Metformin as Maintenance Therapy in Patients With Bone Sarcoma and High Risk of Relapse (Metform-Bone)

August 3, 2023 updated by: Alessandra Longhi,MD, Istituto Ortopedico Rizzoli

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. 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% .

  2. 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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

MATERIALS & METHODS The study is divided in two groups

1. 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%,

2. 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

  1. Evaluate the event free survival (EFS) in osteosarcoma and Ewing sarcoma patients with high risk of relapse compared to the historical control.
  2. Evaluate Metformin's toxicity as maintenance therapy.

Study Type

Interventional

Enrollment (Estimated)

67

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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.
  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin

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.
Drug: Metformin Hydrochloride

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Metformin toxicity
Time Frame: 3 years
Evaluate Metformin's toxicity
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Istituto Ortopedico Rizzoli

Investigators

  • Principal Investigator: Alessandra Longhi, MD, Istituto Ortopedico Rizzoli IRCSS, Bologna, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2021

Primary Completion (Estimated)

July 1, 2027

Study Completion (Estimated)

July 1, 2027

Study Registration Dates

First Submitted

February 14, 2021

First Submitted That Met QC Criteria

February 14, 2021

First Posted (Actual)

February 17, 2021

Study Record Updates

Last Update Posted (Actual)

August 4, 2023

Last Update Submitted That Met QC Criteria

August 3, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 794/2020/Farm/IOR
  • 2020-002579-37 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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