Safety and Efficacy Study of TH-302 CNS Penetration in Recurrent High Grade Astrocytoma Following Bevacizumab
Condition: HIGH GRADE GLIOMA
MeSH terms: Glioma; Astrocytoma
Intervention: TH-302 preoperative; Placebo; TH-302 (escalating) with bevacizumab 10mg/kg
Intervention description: 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 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.; Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2
Intervention MeSH terms: Bevacizumab; Phosphoramide Mustards
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: Single (Participant)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: TH-302; Bevacizumab; Phase 2; Glioma; High Grade Glioma; CNS

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
    

Eligibility 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