Brain NeoplasmsPhase 1SMC 0712-13NCT02149459
Treatment of Recurrent Brain Tumors: Metabolic Manipulation Combined With Radiotherapy
A Phase 1 study testing Partial brain re-irradiation., Metformin and low carbohydrate diet in people with Brain Neoplasms, run by Sheba Medical Center at 1 site in Israel.
Trial summary
Recurrent brain tumours are extremely aggressive and despite optimal treatment, median survival is less than two years. One of the standard treatment options in this situation is radiation therapy. Currently there is intense scientific interest concerning the abnormal energy metabolism in cancer cells. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Brain Neoplasms
- What is being tested?
- Partial brain re-irradiation., Metformin and low carbohydrate diet
- Type of treatment
- Surgery or procedure, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteIsrael
- Study dates
- Jun 2014to Jul 2018
- 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
- Willingness and ability to participate in diet/metformin intervention for the 8 week period.
- Patients must have a previously histologically or cytologically confirmed glioma (astrocytic or oligodendroglial supratentorial tumors grades 2, 3 or 4 according to the WHO 2007 classification 82) that has been previously treated with fractionated radiation therapy and now shows evidence of recurrence. There is no limit regarding the number / type of previous therapies that the patient has received for glioma, aside from exceptions mentioned below. If the brain tumor is in an eloquent location (e.g. brain stem) a clinical diagnosis is sufficient.
- Patients must have recovered from the toxic effects of prior therapy.
- Patients must have recovered from the effects of any prior surgery to any part of the body. There must be a minimum of 10 days from the day of surgery to the day of registration. For core or needle biopsy, a minimum of 7 days must have elapsed prior to registration.
- Patients may have previously undergone more than one craniotomy.
- Prior treatment with cytotoxic and biological agents is permissible. There should be at least a 2 week break between prior treatment and enrollment.
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- Prior treatment with fractionated radiation therapy (up to 66Gy) is an eligibility criterion, however this should have been completed ≥ 4 weeks prior to enrollment.
- One prior single fraction radio-surgical procedure within the treatment field is acceptable if V12<5cc (V12 is the volume of brain receiving 12 or more Gy). Additional radio-surgical procedures outside of the treatment area are acceptable.
- Age >=18 years.
- ECOG performance status <2 (Karnofsky>60%).
- Life expectancy of greater than 2 months.
- Patients must have normal organ and marrow function as defined below:
- -leukocytes >2,000/mcL
- -absolute neutrophil count >1,200/mcL
- -platelets >80,000/mcL
- -AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal
- No contra-indications of metformin use:
- Metformin allergy
- Renal failure, creatinine levels over 150 μmol/l (1.7 mg/dL)
- Liver disease
- Current alcohol abuse
- Women of childbearing potential must have a negative β-HCG pregnancy test documented within 14 days of registration.
- 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 participating in this study, she should inform her treating physician immediately.
- Ability to understand and the willingness to sign a written informed consent document.
Who cannot join
- Known to suffer from one of the following metabolic disorders (all rare):
- Carnitine deficiency (primary)
- Carnitine palmitoyltransferase (CPT) I or II deficiency
- Carnitine translocase deficiency
- β-oxidation defects
- Medium-chain acyldehydrogenase deficiency (MCAD)
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- Long-chain acyl dehydrogenase deficiency (LCAD)
- Short-chain acyl dehydrogenase deficiency (SCAD)
- Long-chain 3-hydroxyacyl-CoA deficiency
- Medium-chain 3-hydroxyacyl-CoA deficiency.
- Pyruvate carboxylase deficiency
- Porphyria
- Patients receiving insulin or oral medication on a daily basis for diabetes mellitus
- Known severe dyslipidemia: total cholesterol >400 mg/dl, LDL cholesterol > 300 mg/dl, triglycerides > 500 mg/dl
- Contraindications to metformin use:
- Metformin allergy
- Renal failure: creatinine levels over 150 μmol/l (1.7 mg/dL)
- Liver disease
- Current alcohol abuse
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Improving the Response of Recurrent Glioma to Radiation Therapy Through Metabolic Intervention
Recurrent brain tumours are extremely aggressive and despite optimal treatment, median survival is less than two years. One of the standard treatment options in this situation is radiation therapy. Currently there is intense scientific interest concerning the abnormal energy metabolism in cancer cells. All cells require energy in order to function, obtaining 'fuel' molecules such as glucose and fatty acids from the blood stream. Brain tumours exhibit "metabolic reprogramming", meaning that their energy requirements and utilization of fuel molecules are quite different from normal cells. Brain tumour cells are exquisitely dependant on glucose as a source of energy. Animal studies have shown that when these tumours are deprived of glucose they are very sensitive to radiation therapy.
