Study of AMG 596 in Patients With EGFRvIII Positive Glioblastoma

Phase 1/1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 as Monotherapy and in Combination With AMG 404 in Subjects With Glioblastoma or Malignant Glioma Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII)

This is a Phase 1/1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 596 monotherapy or in combination with AMG 404 in Subjects with Glioblastoma or Malignant Glioma Expressing Mutant Epidermal Growth Factor Receptor Variant III (EGFRvIII).

This is a first in human (FIH), open-label, sequential-dose-escalation study in subjects with EGFRvIII-positive glioblastoma or malignant glioma. This study will enroll 2 groups of subjects according to disease stage, recurrent disease (Group 1) and maintenance treatment after SoC in newly diagnosed disease (Group 2).

Study Overview

• Status: Completed
• Conditions: Glioblastoma or Malignant Glioma
• Intervention / Treatment: Drug: AMG 596; Drug: AMG 404

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
• France
  • Villejuif, France, 94800
    • Gustave Roussy
• Germany
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Würzburg, Germany, 97080
    • Universitaetsklinikum Wuerzburg
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Vrije Universiteit Medisch Centrum
• Spain
  • Cataluña
    • Badalona, Cataluña, Spain, 08916
      • Hospital Universitari Germans Trias I Pujol
• United States
  • California
    • Los Angeles, California, United States, 90024
      • University of California Los Angeles
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Eastern Cooperative Oncology Group (ECOG, Appendix G) Performance Status of less than or equal to 1
• Life expectancy of at least 3 months, in the opinion of the investigator.
• Must have pathologically documented, and definitively diagnosed World Health Organization (WHO) grade 4, glioblastoma or lower grade malignant gliomas with EGFRvIII positive tumor
• Must have recurrent disease confirmed by MRI (Group 1) or completed SoC therapy such as surgery with adjuvant radiochemotherapy with or without maintenance temozolomide according to local standards for newly diagnosed disease (Group 2)

• Hematological function as follows:

  • Absolute neutrophil count (ANC) greater than 1500/mm3 (1.5 × 10 9/L)
  • Platelet count greater than 100,000 mm3 (100 × 10 9/L)
  • White blood cell (WBC) count greater than 3 × 10 9/L
  • Hemoglobin greater than 9.0 g/dL
• Renal function as follows: serum creatinine less than 2.0 mg/dL and estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73 m2 by MDRD and urine protein quantitative value of less than 30 mg/dL in urinalysis or less than or equal to 1+ on dipstick

• Hepatic function as follows:

  • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) less than or equal to 3.0 x upper limit of normal (ULN)
  • Bilirubin less than or equal to 1.5 x ULN (unless considered due to Gilbert's syndrome or hemolysis)

Exclusion Criteria

• History or evidence of central nervous system bleeding as defined by stroke or intraocular bleed (including embolic stroke) not associated with any antitumor surgery within 6 months before enrolment
• Known hypersensitivity to immunoglobulins or to any other component of the IP formulation
• Active infection requiring intravenous antibiotics that was completed less than 1 week of study enrolment (day 1) with the exemption of prophylactic antibiotics for long line insertion or biopsy
• Known positive test for human immunodeficiency virus (HIV)

• Active hepatitis B and C based on the following results:

