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Solid TumorPhase 1METZOLIMOSNCT02517918

Metronomic Chemotherapy in Patients With Advanced Solid Tumor With Bone Metastasis and Advanced Pretreated Osteosarcoma

A Phase 1 study testing Sirolimus combined with CP, MT and ZA in people with Solid Tumor and Osteosarcoma, run by Institut Bergonié at 3 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This is a prospective open-labeled phase I trial based on a dose escalating study design assessing two dose levels of sirolimus when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) followed by an expansion cohort once the Maximum Tolerated Dose (MTD) is… Read more about this study

Who is it for?
Ages 13 years and older
Conditions the study is for
Solid Tumor, Osteosarcoma
What is being tested?
Sirolimus combined with CP, MT and ZA
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
3 sitesFrance
Study dates
Feb 2015to 16 Nov 2021
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 13 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Histology:
  • Advanced solid tumor with radiologically proven bone metastasis, (dose escalation part)
  • Patients with osteogenic osteosarcoma (dose escalation part and expansion cohort) histologically confirmed by central review
  • Metastatic or unresectable locally advanced disease, not eligible for alternative local treatment (radiotherapy for instance)
  • Age > 18 years for patients with solid tumor and ≥ 13 years for patients with osteosarcoma
  • ECOG, performance status ≤ 1
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  • Life expectancy > 3 months
  • Measurable disease according to RECIST v1.1. At least one site of disease must be uni-dimensionally ≥ 10 mm
  • Patients must have histologically confirmed diagnosis of locally advanced and/or metastatic solid tumors, which are not amenable to standard treatment, including for patients with osteosarcoma conventional agents such as anthracyclines, platinum salts, ifosfamide and/or methotrexate
  • At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy
  • Adequate haematological, renal, metabolic and hepatic function:
  • Haemoglobin ≥ 10 g/dl (patients may have received prior red blood cell transfusion, if clinically indicated); leucocytes ≥ 3 x 10^9/l, absolute neutrophil count ≥ 1.5 x 10^9/l, and platelet count ≥ 120 x 10^9/l.
  • Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 x upper limit of normality (ULN)
  • Total bilirubin ≤ 1.5 x ULN
  • Calculated creatinine clearance > 40 ml/min/1.73 m² (according to MDRD formula)
  • Creatine phosphokinase ≤ 2.5 x ULN
  • Albumin > 25 g/l
  • No prior or concurrent malignant disease diagnosed or treated in the last 2 years except adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
  • Recovery to grade ≤ 1 from any adverse event derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the NCI-CTCAE, version 4
  • Patients with a French social security in compliance with the French law relating to biomedical research
  • Voluntarily signed and dated written informed consent prior to any study specific procedure
  • Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment

Who cannot join

  • Previous treatment with sirolimus
  • Concomitant diseases/conditions:
  • Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural effusions
  • Unstable cardiac disease, pulse oximetry saturation < 90% at rest
  • Clinically significant immunodeficiency, such as HIV or active Hepatitis B or C
  • History of auto-immune disease, transplantation
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  • Central nervous system malignancy
  • Men or women of childbearing potential who are not using an effective method of contraception; women who are pregnant or breast feeding
  • Patients receiving any substances that are inhibitors or inducers of CYP450 3A4
  • Ongoing or recent (<6 weeks) dental problem, including any severe tooth or jaw infection (mandible and maxilla), dental trauma, dental or stomatological surgery (implants). Current dental cares are allowed
  • History of maxillary osteonecrosis or delayed healing after dental surgery
  • Participation to a study involving a medical or therapeutic intervention in the last 30 days
  • Previous enrolment in the present study
  • Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons
  • Known hypersensitivity to any involved study drug or any of its formulation components
  • Patients receiving live vaccines within 30 days prior to the first dose of study therapy and while participating in study

Trial locations and contacts

3 sites in 1 country.

France3 sites

  • Institut Bergonié

    Bordeaux, 33076

  • Centre Oscar Lambret

    Lille, 59000

  • Centre Léon Bérard

    Lyon, 69008

Other trials in France

About this study

Official title: Metronomic Cyclophosphamide and Methotrexate Combined With Zoledronic Acid and Sirolimus in Patients With Advanced Solid Tumor With Bone Metastasis and Advanced Pretreated Osteosarcoma. A Phase Ib Study From the French Sarcoma Group

This is a prospective open-labeled phase I trial based on a dose escalating study design assessing two dose levels of sirolimus when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) followed by an expansion cohort once the Maximum Tolerated Dose (MTD) is established.

Read the detailed description

The dose escalation part of the trial will be concerned on adults with advanced solid tumor with bone metastasis and young and adult patients with unresectable locally advanced or metastatic osteosarcoma.

The Expansion cohort will be conducted on young and adult patients with unresectable locally advanced or metastatic osteosarcoma.

Being tested
Sirolimus combined with CP, MT and ZA
Keywords
Advanced solid tumor, Bone metastasis and advanced pretreated osteosarcoma, Phase I trial, Dose escalation and expansion cohort, Biomarkers study
Medical subject headings
Osteosarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Sirolimus combined with CP, MT and ZADrug

    Also called Endoxan, Methotrexate, Rapamune, Zoledronic acid

    Cyclophosphamide, Methotrexate and Sirolimus will be administrated orally. Zoledronic Acid will be administrated by infusion (IV).

