Trial record 2 of 12 for:    TPI | Open Studies

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Cortice Biosciences, Inc.
Sponsor:
Information provided by (Responsible Party):
Cortice Biosciences, Inc.
ClinicalTrials.gov Identifier:
NCT01933815
First received: August 26, 2013
Last updated: July 24, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Glioblastoma Multiforme
Drug: TPI 287
Drug: Bevacizumab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Cortice Biosciences, Inc.:

Primary Outcome Measures:
  • Phase 1: Safety of TPI 287 + bevacizumab in adults with GBM that progressed following radiation & TMZ 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 ]
  • Phase 1: MTD of TPI 287 + bevacizumab in adults with GBM that progressed following radiation & TMZ [ 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.

  • Phase 2: Efficacy of phase 1 MTD of TPI 287 + bevacizumab versus bevacizumab alone in adults with GBM that progressed following radiation and TMZ as measured by median PFS [ 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.


Secondary Outcome Measures:
  • Phase 1: Efficacy of TPI 287 + bevacizumab in adults with GBM that progressed following radiation and TMZ as measured by median progression free survival (PFS), overall response rate, & progression free survival 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 ]
  • Phase 2: Safety of TPI 287 + bevacizumab versus bevacizumab alone in adults with GBM that progressed following radiation & TMZ 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 ]
  • Phase 2: Efficacy of phase 1 MTD of TPI 287 + bevacizumab versus bevacizumab alone in adults with GBM that progressed following radiation and TMZ as measured by overall survival and overall response rate [ Time Frame: Overall response rate: baseline & on Day 1 of each 42-day treatment cycle starting with Cycle 2, and/or as clinically indicated; overall survival: up to two years after randomization ] [ Designated as safety issue: No ]

Estimated Enrollment: 78
Study Start Date: August 2013
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TPI 287 + bevacizumab

All subjects in phase 1 (dose-escalation) and all subjects randomized to the TPI 287 + bevacizumab arm in phase 2 will be administered TPI 287 as an IV infusion (1-hour target duration) 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).

For phase 1, 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 will be treated at 140 mg/m2 TPI 287. The dose level will be escalated in 10 mg/m2 increments (i.e., 150, 160, etc.). If dose de-escalation is required, dose levels of 130 and 120 mg/m2 will be used.

For phase 2, 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 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:
  • TPI-287
  • NBT 287
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
Active Comparator: Bevacizumab

All subjects randomized to the bevacizumab alone arm in phase 2 will be administered 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 bevacizumab will be 10 mg/kg.

Subjects will be withdrawn from the study if they meet one or more of the discontinuation criteria outlined in the protocol; however, treatment with bevacizumab may continue under the FDA approved labeling for bevacizumab at the discretion of the subject's doctor.

All subjects in phase 1 will be administered TPI 287 in combination with bevacizumab (i.e., there will be no bevacizumab alone arm during phase 1).

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

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 dose level will be escalated in 10 mg/m2 increments (i.e., 150, 160, etc.). If dose de-escalation is required, dose levels of 130 and 120 mg/m2 will be used. Subjects will be assigned to dose cohorts in the order that they are enrolled; there is no randomization for phase 1. Twelve to 18 subjects are planned for enrollment, depending on the number of subjects that experience dose limiting toxicities (DLTs).
  • 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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically proven GBM
  2. Disease progression following radiation and TMZ
  3. Up to 2 prior relapses allowed
  4. Baseline MRI within 17 days of Day 1 & on steroid dosage that has been stable or decreasing for at least 5 days
  5. Recent resection of recurrent or progressive tumor allowed as long as at least 4 weeks have elapsed from date of surgery and the subject has recovered from surgery
  6. Life expectancy >12 weeks
  7. Eighteen years old or older
  8. KPS equal to or greater than 70
  9. Recovered from toxic effects of prior therapy to < Grade 2 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) prior to Day 1. Minimum duration required between prior therapy and Day 1 is:

    1. At least 12 weeks from completion of radiation therapy except if there is unequivocal evidence for tumor recurrence in which case at least 4 weeks
    2. 4 weeks from prior cytotoxic therapy
    3. 4 weeks from prior experimental drug
    4. 6 weeks from nitrosoureas
    5. 3 weeks from procarbazine
    6. 1 week for non-cytotoxic agents, such as interferon, tamoxifen, & cis-retinoic acid
  10. Adequate bone marrow function (absolute neutrophil count > 1,500/mm3 and platelet count of > 100,000/mm3), adequate liver function [ALT and AST <3 x upper limit normal (ULN), alkaline phosphatase <2 x ULN, and total bilirubin <1.5 mg/dL], & adequate renal function (BUN and creatinine <1.5 x ULN)
  11. Minimum hemoglobin of 9 g/dL
  12. Males & women of childbearing potential must agree to abstain from sex or use an adequate method of contraception for the duration of study, & for 6 months after last dose of study drug
  13. Signed & dated informed consent prior to Screening evaluations

