AMG 595 First-in-Human in Recurrent Gliomas

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)

This is an open-label, sequential dose exploration study of single agent AMG 595 administered in subjects with recurrent glioblastoma multiforme (GBM) and/or anaplastic astrocytomas (AA). The purpose of the study is to evaluate safety, tolerability, and pharmacokinetics (PK) of AMG 595, and also to evaluate the objective response rate in subjects receiving AMG 595. This study will be conducted in two parts. Part 1 will explore doses of AMG 595 in subjects with recurrent GBM and/or AA. Part 2 (dose expansion) will examine the MTD established in Part 1 in subjects with recurrent GBM.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme; Advanced Malignant Glioma; Anaplastic Astrocytomas
• Intervention / Treatment: Drug: AMG 595

Detailed Description

This study of AMG 595 will be conducted in two parts: Part 1 (dose exploration) and Part 2 (dose expansion). Part 1 of the study is in subjects with recurrent glioblastoma multiforme (GBM) and/or anaplastic astrocytomas (AA), and Part 2 is examining the MTD in subjects with recurrent GBM. Approximately 30-40 subjects may be enrolled in Part 1, and up to 36 subjects may be enrolled in Part 2. The dose of AMG 595 utilized in Part 2 will be dependent upon data obtained in Part 1 of the study.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90024
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.
• Subjects with recurrent disease (confirmed by MRI and evaluable by Macdonald criteria) at the time of first or second recurrence or progression following initial definitive therapy(s)
• 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.
• For Part 1 (dose escalation): Treatment with bevacizumab or antiangiogenic therapy within 4 weeks before enrollment, or for Part 2 (dose expansion): any prior treatment with bevacizumab or antiangiogenic therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 conjugate 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 conjugate that binds to EGFRvIII.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Clinically significant or > or = to Grade 3 CTCAE changes in safety laboratory tests, physical exams, ECGs or vital signs	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)
PK Parameters: Cmax, Cmin, and if feasible half life - 8 time points up to 6 weeks	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)
Objective response in GBM tumors as assessed by Macdonald criteria	3 years
Dose limiting toxicity used to estimate the MTD	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)

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	3 years
Clinical benefit rate	every 6 months
Progressive free survival	3 years
Anti-AMG 595 antibody formation	3 years

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: September 29, 2011
• First Submitted That Met QC Criteria: November 18, 2011
• First Posted (Estimate): November 21, 2011

Study Record Updates

• Last Update Posted (Estimate): April 15, 2016
• Last Update Submitted That Met QC Criteria: April 14, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Glioma; Glioblastoma Multiforme; brain tumor; EGFRvIII; Antibody drug conjugate; Epidermal Growth Factor Receptor Variant III; Anaplastic Astrocytomas
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Astrocytoma
• Other Study ID Numbers: 20090505