A Phase 1 interventional study of Sirolimus combined with CP, MT and ZA in Solid Tumor and Osteosarcoma, sponsored by Institut Bergonié. Completed at 3 sites in France. Open to participants aged 13 Years and older. Per ClinicalTrials.gov, last updated 2025-06-08.
Sponsored by Institut Bergonié · Phase 1, Interventional, and Treatment
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.
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.
3,517 studies on the registry are indexed under Neoplasm Metastasis; 885 are open to participants now.
This study's enrollment of 23 is below the median of 54 across 2,767 interventional studies indexed under Neoplasm Metastasis.
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Histology:
Adequate haematological, renal, metabolic and hepatic function:
Exclusion Criteria:
Concomitant diseases/conditions:
Drug : 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).
Drug: Sirolimus combined with CP, MT and ZA
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.
Also known as: Endoxan, Methotrexate, Rapamune, Zoledronic acid
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
Time frame: During the first cycle (28 days)
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.
Time frame: 6-month non-progression rate as per RECIST v1.1
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
Time frame: 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.
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).
Time frame: 1-year Progression-free survival (PFS) as per RECIST v1.1
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)
Time frame: 1-year Overall Survival (OS) as per RECIST v1.1
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
Time frame: 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.
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).
Time frame: 1-year Progression-free survival (PFS) as per RECIST v1.1
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)
Time frame: 1-year Overall Survival (OS) as per RECIST v1.1
First patient enrolled: February 16th, 2015 and last patient enrolled: March 11th, 2021
| Milestone | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Expansion Cohort With Dose Sirolimus (SI) 4 mg |
|---|---|---|---|
| Started | 6 | 3 | 14 |
| Completed | 6 | 3 | 14 |
| Not completed | 0 | 0 | 0 |
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
| Number of DLTs | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg |
|---|---|---|
| Dose Escalation Part: Number of Dose-Limiting Toxicities (DLTs) at Each Dose Level on Cycle 1 | 0 | 2 |
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.
| participants | Expansion Cohort With Dose Sirolimus (SI) 4 mg |
|---|---|
| Complete response | 0 |
| Partial response confirmed | 1 |
| Stable disease | 1 |
| Progression | 10 |
| Unevaluable according to RECIST v1.1 | 2 |
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
| participants | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg |
|---|---|---|
| Completed response | 0 | 0 |
| Partial response | 0 | 0 |
| Stable disease | 3 | 1 |
| Progression | 2 | 1 |
| Inevaluable for response | 1 | 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).
| Participants | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg |
|---|---|---|
| Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Progression-free Survival (PFS) | 6 | 1 |
1-year Overall Survival (OS) is defined as the time from first infusion to death (of any cause)
| Participants | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg |
|---|---|---|
| Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS) | 3 | 0 |
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
| participants | Expansion Cohort With Dose Sirolimus (SI) 4 mg |
|---|---|
| Complete response | 0 |
| Confirmed Partial response | 1 |
| Stable disease | 3 |
| Progression | 8 |
| Inevaluable for response | 2 |
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).
| months | Expansion Cohort With Dose Sirolimus (SI) 4 mg |
|---|---|
| Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Progression-free Survival (PFS) as Per RECIST v1.1 | 1.8 (1.4 to 3.6) |
1-year Overall Survival (OS) is defined as the time from first infusion to death (of any cause)
| Participants | Expansion Cohort With Dose Sirolimus (SI) 4 mg |
|---|---|
| Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS) as Per RECIST v1.1 | 7 |
Collected over Safety profile was continuously followed : monitored every 28 days during treatment consultation and up to 30 days after the last treatment administration or until the start of a new antitumor therapy, whichever occurs first. In case of SAE, monitoring could be improved as per investigator's judgement. After treatment discontinuation, patients were followed up 4 weeks later for toxicities. Grade 3 or 4 toxicity were monitored until resolution, through study completion, an average of 13 months.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Dose Escalation Part With Sirolimus (Si) Dose 4 mg | — | 3/6 (50%) | 6/6 (100%) |
| Dose Escalation Part With Sirolimus (SI) Dose 6 mg | — | 3/3 (100%) | 3/3 (100%) |
| Expansion Cohort With Dose Sirolimus (SI) 4 mg | — | 9/14 (64.3%) | 14/14 (100%) |
| Event | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Expansion Cohort With Dose Sirolimus (SI) 4 mg |
|---|---|---|---|
| Musculoskeletal chest painGeneral disorders | 0/6 | 1/3 | 0/14 |
| Interstitial lung diseaseRespiratory, thoracic and mediastinal disorders | 0/6 | 1/3 | 0/14 |
| LymphopeniaInvestigations | 2/6 | 0/3 | 2/14 |
| AnemiaBlood and lymphatic system disorders | 0/6 | 1/3 | 3/14 |
| PneumoniaInfections and infestations | 1/6 | 0/3 | 2/14 |
| AscitesGastrointestinal disorders | 1/6 | 0/3 | 0/14 |
| General physical health deteriorationGeneral disorders | 1/6 | 0/3 | 1/14 |
| Gamma-glutamyltransferase increasedInvestigations | 1/6 | 0/3 | 0/14 |
| Pulmonary embolismVascular disorders | 0/6 | 0/3 | 2/14 |
| Respiratory distressRespiratory, thoracic and mediastinal disorders | 0/6 | 0/3 | 1/14 |
| Event | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Expansion Cohort With Dose Sirolimus (SI) 4 mg |
|---|---|---|---|
| FatigueGeneral disorders | 3/6 | 3/3 | 6/14 |
| Neutrophil count decreasedInvestigations | 0/6 | 3/3 | 2/14 |
| Platelet count decreasedInvestigations | 2/6 | 3/3 | 7/14 |
| AnemiaBlood and lymphatic system disorders | 1/6 | 2/3 | 4/14 |
| Mucositis oralGastrointestinal disorders | 3/6 | 2/3 | 6/14 |
| Bronchial infectionInfections and infestations | 0/6 | 2/3 | 1/14 |
| Aspartate aminotransferase increasedInvestigations | 3/6 | 2/3 | 4/14 |
| AnorexiaMetabolism and nutrition disorders | 2/6 | 2/3 | 1/14 |
| DysgeusiaNervous system disorders | 0/6 | 2/3 | 1/14 |
| Lymphocyte count decreasedInvestigations | 2/6 | 1/3 | 6/14 |
All patients included, regardless of whether or not treatment was administered, and regardless violations of any eligibility criteria.
| Age, Continuous(years) | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Expansion Cohort With Dose Sirolimus (SI) 4 mg | Total |
|---|---|---|---|---|
| Mean | 52.5 ± 13.1 | 65.4 ± 12 | 36.3 ± 21.4 | 44.3 ± 21.0 |
| Sex: Female, Male(Participants) | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Expansion Cohort With Dose Sirolimus (SI) 4 mg | Total |
|---|---|---|---|---|
| Female | 4 | 2 | 6 | 12 |
| Male | 2 | 1 | 8 | 11 |
| Region of Enrollment(participants) | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Expansion Cohort With Dose Sirolimus (SI) 4 mg | Total |
|---|---|---|---|---|
| France | 6 | 3 | 14 | 23 |
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Institut Bergonié