In this clinical trial the investigators combine radiation therapy with a low-carbohydrate diet, in patients with recurrent brain tumours. In addition, subjects will receive medication with metformin, a drug usually used to treat diabetes. Metformin inhibits glucose metabolism within cancer cells, and additionally has reported intrinsic anti-cancer activity. Subjects will undergo advanced imaging and hormonal studies before, during and after the trial in order to obtain maximal translational-scientific impact.
Read more
The hypothesis:
The metabolic changes induced by the combination of a moderately-low carbohydrate diet combined with supplementary MCT and metformin therapy will selectively starve tumor cells. While normal brain cells are capable of deriving energy from ketone bodies during glucose restriction, tumor cells remain largely glucose-dependent for energy due to oncogene induced down-regulation of oxidative phosphorylation. While the tumor cells are in this 'vulnerable' state they will be less able to repair the damage induced by ionizing radiation.
Short-term implementation of the metabolic intervention (i.e. combined diet and metformin therapy) prior to, during, and after hypofractionated (2 week) radiation therapy is expected to increase tolerability, increase compliance and avoid the chronic metabolic complications associated with extreme carbohydrate restriction diets.
- Conditions
- Brain Neoplasms
- Being tested
- Partial brain re-irradiation., Metformin, low carbohydrate diet
- Keywords
- Radiotherapy, Ketosis, Metformin, Magnetic Resonance Imaging, Metabolome, Insulin, recurrent brain tumors, gliomas, glioblastomas, astrocytomas
- Medical subject headings
- Brain Neoplasms, Ketosis, Insulin Resistance, Glioma, Glioblastoma, Astrocytoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Partial brain re-irradiation.Radiation
Also called radiotherapy, radiation therapy (RT), fractionated stereotactic radiation (FSR), hypo-fractionated radiation therapy
Partial brain re-irradiation to a dose of 30-35Gy delivered over 2 weeks (10 fractions).
MetforminDrug
Also called glucophage, antidiabetic drug, biguanide
Different cohorts will receive no, low dose or higher dose metformin.
low carbohydrate dietBehavioural
Under close supervision of a dietician, patients will receive a low carbohydrate diet, enriched as necessary with medium chain triglyceride (MCT) supplements.
| Study group | Role | What they receive |
|---|---|---|
| treatment arm | Experimental | Partial brain re-irradiation combined with metabolic intervention (low carbohydrate diet and/or metformin treatment) Receives: Radiation: Partial brain re-irradiation.; Drug: Metformin; Behavioral: low carbohydrate diet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients with adverse events.
The investigators will track adverse events in order to determine the safety of the intervention.
Measured: 8 weeks
Number of patients completing the trial.
We will track patient compliance in order to determine the tolerability of the intervention.
Measured: 8 weeks
Secondary outcomes (2)
Number of patients whose brain tumors respond on imaging.
Measured: 8 weeks
Number of patients who demonstrate changes in systemic energy metabolism.
We will assess plasma levels of glucose, insulin and other relevant hormones before, during and after the intervention.
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 May 2014 (estimated)
- Study startJun 2014
- Primary completionJul 2018 (estimated)
- Study completionJul 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Brain NeoplasmsStudies of the same condition, open and under way.
- More trials run by Sheba Medical CenterThe sponsor's other registered studies.
- 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
- 18 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sheba Medical Center
- Sponsor type
- Other government
- Collaborators
- European Union
- Responsible party
- Sponsor
- Investigators
- Yaacov R Lawrence, MA MBBS MRCP, Principal investigator, Sheba Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02149459
- Sponsor's protocol ID
- SHEBA-13-0712-YL-CTIL
- Acronym
- SMC 0712-13
- Status last verified
- Oct 2017
- First submitted
- 26 May 2014
- Last updated
- 27 Oct 2017
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Improving the Response of Recurrent Glioma to Radiation Therapy Through Metabolic Intervention
- ClinicalTrials.gov ID
- NCT02149459
- Acronym / sponsor ID
- SMC 0712-13 / SHEBA-13-0712-YL-CTIL
- Conditions
- Brain Neoplasms
- Keywords
- Radiotherapy, Ketosis, Metformin, Magnetic Resonance Imaging, Metabolome, Insulin, recurrent brain tumors, gliomas
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 18 participants (estimated)
- Lead sponsor
- Sheba Medical CenterOther government
- Collaborators
- European Union
- Study start
- Jun 2014
- Primary completion
- Jul 2018 (estimated)
- Study completion
- Jul 2018 (estimated)
- First posted
- 29 May 2014 (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.