  • Positive for hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B)
  • Negative HepBsAg and positive for hepatitis B core antibody: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B
  • Positive hepatitis C virus antibody (HepCAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C
• Unresolved toxicities from prior antitumor therapy, defined as not having resolved to CTCAE, version 4.0 grade 1 (with the exception of myelosuppression, eg, neutropenia, anemia, thrombocytopenia), or to levels dictated in the eligibility criteria with the exception of alopecia or toxicities from prior antitumor therapy that are considered irreversible (defined as having been present and stable for greater than 2 months) which may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and sponsor
• Antitumor therapy (chemotherapy, antibody therapy, molecular-targeted therapy, or investigational agent) within 14 days (Group 2 subjects) or 5 half-lives (whichever is longer: for Group 1 subjects) of day 1. Avastin, Pembrolizumab must be stopped 14 days prior to day 1
• Female with a positive pregnancy test.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose exploration; Dose exploration of the intervention, AMG 596 alone or in combination with AMG 404	Drug: AMG 596; Drug; Drug: AMG 404; Drug
Experimental: Dose expansion; Dose expansion of the intervention, AMG 596 alone or in combination with AMG 404	Drug: AMG 596; Drug; Drug: AMG 404; Drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subject grade of dose limiting toxicities (DTLs)	Subject grade of dose limiting toxicities is the occurrence of any of the toxicities during the DLT evaluation period if judged by the investigator to be related to the administration of AMG 596 and AMG 404	12 months
Number of subject with treatment-emergent adverse events		12 months
Number of subjects with treatment-related adverse events		12 months
Number of subjects with clinically significant changes in vital signs		12 months
Number of subjects with clinically significant changes in physical examinations		12 months
Number of subjects with clinically significant changes in clinical laboratory tests		12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average steady-state concentration (Css) for serum AMG 596		12 months
Area under the concentration-time curve (AUC) for serum AMG 596		12 months
Clearance for serum AMG 596		12 months
Volume of distribution for serum AMG 596		12 months
Half-life (t1/2) for serum AMG 596		12 months
Maximum abserved serum concentration (Cmax) for AMG 404		12 months
Time to achieve Cmax (tmax) for AMG 404		12 months
Area under the concentration-time curve (AUC) for AMG 404		12 months
Average steady-state concentration (Css) for serum AMG 596 in combination with AMG 404		12 months
Area under the concentration-time curve (AUC) for serum AMG 596 in combination with AMG 404		12 months
Clearance for serum AMG 596 in combination with AMG 404		12 months
Half-life (t1/2) for serum AMG 596 in combination with AMG 404		12 months
Objective response (OR) as per modified RANO for AMG 596	Objective response (OR) as per modified RANO (Response Assessment in Neuro-Oncology Criteria).	6 and 12 months
Time to response for serum AMG 596 in combination with AMG 404		6 and 12 months
Response duration for serum AMG 596 in combination with AMG 404		6 and 12 months
Time to progression (TTP) for serum AMG 596 in combination with AMG 404		6 and 12 months
Progression free survival (PFS) at 6 and 12 months after treatment initiation with AMG 596 monotherapy		6 and 12 months
Progression free survival (PFS) at 6 and 12 months after treatment initiation with AMG 596 in combination with AMG 404		6 and 12 months
Objective response (OR) as per modified RANO with AMG 596 monotherapy		6 and 12 months
Time to response with AMG 596 monotherapy		6 and 12 months
Response duration with AMG 596 monotherapy		6 and 12 months
Time to progression (TTP) with AMG 596 monotherapy		6 and 12 months

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Sternjak A, Lee F, Thomas O, Balazs M, Wahl J, Lorenczewski G, Ullrich I, Muenz M, Rattel B, Bailis JM, Friedrich M. Preclinical Assessment of AMG 596, a Bispecific T-cell Engager (BiTE) Immunotherapy Targeting the Tumor-specific Antigen EGFRvIII. Mol Cancer Ther. 2021 May;20(5):925-933. doi: 10.1158/1535-7163.MCT-20-0508. Epub 2021 Feb 25.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2018
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): August 28, 2021

Study Registration Dates

• First Submitted: September 18, 2017
• First Submitted That Met QC Criteria: September 27, 2017
• First Posted (Actual): September 28, 2017

Study Record Updates

• Last Update Posted (Actual): December 23, 2021
• Last Update Submitted That Met QC Criteria: December 21, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: safety and tolerability; Phase 1/1b; EGFRvIII-positive glioblastoma or malignant glioma; AMG 596
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma
• Other Study ID Numbers: 20160132; 2017-001658-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No