Phase 2 Study of Sym004 for Adult Patients With Recurrent Glioblastoma
Condition: Malignant Glioma
MeSH terms: Glioblastoma; Glioma
Intervention: Sym004 - 18 mg/kg; Sym004 - 24 mg/kg
Intervention description: Sym004 was dosed at 18 mg/kg intravenously every two weeks.; Beginning in August 2017, the dose was increased to 24 mg/kg intravenously every two weeks.
Intervention MeSH terms: Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 43.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Sym004; Glioblastoma; Desjardins; Pro00063483; Symphogen; Duke Cancer Institute

Summary:

      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.
    

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.