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: Terminated
• 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: 14 years to 96 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

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 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)

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
• 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
• Unresolved toxicities from prior antitumor therapy, defined as not having resolved to common terminology criteria for adverse events (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
• 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

• Male and female of reproductive potential who are unwilling to practice highly effective method(s) of birth control while on study and through 30 days after receiving the last dose of AMG 596 and through 4 months (120 days) after receiving the last dose of AMG 404.

  • Criteria for women of non-reproductive potential is as follows:
  • Postmenopausal as defined as:
  • Age of 55 years with cessation of menses for 12 months or more, OR
  • Age < 55 years and no spontaneous menses for at least 2 years, OR
  • Age < 55 years and spontaneous menses within the past year, but currently amenorrheic (eg, spontaneous or secondary to chemotherapy) AND with postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating hormone level > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) according to the definition of "postmenopausal range" for the laboratory involved; OR
  • History of hysterectomy; OR
  • History of bilateral oophorectomy
  • Highly effective methods of birth control include sexual abstinence (male, female); vasectomy; bilateral tubal ligation/occlusion; hormonal birth control or intrauterine device (IUD) (female).
• Female who is lactating/breastfeeding or who plans to breastfeed while on study through 30 days after receiving the last dose of AMG 596 and through 4 months (120 days) after receiving the last dose of AMG 404.
• Female with a positive pregnancy test.
• Female planning to become pregnant while on study through 30 days after receiving the last dose of AMG 596 and through 4 months (120 days) after receiving the last dose of AMG 404 infusion.
• Male who is unwilling to abstain from sperm donation while on study through 30 days after receiving the last dose of AMG 596 and through 4 months (120 days) after receiving the last dose of AMG 404.
• Subjects likely to not be available to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.
• History of solid organ transplantation. Prior treatment with anti-PD-1, anti-PD-L1, CTLA-4 or other checkpoint inhibitor drugs
• Prior treatment with AMG 596 monotherapy arm is not eligible to enroll in the combination therapy arm.
• Live vaccine therapies within 4 weeks prior to study drug administration
• Evidence of interstitial lung disease or active, non-infectious pneumonitis
• History of any immune-related colitis. Infectious colitis is allowed if evidence of adequate treatment and clinical recovery exists and at least 3 months interval observed since diagnosis of colitis.
• Active or history of any autoimmune disease or immunodeficiencies. Subjects with Type I diabetes, vitiligo, psoriasis, hypo-or hyper-thyroid disease not requiring immune-suppressive treatment are permitted.
• Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac arrhythmia requiring medication.

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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	There were insufficient evaluable samples collected for the determination of AUC.	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	Clearance (CL) is calculated based on dose and AUC.	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	The formula for volume of distribution is dose/concentration. For this study, the dose is measured in mcg/day and concentration is measure as ng/mL resulting in units of mcg/day/(ng/mL) for volume of distribution.	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
Number of Participants With an Objective Response (OR) Per Modified Response Assessment in Neuro-Oncology Criteria (RANO) Criteria With AMG 596 Monotherapy	Objective response was defined as the number of participants with complete response (CR) or partial response (PR) per modified RANO criteria. CR per modified RANO: disappearance of all enhancing disease, no new lesions, stable or improved T2-weighted fluid-attenuated inversion recovery (T2/FLAIR), no more than physiological steroids, clinically stable or improved, disappearance confirmed with follow-up scans after ≥4 weeks. PR per modified RANO: ≥50% decrease in the sum of perpendicular diameters of enhancing disease from baseline, stable or improved T2/FLAIR, stable or decreased steroid dose, clinically stable or improved, decrease confirmed with follow up scan after ≥ 4 weeks.	Baseline up to 12 Months
Time to Response With AMG 596 Monotherapy	Time to response was calculated as the number of months from the date of first administration of AMG 596 to the date of confirmation of first objective response per magnetic resonance imaging (MRI) scan. If a participant did not respond, time to response was censored at the date of the last evaluable response assessment.	Up to 12 months
Response Duration With AMG 596 Monotherapy	Response duration was analysed as the number of months between the first tumor response assessment of an OR (PR or CR) which is subsequently confirmed to the time of the first tumor response assessment of progressive disease or death if due to disease progression.	Up to 30 months
Time to Progression (TTP) With AMG 596 Monotherapy	The TTP was calculated as the time from the date of first dose of AMG 596 until the date of diagnosis of progression of tumor. Participants who did not have progression were censored at the last radiological non-missing evaluable tumor assessment date.	Up to 12 Months
Progression-free Survival (PFS) With AMG 596 Monotherapy	The PFS was calculated as the time from the date of first dose of AMG 596 until the date of diagnosis of progression of tumor, or date of death, whichever was earlier.	Up to 12 months

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, 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): October 29, 2024
• Last Update Submitted That Met QC Criteria: October 28, 2024
• Last Verified: October 1, 2024

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; Neoplasms by Histologic Type; 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; SAP; ICF; 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