Description:
The purpose of this phase 2, two arm, biomarker-driven study is to determine if treatment of
O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated glioblastoma with VAL-083
improves overall survival (OS), compared to historical control, in the adjuvant or recurrent
setting.
Title
- Brief Title: Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting
- Official Title: Phase 2 Study of VAL-083 Treatment for MGMT Unmethylated Bevacizumab-naïve Glioblastoma in the Adjuvant or Recurrent Setting
Clinical Trial IDs
- ORG STUDY ID:
DLM-16-001
- NCT ID:
NCT02717962
Conditions
- Glioma
- Glioblastoma
- Glioblastoma Multiforme
- GBM
- Brain Cancer
Interventions
Drug | Synonyms | Arms |
---|
VAL-083, Dianhydrogalactitol | | VAL-083, Dianhydrogalactitol (Group 1) |
Purpose
The purpose of this phase 2, two arm, biomarker-driven study is to determine if treatment of
O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated glioblastoma with VAL-083
improves overall survival (OS), compared to historical control, in the adjuvant or recurrent
setting.
Detailed Description
Recurrent GBM is characterized by a dismal prognosis, with a median overall survival of 6.9
months. While a standard of care is established for the initial treatment of GBM - radiation
with concurrent and adjuvant temozolomide chemotherapy - management of recurrent disease
(NCCN, 2014) remains suboptimal. Treatment options include repeat surgery, re-irradiation, or
chemotherapy (including experimental targeted therapies, biologic agents, and
immunotherapies). Only a minority of patients has response to these treatments, and the
resultant benefits in progression-free and overall survival are in the order of weeks to
months.
Prognosis and response to therapy are known to be better in patients with a methylated MGMT
promoter gene. Epigenetic silencing of MGMT by promoter methylation is an important factor in
predicting outcome for patients with GBM treated with temozolomide. Approximately 66% of GBM
tumors are MGMT unmethylated (high expression of MGMT), which through a MGMT repair
mechanism, confers resistance to temozolomide, the standard chemotherapy treatment of GBM.
VAL-083, Dianhydrogalactitol (DAG), unlike temozolomide, is demonstrated to be active
independent of MGMT resistance mechanisms, in vitro. Thus, it may provide a treatment option
for those patients that are considered likely to be poor responders to temozolomide.
This is a non-comparative, two arm, biomarker-driven study with VAL-083 in GBM patients with
either recurrent disease (Group 1) or newly diagnosed GBM patients requiring maintenance
therapy after chemoradiation with temozolomide (Group 2).
Group 1: A total of up to 83 patients with recurrent/progressive GBM will be enrolled. This
will include 35 patients treated at 40 mg/m2 and up to 48 patients treated at 30 mg/m2.
Group 2: Up to an additional 36 newly diagnosed GBM patients who have completed
chemoradiation treatment with temozolomide and received no subsequent maintenance
temozolomide will be enrolled.
Eligible patients will receive VAL-083 IV on days 1, 2, and 3, for up to 12, 21-day treatment
cycles or until they fulfill one of the criteria for study discontinuation (disease
progression, death, intolerable toxicities, investigator's judgment, or withdrawal of
consent). Disease status will be evaluated with clinical and MRI evaluation every other
21-day cycle, while the patient is receiving VAL-083 treatment, and then approximately every
42 ± 7 days while remaining on study. Symptom burden will be evaluated using the MD Anderson
Symptom Inventory-Brain Tumor (MDASI-BT) completed by patients at baseline and at the time of
each imaging evaluation.
Interval medical histories, targeted physical exams, neurologic evaluations, complete blood
counts, and other laboratory and safety assessments will be performed approximately every
21-days. Blood samples will be taken at Cycle 1 Day 1 pre-dose, 15 ± 5 min, 30 ± 5 min, 60 ±
10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of iv infusion with
VAL-083 to determine the PK profile and dose-exposure relationship of VAL-083.
Toxicity will be evaluated and documented using the NCI CTCAE version 4.
This study will take approximately 36 months to enroll.
Trial Arms
Name | Type | Description | Interventions |
---|
VAL-083, Dianhydrogalactitol (Group 1) | Experimental | Patients with recurrent/progressive GBM | - VAL-083, Dianhydrogalactitol
|
VAL-083, Dianhydrogalactitol (Group 2) | Experimental | Newly diagnosed GBM patients who have completed chemoradiation treatment with temozolomide and received no subsequent maintenance temozolomide | - VAL-083, Dianhydrogalactitol
|
Eligibility Criteria
General Inclusion Criteria:
- Patient must willingly provide written consent after being informed of the procedure
to be followed, the experimental nature of the therapy, alternatives, potential
benefits, side effects, risks, and discomforts.
- Patients must be ≥ 18 years old.
- Patients must have histologically confirmed initial diagnosis of primary intracranial
WHO Grade IV malignant glioma (glioblastoma).
- Patients must have preliminary GBM MGMT status (tumor must be MGMT promoter
unmethylated) determined prior to study entry. If initial MGMT status is determined to
be "unmethylated", by an outside institution the patient may be enrolled and begin
treatment. However, MGMT status must be retested following enrollment by central
laboratory CLIA certified testing at MD Anderson.
- Patients must have Karnofsky Performance Status (KPS) > 60% (i.e., 70, 80, 90 or 100).
- Adequate recovery from all recent surgery is required. At least 21-days must have
elapsed from the time of any major surgery, including craniotomy/tumor resection.
Patients must have recovered from all surgery-related toxicities to Grade 1 or less.
- 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 histologic documentation of recurrence, unless the recurrence is a new
lesion outside the irradiated field.
