Preoperative Ceritinib (LDK378) in Glioblastoma Multiforme and CNS Metastasis

• Status: Completed
• Trial end date: 2019-07-12
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: St. Joseph's Hospital and Medical Center, Phoenix
• Collaborators: Novartis; Translational Genomics Research Institute; Wayne State University
• Treatments: Ceritinib

Criteria

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.