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Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma

Primary Purpose

Glioma, Glioblastoma, Glioblastoma Multiforme

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
VAL-083 (Dianhydrogalactitol)
Sponsored by
DelMar Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioma focused on measuring Glioma, Glioblastoma, Glioblastoma multiforme, GBM, brain tumor, brain cancer, recurrent brain tumor, recurrent brain cancer, refractory brain tumor, refractory brain cancer, recurrent GBM, refractory GBM, recurrent glioma, refractory glioma, recurrent glioblastoma, refractory glioblastoma, recurrent glioblastoma multiforme, refractory glioblastoma multiforme, failed temodar, failed temozolomide, temodar refractory, temozolomide refractory, failed avastin, avastin refractory, failed bevacizumab, bevacizumab refractory, avastin failure, bevacizumab failure, temodar failure, temozolomide failure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients must be greater than or equal to 18 years old.
  • Histologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma (glioblastoma), now recurrent; or Cohorts 2 and 3 only: progressive secondary brain tumor, has failed standard brain radiotherapy, and has brain tumor progression after at least one line of systemic therapy. Patients with progressive secondary brain tumors will not be enrolled under this protocol following the completion of Cohort 3.
  • If GBM, previously treated for GBM with surgery and/or radiation, if appropriate, and must have failed both bevacizumab (Avastin) and temozolomide (Temodar), unless either or both are contraindicated.
  • If GBM, greater than or equal to 12 weeks from radiotherapy, or 4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is outside the primary radiation field.
  • Cohorts 2 & 3 only: Patients with secondary brain tumors must be greater than or equal to 4 weeks from radiotherapy. Patients with progressive secondary brain tumors will not be enrolled under this protocol following the completion of Cohort 3.
  • At least 4 weeks from last chemotherapy or bevacizumab (Avastin) therapy (6 weeks for nitrosourea or mitomycin C), or for chemotherapy regimes given continuously or on a weekly basis with limited potential for delayed toxicity, at least 2 weeks from last dose.
  • At least 21 days or 5 half-lives (whichever is shorter) since prior investigational anti-cancer drugs. A minimum of 10 days between termination of the investigational drug and administration of DAG is required
  • Recovered from all treatment-related toxicities to Grade 1 or less.
  • Must have a Karnofsky performance status of > 50 with a predicted life expectancy of at least 12 weeks.
  • Must have known MGMT methylation and IDH1 mutation status to be screened for study entry.

Exclusion Criteria:

  • Current history of neoplasm other than the entry diagnosis. Patients with previous cancers treated and cured with local therapy alone may be considered with approval of the Medical Monitor.
  • Evidence of leptomeningeal spread of disease.
  • Evidence of recent hemorrhage on baseline MRI of the brain.
  • Concurrent severe, intercurrent illness.
  • History of severe cardiac disease.
  • Significant vascular disease.
  • History of stroke or transient ischemic attack within 6 months prior to beginning treatment.
  • Concomitant medications that are known inducers of CYP.
  • Concomitant medications that are strong inhibitors of cytochrome P450 and CYP3A up to 14 days before Cycle 1 Day 1 (pimozide, diltiazem, erythromycin, clarithromycin, and quinidine, and amiodarone up to 90 days before)
  • Known to be HIV positive or to have an AIDS-related illness.
  • Pregnant or breast feeding.

Sites / Locations

  • University of California, San Francisco, Division of Neuro-Oncology
  • Sarah Cannon Research Institute
  • Florida Cancer Specialists
  • Mayo Clinic
  • Sarah Cannon Research Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

VAL-083 (Dianhydrogalactitol)

Arm Description

VAL-083 given by intravenous infusion with a starting dose of 1.5 mg/m2 IV. Escalating doses to be administered in sequential dose cohorts.

Outcomes

Primary Outcome Measures

Determination of maximum tolerated dose (MTD)
The determination of MTD will be based on analysis of tolerance data from the first cycle of therapy in each dose group.

