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| Name | Class |
|---|---|
| Reliable Cancer Therapies | INDUSTRY |
| Pfizer | INDUSTRY |
Not provided
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sirolimus combined with CP, MT and ZA | Experimental | 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). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus combined with CP, MT and ZA | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
| 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 :
| 6-month non-progression rate as per RECIST v1.1 |
| Measure | Description | Time Frame |
|---|---|---|
| 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 :
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 |
Not provided
Inclusion Criteria:
Histology:
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
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:
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
Exclusion Criteria:
Previous treatment with sirolimus
Concomitant diseases/conditions:
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
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| Name | Affiliation | Role |
|---|---|---|
| Maud TOULMONDE, Doctor | Institut Bergonié | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Institut Bergonié | Bordeaux | 33076 | France | |||
| Centre Oscar Lambret |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31401903 | Derived | 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. |
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First patient enrolled: February 16th, 2015 and last patient enrolled: March 11th, 2021
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| ID | Title | Description |
|---|---|---|
| FG000 | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Prospective open-labeled phase I trial. The dose escalation design to identify the maximum tolerated dose will be the traditional 3+3 design. Sirolimus (SI) dose 4 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 6. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
| FG001 | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Prospective open-labeled phase I trial. The dose escalation design to identify the maximum tolerated dose will be the traditional 3+3 design. Sirolimus (SI) dose 6 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 3. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
| FG002 | Expansion Cohort With Dose Sirolimus (SI) 4 mg | Prospective open-labeled phase I trial. The expansion cohort is designed to enable to detect antitumor activity observed with sirolimus (SI) combined with cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA). Sirolimus (SI) dose 4 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 14. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
All patients included, regardless of whether or not treatment was administered, and regardless violations of any eligibility criteria.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Prospective open-labeled phase I trial. The dose escalation design to identify the maximum tolerated dose will be the traditional 3+3 design. Sirolimus (SI) dose 4 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 6. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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:
| Population assessable : Patients who received at least one dose of one of the trial's products and have received the complete C1 cycle (28 days: D1 to D28) or have exhibited a DLT during C1. | Posted | Number | Number of DLTs | During the first cycle (28 days) |
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.
Safety population: all patients having received at least one treatment administration.
All adverse events (related and unrelated to treatment) are reported. All serious adverse events (related and unrelated to treatment) are reported.
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE).
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Prospective open-labeled phase I trial. The dose escalation design to identify the maximum tolerated dose will be the traditional 3+3 design. Sirolimus (SI) dose 4 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 6. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Infections and infestations | Version 4.0 (CTCAE) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | Version 4.0 (CTCAE) | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pr Simone Mathoulin-Pelissier | Institut Bergonié | 0556333333 | S.Mathoulin@bordeaux.unicancer.fr |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 9, 2021 | Apr 13, 2023 | SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D012516 | Osteosarcoma |
| ID | Term |
|---|---|
| D018213 | Neoplasms, Bone Tissue |
| D009372 | Neoplasms, Connective Tissue |
| D018204 | Neoplasms, Connective and Soft Tissue |
| D009370 | Neoplasms by Histologic Type |
Not provided
Not provided
| ID | Term |
|---|---|
| D003520 | Cyclophosphamide |
| D008727 | Methotrexate |
| D020123 | Sirolimus |
| D000077211 | Zoledronic Acid |
| ID | Term |
|---|---|
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
Not provided
Not provided
This is a prospective open-labeled phase I trial based on :
Not provided
Not provided
Not provided
Not provided
|
|
| 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). | 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) | 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 :
| 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). | 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) | 1-year Overall Survival (OS) as per RECIST v1.1 |
| Lille |
| 59000 |
| France |
| Centre Léon Bérard | Lyon | 69008 | France |
| BG001 | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Prospective open-labeled phase I trial. The dose escalation design to identify the maximum tolerated dose will be the traditional 3+3 design. Sirolimus (SI) dose 6 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 3. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
| BG002 | Expansion Cohort With Dose Sirolimus (SI) 4 mg | Prospective open-labeled phase I trial. The expansion cohort is designed to enable to detect antitumor activity observed with sirolimus (SI) combined with cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA). Sirolimus (SI) dose 4 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 14. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | Dose Escalation Part With Sirolimus (Si) Dose 4 mg | Prospective open-labeled phase I trial. The dose escalation design to identify the maximum tolerated dose will be the traditional 3+3 design. Sirolimus (SI) dose 4 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 6. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
| OG001 | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Prospective open-labeled phase I trial. The dose escalation design to identify the maximum tolerated dose will be the traditional 3+3 design. Sirolimus (SI) dose 6 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 3. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. |
