OsteosarcomaPhase 2Metform-BoneNCT04758000
Metformin as Maintenance Therapy in Patients With Bone Sarcoma and High Risk of Relapse
A Phase 2 study testing Metformin Hydrochloride in people with Osteosarcoma and Ewing Sarcoma, run by Istituto Ortopedico Rizzoli at 1 site in Italy.
Trial summary
Primitive bone sarcoma are rare tumors with low options of therapy for patient treatment. 1. OSTEOSARCOMA VERY POOR RESPONDER COHORT. Necrosis on primitive localized osteosarcoma represents one of the principal prognostic factors. Read more about this study
- Who is it for?
- Ages 14 years and older
- Conditions the study is for
- Osteosarcoma, Ewing Sarcoma
- What is being tested?
- Metformin Hydrochloride
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 67 participants
- Where
- 1 siteItaly
- Study dates
- 1 Mar 2021to Jul 2027
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
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 14 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Non metastatic osteosarcoma patients with necrosis ≤ 60 % in the end of post-operatory chemotherapy treatment (within 45 days.from the end of chemotherapy treatment).
- Osteosarcoma or Ewing sarcoma patients free from the disease after first relapse (within 45 days.from the local surgery or 45 days from the end of chemotherapy treatment).
- ≥ 14 years.
- Patient should not be participating in other clinical study.
- Patients should be able to swallow.
- Screening up to 30 days from the end of chemotherapy treatment or relapse.
- Start therapy up to 30 days from the screening.
- Normal renal function (creatinine <1,3 mg/L, clearance creatinine ≥ 70 ml/min) end liver function (total serum bilirubina <1,2 mg/dL, except Gilbert syndrome patients), AST e ALT <1,8 times the normal range value
Who cannot join
- Type B diabetic patient
- Metastatic patients
- Patients with acute metabolic acidosis (lactic acidosis, diabetic ketoacidosis).
- Patients with renal insufficiency (GFR < 70 ml/min).
- Patients with acute conditions that could cause kidney alterations as dehydration, severe infection and shock.
- Patients with hepatic insufficiency as acute alcohol intoxication and alcoholism.
Show all 9Show fewer
- Patients with medical conditions that could cause tissue hypoxia: decompensated heart failure, respiratory failure, recent myocardial infarction, shock.
- Patient who does not meet the inclusion criteria
- Pregnant and breastfeeding patients, or young women at childbearing age who cannot exclude the state of pregnancy (possibly excluded by serum pregnancy test (BhCG test), in accordance with the recommendations of the CTFG.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
Chemotherapy Div, Istituto Ortopedico Rizzoli
Bologna
Alessandra Longhi, MD, alessandra.longhi@ior.it
About this study
Primitive bone sarcoma are rare tumors with low options of therapy for patient treatment.
- OSTEOSARCOMA VERY POOR RESPONDER COHORT. Necrosis on primitive localized osteosarcoma represents one of the principal prognostic factors. Nowadays, for localized osteosarcoma there is no maintenance therapy that have shown to be effective. In ISG-OS1 study in patients with necrosis < 60% had an event free survival (EFS) at 3 yrs of 20% (Ferrari S ) in a more recent analysis (Tsuda Y 2020) patients with a necrosis <60% had a 3 y EFS of 35% .
- OSTEOSARCOMA AND EWING'S SARCOMA AFTER FIRST RELAPSE Maintenance therapy after Complete Remission occurring after Ewing's sarcoma or osteosarcoma patients is not a standard rule.
Read more
These patients when free from disease, after first relapse, are more likely to face a second relapse. EFS at ONE YEAR after first relapse in osteosarcoma is shown in literature to be around 21% (Leary SE 2013) and 16% (Tirtei E 2017). The EFS at ONE YEAR after first relapse in Ewing's sarcoma is inferior to 20% (Barker 2005, Ferrari S 2015). A maintenance therapy with low toxicity in these high risk patients could be an option.
Metformin has been reported to a reduce the incidence of different type of cancer in diabetic patients. Metformin is well tolerated in diabetics an it is used in other conditions in non diabetic, as ovarian polycystic syndrome, metabolic syndrome and obesity. Metformin has been employed as chemoprevention related to its mechanism of action in breast cancer (NCT01101438 ) and in pediatric cancer together with chemotherapy (NCT01528046).
This study aim to explore the effectiveness of metformin (a low cost and well tolerated drug) as maintenance therapy in osteosarcoma and Ewing sarcoma patients at high risk of relapse.
Read the detailed description
MATERIALS \& METHODS The study is divided in two groups
- Group 1-Localized osteosarcoma that have reported a post neoadjuvant chemotherapy primary tumor necrosis ≤ 60% Metformin will be administrated for 3 years maximum or until progression disease or if G3 or G4 toxicity is verified.
37 patients as total population are necessary to evaluate a 3 yrs increase of EFS from 35% ( historical data Tsuda Y ) to 60%,
- Group 2 Osteosarcoma and Ewing sarcoma patients in Complete Remission after the first relapse.Metformin will be administrated for 3 years or until progression .
The Event Free Survival of this second group will be calculated at 1 yr with the aim of an increase of EFS from 20%(historical data) to 45%
STATISTICAL ANALYSIS AND SAMPLE SIZE Sample size was calculated by the Expected Total Study Length minimization criteria to ensure a potency parameter of 80 % and point if there is a benefit in use Metformin compared to the historical control.
EFS will be estimated by Kaplan-Meier and the standard error will be used to calculate the interim analysis Z-factor as well as the final statistical analysis.
The final statistical analysis will be performed
- Group 1 after 3 years after last patient enrollment
- Group 2 at 1 year from the last patient enrollment : EFS at 1 year
OBJECTIVE
- Evaluate the event free survival (EFS) in osteosarcoma and Ewing sarcoma patients with high risk of relapse compared to the historical control.
- Evaluate Metformin's toxicity as maintenance therapy.
- Conditions
- Osteosarcoma, Ewing Sarcoma
- Being tested
- Metformin Hydrochloride
- Keywords
- Metformin, poor responders osteosarcoma, post relapse bone sarcoma
- Medical subject headings
- Osteosarcoma, Sarcoma, Ewing
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin HydrochlorideDrug
Metformin will be administrated according with patients body mass index (BMI).
Patients between 14 and 18 years old or with BMI ≤ 20: 500 mg two times a day Patients older than 18 years or with BMI > 20: 850 mg two times a day.
In all cases, metformin will be administrated for 3 years maximum, unless there is a progression disease or if toxicity is verified.
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Metformin will be administrated according with patients body mass index (BMI). The study is divided into 2 groups.
* Group 1: Localized osteosarcoma that have presented a response ≤ 60% to the pre-operatory chemotherapy).
* Group 2: Osteosarcoma and Ewing sarcoma patients with complete remission after the first relapse. Receives: Drug: Metformin Hydrochloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
Event Free Survival
Evaluate the event free survival (EFS) in osteosarcoma and Ewing sarcoma patients with high risk of relapse compared to the historical control
Measured: 3 years
Secondary outcomes (1)
Metformin toxicity
Evaluate Metformin's toxicity
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Feb 2021
- Study start1 Mar 2021
- Primary completionJul 2027 (estimated)
- Study completionJul 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for OsteosarcomaStudies of the same condition, open and under way.
- More trials run by Istituto Ortopedico RizzoliThe 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 2
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- 1. Group 1 Localized osteosarcoma that have presented a response ≤ 60% to the pre-operatory chemotherapy. Is expected the enrolment of 37 patients as total population, in 44 months. The patients will be followed for 3 years, started from the date of enrolment. Metformin will be administrated for 3 years maximum, unless there is a progression disease or if toxicity is verified. 2. Group 2 Osteosarcoma and Ewing sarcoma patients with complete remission after the first relapse. Is expected the enrolment of 30 patients as total population, in 24 months. Metformin will be administrated at the Group 2 for 1 year. If there is no toxicity verified or relapse, the patient should continue the treatment for other 2 year (in a total 3 years as maximum).
