Phase 2 Study of Sym004 for Adult Patients With Recurrent Glioblastoma

The purpose of this study is to assess the activity of Sym004, a recombinant antibody mixture that specifically binds to EGFR, in patients diagnosed with recurrent glioblastoma whose tumor is EGFR amplified. This is a phase 2 study that will accrue patients with WHO grade IV recurrent malignant glioma (glioblastoma or gliosarcoma) in two cohorts to assess the efficacy of Sym004.

The purpose of this study is to assess the activity of Sym004, a recombinant antibody mixture that specifically binds to EGFR, in patients diagnosed with recurrent glioblastoma whose tumor is EGFR amplified. The primary objective is to assess the activity of Sym004 in patients with recurrent glioblastoma that are either non-bevacizumab failures (Cohort 1) or who have previously failed bevacizumab (Cohort 2), in terms of 6-month progression-free survival (PFS6). Secondary objectives include: 1. Determine the safety of Sym004 in recurrent glioblastoma (GBM) patients; 2. Estimate response rate (RR) within the two cohorts of recurrent GBM patients; 3. Describe overall survival (OS) within the two cohorts of recurrent GBM patients; 4. Describe overall median progress free survival (PFS) within the two cohorts of recurrent GBM patients.

This is a phase 2 study that will accrue patients with WHO grade IV recurrent malignant glioma (glioblastoma or gliosarcoma) in two cohorts to assess the efficacy of Sym004. Both cohorts will accrue simultaneously, with 36 subjects in Cohort 1 and 25 subjects in Cohort 2 at a dose of 18 mg/kg Sym004 given intravenously every 2 weeks. A treatment cycle will be 4 weeks.

Twenty-five subjects have been treated at the 18 mg/kg dose of Sym004. Beginning in August 2017, the dose of Sym004 will be increased to 24 mg/kg. Sixty-five additional subjects (36 in Cohort 1 and 29 in Cohort 2) will be treated at the new dose level.

Eligibility Criteria:
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.