NCT01933815

Dose-Escalation Study of TPI 287 + Avastin Followed by Randomized Study of the Same Versus Avastin for Glioblastoma

Phase 1/2 Dose-Escalation Study of TPI 287 in Combination With Bevacizumab Followed by Randomized Study of the Maximum Tolerated Dose of TPI 287 in Combination With Bevacizumab Versus Bevacizumab Alone in Adults With Recurrent Glioblastoma

• Status: Suspended
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 92 (estimated)
• Sponsor: Cortice Biosciences, Inc. · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This trial is divided into two parts, a dose-escalation study (phase 1) and a randomized study (phase 2). The purpose of the dose-escalation study (phase 1) is to determine the safety, maximum tolerated dose (MTD), and efficacy of TPI 287 in combination with Avastin (bevacizumab) in subjects who have glioblastoma multiforme (GBM) that has progressed following prior radiation therapy and temozolomide (TMZ). The purpose of the randomized study (phase 2) is to determine the safety and efficacy of the phase 1 MTD of TPI 287 in combination with bevacizumab versus bevacizumab alone in subjects who have GBM that has progressed following prior radiation therapy and TMZ.

Detailed description

This multi-center trial is a phase 1/2 study that will be conducted in two sequential phases, phase 1 and phase 2. Phase 1 of the trial is a dose-escalation study of the safety, tolerability (MTD), and efficacy of TPI 287 in combination with bevacizumab in subjects who have GBM that has progressed following prior radiation therapy and TMZ. * All subjects will be administered TPI 287 as an intravenous (IV) infusion (target duration of 1 hour) once every 3 weeks (Days 1 and 22 of a 42-day cycle) and bevacizumab as a 30 to 90 minute IV infusion once every 2 weeks (Days 1, 15, and 29 of the 42-day cycle). The subsequent cycle will start 3 weeks after the last TPI 287 infusion and 2 weeks after the last bevacizumab infusion, maintaining the once every 3 week and once every 2 week schedule, respectively. * The dose of TPI 287 will be escalated in sequential dose cohorts of 3 to 6 subjects, while the dose of bevacizumab remains constant (10 mg/kg). The initial cohort of 3 subjects will be treated at a TPI 287 dose of 140 mg/m2. The next four dose levels will be 150, 160, 170, and 180 mg/m2. Dose levels beyond 180 mg/m2 will be increased in increments of 20 mg/m2 (i.e., 200, 220, 240 mg/m2, etc.). * Once a dose level is identified that exceeds the MTD, dose de-escalation will be used to further refine the MTD. Specifically, 3 subjects will be treated at an intermediate dose level, halfway between the dose level that exceeded the MTD and the dose level immediately prior (e.g., 230 mg/m2, if 240 mg/m2 exceeded the MTD). * Subjects will be assigned to dose cohorts in the order that they are enrolled; there is no randomization for phase 1. Approximately 20 to 32 subjects are planned for enrollment in phase 1, depending on the dose level at which dose limiting toxicities (DLTs) are observed. * Dose modifications and delays will be required as described in the protocol. Subjects may continue on treatment unless they meet one or more of the discontinuation criteria outlined in the protocol. Subjects who are discontinued prior to completing Cycle 1 for any reason other than toxicity will be replaced. * Adverse events (AEs) and concomitant medications will be monitored throughout the study. Subjects will be given a diary to record any AEs or concomitant medications taken between visits. Additional safety evaluations will include physical examination (including neurologic examination), Karnofsky performance status (KPS), weight (body surface area, BSA), vital signs, hematology, serum chemistry, and urinalysis. * Efficacy evaluations will include magnetic resonance imaging \[MRI, including both pre and post-gadolinium T1-weighted scans and T2/fluid attenuated inversion recovery (FLAIR) images\], corticosteroid usage, and neurologic status (as measured by neurologic exam and KPS). Phase 2 of the trial is a randomized study of the safety and efficacy of the phase 1 MTD of TPI 287 in combination with bevacizumab versus bevacizumab alone in subjects who have GBM that has progressed following prior radiation therapy and TMZ. * Sixty subjects will be randomized 1:1 to receive either TPI 287 in combination with bevacizumab or bevacizumab alone. * For the combination arm, the subjects will be administered TPI 287 as an IV infusion (target duration of 1 hour) once every 3 weeks (Days 1 and 22 of a 42-day cycle) and bevacizumab as a 30 to 90 minute IV infusion once every 2 weeks (Days 1, 15, and 29 of the 42-day cycle). The dose of TPI 287 will be the MTD determined in phase 1, and the dose of bevacizumab will be the same as phase 1 (10 mg/kg). * Subjects randomized to the bevacizumab alone arm will be administered 10 mg/kg bevacizumab as a 30 to 90 minute IV infusion once every 2 weeks (Days 1, 15, and 29 of the 42-day cycle). * The same dose modifications and delays required in phase 1 will apply to phase 2. Subjects may continue on treatment unless they meet one or more of the discontinuation criteria outlined in the protocol. There will be no subject replacement for phase 2 of the trial. * The safety and efficacy evaluations during phase 2 will be the same as those in phase 1. In addition, subjects participating in phase 2 will be telephoned every two months following the final study visit (4 weeks after the last dose of study drug) for up to two years after randomization to follow survival. * Subjects that participate in phase 1 of the trial will not be eligible to participate in phase 2 of the trial.

Conditions

• Glioblastoma Multiforme

Interventions

Type	Name	Description
DRUG	TPI 287	TPI 287 is a microtubule inhibitor belonging to the taxane diterpenoid (taxoid) family, and specifically to the abeotaxane class. TPI 287 is an Investigational Drug.
DRUG	Bevacizumab	Avastin (bevacizumab) is an FDA approved drug indicated for multiple cancers, including as a single agent for GBM for adult patients with progressive disease following prior therapy. Single agent effectiveness is based on improvement in objective response rate; no data is available demonstrating improvement in disease-related symptoms or survival with bevacizumab.

Timeline

• Start date: 2013-08-01
• Primary completion: 2024-11-01
• Completion: 2025-05-01
• First posted: 2013-09-02
• Last updated: 2023-02-22

Locations

9 sites across 1 country: United States