VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM

NCT03149575 | Terminated Phase 3 DMC FDA Drug

• 1 other identifier: DLM-16-002
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 5

Brief Summary

This is an adaptive design, randomized controlled, Phase 3 clinical trial in patients with glioblastoma multiforme (GBM) or gliosarcoma (GS), previously treated with surgery (if appropriate), standard of care chemo-radiation with temozolomide, +/- adjuvant temozolomide, and bevacizumab and now has progressive disease during or after bevacizumab. A total of up to 180 eligible patients with recurrent/progressive GBM or GS will be randomized to receive either the investigational drug (VAL-083) or "Investigator's choice of salvage therapy" as a contemporaneous control, in a 2:1 fashion. Up to 120 eligible patients will be randomized to receive VAL-083 at 40 mg/m2 IV on days 1, 2, and 3 of a 21-day treatment-cycle, for up to 12, 21-day treatment cycles or until they fulfill one of the criteria for study discontinuation. Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy", limited to temozolomide, lomustine, or carboplatin, until they fulfill one of the criteria for study discontinuation. The dose level for Investigator's choice salvage therapy (temozolomide, lomustine, or carboplatin), will be in accordance with the product label or institutional guidelines. In both study arms, interval medical histories, targeted physical exams, neurologic evaluations, complete blood counts, and other laboratory and safety assessments will be performed approximately every 21-days while receiving treatment. Tumor assessments are to be performed approximately every 42 ± 7 days while remaining on study. The study is estimated to last approximately 20 months.

Conditions

Glioblastoma Multiforme; Glioblastoma; Glioma; 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; STAR-3

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  Time from patient randomization to patient death

  Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months

Secondary Outcomes (13)

• Progression Free Survival

  Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months

• Duration of Response

  Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months

• Incidence of Treatment-Emergent Adverse Events (Overall Safety and Toxicity)

  Assessed approximately every 42 days for duration of study participation which is estimated to be 12 months

• Cmax

  Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2.

• Tmax

  Assessed on Day 1 and Day 3 of Cycle 1 at pre-dose, and 15, 30, 60, 120, 240 and 360 minutes after study drug administration. Trough levels 24 hr after infusion on Day 1 will also be obtained in these subjects, prior to dosing on Day 2.

Study Arms (2)

VAL-083, Dianhydrogalactitol

EXPERIMENTAL

Up to 120 eligible patients will be randomized to receive VAL-083.

Drug: VAL-083, Dianhydrogalactitol

Physician's Choice of Salvage Therapy

ACTIVE COMPARATOR

Up to 60 patients will be randomized to receive "Investigator's choice of salvage therapy" temozolomide, lomustine, or carboplatin

Drug: Physician's Choice of Salvage Therapy - temozolomide; Drug: Physician's Choice of Salvage Therapy - lomustine; Drug: Physician's Choice of Salvage Therapy - carboplatin

Interventions

VAL-083, Dianhydrogalactitol DRUG

VAL-083 given by intravenous infusion at a dose 40 mg/m2 IV on days 1, 2, and 3 of a 21-day treatment-cycle, for up to 12, 21-day treatment cycles

VAL-083, Dianhydrogalactitol

Physician's Choice of Salvage Therapy - temozolomide DRUG

The product label for temozolomide (Temodar®) provides the following dosing information. Newly Diagnosed GBM: 75 mg/m2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1-5 of a 28-day cycle of Temodar® for 6 cycles. Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle.

Physician's Choice of Salvage Therapy

Physician's Choice of Salvage Therapy - lomustine DRUG

The product label for lomustine (CeeNu; lomustine; CCNU) provides the following dosing information. The recommended dose of lomustine in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks.

Physician's Choice of Salvage Therapy

Physician's Choice of Salvage Therapy - carboplatin DRUG

The product label for (Paraplatin) carboplatin Injection provides the following dosing information. As a single agent at a dosage of 360mg/m2 IV on day 1 every 28 days Alternatively, the carboplatin dose may be calculated by the Calvert formula below Calvert formula for carboplatin dosing: Total Dose (mg) = (target AUC) x (GFR + 25), where AUC = area under the curve and GFR = glomerular filtration rate.

