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

Glioblastoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01478178
• Other study ID #: DLM-10-001
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: November 14, 2011
• Last updated: January 19, 2017
• Start date: October 2011
• Est. completion date: October 2016

Study information

• Verified date: January 2017
• Source: DelMar Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: October 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

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.

Locations

Country	Name	City	State
United States	Sarah Cannon Research Institute	Denver	Colorado
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California, San Francisco, Division of Neuro-Oncology	San Francisco	California
United States	Florida Cancer Specialists	Sarasota	Florida

Sponsors (1)

Lead Sponsor	Collaborator
DelMar Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Study Day 35
Secondary	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.	Every 60 days
Secondary	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).	Cycle 1: 0, 0.25, 0.5, 1, 2, 4, 6 hrs and immediately prior to Cycle 1, Day 2 dosing