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Safety and Efficacy Study of TH-302 CNS Penetration in Recurrent High Grade Astrocytoma Following Bevacizumab

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by The University of Texas Health Science Center at San Antonio
Sponsor:
Information provided by (Responsible Party):
Andrew Brenner, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier:
NCT01403610
First received: July 22, 2011
Last updated: September 16, 2014
Last verified: September 2014
  Purpose

The Primary Objectives are:

  • To determine the extent by which TH-302 is able to penetrate the blood brain barrier and affect tumor tissue
  • To assess the safety of single dose TH-302 in patients with high grade glioma undergoing surgery
  • To assess the safety of TH-302 in combination with bevacizumab for patients with high grade glioma
  • To determine the MTD and DLT(s) of TH-302 in combination with bevacizumab

The Secondary Objectives are:

To determine the progression-free survival with or without debulking craniotomy for patients treated with combination bevacizumab and TH-302 following recurrence on single agent bevacizumab


Condition Intervention Phase
HIGH GRADE GLIOMA
Drug: TH-302
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: A Phase 2, Investigator Initiated Study to Determine the Safety, Efficacy and CNS Penetration of TH-302 in Recurrent High Grade Astrocytoma Following Bevacizumab

Resource links provided by NLM:


Further study details as provided by The University of Texas Health Science Center at San Antonio:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Safety endpoints [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    • MTD of TH-302 in combination with bevacizumab
    • Incidence and severity of adverse events
    • Changes in lab parameters, vital signs and weight


Secondary Outcome Measures:
  • Median γH2AX foci intensity on immunohistochemistry γH2AX band density on western blotting [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    exploratory


Other Outcome Measures:
  • Predictive Biomarkers [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Hypoxic burden by PET scan using F-Misonidazole (F-MISO) and metabolomics analysis of serum.


Estimated Enrollment: 34
Study Start Date: June 2011
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TH-302 Preoperatively
Single center, dose-escalation, prospective study with TH-302 single dose at 575 mg/m2 administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 670 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302 (surgical subjects only).
Drug: TH-302
TH-302 single dose at 575 mg/m2 administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302.
Placebo Comparator: Placebo
Single center, dose-escalation, prospective study with placebo administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 670mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302 (surgical subjects only).
Drug: Placebo
Placebo administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302.
Experimental: TH-302 Non-Surgical
Subjects not receiving surgery will receive combination therapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 at 240 - 670 mg/m2 every 2 weeks (4 week cycles) starting from Cycle 1, Day 1 until disease progression.
Drug: TH-302
TH-302 single dose at 575 mg/m2 administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 480 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302.

Detailed Description:

Single center, dose-escalation, prospective study with TH-302 single dose at 575 mg/m2 or placebo administered preoperatively, followed by postoperative combination therapy bevacizumab at 10mg/kg every 2 weeks and TH-302 at 240 - 670 mg/m2 every 2 weeks (4 week cycle) until disease progression. Subjects will be randomized (2:1) to receive pre-operative dose of TH-302 (surgical subjects only). Subjects not receiving surgery will receive combination therapy of bevacizumab at 10 mg/kg every 2 weeks and TH-302 at 240-670 mg/m2 every 2 weeks (4 week cycle) starting from Cycle 1, Day 1 until disease progression.

This study will use a classic dose escalation design to determine the MTD of TH-302 when used in combination with bevacizumab. The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302 will be 240 mg/m2. A dose level minus 1 will be built into the study in the event that subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue to 340 mg/m2 and 670 mg/m2.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. At least 18 years of age
  2. Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee
  3. Histologically confirmed high grade astrocytoma
  4. Progression following both standard combined modality treatment with radiation and temozolomide chemotherapy, as well as anti-angiogenic therapy (ie, bevacizumab)
  5. Recovered from toxicities of prior therapy to grade 0 or 1
  6. ECOG performance status of 0 or 1
  7. Life expectancy of at least 3 months
  8. Acceptable liver function
  9. Acceptable renal function
  10. Acceptable hematologic status
  11. All women of childbearing potential must have a negative serum pregnancy test and male and female subjects must agree to use effective means of contraception (surgical sterilization or the use or barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 6 months after the last dose

Exclusion Criteria:

  1. The subject is receiving warfarin (or other coumarin derivatives) and is unable to switch to low molecular weight heparin (LMWH) before the first dose of study drug.
  2. The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin are eligible.
  3. The subject is unable to undergo MRI scan (eg, has pacemaker).
  4. The subject has received enzyme-inducing anti-epileptic agents within 14 days of study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone).
  5. The subject has not recovered to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Grade ≤ 1 from AEs (except alopecia, anemia and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered prior to study drug.
  6. The subject has evidence of wound dehiscence
  7. Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia
  8. The subject is pregnant or breast-feeding.
  9. The subject has serious intercurrent illness
  10. The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
  11. The subject has received any of the following prior anticancer therapy:

    • Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy (RIT), or intra-operative radiotherapy (IORT). Note: stereotactic radiosurgery (SRS) is allowed
    • Antiangiogenic agents whose primary mode of action is through the VEGF signaling within 21 days prior to first dose of study drug (surgical subjects only)
    • Non-bevacizumab systemic therapy (including investigational agents and small-molecule kinase inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 7 days or 5 half-lives, whichever is shorter, prior first dose of study drug
    • Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21 days prior to first dose of study drug
    • Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days, prior to first dose of study drug
    • Prior treatment with carmustine wafers
    • Prior treatment with TH-302
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01403610

Contacts
Contact: Cherie Noles 210-450-5964 NolesC@uthscsa.edu

Locations
United States, Texas
Cancer Therapy & Research Center at UTHSCSA Recruiting
San Antonio, Texas, United States, 78229
Contact: Cherie Noles    210-450-5964    NolesC@uthscsa.edu   
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
Investigators
Principal Investigator: Andrew Brenner, MD, Institute for Drug Development
  More Information

No publications provided

Responsible Party: Andrew Brenner, Andrew Brenner, MD, The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT01403610     History of Changes
Other Study ID Numbers: CTRC 11-24, CTRC 11-24
Study First Received: July 22, 2011
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by The University of Texas Health Science Center at San Antonio:
TH-302
Bevacizumab
Phase 2
Glioma
High Grade Glioma
CNS

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

ClinicalTrials.gov processed this record on November 27, 2014