AMG 595 First-in-Human in Recurrent Gliomas

AMG 595 First-in-Human in Recurrent Gliomas
This study is not yet open for participant recruitment.
Verified November 2011 by Amgen

First Received on September 29, 2011.  
Last Updated on November 18, 2011  
History of Changes
Sponsor: Amgen
Information provided by: Amgen Identifier: NCT01475006

This is an open-label, sequential dose exploration study of single agent AMG 595 administered in subjects with recurrent glioblastoma multiforme and/or anaplastic astrocytomas. This study consist of two parts. The dose exploration in Part 1, studies of cohorts of 3 subjects with recurrent Glioblastoma Multiforme (GBM) and/or Anaplastic Astrocytomas (AA) and uses a practical continuous reassessment model [CRM] to guide dose escalation and define the maximum tolerated dose (MTD). The dose expansion in Part 2 will enroll 30 subjects with GBM at a dose no higher than the MTD to further explore the safety, PK, and clinical activity of AMG 595 in this patient population.

Eligible subjects enrolled in the study will receive AMG 595 beginning at study day 1. Following the first two dose of AMG 595 and upon successful completion of a 28 days window for assessing dose limiting toxicities, subject will undergo radiological assessment of their tumors with MRI during week 5. Dosing may resume at week 7 unless there is radiological evidence of progressive disease per Macdonald criteria, the subject becomes intolerant to the study medication, signs and symptoms of clinical progression are evident as determined by the investigator, or the subject withdraws consent.

Condition Intervention Phase
Advanced Malignant Glioma
Anaplastic Astrocytomas
Glioblastoma Multiforme
Drug: AMG 595 Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 First-in-Human Study Evaluating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 595 in Subjects With Recurrent Malignant Glioma Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII)

Resource links provided by NLM:

Further study details as provided by Amgen:

Primary Outcome Measures:

  • Clinically significant or > or = to Grade 3 CTCAE changes in safety laboratory tests, physical exams, ECGs or vitals signs [ Time Frame: 28 Days after last subject enrolled of each cohort in Part 1 and every 10, 20 and 30 subject enrolled in part 2 (if available) ] [ Designated as safety issue: Yes ]
  • PK Parameters: Cmax, Cmin, and if feasible half life [ Time Frame: 28 Days after last subject enrolled of each cohort in Part 1 and every 10, 20 and 30 subject enrolled in part 2 (if available) ] [ Designated as safety issue: Yes ]
  • Objective response in GBM tumors as assessed by Macdonald criteria [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Dose limiting toxicity used to estimate the MTD [ Time Frame: 28 Days after last subject enrolled of each cohort in Part 1 and every 10, 20 and 30 subject enrolled in part 2 (if available) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

  • Clinical benefit rate [ Time Frame: every 6 months ] [ Designated as safety issue: No ]
  • Progressive free survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Anti-AMG 595 antibody formation [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: November 2011
Estimated Study Completion Date: May 2014
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)


Assigned Interventions
Experimental: Part I Dose Exploration

Pre-specified nominal doses are proposed in the dose exploration. Intermediate doses may also be used if required based on the CRM design.
Drug: AMG 595

AMG 595 is an antibody drug conjugated that binds to EGFRvIII.
Experimental: Part II Dose Expansion

Dose selected from Part 1 dose exploration
Drug: AMG 595

AMG 595 is an antibody drug conjugated that binds to EGFRvIII.


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Karnofsky performance score > or = 70%
  • Must have pathologically documented, and definitively diagnosed recurrent WHO Grade IV advanced malignant glioblastoma multiforme (Part 1 and Part 2) and/or WHO Grade III anaplastic astrocytoma (Part 1 only).
  • GBM and/or AA tumors expressing EGFRvIII as assessed on archived tissue by IHC staining of sections containing a minimum of 100 evaluable tumor cells.
  • Archived tumor tissue from the initial diagnosis or subsequent relapse(s) of Grade IV advanced malignant glioblastoma multiforme or Grade III anaplastic astrocytoma available for submission to central review.
  • QTcF ≤ 470 msec
  • Hematological function, as follows: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L, Platelet count ≥ 100 x 10^9/L, Hemoglobin > 9 g/dL
  • Renal function, as follows: Estimated glomerular filtration rate using the Modified Diet in Renal Disease (MDRD) equation > 45 mL/min/1.73m^2, Urinary protein quantitative value of < 30 mg/dL in urinalysis or ≤ 1+ on dipstick, unless quantitative protein is < 500 mg in a 24 hr urine sample

Exclusion Criteria:

  • History of central nervous system bleeding as defined by stroke or intraocular bleed (including embolic stroke) within 6 months before enrollment.
  • Evidence of acute intracranial / intratumoral hemorrhage, except for subjects with stable grade 1 hemorrhage.
  • Peripheral sensory neuropathy > Grade 2.
  • Clinically significant ECG changes which obscure the ability to assess the PR, QT, and QRS interval; congenital long QT syndrome.
  • Recent infection requiring intravenous anti-infective treatment that was completed ≤ 14 days before enrollment.
  • Received radiation therapy within 12 weeks before enrollment or has not recovered from the toxic effects of such therapy.
  • Treated previously with bevacizumab or anti-angiogenic therapy.
  Contacts and Locations

Please refer to this study by its identifier: NCT01475006

Contact: Amgen Call Center 866-572-6436

Sponsors and Collaborators
Study Director: MD Amgen
  More Information

Additional Information:

No publications provided

Responsible Party: Global Development Leader, Amgen Inc. Identifier: NCT01475006    
History of Changes
Other Study ID Numbers: 20090505
Study First Received: September 29, 2011
Last Updated: November 18, 2011
Health Authority: Australia: Royal Adelaide Hospital Research Ethics Committee
Australia:Melbourne Health Office for Research
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Amgen:

Epidermal Growth Factor Receptor Variant III
Anaplastic Astrocytomas
Glioblastoma Multiforme
Antibody drug conjugate
brain tumor

Additional relevant MeSH terms:

Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions processed this record on August 21, 2012

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