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Phase 2 Study of Sym004 for Adult Patients With Recurrent Glioblastoma

This study is currently recruiting participants.
Verified September 2017 by Annick Desjardins, Duke University Medical Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT02540161
First Posted: September 3, 2015
Last Update Posted: September 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Symphogen A/S
Information provided by (Responsible Party):
Annick Desjardins, Duke University Medical Center
  Purpose
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.

Condition Intervention Phase
Malignant Glioma Drug: Sym004 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Sym004 for Adult Patients With Recurrent Glioblastoma

Resource links provided by NLM:


Further study details as provided by Annick Desjardins, Duke University Medical Center:

Primary Outcome Measures:
  • Six-month progression-free survival (PFS6) [ Time Frame: 6 months ]
    Within each cohort, the percentage of participants alive and progression-free at 6 months after the start of Sym004 treatment will be determined. PFS6 will be calculated from the date study treatment started until the date of progression or death, or the date of last follow-up if participants are alive without progression. Kaplan-Meier methods will be used to estimate survival.


Secondary Outcome Measures:
  • Percentage of participants who experience grade 3, 4 or 5 adverse events [ Time Frame: 2 years ]
    Within each cohort, the percentage of participants who experience grade 3, 4 or 5 adverse events that are possibly, probably or definitely related to study treatment will be calculated.

  • Radiographic response [ Time Frame: 2 years ]
    Within each cohort, the percentage of participants with a complete or partial response as determined by modified Response Assessment in Neuro-Oncology (RANO) criteria will be determined. Complete Response (CR) is defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) is defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Tumor assessments are done at baseline and the end of every second cycle (every 8 weeks) thereafter.

  • Median progression-free survival (PFS) [ Time Frame: 2 years ]
    Median PFS will be estimated within each cohort. Progression-free survival is defined as the time in months from the start of protocol treatment until the date of progression or death if death occurred before progression. If the participant is alive and progression-free, PFS will be censored at the date of last follow-up. Kaplan-Meier methods will be used to estimate progression-free survival.

  • Median overall survival (OS) [ Time Frame: 2 years ]
    Median OS will be estimated within each cohort. Overall survival is defined as the time in months from the start of protocol treatment until the date of death, or the date of last follow-up if alive. Kaplan-Meier methods will be used to estimate overall survival.


Estimated Enrollment: 90
Actual Study Start Date: February 1, 2016
Estimated Study Completion Date: May 2020
Estimated Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: non-bevacizumab failures
Non-bevacizumab failure (either no prior bevacizumab or bevacizumab stable/responder, which is defined as stable for at least 6 months from prior treatment with bevacizumab without experiencing a bevacizumab adverse event of special interest (AESI) while on a bevacizumab-containing regimen) will receive Sym004 intravenously every two weeks.
Drug: Sym004
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.
Experimental: bevacizumab failures
Prior progression on a bevacizumab-containing regimen (defined as having progressed/grown through bevacizumab by RANO criteria within 2 months of prior bevacizumab treatment) will receive Sym004 intravenously every two weeks.
Drug: Sym004
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.

Detailed Description:

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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02540161


Contacts
Contact: Annick Desjardins, MD, FRCPC 919 684-6173 annick.desjardins@duke.edu
Contact: Woody Massey, BS, M.Div. 919 668-1814 woody.massey@duke.edu

Locations
United States, North Carolina
The Preston Robert Tisch Brain Tumor Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Annick Desjardins, MD, FRCPC    919-684-6173    annick.desjardins@duke.edu   
Contact: Woody Massey, BS, M.Div.    919 668-1814    woody.massey@duke.edu   
Principal Investigator: Annick Desjardins, MD, FRCPC         
Sponsors and Collaborators
Annick Desjardins
Symphogen A/S
Investigators
Principal Investigator: Annick Desjardins, MD, FRCPC Duke University
  More Information

Additional Information:
Responsible Party: Annick Desjardins, Associate Professor of Neurology, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT02540161     History of Changes
Other Study ID Numbers: Pro00063483
First Submitted: September 1, 2015
First Posted: September 3, 2015
Last Update Posted: September 11, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Annick Desjardins, Duke University Medical Center:
Sym004
Glioblastoma
Desjardins
Pro00063483
Symphogen
Duke Cancer Institute

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents