Study of AMG 596 in Patients With EGFRvIII Positive Glioblastoma

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Glioblastoma or Malignant Glioma

Intervention / Treatment
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* Drug: AMG 596
* Drug: AMG 404


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Bayesian logistic regression model
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose exploration<br>Dose exploration of the intervention, AMG 596 alone or in combination with AMG 404 | Drug: AMG 596<br>* Drug<br>Drug: AMG 404<br>* Drug<br>|
| Experimental: Dose expansion<br>Dose expansion of the intervention, AMG 596 alone or in combination with AMG 404 | Drug: AMG 596<br>* Drug<br>Drug: AMG 404<br>* Drug<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1/1b, EGFRvIII-positive glioblastoma or malignant glioma, safety and tolerability, AMG 596