Details

Details

Title A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered Intravenously Prior to, and Intracranially at the Time of, Subsequent Resection for Recurrent High Grade Glioma and Followed by Treatment with Toca FC, Extended-Release 5-FC

IRB TOG1314

CC 14-284

Hospital Main Campus

Phase Phase 1

Disease Brain, High Grade Glioma

Drug Toca 511, TOCA FC

Description

Description

Primary Objective
  • To identify the highest, or maximum feasible, safe and well tolerated dose of Toca 511 administered intravenously and intracerebrally to the tumor bed in subjects with rHGG undergoing planned resection ≥ 80%.
Secondary Objectives
  • To evaluate vector deposition in the resected tumor specimens following intravenous administration of Toca 511
  • To evaluate vector kinetics following intravenous administration
  • To evaluate the safety and tolerability of repeated treatment with flucytosine (Toca FC) at various doses and schedules following administration of Toca 511
  • To evaluate preliminary efficacy of Toca 511/ Toca FC by assessing overall survival of subjects
  • To evaluate preliminary efficacy of Toca 511/ Toca FC by assessing overall survival at 6 months (OS6), 9 months (OS9), and 12 months (OS12)
  • To evaluate preliminary efficacy of Toca 511/Toca FC by assessing Progression-free survival (PFS) based on independent radiology review (IRR) of MRI data
  • To evaluate preliminary efficacy of Toca 511/ Toca FC by assessing landmark PFS at 6 months based on IRR of MRI data (PFS-6)
  • To evaluate preliminary efficacy of Toca 511/ Toca FC by assessing objective response rates using an IRR of MRI data in addition to clinical data
  • To evaluate safety and tolerability of sunitinib 50 mg administered on the 2 days prior to the first intravenous dose of Toca 511 and on the two days prior to intracranial administration of Toca 511
Exploratory Objectives
  • To evaluate preliminary efficacy of Toca 511/Toca FC by assessing the percentage of subjects who have not progressed or died at 9 months (PFS9)
  • To evaluate preliminary efficacy of Toca 511/Toca FC by assessing the percentage of subjects who have not progressed or died at 12 months (PFS12)
  • To develop a predictive diagnostic based on RNA expression profiling and to begin assessment of its clinical utility
  • To image vector injections at select centers with intraoperative MRI using a gadolinium/vector mixture, and comparing this to point/trajectory tracking using a virtual navigation imaging system
  • To evaluate vector deposition in the resected tumor specimens following intravenous administration of Toca 511 +/- sunitinib
  • To evaluate the immunotherapeutic response to Toca 511
Inclusion Criteria

Inclusion Criteria

All of the following questions must be answered "Yes" in order for the subject to participate in the study.

  1. Has the subject given written informed consent?
  2. Is the subject between 18 years old and 80 years old inclusive?
  3. Has the subject had histologically proven HGG with recurrence or progression following initial definitive therapy(s) such as surgery with or without adjuvant radiation therapy and/or chemotherapy (confirmed by diagnostic biopsy or contrast-enhanced MRI and evaluable by Macdonald criteria)? Note, if first recurrence of HGG is documented by MRI, an interval of at least 12 weeks after the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiotherapy treatment field.
  4. Does the patient have either (1) a single, enhancing tumor recurrence/progression that is ≤ 8 cm in greatest dimension, or (2) multiple enhancing tumor recurrences/progressions within the same surgical field where the sum of their greatest dimensions is ≤ 8 cm?
  5. Based on the pre-operative evaluation, is the tumor recurrence/progression a candidate for ≥ 80% resection?
  6. Has the subject elected not to undergo treatment with the Gliadel® wafer?
  7. Does the subject have a Karnofsky performance status ≥ 70?
  8. Does the subject have an absolute neutrophil count (ANC) ≥ 1500/mm3?
  9. Does the subject have an absolute lymphocyte count ≥ 500/mm3?
  10. Does the subject have a platelet count ≥ 100,000/mm3?
  11. Does the subject have a Hgb ≥ 10 g/dL?
  12. Does the subject have a coagulation profile that would allow for the safe performance of surgery under general anesthesia?
  13. Does the subject have an estimated glomerular filtration rate of at least 50 mL/min (inclusive) by the Cockcroft-Gault formula?
  14. Does the subject have an ALT < 3 times the upper limit of the laboratory reference range and total bilirubin < 1.5 mg/dL?
  15. If the subject is a female of childbearing potential, has she had a negative serum pregnancy test within the past 21 days?
  16. Is the subject willing to use condoms for contraception for 6 months after receiving Toca 511 or until there is no evidence of the virus in his/her blood, whichever is longer. If the subject is a fertile female, is she willing to use contraception for at least 12 months?
  17. Is the subject willing and able to abide by the protocol?
  18. Does the subject have adequate venous access?
Exclusion Criteria

Exclusion Criteria

All of the following questions must be answered "No" in order for the subject to participate in the study.

  1. Has the subject received cytotoxic chemotherapy within the past 3 weeks (6 weeks for nitrosoureas) of the planned date of vector injection?
  2. Does the subject have, or has the subject had, within the past 4 weeks any infection requiring antibiotic, antifungal or antiviral therapy?
  3. Has the subject received Avastin® (bevacizumab) for this recurrence/progression, or within the 4 weeks prior to planned Visit 1?
  4. Does the subject have any bleeding diathesis, or must the subject take any anticoagulants, or antiplatelet agents, including NSAIDs that cannot be stopped for surgery?
  5. Does the subject have a history of allergy or intolerance to flucytosine?
  6. Is the subject HIV positive?
  7. Does the subject have any gastrointestinal disease that would prevent him or her from being able to swallow or absorb flucytosine?
  8. Has the subject received any investigational treatment within the past 30 days?
  9. Is the subject breastfeeding?
  10. Does the patient have a history of prior malignancy, excluding basal or squamous cell carcinoma of the skin, with an expected survival of less than five years?