This is two parallel studies to examine pharmacokinetic (PK), pharmacodynamic (PD), and pharmacogenetic (PG) endpoints following short-interval therapy (10-14) daily doses without dose reduction and interruption) with the ALK (anaplastic lymphoma kinase) small-molecule inhibitor, ceritinib. The Phase 0 study will investigate: 1. first recurrence GBM patients and 2. patients with CNS metastases from solid tumors such as, but not limited to, NSCLC (non-small cell lung cancer) and melanoma. The CNS (central nervous system) metastases Phase 0 is designed to identify PK effects (in addition to PD, and PG effects on ALK-positive NSCLC metastases), while the GBM Phase 0 is designed to identify PK, PD, and PG effects in all patients.
This study is being done to learn about a new drug, Ceritinib (LKD378). The results of the study may reveal how the drug works for cancer that spreads to the brain (metastases) and for a type of brain cancer called glioblastoma (GBM). Subjects are persons scheduled to have surgery to remove the tumor.This study would test how much of the new drug is present in the tumor, blood, and cerebrospinal fluid (CSF) after taking the drug orally for 10-14 days before surgery. It is only given to patients who are already scheduled to have surgery to remove a tumor that has returned. If the drug seems to be working for a subject's tumor, subject will have the option to continue to receive it as part of a continuation study looking at the drug effect on preventing the tumor from recurring. Small samples of blood, tumor tissue, and CSF will be taken. These samples will be sent to and analyzed at the Barbara Ann Karmanos Cancer Institute (KCI) and to the Translational Genomics Research Institute (TGen). Subject involvement will be for 10-14 days before surgery and for 30 days following surgery. Patients with ALK+ solid tumors will be provided the option of continuing therapy until tumor progression. ALK positivity will be assessed by approved FISH test (Abbott Molecular Inc) using Vysis break apart probes (defined as 15% or more positive tumor cells), the Ventana IHC (immunohistochemistry) test, and/or NGS (next generation sequencing).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
10
Barrow Brain and Spine
Phoenix, Arizona, United States
Plasma Concentration
Plasma concentration of Ceritinib after 10-14 oral doses of 750 mg. Will be summarized using descriptive statistics.
Time frame: at pre-dose on day 10-14(Day 0), 0.5, 1, 2, 4, 6, 8, and 24 hours following single dose of CERITINIB
Cerebrospinal Concentration
Cerebrospinal concentration of Ceritinib. Will be summarized using descriptive statistics.
Time frame: collected intraoperatively at 2-4, 4-8, and 22-26 hours following single dose of CERITINIB relative to the final dose on day 10-14
Intratumoral Concentration
Intratumoral concentration of Ceritinib. Will be summarized using descriptive statistics.
Time frame: collected intraoperatively at 2-4, 4-8, and 22-26 hours following single dose of CERITINIB relative to the final dose on day 10-14
Tumor Tissue
Tumor tissue quantification of total and phosphorylated forms of ALK, JAK/STAT5B, and Caspase-3. Will be summarized using descriptive statistics.
Time frame: at baseline(archival) and up to 26 hours post dosing
Tumor Cells in M-Phase
Number of tumor cells in M-phase of cell cycle (PH3). Will be summarized using descriptive statistics.
Time frame: at baseline and up to 26 hours post dose CERITINIB
Double Strand DNA
Presence of double-strand DNA damage (γH2AX). Will be summarized using descriptive statistics.
Time frame: at baseline and up to 26 hours post dose CERITINIB
Tissue Concentration
Tissue concentration of CERITINIB compared to contrast enhancing GBM vs. surrounding nonenhancing FLAIR-hyperintense GBM. Will be summarized using descriptive statistics.
Time frame: 2-4, 4-8, and 22-26 hours post dosing relative to the final Day 10 dose, as compared to the immediate pre-operative MRI scan
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