- Masking
- None (open label)
- Enrolment
- 67 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Istituto Ortopedico Rizzoli
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Alessandra Longhi,MD, Istituto Ortopedico Rizzoli
- Investigators
- Alessandra Longhi, MD, Principal investigator, Istituto Ortopedico Rizzoli IRCSS, Bologna, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04758000
- Sponsor's protocol ID
- 794/2020/Farm/IOR
- Other IDs
- 2020-002579-37
- Acronym
- Metform-Bone
- Status last verified
- Aug 2023
- First submitted
- 14 Feb 2021
- Last updated
- 4 Aug 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Ferrari S, Bacci G, Picci P, Mercuri M, Briccoli A, Pinto D, Gasbarrini A, Tienghi A, Brach del Prever A. Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Ann Oncol. 1997 Aug;8(8):765-71. doi: 10.1023/a:1008221713505.
PubMed 9332684Leary SE, Wozniak AW, Billups CA, Wu J, McPherson V, Neel MD, Rao BN, Daw NC. Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital experience. Cancer. 2013 Jul 15;119(14):2645-53. doi: 10.1002/cncr.28111. Epub 2013 Apr 26.
PubMed 23625626Barker LM, Pendergrass TW, Sanders JE, Hawkins DS. Survival after recurrence of Ewing's sarcoma family of tumors. J Clin Oncol. 2005 Jul 1;23(19):4354-62. doi: 10.1200/JCO.2005.05.105. Epub 2005 Mar 21.
PubMed 15781881Ferrari S, Luksch R, Hall KS, Fagioli F, Prete A, Tamburini A, Tienghi A, DiGirolamo S, Paioli A, Abate ME, Podda M, Cammelli S, Eriksson M, Brach del Prever A. Post-relapse survival in patients with Ewing sarcoma. Pediatr Blood Cancer. 2015 Jun;62(6):994-9. doi: 10.1002/pbc.25388. Epub 2015 Jan 13.
PubMed 25585917Tsuda Y, Tsoi K, Parry MC, Stevenson JD, Fujiwara T, Sumathi V, Jeys LM. Impact of chemotherapy-induced necrosis on event-free and overall survival after preoperative MAP chemotherapy in patients with primary high-grade localized osteosarcoma. Bone Joint J. 2020 Jun;102-B(6):795-803. doi: 10.1302/0301-620X.102B6.BJJ-2019-1307.R1.
PubMed 32475245
Study at a glance
From the registry record, last updated by the sponsor on 4 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metformin as Maintenance Therapy in Patients With Bone Sarcoma and High Risk of Relapse
- ClinicalTrials.gov ID
- NCT04758000
- Acronym / sponsor ID
- Metform-Bone / 794/2020/Farm/IOR
- Conditions
- Osteosarcoma, Ewing Sarcoma
- Keywords
- Metformin, poor responders osteosarcoma, post relapse bone sarcoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 67 participants (estimated)
- Lead sponsor
- Istituto Ortopedico RizzoliUniversity, hospital or other
- Study start
- 1 Mar 2021 (actual)
- Primary completion
- Jul 2027 (estimated)
- Study completion
- Jul 2027 (estimated)
- First posted
- 17 Feb 2021 (actual)
- 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.
Primitive bone sarcoma are rare tumors with low options of therapy for patient treatment.
- OSTEOSARCOMA VERY POOR RESPONDER COHORT. Necrosis on primitive localized osteosarcoma represents one of the principal prognostic factors. Nowadays, for localized osteosarcoma there is no maintenance therapy that have shown to be effective. In ISG-OS1 study in patients with necrosis < 60% had an event free survival (EFS) at 3 yrs of 20% (Ferrari S ) in a more recent analysis (Tsuda Y 2020) patients with a necrosis <60% had a 3 y EFS of 35% .
- OSTEOSARCOMA AND EWING'S SARCOMA AFTER FIRST RELAPSE Maintenance therapy after Complete Remission occurring after Ewing's sarcoma or osteosarcoma patients is not a standard rule.
These patients when free from disease, after first relapse, are more likely to face a second relapse. EFS at ONE YEAR after first relapse in osteosarcoma is shown in literature to be around 21% (Leary SE 2013) and 16% (Tirtei E 2017). The EFS at ONE YEAR after first relapse in Ewing's sarcoma is inferior to 20% (Barker 2005, Ferrari S 2015). A maintenance therapy with low toxicity in these high risk patients could be an option.
Metformin has been reported to a reduce the incidence of different type of cancer in diabetic patients. Metformin is well tolerated in diabetics an it is used in other conditions in non diabetic, as ovarian polycystic syndrome, metabolic syndrome and obesity. Metformin has been employed as chemoprevention related to its mechanism of action in breast cancer (NCT01101438 ) and in pediatric cancer together with chemotherapy (NCT01528046).
This study aim to explore the effectiveness of metformin (a low cost and well tolerated drug) as maintenance therapy in osteosarcoma and Ewing sarcoma patients at high risk of relapse.
Detailed description
MATERIALS \& METHODS The study is divided in two groups
- Group 1-Localized osteosarcoma that have reported a post neoadjuvant chemotherapy primary tumor necrosis ≤ 60% Metformin will be administrated for 3 years maximum or until progression disease or if G3 or G4 toxicity is verified.
37 patients as total population are necessary to evaluate a 3 yrs increase of EFS from 35% ( historical data Tsuda Y ) to 60%,
- Group 2 Osteosarcoma and Ewing sarcoma patients in Complete Remission after the first relapse.Metformin will be administrated for 3 years or until progression .
The Event Free Survival of this second group will be calculated at 1 yr with the aim of an increase of EFS from 20%(historical data) to 45%
STATISTICAL ANALYSIS AND SAMPLE SIZE Sample size was calculated by the Expected Total Study Length minimization criteria to ensure a potency parameter of 80 % and point if there is a benefit in use Metformin compared to the historical control.
EFS will be estimated by Kaplan-Meier and the standard error will be used to calculate the interim analysis Z-factor as well as the final statistical analysis.
The final statistical analysis will be performed
- Group 1 after 3 years after last patient enrollment
- Group 2 at 1 year from the last patient enrollment : EFS at 1 year
OBJECTIVE
- Evaluate the event free survival (EFS) in osteosarcoma and Ewing sarcoma patients with high risk of relapse compared to the historical control.
- Evaluate Metformin's toxicity as maintenance therapy.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- 1. Group 1 Localized osteosarcoma that have presented a response ≤ 60% to the pre-operatory chemotherapy. Is expected the enrolment of 37 patients as total population, in 44 months. The patients will be followed for 3 years, started from the date of enrolment. Metformin will be administrated for 3 years maximum, unless there is a progression disease or if toxicity is verified. 2. Group 2 Osteosarcoma and Ewing sarcoma patients with complete remission after the first relapse. Is expected the enrolment of 30 patients as total population, in 24 months. Metformin will be administrated at the Group 2 for 1 year. If there is no toxicity verified or relapse, the patient should continue the treatment for other 2 year (in a total 3 years as maximum).
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: Metformin HydrochlorideMetformin will be administrated according with patients body mass index (BMI). The study is divided into 2 groups. * Group 1: Localized osteosarcoma that have presented a response ≤ 60% to the pre-operatory chemotherapy). * Group 2: Osteosarcoma and Ewing sarcoma patients with complete remission after the first relapse. |
Who may qualify
- Ages
- 14 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- Non metastatic osteosarcoma patients with necrosis ≤ 60 % in the end of post-operatory chemotherapy treatment (within 45 days.from the end of chemotherapy treatment).
