Malignant GliomaPhase 1NCT01891747
A Phase I Study of High-dose L-methylfolate in Combination With Temozolomide and Bevacizumab in Recurrent High Grade Glioma
A Phase 1 study testing Bevacizumab, Temozolomide and Vitamin C in people with Malignant Glioma, run by Vanderbilt-Ingram Cancer Center at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Malignant Glioma
- What is being tested?
- Bevacizumab, Temozolomide and Vitamin C
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2013to 31 Jan 2022
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232
About this study
Official title: A Phase I/II Study of High-dose L-methylfolate in With Combination Temozolomide and Bevacizumab in Recurrent High Grade Glioma.
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.
Read the 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
- Conditions
- Malignant Glioma
- Being tested
- Bevacizumab, Temozolomide, Vitamin C
- Keywords
- gliomas
- Medical subject headings
- Glioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BevacizumabDrug
bevacizumab at 10mg/kg IV every 14 days (Phase I \& phase II)
TemozolomideDrug
150 mg/m2/day for a 5-day regimen per month (Phase I \& Phase II)
Vitamin CDietary supplement
250 mg vitamin C once a day (oral) - Phase I \& Phase II
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Bevacizumab; Drug: Temozolomide; Dietary Supplement: Vitamin C |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (Phase I)
Measured: 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.
Measured: On treatment to disease progression or death for any reason, up to 12 months
Secondary outcomes (3)
Objective Response (Phase I)
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).
Measured: every 8 weeks, up to 6 months
Number of patients with each worst-grade toxicity. (Phase I)
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.
Measured: every 4 weeks (28-day cycle), up to 6 months
Overall Survival (Phase II)
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.
Measured: on study to date of death, up to 12 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Jul 2013 (estimated)
- Study startJul 2013
- Primary completionJun 2015
- Study completion31 Jan 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Malignant GliomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt-Ingram Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Stephen Clark, MD, Vanderbilt-Ingram Cancer Center
- Investigators
- Stephen Clark, MD, Principal investigator, Vanderbilt-Ingram Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01891747
- Sponsor's protocol ID
- VICC NEU 1308
- Status last verified
- Mar 2022
- First submitted
- 25 Jun 2013
- Last updated
- 10 Mar 2022
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 10 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Study of High-dose L-methylfolate in With Combination Temozolomide and Bevacizumab in Recurrent High Grade Glioma.
- ClinicalTrials.gov ID
- NCT01891747
- Acronym / sponsor ID
- VICC NEU 1308
- Conditions
- Malignant Glioma
- Keywords
- gliomas
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- Vanderbilt-Ingram Cancer CenterUniversity, hospital or other
- Study start
- Jul 2013
- Primary completion
- Jun 2015 (actual)
- Study completion
- 31 Jan 2022 (actual)
- First posted
- 3 Jul 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| L-methylfolate with Bevacizumab & Temozolomide | Experimental | Drug: Bevacizumab, Drug: Temozolomide, Dietary Supplement: Vitamin C28-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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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.
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Bevacizumabbevacizumab at 10mg/kg IV every 14 days (Phase I \& phase II) | Drug | L-methylfolate with Bevacizumab & Temozolomide |
| Temozolomide150 mg/m2/day for a 5-day regimen per month (Phase I \& Phase II) | Drug | L-methylfolate with Bevacizumab & Temozolomide |
| Vitamin C250 mg vitamin C once a day (oral) - Phase I \& Phase II | Dietary supplement | L-methylfolate with Bevacizumab & Temozolomide |
Primary outcome
Maximum Tolerated Dose (Phase I)
Time frame: every 4 weeks, 28-day cycle, up to 6 months
Progression-free survival (Phase II)
Time frame: On treatment to disease progression or death for any reason, up to 12 months
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.
3 secondary outcomes
Objective Response (Phase I)
Time frame: every 8 weeks, up to 6 months
Number of patients with each worst-grade toxicity. (Phase I)
Time frame: every 4 weeks (28-day cycle), up to 6 months
Overall Survival (Phase II)
Time frame: on study to date of death, up to 12 month
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Mar 2022.
- Vanderbilt-Ingram Cancer Center, Find a Clinical TrialLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stephen Clark, MD principal investigator
Vanderbilt-Ingram Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Bevacizumab, Temozolomide and Vitamin C in people with Malignant Glioma, run by Vanderbilt-Ingram Cancer Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (Phase I) (time frame: every 4 weeks, 28-day cycle, up to 6 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Mar 2022.