Safety & Efficacy Study of TPI 287 + Avastin in Adults With Glioblastoma That Progressed Following Prior Avastin Therapy
The purpose of this study is to evaluate 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 and temozolomide (TMZ) therapy and that has progressed following prior bevacizumab therapy.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase 2 Dose-Escalation Study of TPI 287 in Combination With Bevacizumab in Adults With Recurrent or Progressive Glioblastoma Following a Bevacizumab-Containing Regimen|
- Safety of TPI 287 + bevacizumab in adults with GBM that progressed following radiation & TMZ & prior bevacizumab as measured by AEs, physical/neurologic exam, KPS, weight, vital signs, hematology, serum chemistry, & urinalysis [ Time Frame: Continuously over study treatment through 4 weeks after last dose of study drug ] [ Designated as safety issue: Yes ]
- MTD of TPI 287 + bevacizumab in adults with GBM that progressed following radiation & TMZ & prior bevacizumab [ Time Frame: Within 42 days of receiving the first dose of study drug ] [ Designated as safety issue: Yes ]The MTD will be defined as the highest dose level achieved at which no more than 1 out of 6 subjects experienced a DLT that initiated within 42 days of receiving the first dose of study drug.
- Efficacy of TPI 287 + bevacizumab in adults with GBM that progressed following radiation & TMZ & prior bevacizumab as measured by median progression free survival (PFS), overall response rate, & PFS rate at 4 & 6 months (PFS4 & PFS6) [ Time Frame: Baseline & on Day 1 of each 42-day treatment cycle starting with Cycle 2, and/or as clinically indicated ] [ Designated as safety issue: No ]The Response Assessment in Neuro-Oncology (RANO) working group recommendations for updated response criteria for high-grade gliomas (Wen et al. 2010) will be used to determine response for this trial.
|Study Start Date:||January 2014|
|Estimated Study Completion Date:||April 2015|
|Estimated Primary Completion Date:||April 2015 (Final data collection date for primary outcome measure)|
Experimental: TPI 287 + bevacizumab
All subjects will be administered TPI 287 as an IV infusion (1-hour target duration) once every 3 weeks (Days 1 and 22) and bevacizumab as a 30 to 90 minute IV infusion once every 2 weeks (Days 1, 15, and 29) of a 42-day cycle. 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 planned dose escalation levels are 140, 160, 170, and 180 mg/m2; subsequent dose levels will be increased in increments of 10 mg/m2. If dose de-escalation below the starting dose level of 140 mg/m2 is required, dose levels of 130 and 120 mg/m2 will be used. Once the MTD is identified, 6 additional subjects will be enrolled at the MTD to better characterize the toxicity profile at this level. Subjects may continue on treatment unless they meet one or more of the discontinuation criteria outlined in the protocol.
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.
Other Names: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.
Other Name: Avastin
This multi-center trial is a phase 2, 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 and TMZ therapy and that has progressed following prior bevacizumab therapy.
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 (dose level 0). The next dose level will be 160 mg/m2 (dose level 1). Subsequent dose levels will be increased in increments of 10 mg/m2 (i.e., dose level 2 = 170 mg/m2, dose level 3 = 180 mg/m2, etc.). If dose de-escalation below the starting dose level is required, dose levels of 130 and 120 mg/m2 will be used. Twelve (12) to 18 subjects are planned for enrollment during the dose escalation phase, depending on the number of subjects that experience dose limiting toxicities (DLTs).
Once the MTD is identified, 6 additional subjects will be enrolled at the MTD (for a total of 12) to better characterize the toxicity profile at this level.
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).
