The purpose of the Cerebral EDV study is to determine the safety and tolerability of
EGFR(V)-EDV-Dox in order to establish the best dose level to be used in future studies. The
study will also examine the body's immune response to EGFR(V)-EDV-Dox and assess if it is
effective in the treatment of patients with recurrent glioblastoma multiforme (GBM).
This is an open-label, Phase 1, dose exploration and preliminary immunogenicity study of
single agent EGFR(V)-EDV-Dox in subjects with recurrent glioblastoma (GBM). Eligible subjects
enrolled in the study will receive EGFR(V)-EDV-Dox administered weekly for 7 weeks via IV 20
minute infusion, followed by radiological evaluation at week 8 (1 Cycle). Subjects may
continue to receive subsequent cycles of EGFR(V)-EDV-Dox unless the subject becomes
intolerant to investigational product (IP), withdraw consent or the individual is no longer
receiving clinical benefit (factors taken in to consideration will be disease progression
radiologically or clinically, and clinical benefits to quality of life). Tumour assessment
will be repeated after each 7 week cycle (week 8).
The study will take place in two parts, Part 1 (Dose Exploration) and Part 2 (Dose
Expansion).
Part 1 - Dose Exploration will assess the safety and tolerability of multiple doses of drug
at two dose levels (5 x 10^9 and 8 x 10^9) and will enroll prior to Part 2. Three subjects
will be recruited per dose level. Enrollment will begin with the 5 x 10^9 dose level, and the
decision to enroll to the 8 x 10^9 dose level will follow a comprehensive safety evaluation
and a standard 3 + 3 dose escalation study design.
Part 2 - Dose Expansion will be conducted pending safety results of Part 1 to provide
guidance regarding the recommended phase 2 dose (RP2D). Subjects will be treated and assessed
as outlined in Part 1 above. If 0 out of 3 subjects, or 1 out of 6 subjects, experience dose
limiting toxicities (DLTs) at the 5 x 10^9 dose level in Part 1, additional subjects to a
total of 10 will be recruited to this dose level in Part 2. Similarly, if 0 out of 3
subjects, or 1 out of 6 subjects, experience DLTs at the 8 x 10^9 dose level in Part 1,
additional subjects to a total of 10 will be recruited to this dose level in Part 2. If both
dose levels are tolerated, a total of 10 subjects per dose level will be enrolled.
A safety follow-up visit must be performed 30 (+5) days after the last dose of drug for all
subjects.All subjects who discontinue investigational product and who have not withdrawn full
consent to participate in the study will continue in the long term follow-up phase. Long term
follow-up will continue approximately every 1 month for 12 months, from the 30 (+5) day
follow-up visit, then approximately every 2-3 months for the extent of subject survival.
Inclusion Criteria:
1. Karnofsky Performance Status (KPS) ≥ 60%.
2. Life expectancy ≥ 3 months.
3. Pathologically documented, and definitively diagnosed recurrent World Health
Organization (WHO) Grade IV astrocytoma (GBM).
4. Participant must have archived tumor tissue available from initial diagnosis or
subsequent relapse(s) of Grade IV GBM for submission for central review at
Investigational sites local laboratories.
5. Recurrence or progression of disease (confirmed by MRI and measurable by RANO
criteria) following receipt of standard of care therapy, which includes maximum safe
surgical resection, standard adjuvant radiation/temozolomide treatment. Participants
must have completed at least 21 days of temozolomide treatment in combination with
radiation therapy to be considered to have received standard of care therapy.
6. Participant has received no more than 1 other therapeutic regimen other than those
listed above in (5).
7. Participant may be receiving steroid therapy at time of enrollment (stable dose of ≤ 4
mg/day of dexamethasone or steroid equivalent).
8. Ability to undergo MRI evaluation.
9. Participant has ≥ 1 site of bi-dimensionally measurable disease measured using
contrast enhanced MRI.
10. Hematological function:
- White blood cell count (WBC) ≥ 3.0 x 109/L
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Hemoglobin > 9 g/dL
- Prothrombin time (PT) or partial thromboplastin time (PTT) < 1.5 x upper limit of
normal (ULN)
- International normalized ratio (INR) < 1.5 x ULN
11. Renal function:
- Blood urea nitrogen (BUN) < 30 mg/dL
- Creatinine serum levels ≤ 1.5 x ULN
- Or creatinine clearance ≥ 60 mL/minute for subjects with serum creatinine outside
the normal range (calculated using the Cockcroft-Gault equation).
