous deletion of PTEN or PTEN negative (H score < 10) by IHC or c-Met amplification (GCN > 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.
*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 < 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 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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>-Phase Ib: Incidence of dose limiting toxicities (DLTs)<br /><br>-Phase II: Progression free survival rate (PFSR)<br /><br>-Surgical arm: Concentrations of INC280 and buparlisib in tumor </p><br>
- Secondary Outcome Measures
Name Time Method <p>-Type, frequency, and severity of adverse events and serious adverse events.<br /><br>-Tolerability: dose interruptions, reductions and dose intensity.<br /><br>-Plasma concentration of INC280 and buparlisib, and PK parameters, including<br /><br>but not limited to Cmax, Tmax, AUCtau, and T1/2.<br /><br>-Overall response rate (ORR)<br /><br>-Overall survival (OS) </p><br>