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

Sponsor

DelMar Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT01478178

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Glioma Glioblastoma Glioblastoma Multiforme GBM Brain Cancer	Drug: VAL-083 (Dianhydrogalactitol)	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

55 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Open-label, Single Arm, Safety and Tolerability Dose Escalation Study of VAL-083 in Patients With Recurrent Malignant Glioma

Study Start Date :

Oct 1, 2011

Actual Primary Completion Date :

Dec 1, 2015

Actual Study Completion Date :

Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
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.	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.

Arm

Intervention/Treatment

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.

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.

Outcome Measures

Primary Outcome Measures

Determination of maximum tolerated dose (MTD) [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.

Secondary Outcome Measures

Evaluate tumor response in patients with recurrent malignant glioma [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 [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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco, Division of Neuro-Oncology	San Francisco	California	United States	94143
2	Sarah Cannon Research Institute	Denver	Colorado	United States	80218
3	Florida Cancer Specialists	Sarasota	Florida	United States	34232
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

DelMar Pharmaceuticals, Inc.

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