Overview

This trial has been completed.

Condition high grade glioma
Treatments th-302, placebo
Phase phase 2
Sponsor The University of Texas Health Science Center at San Antonio
Start date June 2011
End date October 2015
Trial size 29 participants
Trial identifier NCT01403610, CTRC 11-24

Summary

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

United States No locations recruiting
Other countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking single blind (subject)
Primary purpose treatment
Arm
(Experimental)
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).
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)
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).
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)
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.
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.

Primary Outcomes

Measure
Progression-free survival
time frame: 2 years
Safety endpoints
time frame: 2 years

Secondary Outcomes

Measure
Median γH2AX foci intensity on immunohistochemistry γH2AX band density on western blotting
time frame: 2 years

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria

  • At least 18 years of age
  • 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
  • Histologically confirmed high grade astrocytoma
  • Progression following both standard combined modality treatment with radiation and temozolomide chemotherapy, as well as anti-angiogenic therapy (ie, bevacizumab)
  • Recovered from toxicities of prior therapy to grade 0 or 1
  • ECOG performance status of 0 or 1
  • Life expectancy of at least 3 months
  • Acceptable liver function
  • Acceptable renal function
  • Acceptable hematologic status
  • 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

  • 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.
  • 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.
  • The subject is unable to undergo MRI scan (eg, has pacemaker).
  • The subject has received enzyme-inducing anti-epileptic agents within 14 days of study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone).
  • 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.
  • The subject has evidence of wound dehiscence
  • 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
  • The subject is pregnant or breast-feeding.
  • The subject has serious intercurrent illness
  • The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
  • 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

Additional Information

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
Principal investigator Andrew Brenner, MD,
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.
Trial information was received from ClinicalTrials.gov and was last updated in December 2016.
Information provided to ClinicalTrials.gov by The University of Texas Health Science Center at San Antonio.