A Study to Evaluate the Safety, Tolerability and Immunogenicity of EGFR(V)-EDV-Dox in Subjects With Recurrent 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days after the last dose of drug for all subjects.All subjects who discontinue investigational product and who have not withdrawn full consent to participate in the study will continue in the long term follow-up phase.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

• Karnofsky Performance Status (KPS) ≥ 60%.
• Life expectancy ≥ 3 months.
• Pathologically documented, and definitively diagnosed recurrent World Health Organization (WHO) Grade IV astrocytoma (GBM).
• 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.
• 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.
• Participant has received no more than 1 other therapeutic regimen other than those listed above in (5).
• Participant may be receiving steroid therapy at time of enrollment (stable dose of ≤ 4 mg/day of dexamethasone or steroid equivalent).
• Ability to undergo MRI evaluation.
• Participant has ≥ 1 site of bi-dimensionally measurable disease measured using contrast enhanced MRI.
• 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
• 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).
• 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).
• Adequate cardiac function with left ventricular ejection fraction (LVEF) ≥ 55% at baseline.
• Serum phosphate levels that are within normal limits (2.4 - 4.1 milligrams per deciliter mg/dL) at baseline.
• 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

• History of central nervous system bleeding as defined by stroke or intraocular bleed within 6 months of enrollment.
• Evidence of acute intracranial / intra-tumoral hemorrhage, except for participants with stable grade 1 hemorrhage.
• 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.
• Clinically significant electrocardiogram (ECG) changes at enrollment which obscure the ability to assess the PR, QT, and QRS interval; congenital long QT syndrome.
• Active infection requiring treatment.
• 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.
• Known positive test for human immunodeficiency virus infection (HIV), or active hepatitis B or hepatitis C infection.
• 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).
• 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)).
• If female, is pregnant or is breast feeding.