Study of AMG 596 in Patients With EGFRvIII Positive Glioblastoma

• ClinicalTrials.gov Identifier: NCT03296696
• Recruitment Status: Active, not recruiting
• First Posted: September 28, 2017
• Last Update Posted: December 30, 2020
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Glioblastoma or Malignant Glioma	Drug: AMG 596; Drug: AMG 404	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Bayesian logistic regression model
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: April 18, 2018
• Estimated Primary Completion Date: December 31, 2021
• Estimated Study Completion Date: December 31, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Subject grade of dose limiting toxicities (DTLs) [ Time Frame: 12 months ]
   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
2. Number of subject with treatment-emergent adverse events [ Time Frame: 12 months ]
3. Number of subjects with treatment-related adverse events [ Time Frame: 12 months ]
4. Number of subjects with clinically significant changes in vital signs [ Time Frame: 12 months ]
5. Number of subjects with clinically significant changes in physical examinations [ Time Frame: 12 months ]
6. Number of subjects with clinically significant changes in clinical laboratory tests [ Time Frame: 12 months ]

Secondary Outcome Measures :

1. Average steady-state concentration (Css) for serum AMG 596 [ Time Frame: 12 months ]
2. Area under the concentration-time curve (AUC) for serum AMG 596 [ Time Frame: 12 months ]
3. Clearance for serum AMG 596 [ Time Frame: 12 months ]
4. Volume of distribution for serum AMG 596 [ Time Frame: 12 months ]
5. Half-life (t1/2) for serum AMG 596 [ Time Frame: 12 months ]
6. Maximum abserved serum concentration (Cmax) for AMG 404 [ Time Frame: 12 months ]
7. Time to achieve Cmax (tmax) for AMG 404 [ Time Frame: 12 months ]
8. Area under the concentration-time curve (AUC) for AMG 404 [ Time Frame: 12 months ]
9. Average steady-state concentration (Css) for serum AMG 596 in combination with AMG 404 [ Time Frame: 12 months ]
10. Area under the concentration-time curve (AUC) for serum AMG 596 in combination with AMG 404 [ Time Frame: 12 months ]
11. Clearance for serum AMG 596 in combination with AMG 404 [ Time Frame: 12 months ]
12. Half-life (t1/2) for serum AMG 596 in combination with AMG 404 [ Time Frame: 12 months ]
13. Objective response (OR) as per modified RANO for AMG 596 [ Time Frame: 6 and 12 months ]
    Objective response (OR) as per modified RANO (Response Assessment in Neuro-Oncology Criteria).
14. Time to response for serum AMG 596 in combination with AMG 404 [ Time Frame: 6 and 12 months ]
15. Response duration for serum AMG 596 in combination with AMG 404 [ Time Frame: 6 and 12 months ]
16. Time to progression (TTP) for serum AMG 596 in combination with AMG 404 [ Time Frame: 6 and 12 months ]
17. Progression free survival (PFS) at 6 and 12 months after treatment initiation with AMG 596 monotherapy [ Time Frame: 6 and 12 months ]
18. Progression free survival (PFS) at 6 and 12 months after treatment initiation with AMG 596 in combination with AMG 404 [ Time Frame: 6 and 12 months ]
19. Objective response (OR) as per modified RANO with AMG 596 monotherapy [ Time Frame: 6 and 12 months ]
20. Time to response with AMG 596 monotherapy [ Time Frame: 6 and 12 months ]
21. Response duration with AMG 596 monotherapy [ Time Frame: 6 and 12 months ]
22. Time to progression (TTP) with AMG 596 monotherapy [ Time Frame: 6 and 12 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Research Site

Los Angeles, California, United States, 90095

United States, New York

Research Site

New York, New York, United States, 10065

Australia, New South Wales

Research Site

St. Leonards, New South Wales, Australia, 02065

Australia, Victoria

Research Site

Melbourne, Victoria, Australia, 3000

France

Research Site

Villejuif, France, 94805

Germany

Research Site

Dresden, Germany, 01307

Research Site

Hamburg, Germany, 20246

Research Site

Würzburg, Germany, 97080

Netherlands

Research Site

Amsterdam, Netherlands, 1081 HV

Spain

Research Site

Badalona, Cataluña, Spain, 08916

Sponsors and Collaborators

Amgen

Investigators

• Study Director: MD; Amgen

More Information

Additional Information:

AmgenTrials clinical trials website 

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03296696
• Other Study ID Numbers: 20160132; 2017-001658-32 ( EudraCT Number )
• First Posted: September 28, 2017
• Last Update Posted: December 30, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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.
• URL: https://www.amgen.com/datasharing

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Amgen:

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

Additional relevant MeSH terms:

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