HIGH GRADE GLIOMA
Conditions
Keywords
TH-302, Bevacizumab, Phase 2, Glioma, High Grade Glioma, CNS
Brief 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
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.
Interventions
DRUGTH-302 preoperative
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.
DRUGPlacebo
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.
DRUGTH-302 (escalating) with bevacizumab 10mg/kg
Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2
Sponsors
The University of Texas Health Science Center at San Antonio
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | 2 years | Time from initiation study until radiographic progression by RANO criteria |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Prior to surgery subjects will be assigned to this group in a 2:1 randomization, ie. 2 subjects will be assigned to TH-302 and one to placebo. A single dose of 575 mg/m2 or placebo will be administered pre-operatively with hypoxyprobe-1 at 500 mg/m2 over 20 minutes. Subjects in this group receive TH-302 at a dose of 240mg/m2 post surgery. | 3 |
| Cohort 2 Subjects received 340mg/m2 of TH-302 post surgery | 3 |
| Cohort 3 Subjects were dosed with 480mg/m2 of TH-302 regardless of whether or not surgery was performed. 3 subjects in this arm had surgery prior to this dose of TH-302. | 4 |
| Cohort 4 Subjects in this cohort did not undergo any surgery, a dose of 670mg/m2 was administered to all. | 13 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Didn't recover from surgery sufficiently | 0 | 3 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 | Cohort 3 | Cohort 4 | Total | Cohort 1 |
|---|---|---|---|---|---|
| Age, Continuous | 47 Years | 50 Years | 61 Years | 56 Years | 56 Years |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants | — |
| Region of Enrollment United States | 3 participants | 4 participants | 13 participants | 23 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 3 Participants | 9 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 10 Participants | 14 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 4 | 0 / 13 |
| other Total, other adverse events | 1 / 3 | 2 / 3 | 1 / 4 | 7 / 13 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 1 / 4 | 0 / 13 |
Outcome results
Primary
Time to Progression
Time from initiation study until radiographic progression by RANO criteria
Time frame: 2 years
Population: See full published data at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071657/
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Time to Progression | 11.3 months |
| Cohort 2 | Time to Progression | 9 months |
| Cohort 3 | Time to Progression | 15.6 months |
| Cohort 4 | Time to Progression | 4.5 months |