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A Phase I Study of High-dose L-methylfolate in Combination With Temozolomide and Bevacizumab in Recurrent High Grade Glioma

NCT01891747

Description:

This is a Phase I/II non-randomized prospective study of high-dose L-methylfolate in combination with bevacizumab and temozolomide in patients with recurrent high-grade glioma. The primary objective of this phase II trial is to determine whether the addition of high-dose L-methylfolate to bevacizumab and temozolomide therapy improves progression-free survival (PFS) compared to previously reported results.

Related Conditions:
  • Glioma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase I/II Study of High-dose L-methylfolate in Combination With Temozolomide and Bevacizumab in Recurrent High Grade Glioma
  • Official Title: A Phase I/II Study of High-dose L-methylfolate in With Combination Temozolomide and Bevacizumab in Recurrent High Grade Glioma.

Clinical Trial IDs

  • ORG STUDY ID: VICC NEU 1308
  • NCT ID: NCT01891747

Conditions

  • Malignant Glioma

Interventions

DrugSynonymsArms
BevacizumabL-methylfolate with Bevacizumab & Temozolomide
TemozolomideL-methylfolate with Bevacizumab & Temozolomide

Purpose

This is a Phase I/II non-randomized prospective study of high-dose L-methylfolate in combination with bevacizumab and temozolomide in patients with recurrent high-grade glioma. The primary objective of this phase II trial is to determine whether the addition of high-dose L-methylfolate to bevacizumab and temozolomide therapy improves progression-free survival (PFS) compared to previously reported results.

Detailed Description

      The phase I part of the study will be completed to determine the Maximum Tolerated Dose (MTD)
      of high-dose L-methylfolate in combination with bevacizumab at 10mg/kg IV every 14 days, a
      5-day regimen per month of temozolomide at 150 mg/m2/day and a 250 mg tablet of vitamin C.
      Dose escalation will involve 3 patients treated at each dose level of L-methylfolate (15mg,
      30 mg, 60 mg or 90 mg), and the MTD will be confirmed by expansion of 3 additional patients.
      It is anticipated that 6 to 15 patients will be enrolled in the phase 1 part of the study.
      Patients will continue treatment until disease progression. Once the MTD of L-methylfolate
      has been determined, patients enrolled at a lower dose level may increase L-methylfolate dose
      to the MTD dose, per investigator discretion.

      The phase II part of the study will consist of patients taking the MTD of L-methylfolate
      daily in combination with bevacizumab at 10 mg/kg IV every 14 days, a 5-day regimen per month
      of temozolomide at 150 mg/m2/day and a 250 mg tablet of vitamin C. There will be 32 patients
      treated in the Phase II study and the patients will continue treatment until progression. The
      6 patients treated at the MTD cohort in Phase
    

Trial Arms

NameTypeDescriptionInterventions
L-methylfolate with Bevacizumab & TemozolomideExperimental28-day cycle, dose levels L-methylfolate: Phase I 15 mg (once a day) 30 mg (15 mg twice a day) 60 mg (30 mg twice a day) 90 mg (45 mg twice a day) Phase II will use the MTD of L-methylfolate daily with bevacizumab & temozolomide.
  • Bevacizumab
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed malignant glioma (anaplastic
             oligodendroglioma, anaplastic astrocytoma, anaplastic oligoastroctyoma or
             glioblastoma). Patients must have genetically confirmed Isocitrate dehydrogenase I
             (IDH1) wild-type tumor.

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension as greater than or equal to 5 mm.
             Patients can have non-measurable disease if they have had recent surgery for
             radiographic progression.

          -  Patients can have been treated with standard therapy for high grade glioma, including
             surgical resection, chemoradiation with temozolomide, adjuvant temozolomide and
             bevacizumab. Patients can have received experimental therapy for high grade glioma.

          -  Patients must be 18 years of age or older.

          -  Patients may not be breast-feeding a child.

          -  Patients must have a Karnofsky Performance Score of greater than or equal to 60
             percent.

