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.
