Safety and Efficacy of Trans Sodium Crocetinate (TSC) With Radiation and Temozolomide in Newly Diagnosed Glioblastoma

Open-label Phase 1/2 (Safety Lead-in) Study of Trans Sodium Crocetinate (TSC) With Concomitant Treatment of Fractionated Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM) Patients to Evaluate Safety and Efficacy

This open-label study evaluated the safety and efficacy of TSC when dosed concomitantly with the standard of care (radiation therapy and temozolomide) for newly diagnosed glioblastoma in adults. All patients received TSC in the study. The objective of the study was to evaluate the effect of TSC on survival and tumor response in patients with GBM while establishing an acceptable patient risk profile.

Study Overview

• Status: Completed
• Conditions: Glioma; Glioblastoma; GBM
• Intervention / Treatment: Drug: Trans Sodium Crocetinate (TSC)

Detailed Description

The overall objectives of this Phase 1/2 clinical study in newly diagnosed GBM patients was to evaluate the safety and tolerability, efficacy, PK profile, PFS/time to disease progression, QoL, and overall survival in adults when TSC is added to the standard of care regimen of radiation therapy and temozolomide. All patients received TSC in this study. The primary objective of the Phase 1 portion of the study was to evaluate the safety (DLT rate) and to define the dosing regimen of TSC for the larger Phase 2 study. The primary clinical endpoint was overall survival at 24 months and patients will be followed for up to 3 years.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Medical Center Barrow Neurology Clinics
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas Winthrop P. Rockefeller Cancer Institute
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20037
      • The George Washington University Medical Center
  • Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida McKnight Brain Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Winship Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern University Robert H. Lurie Comprehensive Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Markey Cancer Center
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Forsyth Regional Cancer Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State University Milton S. Hershey Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center Memorial Hermann Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • UVA Health Sciences Center Emily Couric Clinical Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert & Medical College of Wisconsin Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged at least 18 years of age; male or female. A patient who is 70 years of age or older may be considered for enrollment after review of patient clinical and laboratory data by the Protocol Medical Monitor.
• Histologically confirmed diagnosis of GBM.
• Contrast enhancing disease on MRI within 21 days prior to screening.
• Karnofsky score (KPS) of ≥ 60 at Screening.
• No prior RT, chemotherapy (including Gliadel wafer), immunotherapy or therapy with a biologic agent, or hormonal therapy. Glucocorticoid therapy is allowed.
• Within 2 weeks of baseline visit, hematologic and renal functions as specified: Absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100,000/mm3, Hgb ≥ 9.0g/dL, creatinine ≤ 1.7mg/dl, total bilirubin ≤ 1.5mg/dL, blood urea nitrogen (BUN) within 2 times the upper limit of normal, transaminases ≤ 4 times above the upper limits of the institutional norm.
• Sexually active patients must use an acceptable method of contraception while receiving doses of study medication.
• Females of childbearing potential must have a negative serum or urine pregnancy test at screening and have additional pregnancy tests during study.

Exclusion Criteria:

• Patient who cannot undergo MRI.
• Pregnant or lactating.
• Serious concurrent infection or medical illness that would jeopardize the ability of the patient to receive study treatment with reasonable safety.
• Patient receiving concurrent chemotherapeutics or investigational agents within 30 days of baseline assessments, including gliadel wafers or gliasite application.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: TSC 0.25 mg/kg for 9 or 18 doses; This was an open-label, sequential-cohort, dose-escalation study in two phases. Phase 1 was a safety run-in evaluating Trans Sodium Crocetinate (TSC) in 3 subjects who received 3 doses per week for 3 weeks (9 doses in total). Phase 2 engaged 56 subjects who received 3 doses per week for 6 weeks (18 doses in total). TSC was consistently dosed at 0.25mg/kg in both phases.

Drug: Trans Sodium Crocetinate (TSC); TSC administered intravenously as a bolus injection prior to radiation therapy sessions during 6 weeks of radiotherapy.; Other Names: TSC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicities (DLTs)	Number of Participants in Phase 1 with Dose Limiting Toxicities (DLTs)	During phase 1
Overall Survival	Participants in phase 2 (18 dose group, 6 weeks treatment with TSC) were monitored for up to 3 years (last follow-up - February 16, 2016). Overall Survival (OS) was defined as the length of time from the date of tumor resection surgery or definitive biopsy to the date of death. The OS analyses were performed using the Kaplan-Meier estimate method. The OS rates at 6, 12, 18 and 24 months were estimated. Median OS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. The length of OS (in months) was calculated as follows: date of death or censored - date of surgery or definitive biopsy / 30.4375.	6, 12, 18, 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	The PFS analyses were performed using the Kaplan-Meier estimate method. The PFS rates at 6, 12, 18 and 24 months were estimated. Median PFS values were calculated; a corresponding 95% confidence interval for each median value was determined using a log rank analysis. Time to disease progression (in months) was calculated as follows: date of event* or censoring - date of surgery or definitive biopsy / 30.4375; *event = first tumor progression or death.	6,12,18, 24 months
Number of Participants With Reduction in Tumor Size, According to Percentage of Tumor Reduction	The sum of the product of the diameters of the tumor (using recorded tumor diameter measurements made from brain MRI images) was used to express tumor size. Results were summarized for actual and percentage change from baseline. Individual subjects results were listed, including tumor volume and tumor response from independent reviewers. Investigator data were listed but not used in the analysis. Percent response (according to independent reviewer assessments) by percentage tumor reduction from tumor resection or definitive biopsy to the last MRI were summarized.	From Baseline to Week 110

Collaborators and Investigators

• Sponsor: Diffusion Pharmaceuticals Inc
• Investigators: Study Chair: David R. Jones, M.D., Diffusion Pharmaceuticals Inc

Publications and helpful links

General Publications

• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.
• Gainer JL, Sheehan JP, Larner JM, Jones DR. Trans sodium crocetinate with temozolomide and radiation therapy for glioblastoma multiforme. J Neurosurg. 2017 Feb;126(2):460-466. doi: 10.3171/2016.3.JNS152693. Epub 2016 May 13.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: November 2, 2011
• First Submitted That Met QC Criteria: November 2, 2011
• First Posted (Estimate): November 4, 2011

Study Record Updates

• Last Update Posted (Actual): July 14, 2017
• Last Update Submitted That Met QC Criteria: June 16, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Glioma; GBM; Glioblastoma; Radiation therapy; Primary brain tumor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protective Agents; Antioxidants; Anticarcinogenic Agents; Trans-sodium crocetinate
• Other Study ID Numbers: DP100-202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No