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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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A Phase 2, Investigator Initiated Study to Determine the Safety, Efficacy and CNS Penetration of TH-302 in Recurrent High Grade Astrocytoma Following Bevacizumab

Conditions
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HIGH GRADE GLIOMA

Intervention / Treatment
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* Drug: TH-302 preoperative
* Drug: Placebo
* Drug: TH-302 (escalating) with bevacizumab 10mg/kg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects received TH-302 single dose at 575 mg/m2 or placebo administered preoperative in a 2:1 randomization and were then administered 240 mg/m2 of TH-302 post-operative. | Drug: TH-302 preoperative<br>* 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.<br>* Other names: Study drug;Drug: Placebo<br>* 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.<br>* Other names: Study placebo;Drug: TH-302 (escalating) with bevacizumab 10mg/kg<br>* Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2<br>* Other names: Study drug escalating dose;|
| Experimental: Cohort 2<br>Surgical subjects will receive TH-302 at 340 mg/m2 every 2 weeks (4 week cycles) starting after surgery from Cycle 1, Day 1 until disease progression. | Drug: TH-302 preoperative<br>* 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.<br>* Other names: Study drug;Drug: TH-302 (escalating) with bevacizumab 10mg/kg<br>* Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2<br>* Other names: Study drug escalating dose;|
| Experimental: Cohort 3<br>Surgical or Non-Surgical subjects will receive TH-302 at 480 mg/m2 every 2 weeks (4 week cycles) starting after surgery from Cycle 1, Day 1 until disease progression. | Drug: TH-302 (escalating) with bevacizumab 10mg/kg<br>* Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2<br>* Other names: Study drug escalating dose;|
| Experimental: Cohort 4<br>Non-surgical subjects will receive a dose up to 670 mg/m2 of TH-302 | Drug: TH-302 (escalating) with bevacizumab 10mg/kg<br>* Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2<br>* Other names: Study drug escalating dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time from initiation study until radiographic progression by RANO criteria | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TH-302, Bevacizumab, Phase 2, Glioma, High Grade Glioma, CNS