Study of AMG 596 in Patients With EGFRvIII Positive Glioblastoma

NCT03296696 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 201601322017-001658-32
• Study Type: interventional
• Target: 30
• Locations: 6 countries
• Sites: 10

Brief Summary

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).

Conditions

Glioblastoma or Malignant Glioma

Keywords

Phase 1/1b; EGFRvIII-positive glioblastoma or malignant glioma; safety and tolerability; AMG 596

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Dose-Limiting Toxicities (DLTs)

  A DLT was any of the following occurring and regarded by the investigator as related to AMG 596. Hematological DLTs: absolute neutrophil count (ANC) \<0.5×10\^9/L for ≥7 days, febrile neutropenia with ANC\<0.5×10\^9/L and fever ≥38.5°C, platelets\<50×10\^9/L\>7 days or clinically significant bleeding. Non-hematological DLTs: any grade 4 non-hematological toxicity, any grade ≥3 non-hematological toxicity if nausea and vomiting, grade 3 non-hematologic toxicity lasting \>3 days despite treatment, grade 3 fatigue wasn't classified as DLT, grade 3 acute kidney injury, grade 3 seizure, ataxia, encephalopathy, other grade 3 neurologic-related adverse events lasting \>3 days despite treatment, neurologic-related adverse event leading to treatment interruption needing\>1 week to resolve to grade≤1, any grade 3 endocrinopathy that can't be controlled by hormonal replacement. Toxicity grading was graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

  Up to 28 days

• Number of Participants With Treatment Emergent Adverse Events (TEAEs)

  An adverse event (AE) was defined as any untoward medical occurrence in a clinical trial participant. A TEAE was any AE that begun or worsened after the initial dose of investigational product. Any clinically significant changes in vital signs, physical examinations, and clinical laboratory tests that begun or worsened after the initial dose of investigational product were recorded as TEAEs.

  First dose of study drug until 37 days after last dose or end of study, whichever is earlier. Duration with median (min, max) in months: 3.32 (1.28, 29.31)

• Number of Participants With Treatment-Related Adverse Events (AEs)

  A treatment-related AE was defined as any untoward medical occurrence in a clinical trial participant that was considered related to the investigational product. Any clinically significant changes in vital signs, physical examinations, and clinical laboratory tests that were considered related to the investigational product were recorded as treatment-related AEs.

  First dose of study drug until 37 days after last dose or end of study, whichever is earlier. Duration with median (min, max) in months: 3.32 (1.28, 29.31)

Secondary Outcomes (10)

• Average Steady-state Concentration (Css) of Serum AMG 596

  Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end

• Area Under the Concentration-time Curve (AUC) for Serum AMG 596

  Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end

• Clearance for Serum AMG 596

  Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end

• Apparent Volume of Distribution at Steady-State for Serum AMG 596

  Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end

• Terminal Half-life (t1/2) Associated With Lambda z (λz) for Serum AMG 596

  Cycle1 to Cycle2 (cycle=14 days in single participant cohorts,42 days in multiple participant cohorts):7-days on/7-days off dosing and 28-days on/14-days off dosing:pre-infusion,2,6,8,24,48hrs post-infusion start,0.5,2,4,8,24hrs post infusion end

Study Arms (2)

Dose exploration

EXPERIMENTAL

Dose exploration of the intervention, AMG 596 alone or in combination with AMG 404

Drug: AMG 596; Drug: AMG 404

Dose expansion

EXPERIMENTAL

Dose expansion of the intervention, AMG 596 alone or in combination with AMG 404

Drug: AMG 596; Drug: AMG 404

Interventions

AMG 596 DRUG

Drug

Dose expansion; Dose exploration

AMG 404 DRUG

Drug

Dose expansion; Dose exploration

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 epidermal growth factor receptor variant III (EGFRvIII) positive tumor
• Must have recurrent disease confirmed by magnetic resonance imaging (MRI) (Group 1) or completed standard of care (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 Modification of Diet in Renal Disease (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)

You may not qualify if:

• 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
• Evidence of acute intracranial / intratumoral hemorrhage, except for subjects with stable grade 1 hemorrhage or fresh biopsy
• Known hypersensitivity to immunoglobulins or to any other component of the investigational product (IP) formulation
• Prior malignancy (other than in situ cancer) unless treated with curative intent and without evidence of disease for \> 2 years before screening
• 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 deoxyribonucleic acid (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 ribonucleic acid (RNA) by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C Common terminology criteria for adverse events
• 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
• Treatment with non-topical systemic corticosteroids within 14 days before enrollment (day 1) (exemption: prophylactic treatment with dexamethasone as defined in section 6.5, and systemic corticosteroid doses of ≤ 2 mg of dexamethasone (or equivalent) per day after consultation with Sponsor,)
• Prior participation in an investigational study (drug, procedure or device) within 21 days of study day 1
• Major surgery within 7 days of study day 1 with the exception of biopsy and long line insertion
• History or evidence of any other clinically significant disorder, condition or disease that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion

Sponsors & Collaborators

• Amgen: lead

Study Sites (10)

University of California Los Angeles

Los Angeles, California, 90024, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Royal North SHore Hospital

St Leonards, New South Wales, 2065, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Gustave Roussy

Villejuif, 94800, France

Location

Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden

Dresden, 01307, Germany

Location

Universitatsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Universitaetsklinikum Wuerzburg

Würzburg, 97080, Germany

Location

Vrije Universiteit Medisch Centrum

Amsterdam, 1081 HV, Netherlands

Location

Hospital Universitari Germans Trias i Pujol

Badalona, Cataluña, 08916, Spain

Location

Related Publications (1)

• 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.

  PMID: 33632870 BACKGROUND

Related Links

• AmgenTrials clinical trials website

MeSH Terms

Conditions

Glioblastoma; Glioma

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Limitations and Caveats

The study was terminated early. Therefore, a smaller number of participants than planned were enrolled and analysed.

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

medinfo@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Bayesian logistic regression model

Study Record Dates

• First Submitted: September 18, 2017
• First Posted: September 28, 2017
• Study Start: April 18, 2018
• Primary Completion: July 1, 2021
• Study Completion: August 28, 2021
• Last Updated: October 29, 2024
• Results First Posted: October 29, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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.
• 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.

Locations

FR (1); US (2); ES (1); DE (3); AU (2); NL (1)