Please refer to this study by its ClinicalTrials.gov identifier: NCT02047214
|United States, Alabama|
|University of Alabama at Birmingham||Recruiting|
|Birmingham, Alabama, United States, 35249|
|Contact: Thiru Pillay, RN, BSN 205-934-1842 firstname.lastname@example.org|
|Principal Investigator: Louis B. Nabors, III, M.D.|
|United States, Florida|
|H Lee Moffitt Cancer Center and Research Institute, Inc.||Recruiting|
|Tampa, Florida, United States, 33612|
|Contact: Allie Drew 813-745-3229 email@example.com|
|Principal Investigator: Solmaz Sahebjam, M.D.|
|United States, Illinois|
|Northwestern Medical Faculty Foundation||Recruiting|
|Chicago, Illinois, United States, 60611|
|Contact: Laurel Chadde 312-695-1371 firstname.lastname@example.org|
|Contact: Leanne Fountas 312-695-1342 Leanne.email@example.com|
|Principal Investigator: Priya Kumthekar, M.D.|
|United States, Missouri|
|Washington University, School of Medicine||Recruiting|
|St. Louis, Missouri, United States, 63110|
|Contact: Andrew Wegrzyn 314-747-1825 firstname.lastname@example.org|
|Principal Investigator: Jian Campian, M.D., Ph.D.|
|United States, New Hampshire|
|Dartmouth-Hitchcock Medical Center||Recruiting|
|Lebanon, New Hampshire, United States, 03756|
|Contact: Sandra E. Steel 603 650-0786 Sandra.E.Steel@hitchcock.org|
|Contact: Neal A. Wilson 603 653-0590 Neal.A.Wilson@hitchcock.org|
|Principal Investigator: Camilo E. Fadul, M.D., F.A.A.N.|
|United States, New Jersey|
|John Theurer Cancer Center at Hackensack University Medical Center||Recruiting|
|Hackensack, New Jersey, United States, 07601|
|Contact: Lori Cappello 551-996-5098 LCappello@HackensackUMC.org|
|Principal Investigator: Samuel A. Goldlust, M.D.|
|United States, New York|
|University of Rochester Medical Center||Recruiting|
|Rochester, New York, United States, 14642|
|Contact: Jennifer Serventi, RPA-C, CCRP 585-276-3971 Jennifer_Serventi@URMC.Rochester.edu|
|Principal Investigator: Nimish Mohile, M.D.|
|United States, Texas|
|Memorial Hermann Hospital||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Lu (Greg) GuangRong, M.D., M.S. 713-704-2359 GuangRong.Lu@uth.tmc.edu|
|Principal Investigator: Sigmund Hsu, M.D.|
|United States, Virginia|
|University of Virginia Health System||Recruiting|
|Charlottesville, Virginia, United States, 22908|
|Contact: Heather Tribout 434-243-9360 email@example.com|
|Contact: Johanna Loomba 434-924-5859 JJL4D@hscmail.mcc.virginia.edu|
|Principal Investigator: David Schiff, M.D.|
|United States, Washington|
|Swedish Neuroscience Institute||Recruiting|
|Seattle, Washington, United States, 98122|
|Contact: Nathan Hansen 206-320-3542 Nathan.firstname.lastname@example.org|
|Contact: Mary Lessig 206-386-3878 email@example.com|
|Principal Investigator: Tara L. Benkers, M.D.|
|Principal Investigator:||Samuel A. Goldlust, M.D.||John Theurer Cancer Center at Hackensack University Medical Center|
|Principal Investigator:||Louis B. Nabors, III, M.D.||University of Alabama at Birmingham|
|Principal Investigator:||Sigmund Hsu, M.D.||Memorial Hermann Hospital|
|Principal Investigator:||Nimish Mohile, M.D.||University of Rochester|
|Principal Investigator:||Solmaz Sahebjam, M.D.||H Lee Moffitt Cancer Center and Research Institute, Inc.|
|Principal Investigator:||Tara L. Benkers, M.D.||Swedish Neuroscience Institute|
|Principal Investigator:||Priya Kumthekar, M.D.||Northwestern University|
|Principal Investigator:||Jian Campian, M.D., Ph.D.||Washington University School of Medicine|
|Principal Investigator:||David Schiff, M.D.||University of Virginia Health System|
|Principal Investigator:||Camilo E. Fadul, M.D., F.A.A.N.||Dartmouth-Hitchcock Medical Center|