12. Hepatic function:
- Aspartate aminotransferase (AST) < 2.5 x ULN (3 x ULN for subjects on chronic
anticonvulsive therapies known to increase transaminases).
- Alanine aminotransferase (ALT) < 2.5 x ULN (3 x ULN for subjects on chronic
anticonvulsive therapies known to increase transaminases).
- Alkaline phosphatase (ALP) < 2.5 x ULN (3 x ULN for subjects on chronic
anticonvulsive therapies).
- Total bilirubin ≤ 1 x ULN (unless elevated due to Gilbert's syndrome or
extrahepatic source as denoted by increased indirect bilirubin fraction. Subjects
with ≥1 x ULN will be tested for direct bilirubin fraction so that the indirect
fraction can be calculated).
13. Adequate cardiac function with left ventricular ejection fraction (LVEF) ≥ 55% at
baseline.
14. Serum phosphate levels that are within normal limits (2.4 - 4.1 milligrams per
deciliter mg/dL) at baseline.
15. Subject meets the reproductive criteria as follows:
- Female subjects who are of non-reproductive potential (ie, post menopausal by
history - no menses for ≥ 1 year and follicle-stimulating hormone (FSH) level
consistent with post-menopausal status; OR history of hysterectomy; OR history of
bilateral tubal ligation; OR history of bilateral oophorectomy).
- Female subjects of childbearing potential must have a negative serum pregnancy
test within 7 days prior to the 1st dose, if more than 7 days prior, a urine
pregnancy test must be performed before the 1st dose. The female subject must be
willing to use highly effective methods of birth control during the period of
therapy and for 6 months following the last study IP administration. Highly
effective methods of birth control include sexual abstinence, hormonal birth
control, or intrauterine device (women), vasectomy or a condom with spermicide
(men) in combination with barrier methods.
- Male subjects who are willing to use highly effective methods of birth control
during the period of therapy and for 6 months following the last IP
administration.
- All study subjects must be willing to ensure that corresponding sexual partners
practice these same methods of highly effective birth control for the same
duration.
Exclusion Criteria:
1. History of central nervous system bleeding as defined by stroke or intraocular bleed
within 6 months of enrollment.
2. Evidence of acute intracranial / intra-tumoral hemorrhage, except for participants
with stable grade 1 hemorrhage.
3. History of coronary artery disease, with or without angina pectoris or myocardial
infarction, symptomatic congestive heart failure (New York Heart Association > Class
II), uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100 mmHg) or
cardiac arrhythmias requiring anti-arrrhythmic therapy.
4. Clinically significant electrocardiogram (ECG) changes at enrollment which obscure the
ability to assess the PR, QT, and QRS interval; congenital long QT syndrome.
5. Active infection requiring treatment.
6. History of other malignancies, except: adequately treated non-melanoma skin cancer,
curatively treated in-situ cancer, or other malignancies curatively treated with no
evidence of disease for ≥ 2 years.
7. Known positive test for human immunodeficiency virus infection (HIV), or active
hepatitis B or hepatitis C infection.
8. Receipt of therapies or procedures prior to first dose including:
- Radiation therapy within 6 months of Study Day 1 or has not recovered from the
toxic effects of such therapy.
- Bevacizumab® or other anti-angiogenic therapy.
- Gliadel® Wafer (within 6 months of Study Day 1, or has not recovered from the
toxic effects of such therapy).
- Immunotherapeutic agents, vaccines, or monoclonal antibody therapy (within 4
weeks of Study Day 1 or has not recovered from the toxic effects of such cancer
therapy).
- Temozolomide or other chemotherapy (within 4 weeks of Study Day 1 or 6 weeks for
nitrogen mustards, or has not recovered from the toxic effects of such cancer
therapy).
- Anticoagulation therapy (within 7 days of Study Day 1), except low molecular
weight heparins or low dose aspirin.
- Other investigational therapy (within 30 days of Study Day 1).
- Surgical resection of brain tumor (within 4 weeks of Study Day 1 or has not
recovered from acute side effects of such therapy except for neurological
effects).
- Any major surgery (within 4 weeks of Study Day 1, or has not recovered from the
effects of such surgery).
9. Subject has a known allergic/hypersensitivity to investigational components or
excipients (doxorubicin, trehalose, monoclonal antibody therapy, penicillin class of
antibiotics, gentamicin (or other aminoglycosides), or ciprofloxacin hydrochloride (or
other quinolones)).
10. If female, is pregnant or is breast feeding.