Secondary Outcome Measures

Evaluate tumor response in patients with recurrent malignant glioma
Tumor assessment every other treatment cycle, as long as patient continues to demonstrate response or stable disease and tolerates therapy.
Characterization of Cycle 1 plasma pharmacokinetics
Plasma will be analyzed to estimate appropriate PK parameters (Cmax, Tmax, AUC, elimination half-life, drug clearance, mean residence time, and volume of distribution).

Full Information

First Posted
November 14, 2011
Last Updated
January 19, 2017
Sponsor
DelMar Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01478178
Brief Title
Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma
Official Title
Open-label, Single Arm, Safety and Tolerability Dose Escalation Study of VAL-083 in Patients With Recurrent Malignant Glioma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
October 2011 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
October 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
DelMar Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this Phase 1/2, open-label, single-arm study is to determine the safety and the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent malignant glioma. Pharmacokinetic (PK) properties will be explored and tumor responses to treatment will be evaluated.
Detailed Description
Recurrent glial tumors of the brain continue to be one of the most challenging malignancies to treat. Median survival for patients with recurrent disease is approximately 6 months for glioblastoma multiforme. Bevacizumab is used for treatment of recurrent disease; however patients who fail bevacizumab do not have many treatment options. Metastases to the brain are the most common intracranial tumors in adults and occur ten times more frequently than primary brain tumors. It is estimated that 8 - 10% of cancer patients may develop symptomatic metastatic tumors in the brain. Systemic therapy is rarely used for primary treatment of brain metastases because many tumors that metastasize to the brain are not chemosensitive or have been already heavily pretreated with potentially effective agents, and poor penetration through the blood brain barrier is an additional concern. Dianhydrogalactitol (DAG) rapidly penetrates both the cerebrospinal fluid (CSF) and the blood-brain barrier and accumulates in brain tissue. Clinical study of DAG in patients with GBM or with progressive secondary brain tumors is warranted. Patients with secondary brain metastases were allowed to enroll into the current protocol in Cohorts 2 and 3; however, enrollment ceased with Amendment 5 and will not be continued beyond Cohort 3. This study will utilize a standard 3 + 3 dose escalation design, until the MTD or the maximum specified dose has been reached. In Phase 2, additional patients with GBM will be treated at the MTD (or other selected optimum Phase 2 dose) to measure tumor responses to treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioma, Glioblastoma, Glioblastoma Multiforme, GBM, Brain Cancer
Keywords
Glioma, Glioblastoma, Glioblastoma multiforme, GBM, brain tumor, brain cancer, recurrent brain tumor, recurrent brain cancer, refractory brain tumor, refractory brain cancer, recurrent GBM, refractory GBM, recurrent glioma, refractory glioma, recurrent glioblastoma, refractory glioblastoma, recurrent glioblastoma multiforme, refractory glioblastoma multiforme, failed temodar, failed temozolomide, temodar refractory, temozolomide refractory, failed avastin, avastin refractory, failed bevacizumab, bevacizumab refractory, avastin failure, bevacizumab failure, temodar failure, temozolomide failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
55 (Actual)

8. Arms, Groups, and Interventions

Arm Title
VAL-083 (Dianhydrogalactitol)
Arm Type
Experimental
Arm Description
VAL-083 given by intravenous infusion with a starting dose of 1.5 mg/m2 IV. Escalating doses to be administered in sequential dose cohorts.
Intervention Type
Drug
Intervention Name(s)
VAL-083 (Dianhydrogalactitol)
Intervention Description
VAL-083 given by intravenous infusion with a starting dose of 1.5 mg/m2 IV. Escalating doses to be administered in sequential dose cohorts.
Primary Outcome Measure Information:
Title
Determination of maximum tolerated dose (MTD)
Description
The determination of MTD will be based on analysis of tolerance data from the first cycle of therapy in each dose group.
Time Frame
Study Day 35
Secondary Outcome Measure Information:
Title
Evaluate tumor response in patients with recurrent malignant glioma
Description
Tumor assessment every other treatment cycle, as long as patient continues to demonstrate response or stable disease and tolerates therapy.
Time Frame
Every 60 days
Title
Characterization of Cycle 1 plasma pharmacokinetics
Description
Plasma will be analyzed to estimate appropriate PK parameters (Cmax, Tmax, AUC, elimination half-life, drug clearance, mean residence time, and volume of distribution).
Time Frame
Cycle 1: 0, 0.25, 0.5, 1, 2, 4, 6 hrs and immediately prior to Cycle 1, Day 2 dosing

