- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02605746
Preoperative Ceritinib (LDK378) in Glioblastoma Multiforme and CNS Metastasis
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
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:
- first recurrence GBM patients and
- 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.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
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Arizona
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Phoenix, Arizona, United States, 85013
- Barrow Brain and Spine
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 2-4 hours
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.
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Experimental: 4-8 hours
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.
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Experimental: 22-26 hours
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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Plasma Concentration
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
|
Plasma concentration of Ceritinib after 10-14 oral doses of 750 mg.
Will be summarized using descriptive statistics.
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at pre-dose on day 10-14(Day 0), 0.5, 1, 2, 4, 6, 8, and 24 hours following single dose of CERITINIB
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Cerebrospinal Concentration
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
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Cerebrospinal concentration of Ceritinib.
Will be summarized using descriptive statistics.
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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
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Intratumoral Concentration
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
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Intratumoral concentration of Ceritinib.
Will be summarized using descriptive statistics.
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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
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Tumor Tissue
Time Frame: at baseline(archival) and up to 26 hours post dosing
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Tumor tissue quantification of total and phosphorylated forms of ALK, JAK/STAT5B, and Caspase-3.
Will be summarized using descriptive statistics.
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at baseline(archival) and up to 26 hours post dosing
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Tumor Cells in M-Phase
Time Frame: at baseline and up to 26 hours post dose CERITINIB
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Number of tumor cells in M-phase of cell cycle (PH3).
Will be summarized using descriptive statistics.
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at baseline and up to 26 hours post dose CERITINIB
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Double Strand DNA
Time Frame: at baseline and up to 26 hours post dose CERITINIB
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Presence of double-strand DNA damage (γH2AX).
Will be summarized using descriptive statistics.
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at baseline and up to 26 hours post dose CERITINIB
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Tissue Concentration
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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Tissue concentration of CERITINIB compared to contrast enhancing GBM vs. surrounding nonenhancing FLAIR-hyperintense GBM.
Will be summarized using descriptive statistics.
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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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Collaborators and Investigators
Investigators
- Principal Investigator: Nader Sanai, MD, Barrow Brain and Spine, Phoenix AZ
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Neoplasms, Glandular and Epithelial
- Astrocytoma
- Glioma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neoplastic Processes
- Central Nervous System Neoplasms
- Nervous System Neoplasms
- Glioblastoma
- Neoplasm Metastasis
- Brain Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Ceritinib
Other Study ID Numbers
- PHX15BN068
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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