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

Study of VAL-083 in Patients With <span class="go-doc-concept go-doc-alteration">MGMT Unmethylated</span>, <span class="go-doc-concept go-doc-intervention">Bevacizumab</span>-naive Recurrent <span class="go-doc-concept go-doc-disease">Glioblastoma</span>

Title

  • Brief Title: Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Recurrent Glioblastoma
  • Official Title: Phase II Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Recurrent Glioblastoma
  • Clinical Trial IDs

    NCT ID: NCT02717962

    ORG ID: DLM-16-001

    Trial Conditions

    Glioma

    Glioblastoma

    Glioblastoma Multiforme

    GBM

    Brain Cancer

    Trial Interventions

    Drug Synonyms Arms
    VAL-083 VAL-083
    Lomustine Lomustine

    Trial Purpose

    The purpose of this phase 2, randomized, non-comparative, biomarker-driven, two-arm study is
    to determine if treatment of O-6-methylguanine-DNA methyltransferase (MGMT) unmethylated
    recurrent glioblastoma with VAL-083 improves overall survival at 9 months, compared to
    historical control.

    Detailed Description

    Recurrent glioblastoma (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 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 on the order of weeks to
    months.

    Prognosis and response to therapy is 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 two-arm study will compare VAL-083 to lomustine, a standard of care chemotherapy drug
    for recurrent glioblastoma.

    Trial Arms

    Name Type Description Interventions
    VAL-083 Experimental VAL-083
    Lomustine Active Comparator Lomustine

    Eligibility Criteria

    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
    World Health Organization (WHO) Grade IV malignant glioma (glioblastoma, GBM), now
    recurrent. Patients with 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
    Response Assessment in Neuro-Oncology Criteria (RANO) criteria. Histologically
    documented transformation from a lower grade gliomas will be considered first
    recurrence.

    - Patients must have confirmed GBM MGMT status (tumor must be MGMT promoter
    unmethylated) by central laboratory Clinical Laboratory Improvement Amendments (CLIA)
    certified testing at MD Anderson, prior to registration. If initial MGMT testing
    obtained at an outside institution, MGMT status must be centrally retested at MD
    Anderson.

    - Patients must have Karnofsky Performance Status (KPS) > 60%.

    - Patients must have been previously treated for GBM with radiation with concurrent and
    adjuvant temozolomide chemotherapy.

    - 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.

    - Patients must 12 weeks from radiotherapy, to minimize the potential for magnetic
    resonance imaging (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.

    - 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 must be at least 4 weeks from last dose of 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.

    - 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.

    - 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 - Women of childbearing potential must have a negative B-HCG documented
    within 7 days prior to registration

    Exclusion Criteria:

    - Within 12 weeks of chemoradiation unless the patient fulfills criteria for early
    progressive disease by RANO

    - 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

    - Forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) <70% on
    pulmonary function testing; the principal investigator (PI) may make an exception to
    this, on a case-by-case basis, based on overall assessment of the patient, and the
    Sponsor agrees, on a case-by-case basis;

    - 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 PI

    - 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

    - Use of medications known to be strong inhibitors of P450 or CYP3A4 up to 14 days
    before Cycle 1 Day 1

    - 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Overall Survival

    Secondary Outcome Measures

    Progression-free Survival

    Median Progression-Free Survival

    Median Overall Survival

    Overall Response Rate

    Duration of Response Rate

    Number of participants with treatment-related adverse events assessed using NCI CTCAE v.4

    Quality of Life

    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