Study of AMG 596 in Patients With EGFRvIII Positive Glioblastoma

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).


Eligibility 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 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.