Recurrent brain tumours are extremely aggressive and despite optimal treatment, median survival is less than two years. One of the standard treatment options in this situation is radiation therapy. Currently there is intense scientific interest concerning the abnormal energy metabolism in cancer cells. All cells require energy in order to function, obtaining 'fuel' molecules such as glucose and fatty acids from the blood stream. Brain tumours exhibit "metabolic reprogramming", meaning that their energy requirements and utilization of fuel molecules are quite different from normal cells. Brain tumour cells are exquisitely dependant on glucose as a source of energy. Animal studies have shown that when these tumours are deprived of glucose they are very sensitive to radiation therapy.
In this clinical trial the investigators combine radiation therapy with a low-carbohydrate diet, in patients with recurrent brain tumours. In addition, subjects will receive medication with metformin, a drug usually used to treat diabetes. Metformin inhibits glucose metabolism within cancer cells, and additionally has reported intrinsic anti-cancer activity. Subjects will undergo advanced imaging and hormonal studies before, during and after the trial in order to obtain maximal translational-scientific impact.
The hypothesis:
The metabolic changes induced by the combination of a moderately-low carbohydrate diet combined with supplementary MCT and metformin therapy will selectively starve tumor cells. While normal brain cells are capable of deriving energy from ketone bodies during glucose restriction, tumor cells remain largely glucose-dependent for energy due to oncogene induced down-regulation of oxidative phosphorylation. While the tumor cells are in this 'vulnerable' state they will be less able to repair the damage induced by ionizing radiation.
Short-term implementation of the metabolic intervention (i.e. combined diet and metformin therapy) prior to, during, and after hypofractionated (2 week) radiation therapy is expected to increase tolerability, increase compliance and avoid the chronic metabolic complications associated with extreme carbohydrate restriction diets.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| treatment arm | Experimental | Radiation: Partial brain re-irradiation., Drug: Metformin, Behavioral: low carbohydrate dietPartial brain re-irradiation combined with metabolic intervention (low carbohydrate diet and/or metformin treatment) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (24 listed)
- Willingness and ability to participate in diet/metformin intervention for the 8 week period.
- Patients must have a previously histologically or cytologically confirmed glioma (astrocytic or oligodendroglial supratentorial tumors grades 2, 3 or 4 according to the WHO 2007 classification 82) that has been previously treated with fractionated radiation therapy and now shows evidence of recurrence. There is no limit regarding the number / type of previous therapies that the patient has received for glioma, aside from exceptions mentioned below. If the brain tumor is in an eloquent location (e.g. brain stem) a clinical diagnosis is sufficient.
- Patients must have recovered from the toxic effects of prior therapy.
- Patients must have recovered from the effects of any prior surgery to any part of the body. There must be a minimum of 10 days from the day of surgery to the day of registration. For core or needle biopsy, a minimum of 7 days must have elapsed prior to registration.
- Patients may have previously undergone more than one craniotomy.
Key exclusion criteria (19 listed)
- Known to suffer from one of the following metabolic disorders (all rare):
- Patients receiving insulin or oral medication on a daily basis for diabetes mellitus
- Known severe dyslipidemia: total cholesterol >400 mg/dl, LDL cholesterol > 300 mg/dl, triglycerides > 500 mg/dl
- Contraindications to metformin use:
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 |
|---|---|---|
| Partial brain re-irradiation.Also: radiotherapy, radiation therapy (RT), fractionated stereotactic radiation (FSR), hypo-fractionated radiation therapyPartial brain re-irradiation to a dose of 30-35Gy delivered over 2 weeks (10 fractions). | Radiation | treatment arm |
| MetforminAlso: glucophage, antidiabetic drug, biguanideDifferent cohorts will receive no, low dose or higher dose metformin. | Drug | treatment arm |
| low carbohydrate dietUnder close supervision of a dietician, patients will receive a low carbohydrate diet, enriched as necessary with medium chain triglyceride (MCT) supplements. | Behavioural | treatment arm |
Primary outcome
Number of patients with adverse events.
Time frame: 8 weeks
The investigators will track adverse events in order to determine the safety of the intervention.
Number of patients completing the trial.
Time frame: 8 weeks
We will track patient compliance in order to determine the tolerability of the intervention.
2 secondary outcomes
Number of patients whose brain tumors respond on imaging.
Time frame: 8 weeks
Number of patients who demonstrate changes in systemic energy metabolism.
Time frame: 8 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2017.
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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.
Yaacov R Lawrence, MA MBBS MRCP principal investigator
Sheba Medical 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 Partial brain re-irradiation., Metformin and low carbohydrate diet in people with Brain Neoplasms, run by Sheba Medical Center at 1 site in Israel.
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 24 inclusion and 19 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: status not confirmed, as of the sponsor's last update on 27 Oct 2017. 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 Israel. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Yaacov R Lawrence, MBBS MA MRCP (972-3-530-4410, yaacovla@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of patients with adverse events. (time frame: 8 weeks). 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 27 Oct 2017.