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

Phase 1

Completed

• Conditions: Solid Tumor; Osteosarcoma
• Interventions: Drug: Sirolimus combined with CP, MT and ZA

• Registration Number: NCT02517918
• Lead Sponsor: Institut Bergonié

Brief 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 established.

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.

Study Timeline

• Study Start: 2015-02
• Study First Submitted: 2015-02-19
• Study First Submitted QC: 2015-08-04
• Study First Posted: 2015-08-07
• Primary Completion: 2016-09-05
• Study Completion: 2021-11-16
• Results First Submitted: 2023-04-14
• Status Verified: 2025-06
• Results First Submitted QC: 2025-06-05
• Last Update Submitted: 2025-06-05
• Results First Posted: 2025-06-08
• Last Update Posted: 2025-06-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

1. 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

2. Metastatic or unresectable locally advanced disease, not eligible for alternative local treatment (radiotherapy for instance)

3. Age > 18 years for patients with solid tumor and ≥ 13 years for patients with osteosarcoma

4. ECOG, performance status ≤ 1

5. Life expectancy > 3 months

6. Measurable disease according to RECIST v1.1. At least one site of disease must be uni-dimensionally ≥ 10 mm

7. 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

8. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy

9. 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

10. 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,

11. 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

12. Patients with a French social security in compliance with the French law relating to biomedical research

13. Voluntarily signed and dated written informed consent prior to any study specific procedure

14. 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

Exclusion Criteria

1. Previous treatment with sirolimus

2. 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

3. Central nervous system malignancy

4. Men or women of childbearing potential who are not using an effective method of contraception; women who are pregnant or breast feeding

5. Patients receiving any substances that are inhibitors or inducers of CYP450 3A4

6. 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

7. History of maxillary osteonecrosis or delayed healing after dental surgery

8. Participation to a study involving a medical or therapeutic intervention in the last 30 days

9. Previous enrolment in the present study

10. Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons

11. Known hypersensitivity to any involved study drug or any of its formulation components

12. Patients receiving live vaccines within 30 days prior to the first dose of study therapy and while participating in study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Sirolimus combined with CP, MT and ZA	Sirolimus combined with CP, MT and ZA	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).

Primary Outcome Measures

Name	Time	Method
Dose Escalation Part: Number of Dose-Limiting Toxicities (DLTs) at Each Dose Level on Cycle 1	During the first cycle (28 days)	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
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 as per RECIST v1.1	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.

Secondary Outcome Measures

Name	Time	Method
Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per RECIST v1.1	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.	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
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) 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).
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) 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).
Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS)	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)
Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per RECIST v1.1	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.	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
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) as per RECIST v1.1	1-year Overall Survival (OS) is defined as the time from first infusion to death (of any cause)

Trial Locations

Locations (3)

Institut Bergonié; 🇫🇷 Bordeaux, France

Centre Oscar Lambret; 🇫🇷 Lille, France

Centre Léon Bérard; 🇫🇷 Lyon, France