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must be greater than or equal to 18 years old. Histologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma (glioblastoma), now recurrent; or Cohorts 2 and 3 only: progressive secondary brain tumor, has failed standard brain radiotherapy, and has brain tumor progression after at least one line of systemic therapy. Patients with progressive secondary brain tumors will not be enrolled under this protocol following the completion of Cohort 3. If GBM, previously treated for GBM with surgery and/or radiation, if appropriate, and must have failed both bevacizumab (Avastin) and temozolomide (Temodar), unless either or both are contraindicated. If GBM, greater than or equal to 12 weeks from radiotherapy, or 4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is outside the primary radiation field. Cohorts 2 & 3 only: Patients with secondary brain tumors must be greater than or equal to 4 weeks from radiotherapy. Patients with progressive secondary brain tumors will not be enrolled under this protocol following the completion of Cohort 3. At least 4 weeks from last chemotherapy or bevacizumab (Avastin) therapy (6 weeks for nitrosourea or mitomycin C), or for chemotherapy regimes given continuously or on a weekly basis with limited potential for delayed toxicity, at least 2 weeks from last dose. At least 21 days or 5 half-lives (whichever is shorter) since prior investigational anti-cancer drugs. A minimum of 10 days between termination of the investigational drug and administration of DAG is required Recovered from all treatment-related toxicities to Grade 1 or less. Must have a Karnofsky performance status of > 50 with a predicted life expectancy of at least 12 weeks. Must have known MGMT methylation and IDH1 mutation status to be screened for study entry. Exclusion Criteria: Current history of neoplasm other than the entry diagnosis. Patients with previous cancers treated and cured with local therapy alone may be considered with approval of the Medical Monitor. Evidence of leptomeningeal spread of disease. Evidence of recent hemorrhage on baseline MRI of the brain. Concurrent severe, intercurrent illness. History of severe cardiac disease. Significant vascular disease. History of stroke or transient ischemic attack within 6 months prior to beginning treatment. Concomitant medications that are known inducers of CYP. Concomitant medications that are strong inhibitors of cytochrome P450 and CYP3A up to 14 days before Cycle 1 Day 1 (pimozide, diltiazem, erythromycin, clarithromycin, and quinidine, and amiodarone up to 90 days before) Known to be HIV positive or to have an AIDS-related illness. Pregnant or breast feeding.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Howard A Burris, M.D.
Organizational Affiliation
Sarah Cannon Research Institute; Nashville, Tennessee 37203, USA
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Manish Patel, M.D.
Organizational Affiliation
Florida Cancer Specialists, Sarasota, Florida 34232, USA
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nicholas Butowski, M.D.
Organizational Affiliation
University of California, San Francisco, 94143, USA
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sani Kizilbash, M.D.
Organizational Affiliation
Mayo Clinic, Rochester, Minnesota 55905, USA
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gerald Falchook, M.D.
Organizational Affiliation
Sarah Cannon Research Institute; Denver, Colorado 80218 USA
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco, Division of Neuro-Oncology
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Sarah Cannon Research Institute
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Florida Cancer Specialists
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34232
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Sarah Cannon Research Institute
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
The Clinical Study Report for this trial will be prepared and provided to U.S. F.D.A. as required by applicable regulatory requirement(s). Each participating trial investigator has been provided a copy their patient data captured in the electronic data base for this trial.

Learn more about this trial

Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma

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