Clinical Trials /

Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Glioblastoma in the Adjuvant or Recurrent Setting

NCT02717962

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

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

DrugSynonymsArms
VAL-083, DianhydrogalactitolVAL-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 24 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

NameTypeDescriptionInterventions
VAL-083, Dianhydrogalactitol (Group 1)ExperimentalPatients with recurrent/progressive GBM
  • VAL-083, Dianhydrogalactitol
VAL-083, Dianhydrogalactitol (Group 2)ExperimentalNewly 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 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 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 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 have confirmed GBM MGMT status (tumor must be MGMT promoter
             unmethylated) determined prior to study entry by central laboratory CLIA certified
             testing at MD Anderson.

          -  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:Recruiting
Lead Sponsor:DelMar Pharmaceuticals, 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

May 24, 2019