    Trial based on a dose escalating study design assessing two dose levels of sirolimus when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) followed by an expansion cohort once the MTD is established.

Study groups in NCT02517918
Study groupRoleWhat they receive
Sirolimus combined with CP, MT and ZAExperimentalDrug : Metronomic Cyclophosphamide, Methotrexate, Sirolimus, Zoledronic acid Assessment of the maximum tolerated dose of sirolimus Cyclophosphamide, Methotrexate and Sirolimus will be administrated orally. Zoledronic Acid will be administrated by infusion (IV).
Receives: Drug: Sirolimus combined with CP, MT and ZA

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Dose Escalation Part: Number of Dose-Limiting Toxicities (DLTs) at Each Dose Level on Cycle 1

    A DLT is defined as an adverse event (AE) or laboratory abnormality that fulfills the criteria below:

    • Is considered to be at least possibly related to the study treatment
    • Occurs during the first cycle of treatment
    • Is unrelated to disease, disease progression, inter-current illness, or concomitant medications
    • Meets one of the criteria below, graded as outlined or according to NCI CTCAEv4.3:
    • Grade 4 non-haematological toxicity (not laboratory)
    • Grade 3 non-haematological toxicity > 3 days (not laboratory) (except for asthenia, 1rst episode of nausea/vomiting without maximal symptomatic/prophylactic treatment)
    • Grade ≥ 3 non-hematologic laboratory value if medical intervention is required to treat the patient, or the abnormality leads to hospitalization, or the abnormality persists for > 1 week
    • Grade ≥ 3 hematologic toxicity > 3 days (except for lymphopenia)
    • Grade 4 lymphopenia
    • Confirmed febrile neutropenia

    Measured: During the first cycle (28 days)

  2. Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, in Terms of 6-month Non-progression Rate

    6-month non-progression rate defined as the rate of complete or partial response or stable disease at 6 months using RECIST v1.1 :

    • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
    • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
    • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions and also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
    • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
    • Unevaluable : patients stopped the treatment before tumor assessment.

    Measured: 6-month non-progression rate as per RECIST v1.1

Secondary outcomes (6)

  1. Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per RECIST v1.1

    The best objective response (BOR) is the best response recorded for each patient from the start of the study treatment until the end of treatment for progressive disease, death, patient or investigator decision.

    BOR is determined by investigator review of tumor assessments using RECIST v1.1 :

    • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm
    • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters
    • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions and also demonstrate an absolute increase of at least 5 mm
    • Stable Disease (SD)

    Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, average of 4 months

    Measured: Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from the start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, an average of 4 months.

  2. Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Progression-free Survival (PFS)

    1-year Progression-free survival (PFS) is defined as the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST v1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).

    Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

    Measured: 1-year Progression-free survival (PFS) as per RECIST v1.1

  3. Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS)

    1-year Overall Survival (OS) is defined as the time from first infusion to death (of any cause)

    Measured: 1-year Overall Survival (OS) as per RECIST v1.1

  4. Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per RECIST v1.1

    The best objective response (BOR) is the best response recorded for each patient from the start of the study treatment until the end of treatment for progressive disease, death, patient or investigator decision.

    BOR is determined by investigator review of tumor assessments using RECIST v1.1 :

    • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm
    • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters
    • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions and also demonstrate an absolute increase of at least 5 mm
    • Stable Disease (SD) Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, an average of 4 months

    Measured: Tumor assessment were repeated every 8 weeks (±7 days, i.e Week 8, 16, 24, etc.) from the start of treatment and at least 4 weeks after the first CR or PR, even if there are treatment delays, an average of 4 months.

  5. Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Progression-free Survival (PFS) as Per RECIST v1.1

    1-year Progression-free survival (PFS) is defined as the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST v1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).

    Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

    Measured: 1-year Progression-free survival (PFS) as per RECIST v1.1

  6. Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS) as Per RECIST v1.1

    1-year Overall Survival (OS) is defined as the time from first infusion to death (of any cause)

    Measured: 1-year Overall Survival (OS) as per RECIST v1.1

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Aug 2015 (estimated)
  2. Study startFeb 2015
  3. Primary completion5 Sep 2016
  4. Study completion16 Nov 2021

Resources

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
Sequential
Model description
This is a prospective open-labeled phase I trial based on : * a dose escalating study design assessing two dose levels of sirolimus when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) * an expansion cohort once the MTD is established.
Masking
None (open label)
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02517918
Sponsor's protocol ID
IB 2014-01
Acronym
METZOLIMOS
Status last verified
Jun 2025
First submitted
19 Feb 2015
Last updated
8 Jun 2025
Data monitoring committee
Yes

Publications

  • Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.

    PubMed 31401903

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Sirolimus combined with CP, MT and ZA in people with Solid Tumor and Osteosarcoma, run by Institut Bergonié at 3 sites in France.

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 22 inclusion and 16 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 8 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in France. 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?

Yes. Results are posted in the registry (first posted 8 Jun 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Dose Escalation Part: Number of Dose-Limiting Toxicities (DLTs) at Each Dose Level on Cycle 1 (time frame: During the first cycle (28 days)). 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?

On the ClinicalTrials.gov record for NCT02517918, which also lists 1 linked publication.

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 8 Jun 2025.

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