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

NCT01933815 | Suspended Phase 1

• 1 other identifier: TPI-287-17
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 9

Brief 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.

Conditions

Glioblastoma Multiforme

Keywords

Glioblastoma multiforme; Glioblastoma; Radiotherapy; Temozolomide; TPI 287; Taxoid; Avastin; Bevacizumab

Outcome Measures

Primary Outcomes (3)

• 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

  Continuously over study treatment through 4 weeks after last dose of study drug

• Phase 1: MTD of TPI 287 + bevacizumab in adults with GBM that progressed following radiation & TMZ

  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.

  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

  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.

  Baseline & on Day 1 of each 42-day treatment cycle starting with Cycle 2, and/or as clinically indicated

Secondary Outcomes (3)

• 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)

  Baseline & on Day 1 of each 42-day treatment cycle starting with Cycle 2, and/or as clinically indicated

• 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

  Continuously over study treatment through 4 weeks after last 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 overall survival and overall response rate

  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

Study Arms (2)

TPI 287 + bevacizumab

EXPERIMENTAL

All subjects in phase 1 \& subjects randomized to the TPI 287 + bevacizumab arm in phase 2 will be administered a 1-hour IV infusion of TPI 287 once every 3 weeks (Days 1 \& 22 of 42-day cycle) \& a 30-90 minute IV infusion of bevacizumab once every 2 weeks (Days 1, 15, \& 29). In phase 1, the dose of TPI 287 will be escalated in sequential dose cohorts of 3 to 6, while the dose of bevacizumab remains constant (10 mg/kg). The first 5 dose levels will be 140, 150, 160, 170, \& 180 mg/m2. Dose levels beyond 180 mg/m2 will be increased in increments of 20 mg/m2. Three subjects will be treated at a dose level halfway between the dose level that exceeds the MTD and the dose level immediately prior to further refine the MTD. In phase 2, the dose of TPI 287 will be the MTD determined in phase 1, \& 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 protocol discontinuation criteria.

Drug: TPI 287; Drug: Bevacizumab

Bevacizumab

ACTIVE COMPARATOR

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

Interventions

TPI 287 DRUG

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.

Also known as: TPI-287, NBT 287

TPI 287 + bevacizumab

Bevacizumab DRUG

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.

Also known as: Avastin

Bevacizumab; TPI 287 + bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically proven GBM
• Disease progression following radiation and TMZ
• Up to 2 prior relapses allowed
• Baseline MRI within 17 days of Day 1 \& on steroid dosage that has been stable or decreasing for at least 5 days
• 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
• Life expectancy \>12 weeks
• Eighteen years old or older
• KPS equal to or greater than 70
• 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:
• 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
• weeks from prior cytotoxic therapy
• weeks from prior experimental drug
• weeks from nitrosoureas
• weeks from procarbazine
• week for non-cytotoxic agents, such as interferon, tamoxifen, \& cis-retinoic acid

You may not qualify if:

• Radiographic evidence of contrast-enhancing tumor crossing midline, leptomeningeal dissemination, gliomatosis cerebri or infratentorial tumor
• Evidence or suspicion of disease metastatic to sites remote from the supratentorial brain
• Prior treatment with bevacizumab or other anti-vascular endothelial growth factor (VEGF) drugs
• 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)
• Prior treatment with histone deacetylase inhibitors or mammalian target of rapamycin (mTOR) inhibitors
• Prior treatment with TPI 287
• Treatment with Enzyme-Inducing Anti-Epileptic Drugs within 2 weeks prior to Day 1
• 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
• 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.
• Prior taxane, vincristine, or other microtubule inhibitor chemotherapies for treatment of GBM or other malignancy
• 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
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1
• 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:
• Active infection including known AIDS or Hepatitis C or with a fever ≥38.5°C within 3 days prior to enrollment
• Diseases or conditions that obscure toxicity or dangerously alter drug metabolism

Sponsors & Collaborators

• Cortice Biosciences, Inc.: lead

Study Sites (9)

University of Alabama at Birmingham

Birmingham, Alabama, 35249, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

The Long Island Brain Tumor Center at Neurological Surgery, P.C.

Commack, New York, 11725, United States

Location

The Long Island Brain Tumor Center at Neurological Surgery, P.C.

Lake Success, New York, 11042, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Memorial Hermann Hospital

Houston, Texas, 77030, United States

Location

Swedish Neuroscience Institute

Seattle, Washington, 98122, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

TPI-287; Bevacizumab

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

• Jian Campian, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

• Pierre Giglio, M.D.

  Ohio State University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 26, 2013
• First Posted: September 2, 2013
• Study Start: August 1, 2013
• Primary Completion: November 1, 2024
• Study Completion: May 1, 2025
• Last Updated: February 22, 2023

Record last verified: 2022-07

Locations

US (9)