- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02423525
Safety Study of Afatinib for Brain Cancer
A Phase I Dose Escalation and Central Nervous System (CNS) Pharmacokinetic Study of the ErbB Family Inhibitor Afatinib in Patients With Recurrent or Progressive Brain Cancer
The purpose of this study is to try to determine the maximum safe dose of afatinib that can be administered to people with brain cancer. Other purposes of this study are to:
- find out what effects (good and bad) afatinib has;
- see how much drug gets into the body by collecting blood and cerebrospinal fluid for use in pharmacokinetic (PK) studies;
- learn more about how afatinib might affect the growth of cancer cells;
- look at biomarkers (biochemical features that can be used to measure the progress of disease or the effects of a drug).
Study Overview
Detailed Description
This is an open-label, single institution, Phase I 3+3 dose escalation study to describe the safety and tolerability of afatinib in patients with brain cancer having failed prior therapy and to determine the recommended phase II dose.
Eligible patients will receive afatinib in treatment cycles of 28 days that will consist of afatinib administered orally by mouth once every four days. Patients will be assigned to the dose level open at the time of their enrollment. Patients will continue dosing of afatinib until disease progression, unacceptable toxicity, withdrawal of consent, or treating physician determines it is in their best interest to stop. Guidelines for modifying study drug doses is provided for the management of adverse treatment effects.
All patients will have regular evaluations for assessment of safety parameters as detailed in the study flow chart. Lumbar puncture and blood draw for assessing afatinib levels will occur as detailed in the study flow chart.
Neurological imaging and assessment for response will be performed approximately every eight weeks. Tumor response will be assessed according to Response Assessment in Neuro-Oncology (RANO) Working Group criteria.
An end of treatment evaluation will occur when a patient permanently discontinues study drug, as detailed in the study flow chart. Patients will then be followed every four months for survival.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
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California
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Santa Monica, California, United States, 90404
- John Wayne Cancer Institute
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Diagnosis
Dose Escalation Cohorts: Histologically confirmed diagnosis of brain cancer:
- glioblastoma (GBM),
- anaplastic astrocytoma (AA),
- anaplastic oligodendroglioma (AO),
- anaplastic mixed oligoastrocytoma (AMO),
- low grade gliomas,
- brain metastases,
- meningiomas,
- leptomeningeal metastases
- chordomas
- pituitary tumors
- medulloblastomas
Expansion Cohort: Histologically confirmed diagnosis of high-grade glioma with altered EGFR (e.g., amplification, mutation), including:
- glioblastoma (GBM),
- anaplastic astrocytoma (AA),
- anaplastic oligodendroglioma (AO),
- anaplastic mixed oligoastrocytoma (AMO)
- Has failed prior standard therapy including maximal safe surgical resection (when appropriate for the specific cancer type), radiation therapy (when appropriate for the specific cancer type), and systemic therapy (when appropriate for the specific cancer type).
- For diagnosis of GBM: has undergone maximal safe surgical resection, a course of postoperative radiation therapy with concurrent temozolomide, and maintenance temozolomide.
- For diagnosis of meningioma: has no other option of standard therapy such as surgical resection (partial or total resection) or radiation.
- Age 18 years and older.
- Karnofsky Performance Status ≥ 60%.
Adequate organ function, defined as all of the following:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
- Platelet count ≥ 100 x 109/L.
- Hemoglobin ≥ 9.0 g/dL.
- Total Bilirubin ≤ 1.5 institution's upper limit of normal (ULN).
- Aspartate amino transferase (AST) ≤ 2.5 x institution's ULN.
- Alanine amino transferase (ALT) ≤ 2.5 x institution's ULN.
- Alkaline phosphatase (ALP) ≤ 2.5 x ULN unless considered tumor related.
- Recovered from any previous therapy-related toxicity to Grade 1 or to their clinical baseline at study entry.
- Women of child-bearing potential has negative serum or urine pregnancy test before the initiation of study drug dosing.
Exclusion Criteria:
Insufficient time from prior therapy to study entry:
- less than 28 days from whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS);
- less than 28 days from any investigational agent;
- less than 28 days from prior cytotoxic therapy (except 23 days from prior temozolomide, 14 days from vincristine (for GBM: 14 days from irinotecan or topotecan), 42 days from nitrosoureas, 21 days from procarbazine, irinotecan or topotecan administration);
- less than 14 days from hormonal treatment
- less than 7 days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.
- When radiation necrosis is suspected, standard of care confirmatory imaging, such as MRI perfusion, magnetic resonance (MR) spectroscopy and or PET will be performed, and patients with findings consistent with radiation necrosis will be excluded.
- Current or anticipated use of enzyme-inducing anti-epileptic drugs (EIAED).
- Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study.
- Known hypersensitivity to afatinib or its excipients.
- History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3 or 4, unstable angina or poorly controlled arrhythmia, or myocardial infarction within 6 months prior to enrollment.
- Pregnant, nursing, or not using acceptable method of birth control.
- Any history of or concomitant condition that would compromise the patient's ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug.
- Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured.
- Known pre-existing interstitial lung disease.
- Known active hepatitis B infection (defined as presence of Hep B sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier.
- Prior participation in a blinded afatinib clinical study, even if not assigned to afatinib treatment.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Afatinib
Afatinib tablets are taken by mouth.
Dose Level 1: 80 mg every 4 days Dose Level 2: 120 mg every 4 days Dose Level 3: 180 mg every 4 days Dose Level 4: 280 mg every 7 days
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Rate of dose limiting toxicities of pulsatile afatinib
Time Frame: first 28 days of treatment
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Number of side effects of study treatment that prevent an increase in dose or level of that treatment
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first 28 days of treatment
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Maximum tolerated dose (MTD) of pulsatile afatinib
Time Frame: first 28 days of treatment
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The highest dose evaluated that does not cause unacceptable side effects
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first 28 days of treatment
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Treatment-emergent adverse events
Time Frame: 7 months
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Type, number, grade and seriousness of adverse events reported after the first dose of study treatment
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7 months
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Afatinib levels in cerebrospinal fluid (CSF) and blood
Time Frame: 52 days
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Measurement of afatinib concentration in CSF and blood at defined timepoints
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52 days
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Objective response rate as assessed by the RANO criteria
Time Frame: approximately 6 months to 1 year
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Tumor response compared to baseline as assessed by the RANO criteria
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approximately 6 months to 1 year
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Best overall response rate
Time Frame: approximately 6 months to 1 year
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Best tumor response compared to baseline
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approximately 6 months to 1 year
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Progression free survival
Time Frame: up to 5 years
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Time between the start of treatment to disease progression
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up to 5 years
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Overall Survival
Time Frame: up to 5 years
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Time between the start of treatment to death
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up to 5 years
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Collaborators and Investigators
Sponsor
Collaborators
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
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1200.229
- 20161975 (Other Identifier: Western Institutional Review Board)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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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