Phase 2 Study of Sym004 for Adult Patients With Recurrent Glioblastoma

Inclusion Criteria:

1. Patients must have histologically confirmed diagnosis of World Health Organization (WHO) grade 4 malignant glioma and radiographic evidence of recurrence or disease progression (as defined by the Response Assessment in Neuro-Oncology (RANO) criteria as a greater than 25% increase in the largest bi-dimensional product of enhancement or a new enhancing lesion, or a significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) abnormality without another co-morbid cause);
2. Age ≥ 18 years;
3. Karnofsky Performance Status ≥ 70%;
4. No more than 3 prior progressions;
5. Cohort 1 only: Non-bevacizumab failure, i.e. either no prior bevacizumab or bevacizumab stable/responder, which is defined as stable within 6 months of prior treatment with bevacizumab without experiencing a bevacizumab adverse event of special interest (AESI) while on a bevacizumab-containing regimen, such as:

   1. ≥ grade 3 hypertension not controlled by medication, hypertensive crisis, or hypertensive encephalopathy
   2. ≥ grade 3 proteinuria that does not resolve or nephrotic syndrome
   3. Any grade GI perforation
   4. ≥ grade 3 infusion-related reaction
   5. ≥ grade 3 woundhealing complications
   6. ≥ grade 3 hemorrhage or any grade central nervous system (CNS) hemorrhage or ≥ grade 2 hemoptysis
   7. Any grade arterial thromboembolic event (e.g. myocardial infarction or cerebral infarction) or ≥ grade 3 venous thromboembolic event
   8. Any grade posterior reversible encephalopathy syndrome (PRES)
   9. ≥ grade 3 congestive heart failure
   10. ≥ grade 2 non-gastrointestinal (GI) abscesses and fistulae;
6. Cohort 2 only: Prior progression on a bevacizumab-containing regimen (defined as having progressed/grown through bevacizumab by RANO criteria within 2 months of prior bevacizumab treatment);
7. Pathology consistent with Epidermal Growth Factor Receptor (EGFR)-amplification of tumor (i.e. greater than 15% of cells exhibiting \> 5 copies of EGFR loci); archival tissue may be tested for EGFR status in a separate consent;
8. Absolute Neutrophil Count (ANC) ≥ 1,000 cells/µl, platelets ≥ 100,000 cells/µl, hemoglobin ≥ 9 g/dL;
9. Adequate renal function as indicated by the following:

   1. Serum creatinine \< 1.25 times upper limit of normal or calculated creatinine clearance ≥ 50 ml/min;
   2. Urine dipstick for proteinuria \< 2+ unless a 24-hour urine protein \<1 g of protein is demonstrated;
10. Adequate liver function as indicated by the following:

    1. Total bilirubin ≤ 1.6 mg/dL;
    2. Aspartate transaminase/alanine transaminase (AST/ALT) ≤ 2.5 x the upper limit of normal (ULN);
11. Magnesium ≥ 0.9 mg/dL;
12. For subjects on corticosteroids, they must be on a stable dose for 7 days prior to anticipated start of study drug;
13. No evidence of \> grade 1 active CNS hemorrhage on the baseline magnetic resonance imaging (MRI) or X-ray computed tomography (CT) scan;
14. Signed informed consent approved by the Institutional Review Board prior to patient entry;
15. If the patient is a sexually active female of child bearing potential whose partner is male, or if the patient is a sexually active male whose partner is a female of child bearing potential, the patient must agree to use appropriate contraceptive measures for the duration of the treatment of the tumor and for 6 months afterwards as stated in the informed consent. Female patients of child bearing potential must have a negative serum pregnancy test within 48 hours of starting study treatment;
16. Fertile male subjects must agree to use a medically acceptable contraceptive method (allowed methods of birth control include vasectomy or condom with spermicide) during the trial and for a period of at least 6 months following the last administration of trial drugs.

Exclusion Criteria:

1. Pregnancy or breastfeeding;
2. Prior treatment with EGFR-targeted therapy, including, but not limited to, the following examples: Gilotrif® (afatinib),Tarceva® (erlotinib), Erbitux® (cetuximab), Iressa™ (gefitinib), Vectibix® (panitumumab), Caprelsa® (vandetanib), Tykerb® (lapatinib), CDX110, D2C7-immunotoxin;
3. Active infection requiring intravenous antibiotics within 7 days before enrollment;
4. Prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin;
5. Less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation;
6. Treated with immunotherapeutic agents, vaccines, or Mab therapy within 4 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy
7. Treated with alkylating agents within 4 weeks (6 weeks for nitrosoureas) before enrollment or treated within 1 week before enrollment with daily or metronomic chemotherapy, unless the patient has recovered from the expected toxic effects of such therapy to their baseline or to grade 1;
8. Prior treatment (non-alkylating agents) within 2 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy;
9. Known hypersensitivity reactions to any of the components of Sym004;
10. Known current drug abuse or alcohol abuse;
11. Known Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C infection. Testing is not required as part of this study.