AMG 595 First-in-Human in Recurrent Gliomas

Phase 1

Completed

• Conditions: Glioblastoma Multiforme; Anaplastic Astrocytomas; Advanced Malignant Glioma
• Interventions: Drug: AMG 595

• Registration Number: NCT01475006
• Lead Sponsor: Amgen

Brief Summary

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.

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 Timeline

• Study First Submitted: 2011-09-29
• Study First Submitted QC: 2011-11-18
• Study First Posted: 2011-11-21
• Study Start: 2012-02
• Status Verified: 2016-04
• Primary Completion: 2016-04
• Study Completion: 2016-04
• Last Update Submitted: 2016-04-14
• Last Update Posted: 2016-04-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Part II Dose Expansion	AMG 595	Dose selected from Part 1 dose exploration
Part I Dose Exploration	AMG 595	Pre-specified nominal doses are proposed in the dose exploration. Intermediate doses may also be used if required based on the CRM design.

Primary Outcome Measures

Name	Time	Method
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)
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)
Objective response in GBM tumors as assessed by Macdonald criteria	3 years

Secondary Outcome Measures

Name	Time	Method
Overall survival	3 years
Anti-AMG 595 antibody formation	3 years
Clinical benefit rate	every 6 months
Progressive free survival	3 years

Trial Locations

Locations (1)

Research Site; 🇦🇺 Parkville, Victoria, Australia