- Patients having 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
- Patients must be at least 4 weeks from last dose of chemotherapy.
- Patients must have recovered from all treatment-related toxicities to Grade 1 or less.
- If receiving corticosteroids, patients must be on a stable or decreasing dose of
corticosteroids for ≥ 5 days prior to baseline MRI.
- Patients must have a predicted life expectancy of at least 12 weeks.
- Patients must have adequate bone marrow and organ function.
- Patients must be willing and able to comply with scheduled visits, treatment plan, and
laboratory tests and accessible for follow-up after treatment termination.
- If the patient has been using the Optune™ device, it will be discontinued before
initiating treatment with either study medication, and per inclusion criterion listed
above, the patient must have recovered from all treatment-related toxicities to Grade
1 or less.
- Pregnancy restrictions - Women of childbearing potential must have a negative B-HCG
documented within 7 days prior to registration
Group Specific Inclusion Criteria - Recurrent GBM (Group 1):
- Patients must have recurrent disease whose initial diagnostic pathology confirmed
glioblastoma will not need re-biopsy. Alternately, patients with prior intracranial
low-grade glioma or anaplastic glioma will be eligible, if histologic assessment
demonstrates transformation to GBM (first diagnosis of secondary GBM).
- Patients must have radiographic evidence of recurrent/progressive GBM after prior
therapy (biopsy or resection and chemoradiation); 1st recurrence of GBM only, per RANO
criteria. Histologically documented transformation from a lower grade gliomas will be
considered first recurrence.
- Patients must be >12 weeks from radiotherapy, to minimize the potential for MRI
changes related to treatment (pseudoprogression) that might be misdiagnosed as true
progression of disease, unless the patient fulfills criteria for early progressive
disease by RANO.
- Patients must have been previously treated for GBM with concurrent temozolomide and
radiation followed by adjuvant temozolomide chemotherapy.
- Patients must be at least 4 weeks or 5 half-lives (whichever is shorter) from the last
dose of prior investigational anti-cancer drugs.
Group Specific Inclusion Criteria - Newly Diagnosed GBM requiring maintenance therapy
(Group 2)
- Patients must not have recurrent disease.
- Patients must be < 6 weeks from radiotherapy to start of treatment with VAL-083.
- Patients must have been previously treated for GBM with concurrent temozolomide and
radiation, and received no subsequent maintenance temozolomide chemotherapy.
- No prior investigational agent.
Exclusion Criteria:
- Within 12 weeks of chemoradiation unless the patient fulfills criteria for early
progressive disease by RANO, for Group 1; and, more than 6 weeks from chemoradiation
for Group 2.
- Receipt of investigational agents within 5 half-lives of last dose of investigational
agent.
- Concurrent use of other investigational agents or Optune™ device
- Prior therapy with lomustine.
- Prior therapy with bevacizumab.
- 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 Sponsor.
- Evidence of leptomeningeal spread of disease.
- Need for urgent palliative intervention (e.g., impending herniation).
- 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.
- Patients with a known sensitivity to any of the products to be administered during
treatment.
- Patients unable to undergo MRI of the brain.
- Women who are pregnant or lactating. Women of childbearing potential must have a
negative serum or urine pregnancy test performed within 7 days prior to start of
treatment. Women of childbearing potential or men with partners of childbearing
potential must use effective birth control measures during treatment.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Overall Survival |
Time Frame: | Every 30 days from randomization until patient death |
Safety Issue: | |
Description: | Length of time from start of treatment (Day 1) until patient death |
Secondary Outcome Measures
Measure: | Estimate Progression-free Survival |
Time Frame: | Every 30 days from randomization until disease progression or patient death, whichever occurs earlier |
Safety Issue: | |
Description: | Time from start of treatment (Day 1) until to the first occurrence of progression or patient death, whichever occurs first |
Measure: | Estimate Median Progression-Free Survival |
Time Frame: | Every 30 days from randomization until disease progression or patient death, whichever occurs earlier |
Safety Issue: | |
Description: | The median length of time from start of treatment (Day 1) until to the first occurrence of progression or patient death, whichever occurs first |
Measure: | Estimate Median Overall Survival |
Time Frame: | Every 30 days from randomization until patient death |
Safety Issue: | |
Description: | The median length of time from start of treatment (Day 1) until patient death |
Measure: | Estimate Overall Response Rate |
Time Frame: | Every 42 days from randomization to achievement of either complete response (CR) or partial response (PR) |
Safety Issue: | |
Description: | Overall number of tumor complete response (CR) or partial response (PR) determined via MRI assessment |
Measure: | Estimate Duration of Response |
Time Frame: | Every 42 days from the first occurrence of a documented, objective response until the time of relapse or patient death |
Safety Issue: | |
Description: | Length of time tumor continues to demonstrate either complete response (CR) or partial response (PR) via MRI assessment |
Measure: | Safety evaluation of VAL-083 in patients |
Time Frame: | From randomization up to 28 days following last study treatment |
Safety Issue: | |
Description: | To confirm safety and tolerability of VAL-083 using NCI CTCAE v.4 to assess adverse events |
Measure: | Quality of Life |
Time Frame: | Every 42 days from randomization until disease progression |
Safety Issue: | |
Description: | MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) |
Measure: | Plasma Pharmacokinetics |
Time Frame: | Cycle 1 Day 1 predose, 15 ± 5 min, 30 ± 5 min, 60 ± 10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of iv infusion of VAL-083 |
Safety Issue: | |
Description: | PK profile and dose-exposure relationship of VAL-083 |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Kintara Therapeutics, Inc. |
Trial 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 bevacizumab
- temodar failure
- temozolomide failure
- adjuvant therapy
Last Updated
June 8, 2021