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

• ClinicalTrials.gov Identifier: NCT01478178
• Recruitment Status: Completed
• First Posted: November 23, 2011
• Last Update Posted: January 20, 2017
• Sponsor: DelMar Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Kintara Therapeutics, Inc. ( DelMar Pharmaceuticals, Inc. )

Tracking Information

• First Submitted Date: November 14, 2011
• First Posted Date: November 23, 2011
• Last Update Posted Date: January 20, 2017
• Study Start Date: October 2011
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 22, 2011)

Determination of maximum tolerated dose (MTD) [ Time Frame: Study Day 35 ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 22, 2011)

• Evaluate tumor response in patients with recurrent malignant glioma [ Time Frame: Every 60 days ]
  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 [ Time Frame: Cycle 1: 0, 0.25, 0.5, 1, 2, 4, 6 hrs and immediately prior to Cycle 1, Day 2 dosing ]
  Plasma will be analyzed to estimate appropriate PK parameters (Cmax, Tmax, AUC, elimination half-life, drug clearance, mean residence time, and volume of distribution).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Glioma
• Glioblastoma
• Glioblastoma Multiforme
• GBM
• Brain Cancer

Intervention

Drug: VAL-083 (Dianhydrogalactitol)

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.

Study Arms

Experimental: VAL-083 (Dianhydrogalactitol)

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: Drug: VAL-083 (Dianhydrogalactitol)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 25, 2014): 55
• Original Estimated Enrollment (submitted: November 22, 2011): 30
• Actual Study Completion Date: October 2016
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01478178
• Other Study ID Numbers: DLM-10-001
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• 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.

• Responsible Party: Kintara Therapeutics, Inc. ( DelMar Pharmaceuticals, Inc. )
• Study Sponsor: DelMar Pharmaceuticals, Inc.
• Collaborators: Not Provided

Investigators

• Principal Investigator: Howard A Burris, M.D.; Sarah Cannon Research Institute; Nashville, Tennessee 37203, USA
• Principal Investigator: Manish Patel, M.D.; Florida Cancer Specialists, Sarasota, Florida 34232, USA
• Principal Investigator: Nicholas Butowski, M.D.; University of California, San Francisco, 94143, USA
• Principal Investigator: Sani Kizilbash, M.D.; Mayo Clinic, Rochester, Minnesota 55905, USA
• Principal Investigator: Gerald Falchook, M.D.; Sarah Cannon Research Institute; Denver, Colorado 80218 USA

• PRS Account: Kintara Therapeutics, Inc.
• Verification Date: January 2017