Physician's Choice of Salvage Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must agree to testing of GBM tumor promoter methylation status of the MGMT gene and tumor (IDH1) gene mutation status. Tissue may be tested at study entry, if not done previously, or data may be obtained from last known test result for MGMT and IDH1. IDH1 status may be assessed at study entry, but MGMT status is required prior to randomization.
• Agree to allow the sponsor to collect data on all GBM-related treatments received after the patient comes off the current study, and to collect survival data after the patient comes off the current study.
• Patient must be ≥ 18 years old.
• Histologically confirmed initial diagnosis of primary glioblastoma multiforme (GBM) or gliosarcoma (GS), now recurrent. Patients with recurrent/progressive disease whose initial diagnostic pathology confirmed GBM or GS will not need re-biopsy. Patients with prior low-grade glioma or anaplastic glioma are eligible, if histologic assessment demonstrates transformation to GBM or GS.
• Patient has previously received standard of care chemo-radiation with temozolomide, ± adjuvant temozolomide and bevacizumab and now has radiographic evidence of recurrent/progressive GBM or GS during or after bevacizumab.
• Patient must have bi dimensionally measurable disease, per the proposed Response Assessment in NeuroOncology (RANO; Appendix C) (Wen et al., 2010), with measurement of \>1 cm in one diameter and ≤5 cm diameter in any plane on MRI performed within 2 weeks prior to randomization.
• At least 4 weeks from last chemotherapy or bevacizumab (Avastin®) therapy (6 weeks for nitrosourea or mitomycin C), or for chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity, at least 2 weeks from last dose.
• If the patient has been using the Optune™ device, it will be discontinued at least four days prior to commencing treatment with VAL-083, and the patient must have recovered from all treatment-related toxicities to Grade 1 or less.
• Baseline MRI must be obtained ≥ 4 weeks after surgical resection but within 2 weeks prior to randomization.
• Adequate recovery from all recent surgery is required; at least 1 week must have elapsed from the time of a minor surgery; at least 21 days must have elapsed from the time of a major surgery. Patients must have recovered from all surgery-related toxicities to Grade 1 or less.
• Prior therapy with Laser-Induced Thermal Therapy (LITT) is allowed but at least 21 days must have elapsed from last LITT, with recovery from all LITT-related toxicities to Grade 1 or less and subsequent histologic documentation of recurrence.
• Greater than 12 weeks from radiotherapy, to minimize the potential for MRI changes related to radiation necrosis that might be misdiagnosed as pseudoprogression of disease, unless the recurrence is a new lesion, outside the primary radiation field or the patient fulfills criteria for early progressive disease by RANO ((Wen et al., 2010); Appendix C).
• Prior therapy with gamma knife or other focal high-dose radiation is allowed, but at least 2 weeks must have elapsed from the time of treatment, and the patient must have subsequent post-radiotherapy histologic documentation of recurrence in the irradiated field, unless the recurrence is a new lesion outside the irradiated field.
• If receiving corticosteroids, patients must be on a stable or decreasing dose of corticosteroids for ≥ 5 days prior to baseline MRI.
• At least 28 days or 5 half-lives (whichever is shorter) since prior investigational anti-cancer drugs. A minimum of 21 days between termination of the investigational drug and administration of VAL-083 is required.

You may not qualify if:

• Current history of neoplasm other than the entry diagnosis. Exceptions are:
• Curatively treated basal cell/squamous cell skin cancer
• Carcinoma in situ of the cervix
• Patients with previous solid and hematologic tumors, that have been treated with no evidence of recurrence within the last 5 years, are permitted.
• Evidence of diffuse subependymal disease or tumor in the brainstem, cerebellum, spinal cord, or CSF.
• Radiological evidence of multifocal disease, tumors extending into or crossing the corpus callosum or leptomeningeal disease.
• Need for urgent palliative intervention for primary disease (e.g., impending herniation).
• Evidence of recent hemorrhage on baseline MRI of the brain with the following exceptions:
• Presence of hemosiderin.
• Resolving hemorrhagic changes related to surgery.
• Presence of punctate hemorrhage in the tumor.
• Concurrent severe, intercurrent illness including, but not limited to unstable systemic disease, including ongoing or active infection, uncontrolled hypertension, serious cardiac arrhythmia requiring medication, or psychiatric illness/social situations that would limit compliance with study requirements.
• Any of the following cardiac conditions:
• History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, and/or stenting up to 12 weeks before Cycle 1, Day 1.
• Class III or IV heart failure as defined by the New York Heart Association functional classification system up to 6 months before Cycle 1, Day 1.

Sponsors & Collaborators

• DelMar Pharmaceuticals, Inc.: lead

Study Sites (5)

Kaiser Permanente Los Angeles Medical Center

Los Angeles, California, 90027, United States

Location

University of California, San Francisco - Division of Neuro-Oncology

San Francisco, California, 94143, United States

Location

Mayo Clinic Cancer Center

Rochester, Minnesota, 55905, United States

Location

Atlantic Neuroscience Institute - Brain Tumor Center of NJ

Summit, New Jersey, 07901, United States

Location

Dent Neurosciences Research Center

Amherst, New York, 14226, United States

Location

MeSH Terms

Conditions

Glioblastoma; Glioma; Brain Neoplasms

Interventions

Dianhydrogalactitol

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Galactitol; Sugar Alcohols; Alcohols; Organic Chemicals; Carbohydrates

Study Officials

• Nicholas Butowski, M.D.

  University of California, San Francisco, California, USA 94143

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: May 3, 2017
• First Posted: May 11, 2017
• Study Start: October 27, 2017
• Primary Completion: May 31, 2019
• Study Completion: August 31, 2019
• Last Updated: September 4, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)