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Safety Study of Afatinib for Brain Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02423525
Recruitment Status : Completed
First Posted : April 22, 2015
Last Update Posted : March 10, 2022
Boehringer Ingelheim
Information provided by (Responsible Party):
Santosh Kesari, Saint John's Cancer Institute

Brief Summary:

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).

Condition or disease Intervention/treatment Phase
Brain Cancer Drug: Afatinib Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : December 2016
Actual Primary Completion Date : August 2020
Actual Study Completion Date : August 2021

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
Drug: Afatinib
Other Name: Gilotrif

Primary Outcome Measures :
  1. Rate of dose limiting toxicities of pulsatile afatinib [ Time Frame: first 28 days of treatment ]
    Number of side effects of study treatment that prevent an increase in dose or level of that treatment

  2. Maximum tolerated dose (MTD) of pulsatile afatinib [ Time Frame: first 28 days of treatment ]
    The highest dose evaluated that does not cause unacceptable side effects

Secondary Outcome Measures :
  1. Treatment-emergent adverse events [ Time Frame: 7 months ]
    Type, number, grade and seriousness of adverse events reported after the first dose of study treatment

  2. Afatinib levels in cerebrospinal fluid (CSF) and blood [ Time Frame: 52 days ]
    Measurement of afatinib concentration in CSF and blood at defined timepoints

  3. Objective response rate as assessed by the RANO criteria [ Time Frame: approximately 6 months to 1 year ]
    Tumor response compared to baseline as assessed by the RANO criteria

  4. Best overall response rate [ Time Frame: approximately 6 months to 1 year ]
    Best tumor response compared to baseline

  5. Progression free survival [ Time Frame: up to 5 years ]
    Time between the start of treatment to disease progression

  6. Overall Survival [ Time Frame: up to 5 years ]
    Time between the start of treatment to death

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Diagnosis

    1. Dose Escalation Cohorts: Histologically confirmed diagnosis of brain cancer:

      1. glioblastoma (GBM),
      2. anaplastic astrocytoma (AA),
      3. anaplastic oligodendroglioma (AO),
      4. anaplastic mixed oligoastrocytoma (AMO),
      5. low grade gliomas,
      6. brain metastases,
      7. meningiomas,
      8. leptomeningeal metastases
      9. chordomas
      10. pituitary tumors
      11. medulloblastomas
    2. Expansion Cohort: Histologically confirmed diagnosis of high-grade glioma with altered EGFR (e.g., amplification, mutation), including:

      1. glioblastoma (GBM),
      2. anaplastic astrocytoma (AA),
      3. anaplastic oligodendroglioma (AO),
      4. 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:

    1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
    2. Platelet count ≥ 100 x 109/L.
    3. Hemoglobin ≥ 9.0 g/dL.
    4. Total Bilirubin ≤ 1.5 institution's upper limit of normal (ULN).
    5. Aspartate amino transferase (AST) ≤ 2.5 x institution's ULN.
    6. Alanine amino transferase (ALT) ≤ 2.5 x institution's ULN.
    7. 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:

    1. less than 28 days from whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS);
    2. less than 28 days from any investigational agent;
    3. 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);
    4. less than 14 days from hormonal treatment
    5. less than 7 days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.
    6. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02423525

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United States, California
John Wayne Cancer Institute
Santa Monica, California, United States, 90404
Sponsors and Collaborators
Santosh Kesari
Boehringer Ingelheim
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Principal Investigator: Santosh Kesari, MD, PhD Saint John's Cancer Institute
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Responsible Party: Santosh Kesari, Director, Neuro-Oncology, Saint John's Cancer Institute Identifier: NCT02423525    
Other Study ID Numbers: 1200.229
20161975 ( Other Identifier: Western Institutional Review Board )
First Posted: April 22, 2015    Key Record Dates
Last Update Posted: March 10, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Santosh Kesari, Saint John's Cancer Institute:
mixed oligoastrocytoma
low grade gliomas
brain metastases
leptomeningeal metastases
Additional relevant MeSH terms:
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Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action