Clinical Trials /

Preoperative Ceritinib (LDK378) in Glioblastoma Multiforme and CNS Metastasis

NCT02605746

Description:

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.

Related Conditions:
  • Central Nervous System Neoplasm
  • Glioblastoma
Recruiting Status:

Unknown status

Phase:

Early Phase 1

Trial Eligibility

Document

Preoperative <span class="go-doc-concept go-doc-intervention">Ceritinib (LDK378)</span> in <span class="go-doc-concept go-doc-disease">Glioblastoma</span> Multiforme and <span class="go-doc-concept go-doc-disease">CNS</span> Metastasis

Title

  • Brief Title: Preoperative Ceritinib (LDK378) in Glioblastoma Multiforme and CNS Metastasis
  • Official Title: A Phase 0/II Study of Ceritinib (LDK378) in Preoperative Glioblastoma Multiforme (GBM) and CNS Metastasis Patients Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration
  • Clinical Trial IDs

    NCT ID: NCT02605746

    ORG ID: PHX15BN068

    Trial Conditions

    Glioblastoma

    Brain Metastases

    Trial Interventions

    Drug Synonyms Arms
    ceritinib 750mg 2-4 hours, 4-8 hours, 22-26 hours

    Trial Purpose

    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.

    Detailed Description

    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).

    Trial Arms

    Name Type Description Interventions
    2-4 hours Experimental All patients will be orally-administered 10-14 doses of ceritinib 750mg with the final dose occurring at one of three intervals before brain tumor resection. This arm has the last ceritinib dose 2-4 hours prior to craniotomy for tumor resection. ceritinib 750mg
    4-8 hours Experimental All patients will be orally-administered 10-14 doses of ceritinib 750mg with the final dose occurring at one of three intervals before brain tumor resection. This arm has the last ceritinib dose 4-8 hours prior to craniotomy for tumor resection. ceritinib 750mg
    22-26 hours Experimental All patients will be orally-administered 10-14 doses of ceritinib 750mg with the final dose occurring at one of three intervals before brain tumor resection. This arm has the last ceritinib dose 22-26 hours prior to craniotomy for tumor resection. ceritinib 750mg

    Eligibility 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 > 38.5C

    - 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Plasma Concentration

    Cerebrospinal Concentration

    Intratumoral Concentration

    Secondary Outcome Measures

    Tumor Tissue

    Tumor Cells in M-Phase

    Double Strand DNA

    Tissue Concentration

    Trial Keywords