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A Study to Evaluate the Safety, Tolerability and Immunogenicity of EGFR(V)-EDV-Dox in Subjects With Recurrent Glioblastoma Multiforme (GBM)

NCT02766699

Description:

The purpose of the Cerebral EDV study is to determine the safety and tolerability of EGFR(V)-EDV-Dox in order to establish the best dose level to be used in future studies. The study will also examine the body's immune response to EGFR(V)-EDV-Dox and assess if it is effective in the treatment of patients with recurrent glioblastoma multiforme (GBM).

Related Conditions:
  • Glioblastoma
  • High Grade Astrocytic Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety, Tolerability and Immunogenicity of EGFR(V)-EDV-Dox in Subjects With Recurrent Glioblastoma Multiforme (GBM)
  • Official Title: A Phase 1 Study to Evaluate the Safety, Tolerability, and Immunogenicity of EGFR (Vectibix® Sequence)-Targeted EnGeneIC Dream Vectors Containing Doxorubicin (EGFR(V)-EDV-Dox) in Subjects With Recurrent Glioblastoma Multiforme (GBM)

Clinical Trial IDs

  • ORG STUDY ID: ENG7
  • NCT ID: NCT02766699

Conditions

  • Glioblastoma
  • Astrocytoma, Grade IV

Interventions

DrugSynonymsArms
EGFR(V)-EDV-DoxEnGeneIC Dream Vector™, EnGeneIC Delivery Vehicle™EGFR(V)-EDV-Dox

Purpose

The purpose of the Cerebral EDV study is to determine the safety and tolerability of EGFR(V)-EDV-Dox in order to establish the best dose level to be used in future studies. The study will also examine the body's immune response to EGFR(V)-EDV-Dox and assess if it is effective in the treatment of patients with recurrent glioblastoma multiforme (GBM).

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
EGFR(V)-EDV-DoxExperimentalEGFR(V)-EDV-Dox administered via 20 minute intravenous infusion once a week for seven weeks (1 Cycle). Subjects will receive one of two dose levels: 5 x 10^9 or 8 x 10^9. Subjects may receive further cycles of treatment if the tumor remains stable or is responding, and/or they are deriving clinical benefit from the therapy and are tolerating treatment.
  • EGFR(V)-EDV-Dox

Eligibility Criteria

        Inclusion Criteria:

          1. Karnofsky Performance Status (KPS) ≥ 60%.

          2. Life expectancy ≥ 3 months.

          3. Pathologically documented, and definitively diagnosed recurrent World Health
             Organization (WHO) Grade IV astrocytoma (GBM).

          4. 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.

          5. 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.

          6. Participant has received no more than 1 other therapeutic regimen other than those
             listed above in (5).

          7. Participant may be receiving steroid therapy at time of enrollment (stable dose of ≤ 4
             mg/day of dexamethasone or steroid equivalent).

          8. Ability to undergo MRI evaluation.

          9. Participant has ≥ 1 site of bi-dimensionally measurable disease measured using
             contrast enhanced MRI.

         10. 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

         11. 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).

         12. 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).

         13. Adequate cardiac function with left ventricular ejection fraction (LVEF) ≥ 55% at
             baseline.

         14. Serum phosphate levels that are within normal limits (2.4 - 4.1 milligrams per
             deciliter mg/dL) at baseline.

         15. 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:

          1. History of central nervous system bleeding as defined by stroke or intraocular bleed
             within 6 months of enrollment.

          2. Evidence of acute intracranial / intra-tumoral hemorrhage, except for participants
             with stable grade 1 hemorrhage.

          3. 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.

          4. Clinically significant electrocardiogram (ECG) changes at enrollment which obscure the
             ability to assess the PR, QT, and QRS interval; congenital long QT syndrome.

          5. Active infection requiring treatment.

          6. 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.

          7. Known positive test for human immunodeficiency virus infection (HIV), or active
             hepatitis B or hepatitis C infection.

          8. Receipt of therapies or procedures prior to first dose including:

               -  Radiation therapy (within 12 weeks 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).

               -  Medications known to cause QTc interval prolongation (within 7 days OR five
                  half-lives prior to Study Day 1, whichever is longer).

               -  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).

          9. 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)).

         10. If female, is pregnant or is breast feeding.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety outcome measures: Adverse Events (AE's) graded according to CTCAE V.4.3, physical/neurologic examination, Karnofsky Performance Status (KPS), vital signs, echocardiogram, ECG, hematology, serum chemistry & urinalysis.
Time Frame:Safety measures will be conducted from Study Day 1 as per study schedule to safety follow-up visit 30 (+5 days) post last dose.
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Efficacy outcome measure: Disease response will be measured by Magnetic Resonance Imaging (MRI) using Response Assessment in Neuro-Oncology (RANO).
Time Frame:Screening, then post cycle (Days 50-56)
Safety Issue:
Description:
Measure:Identification of a recommended Phase 2 dose (RP2D) of EGFR(V)-EDV-Dox in subjects with recurrent GBM : Dose limiting toxicity (DLT) evaluable subjects.
Time Frame:DLT evaluable subjects are those who experience a DLT during the evaluation period, between days 1-28. In subjects with an elevated interleukin-6 (IL-6) the DLT evaluation period is days 1-42 for 5 x 10^9 and days 1-49 for 8 x 10^9.
Safety Issue:
Description:
Measure:Overall survival outcome measure.
Time Frame:The number of days from the date of first administration of EGFR(V)-EDV-Dox to the date of death, regardless of cause up to 60 months.
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Engeneic Pty Limited

Trial Keywords

  • Astrocytoma, Grade IV
  • Doxorubicin
  • Glioblastoma
  • Neoplasms
  • Neoplasms by Site
  • Antineoplastic Agents
  • Drug Delivery Systems
  • Molecular Targeted Therapy
  • Nanoparticles
  • Disease Progression
  • Recurrence
  • Brain Neoplasms
  • Immunotherapy
  • Receptor, Epidermal Growth Factor
  • Antibodies, Bispecific

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