- Osteosarcoma or Ewing sarcoma patients free from the disease after first relapse (within 45 days.from the local surgery or 45 days from the end of chemotherapy treatment).
- ≥ 14 years.
- Patient should not be participating in other clinical study.
- Patients should be able to swallow.
Key exclusion criteria (9 listed)
- Type B diabetic patient
- Metastatic patients
- Patients with acute metabolic acidosis (lactic acidosis, diabetic ketoacidosis).
- Patients with renal insufficiency (GFR < 70 ml/min).
- Patients with acute conditions that could cause kidney alterations as dehydration, severe infection and shock.
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 |
|---|---|---|
| Metformin HydrochlorideMetformin will be administrated according with patients body mass index (BMI). Patients between 14 and 18 years old or with BMI ≤ 20: 500 mg two times a day Patients older than 18 years or with BMI > 20: 850 mg two times a day. In all cases, metformin will be administrated for 3 years maximum, unless there is a progression disease or if toxicity is verified. | Drug | Metformin |
Primary outcome
Event Free Survival
Time frame: 3 years
Evaluate the event free survival (EFS) in osteosarcoma and Ewing sarcoma patients with high risk of relapse compared to the historical control
1 secondary outcome
Metformin toxicity
Time frame: 3 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Aug 2023.
- Background: PubMed 9332684Ferrari S, Bacci G, Picci P, Mercuri M, Briccoli A, Pinto D, Gasbarrini A, Tienghi A, Brach del Prever A. Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy. Ann Oncol. 1997 Aug;8(8):765-71. doi: 10.1023/a:1008221713505.
- Background: PubMed 23625626Leary SE, Wozniak AW, Billups CA, Wu J, McPherson V, Neel MD, Rao BN, Daw NC. Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital experience. Cancer. 2013 Jul 15;119(14):2645-53. doi: 10.1002/cncr.28111. Epub 2013 Apr 26.
- Background: PubMed 15781881Barker LM, Pendergrass TW, Sanders JE, Hawkins DS. Survival after recurrence of Ewing's sarcoma family of tumors. J Clin Oncol. 2005 Jul 1;23(19):4354-62. doi: 10.1200/JCO.2005.05.105. Epub 2005 Mar 21.
- Background: PubMed 25585917Ferrari S, Luksch R, Hall KS, Fagioli F, Prete A, Tamburini A, Tienghi A, DiGirolamo S, Paioli A, Abate ME, Podda M, Cammelli S, Eriksson M, Brach del Prever A. Post-relapse survival in patients with Ewing sarcoma. Pediatr Blood Cancer. 2015 Jun;62(6):994-9. doi: 10.1002/pbc.25388. Epub 2015 Jan 13.
- Background: PubMed 32475245Tsuda Y, Tsoi K, Parry MC, Stevenson JD, Fujiwara T, Sumathi V, Jeys LM. Impact of chemotherapy-induced necrosis on event-free and overall survival after preoperative MAP chemotherapy in patients with primary high-grade localized osteosarcoma. Bone Joint J. 2020 Jun;102-B(6):795-803. doi: 10.1302/0301-620X.102B6.BJJ-2019-1307.R1.
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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.
Alessandra Longhi, MD principal investigator
Istituto Ortopedico Rizzoli IRCSS, Bologna, Italy
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Metformin Hydrochloride in people with Osteosarcoma and Ewing Sarcoma, run by Istituto Ortopedico Rizzoli at 1 site in Italy.
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 8 inclusion and 9 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: looking for participants now, as of the sponsor's last update on 4 Aug 2023. 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 Italy. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Alessandra Longhi, MD (+39(051)6366668, alessandra.longhi@ior.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Event Free Survival (time frame: 3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04758000, which also lists 5 linked publications.
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 4 Aug 2023.