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

NCT01891747 | Completed Phase 1 DMC

• 1 other identifier: VICC NEU 1308
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Malignant Glioma

Keywords

gliomas

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (Phase I)

  every 4 weeks, 28-day cycle, up to 6 months

• Progression-free survival (Phase II)

  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.

  On treatment to disease progression or death for any reason, up to 12 months

Secondary Outcomes (3)

• Objective Response (Phase I)

  every 8 weeks, up to 6 months

• Number of patients with each worst-grade toxicity. (Phase I)

  every 4 weeks (28-day cycle), up to 6 months

• Overall Survival (Phase II)

  on study to date of death, up to 12 month

Study Arms (1)

L-methylfolate with Bevacizumab & Temozolomide

EXPERIMENTAL

28-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.

Drug: Bevacizumab; Drug: Temozolomide; Dietary Supplement: Vitamin C

Interventions

Bevacizumab DRUG

bevacizumab at 10mg/kg IV every 14 days (Phase I \& phase II)

L-methylfolate with Bevacizumab & Temozolomide

Temozolomide DRUG

150 mg/m2/day for a 5-day regimen per month (Phase I \& Phase II)

L-methylfolate with Bevacizumab & Temozolomide

Vitamin C DIETARY_SUPPLEMENT

250 mg vitamin C once a day (oral) - Phase I \& Phase II

L-methylfolate with Bevacizumab & Temozolomide

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Vanderbilt-Ingram Cancer Center: lead

Study Sites (1)

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Related Links

• Vanderbilt-Ingram Cancer Center, Find a Clinical Trial

MeSH Terms

Conditions

Glioma

Interventions

Bevacizumab; Temozolomide; Ascorbic Acid

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Carbohydrates

Study Officials

• Stephen Clark, MD

  Vanderbilt-Ingram Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Neurology, Neuro-oncologist

Study Record Dates

• First Submitted: June 25, 2013
• First Posted: July 3, 2013
• Study Start: July 1, 2013
• Primary Completion: June 1, 2015
• Study Completion: January 31, 2022
• Last Updated: March 10, 2022

Record last verified: 2022-03

Locations

US (1)