          -  Patients must have normal organ and marrow function as defined below:

        leukocytes greater than or equal to 3,000/milliliter (mcL) absolute neutrophil count
        greater than or equal to 1,500/mcL platelets greater than or equal to 100,000/mcL total
        bilirubin within normal institutional limits Aspartate transaminase (serum glutamic
        oxaloacetic transaminase)Alanine transaminase (Serum Glutamic Pyruvate Transaminase) less
        than or equal to 2.5 times institutional upper limit of normal Creatinine within normal
        institutional limits OR creatinine clearance greater than or equal to 60/mL/min 1.73 m2 for
        patients with creatinine levels above institutional normal

          -  Patients must have no concurrent malignancy except curatively treated basal or
             squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast.
             Patients with prior malignancies must be disease-free for greater than or equal to 3
             years.

          -  The effects of high-dose L-methylfolate on the developing human fetus at the
             recommended therapeutic dose are unknown, but, there is evidence that folic acid can
             be protective against neural tube defects. However, there is some concern that folate
             supplementation can increase the incidence of autism, and thus women of child-bearing
             potential and men must agree to use adequate contraception (hormonal or barrier method
             of birth control; abstinence) prior to study entry and for the duration of study
             participation. Should a woman become pregnant or suspect she is pregnant while she or
             her partner is participating in this study, the patient should inform the treating
             physician immediately. All women will have pregnancy testing performed prior to
             entering the trial.

          -  Patients must have the ability to understand and the willingness to sign a written
             informed consent document.

          -  Patients must be able to tolerate MRIs. CT scans can NOT be substituted for MRI in
             this study.

          -  Patients on therapeutic warfarin or enoxaparin are eligible.

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events (greater than grade I) due to agents administered more
             than 4 weeks earlier.

          -  Patients with genetically confirmed IDH1-mutated tumor.

          -  Patients may not be receiving any other investigational agents.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to folic acid.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, stage II hypertension, or psychiatric illness/social situations that would
             limit compliance with study requirements.

          -  Pregnant women are excluded from this study because high-dose folic acid has the
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with high-dose folic acid breastfeeding should be discontinued if the mother is
             treated with high-dose folic acid.

          -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
             the potential for pharmacokinetic interactions with high-dose folic acid. In addition,
             these patients are at increased risk of lethal infections when treated with
             marrow-suppressive therapy. Appropriate studies will be undertaken in patients
             receiving combination antiretroviral therapy when indicated.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (Phase I)
Time Frame:every 4 weeks, 28-day cycle, up to 6 months
Safety Issue:
Description:Disease progression is defined as either radiological or clinical/neurological progression (whichever occurs first), PFS is the time interval between the date of starting treatment and the date of disease progression or death, whichever comes first. If neither event has been observed, then the patient is censored at the date last documented to be free of progression. Progression-free and overall survival will be summarized non-parametrically using the method of Kaplan and Meier with standard errors based on Greenwood's formula.

Secondary Outcome Measures

Measure:Objective Response (Phase I)
Time Frame:every 8 weeks, up to 6 months
Safety Issue:
Description:Response will be determined by neurologic examination and contrast-enhanced MRI initially after 8 weeks and then subsequently prior to every other cycle based on the Response Assessment in Neuro-Oncology criteria (RANO).
Measure:Number of patients with each worst-grade toxicity. (Phase I)
Time Frame:every 4 weeks (28-day cycle), up to 6 months
Safety Issue:
Description:To determine the safety profile of high-dose L-methylfolate (15mg, 30 mg, 60 mg or 90 mg) in combination with bevacizumab and temozolomide in patients with recurrent high-grade glioma as determined by number of patients with each worst grade toxicity using the Common Terminology Criteria for Adverse Events 4.0, 1 = mild through 5 = death.
Measure:Overall Survival (Phase II)
Time Frame:on study to date of death, up to 12 month
Safety Issue:
Description:median overall survival and time to survival in patients treated with L-methylfolate in combination with temozolomide and bevacizumab. The Duration of survival is the time interval between the date of starting treatment and the date of death. Patients still alive will be censored at the date of last follow-up.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Vanderbilt-Ingram Cancer Center

Trial Keywords

  • gliomas

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