Exclusion Criteria:

  1. Radiographic evidence of contrast-enhancing tumor crossing midline, leptomeningeal dissemination, gliomatosis cerebri or infratentorial tumor
  2. Evidence or suspicion of disease metastatic to sites remote from the supratentorial brain
  3. Prior treatment with bevacizumab or other anti-vascular endothelial growth factor (VEGF) drugs
  4. Prior treatment with tyrosine-kinase inhibitors targeting VEGF, platelet-derived growth factor, fibroblast growth factor, tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2 (TIE-2), or angiopoietin (or their receptors)
  5. Prior treatment with histone deacetylase inhibitors or mammalian target of rapamycin (mTOR) inhibitors
  6. Prior treatment with TPI 287
  7. Treatment with Enzyme-Inducing Anti-Epileptic Drugs within 2 weeks prior to Day 1
  8. Treatment with drugs or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 3A4 or cytochrome P450 2C8 within 2 weeks prior to Day 1
  9. Received more than one course of radiation therapy or more than a total dose of 65 Gy. May have received radiosurgery as part of initial therapy; however, the dose counts against the total dose limit.
  10. Prior taxane, vincristine, or other microtubule inhibitor chemotherapies for treatment of GBM or other malignancy
  11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study
  12. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
  13. Any condition, including the presence of clinically significant laboratory abnormalities, which places subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study, including:

    1. Active infection including known AIDS or Hepatitis C or with a fever ≥38.5°C within 3 days prior to enrollment
    2. Diseases or conditions that obscure toxicity or dangerously alter drug metabolism
    3. Serious intercurrent medical illness (e.g., symptomatic congestive heart failure)
  14. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent
  15. Inadequately controlled hypertension (defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure > 90 mmHg)
  16. Prior history of hypertensive crisis or hypertensive encephalopathy
  17. New York Heart Association Grade II or greater congestive heart failure
  18. History of myocardial infarction or unstable angina within 6 months prior to Day 1
  19. History of stroke or transient ischemic attack within 6 months prior to Day1
  20. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1
  21. History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1
  22. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  23. Grade 2 or higher peripheral neuropathy per NCI CTCAE
  24. History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1
  25. Serious, non-healing wound, active ulcer, or untreated bone fracture
  26. Proteinuria at Screening. Subjects with a urine dipstick protein ≥2+ at Screening should undergo a 24-hour urine collection and must demonstrate ≤1g of protein in 24 hours to be eligible
  27. Known hypersensitivity to inactive ingredient of bevacizumab
  28. Known hypersensitivity to inactive ingredient of TPI 287
  29. Pregnancy or lactation
  30. Inability to comply with protocol
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01933815

Locations
United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35249
Contact: Thirumanie Pillay    205-934-1842    thiru@uab.edu   
Principal Investigator: Louis B. Nabors, III, M.D.         
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
The Long Island Brain Tumor Center at Neurological Surgery, P.C. Recruiting
Commack, New York, United States, 11725
Contact: Kimberly Prabhu    631-864-3900    kprabhu@nspc.com   
Principal Investigator: J. P. Duic, M.D.         
The Long Island Brain Tumor Center at Neurological Surgery, P.C. Recruiting
Lake Success, New York, United States, 11042
Contact: Kimberly Prabhu    516-478-0010    kprabhu@nspc.com   
Principal Investigator: J. P. Duic, M.D.         
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, Washington
Swedish Neuroscience Institute Recruiting
Seattle, Washington, United States, 98122
Contact: Nathan Hansen    206-320-3542    Nathan.hansen@swedish.org   
Contact: Mary Lessig    206-386-3878    mary.lessig@swedish.org   
Principal Investigator: Tara L. Benkers, M.D.         
Sponsors and Collaborators
Cortice Biosciences, Inc.
Investigators
Principal Investigator: J. P. Duic, M.D. The Long Island Brain Tumor Center at Neurological Surgery, P.C.
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: Tara L. Benkers, M.D. Swedish Neuroscience Institute
  More Information

No publications provided

Responsible Party: Cortice Biosciences, Inc.
ClinicalTrials.gov Identifier: NCT01933815     History of Changes
Other Study ID Numbers: TPI-287-17
Study First Received: August 26, 2013
Last Updated: July 24, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Cortice Biosciences, Inc.:
Glioblastoma multiforme
Glioblastoma
Radiotherapy
Temozolomide
TPI 287
Taxoid
Avastin
Bevacizumab

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 21, 2014