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

NCT ID: NCT01403610

Last Updated: 2019-07-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 28 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-06-30
• Study Completion Date: 2015-10-31

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.

Conditions

HIGH GRADE GLIOMA

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Cohort 1

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.

Group Type: EXPERIMENTAL

TH-302 preoperative

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

TH-302 (escalating) with bevacizumab 10mg/kg

Intervention Type: DRUG

Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2

Cohort 2

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.

Group Type: EXPERIMENTAL

TH-302 preoperative

Intervention Type: DRUG

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.

TH-302 (escalating) with bevacizumab 10mg/kg

Intervention Type: DRUG

Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2

Cohort 3

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.

Group Type: EXPERIMENTAL

TH-302 (escalating) with bevacizumab 10mg/kg

Intervention Type: DRUG

Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2

Cohort 4

Non-surgical subjects will receive a dose up to 670 mg/m2 of TH-302

Group Type: EXPERIMENTAL

TH-302 (escalating) with bevacizumab 10mg/kg

Intervention Type: DRUG

Combination of 10mg/m2 of bevacizumab with an escalating dose of TH-302 from 240 to 670 mg/m2

Interventions

TH-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.

Intervention Type: 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.

Intervention Type: DRUG

TH-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

Intervention Type: DRUG

Other Intervention Names

Study drug; Study placebo; Study drug escalating dose

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andrew Brenner, MD,

Role: PRINCIPAL_INVESTIGATOR

Institute for Drug Development

Locations

Cancer Therapy & Research Center at UTHSCSA

San Antonio, Texas, United States

Countries

United States

Other Identifiers

CTRC 11-24

Identifier Type: OTHER

Identifier Source: secondary_id

CTRC 11-24

Identifier Type: -

Identifier Source: org_study_id