Preoperative Ceritinib (LDK378) in Glioblastoma Multiforme and CNS Metastasis

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).

Inclusion Criteria:

- One prior resection of GBM or MRI evidence of solid tumor CNS metastasis

- All GBM and NSLC metastases must be ALK+

- Eastern Cooperative Oncology Group performance status ≤2

- Archival tumor tissue block available for research use

- Ability to understand written informed consent

- Recovery from toxicities related to prior anticancer therapies to ≤ grade 2 (CTCAE v
4.03). Exception: patients with any grade alopecia

- The following lab criteria are met:

- Absolute neutrophil count ≥ 1.5 x 10(9th power)/L

- Hemoglobin ≥ 8 g/dL

- Platelets ≥ 75 x 10(9th power)/L

- Serum total bilirubin ≤ 1.5 x upper limit of normal(ULN), except for patients
with Gilbert's syndrome who may be included if total bilirubin ≤ 3.0 x ULN and
direct bilirubin ≤ 1.5 x ULN

- Aspartate transaminase (AST) < 3.0 x ULN, except for patients with liver
metastasis, who are only included if AST < 5 x ULN; alanine transaminase (ALT) <
3.0 x ULN, except for patients with liver metastasis, who are only included if
ALT < 5 x ULN

- Creatinine clearance ≥ 30 mL/min

- Patient has following lab values or has lab values corrected with supplements to be
within normal limits at screening:

- Potassium ≥ LLN

- Magnesium ≥ LLN

- Phosphorus ≥ LLN

- Total calcium (corrected for serum albumin) ≥ LLN

Exclusion Criteria:

- Co-morbid condition(s) that prevent safe surgical treatment

- Active infection or fever > 38.5°C

- Patients with known hypersensitivity to any excipients of ceritinib

- Prior therapy with ceritinib

- Patients with known history of extensive disseminated bilateral interstitial fibrosis
or interstitial lung disease, including a history of pneumonitis, hypersensitivity
pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and clinically
significant radiation pneumonitis (affecting activities of daily living or requiring
therapeutic intervention)

- Clinically significant uncontrolled heart disease and/or recent cardiac event (within
6 months), such as:

- history of documented congestive heart failure (New York Heart Association
functional classification III-IV);

- uncontrolled hypertension defined by a Systolic Blood Pressure ≥ 160 mm Hg
and/or Diastolic Blood Pressure ≥ 100 mm Hg, with or without antihypertensive
medication

- initiation or adjustment of antihypertensive medication(s) is allowed prior to
screening;

- ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled
with medication;

- other cardiac arrhythmia not controlled with medication;

- corrected QTc > 450 msec using Fridericia correction on the screening ECG

- Impaired GI function or GI disease that may alter absorption of ceritinib or
inability to swallow up to five ceritinib capsules daily

- Ongoing GI adverse events > grade 2 (e.g. nausea, vomiting, or diarrhea) at the start
of the study

- Receiving medications that meet 1 of the following criteria and cannot be
discontinued at least 1 week prior to start of treatment with ceritinib and for the
duration of participation:

- Medication with a known risk of prolonging the QT interval or inducing Torsades
de Pointes

- Strong inhibitors or strong inducers of CYP3A4/5

- Medications with a low therapeutic index that are primarily metabolized by
CYP3A4/5, CYP2C8 and/or CYP2C9

- Therapeutic doses of warfarin sodium (Coumadin) or any other coumadin-derived
anti-coagulant. Anticoagulants not derived from warfarin are allowed

- Pregnant or nursing (lactating) women.

- Women of child-bearing potential, unless they are using highly effective methods of
contraception during dosing and for 3 months after the last dose of study treatment.