|
|
| Primary | 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 :
| Population assessable : Patients eligible and who received at least one complete or two incomplete treatment cycles and least one disease measurement recorded not less than eight weeks after treatment onset. | Posted | Number | participants | 6-month non-progression rate as per RECIST v1.1 |
|
|
|
| Secondary | 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 :
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 | Population assessable : Patients who received at least one dose of one of the trial's products and have received the complete C1 cycle (28 days: D1 to D28) or have exhibited a DLT during C1. | Posted | Number | participants | 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. |
|
|
|
| Secondary | 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). | Population assessable : Patients who received at least one dose of one of the trial's products and have received the complete C1 cycle (28 days: D1 to D28) or have exhibited a DLT during C1. | Posted | Count of Participants | Participants | 1-year Progression-free survival (PFS) as per RECIST v1.1 |
|
|
|
| Secondary | 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) | Population assessable : Patients who received at least one dose of one of the trial's products and have received the complete C1 cycle (28 days: D1 to D28) or have exhibited a DLT during C1. | Posted | Count of Participants | Participants | 1-year Overall Survival (OS) as per RECIST v1.1 |
|
|
|
| Secondary | 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 :
| Population assessable : Patients eligible and who received at least one complete or two incomplete treatment cycles and least one disease measurement recorded not less than eight weeks after treatment onset. | Posted | Number | participants | 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. |
|
|
|
| Secondary | 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). | Population assessable : Patients eligible and who received at least one complete or two incomplete treatment cycles and least one disease measurement recorded not less than eight weeks after treatment onset. | Posted | Median | 95% Confidence Interval | months | 1-year Progression-free survival (PFS) as per RECIST v1.1 |
|
|
|
| Secondary | 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) | Population assessable : Patients eligible and who received at least one complete or two incomplete treatment cycles and least one disease measurement recorded not less than eight weeks after treatment onset. | Posted | Count of Participants | Participants | 1-year Overall Survival (OS) as per RECIST v1.1 |
|
|
|
| 3 |
| 6 |
| 6 |
| 6 |
| EG001 | Dose Escalation Part With Sirolimus (SI) Dose 6 mg | Prospective open-labeled phase I trial. The dose escalation design to identify the maximum tolerated dose will be the traditional 3+3 design. Sirolimus (SI) dose 6 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 3. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. | 3 | 3 | 3 | 3 |
| EG002 | Expansion Cohort With Dose Sirolimus (SI) 4 mg | Prospective open-labeled phase I trial. The expansion cohort is designed to enable to detect antitumor activity observed with sirolimus (SI) combined with cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA). Sirolimus (SI) dose 4 mg when prescribed in combination with metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) Sirolimus will be administered per os once daily, continuously. One cycle consits of 28 days. Number of subjects : 14. Cyclophosphamide will be administered per os bi-daily (50 mg x 2), and given on a week on/week off schedule. Methotrexate will be administered per os bi-daily (2.5 mg x 2), and given on day 1 and 4 every week. Zoledronic acid will be administered at home by intravenous infusion (4 mg) on Day 2 of each cycle, every 4 weeks. | 9 | 14 | 14 | 14 |
| Musculoskeletal chest pain | General disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Interstitial lung disease | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Ascites | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| General physical health deterioration | General disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Lymphopenia | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Sepsis | Infections and infestations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Diverticulitis | Infections and infestations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Fever | General disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Pulmonary embolism | Vascular disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Sinus tachycardia | Cardiac disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Glaucoma | Eye disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Cheilitis | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Gastritis | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Gastroesophageal reflux disease | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Gastrointestinal pain | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hemorrhoids | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
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| Mucositis oral | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
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| Edema face | General disorders | Version 4.0 (CTCAE) | Systematic Assessment |
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| Fatigue | General disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Fever | General disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Flu like symptoms | General disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Bronchial infection | Infections and infestations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Gum infection | Infections and infestations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Nail infection | Infections and infestations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Skin infection | Infections and infestations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Alkaline phosphatase increased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| CPK increased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Cholesterol high | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| GGT increased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Lymphocyte count decreased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Lymphocyte count increased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Neutrophil count decreased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Platelet count decreased | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Weight loss | Investigations | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hypoalbuminemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hypokalemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hypomagnesemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hypophosphatemia | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Tumor pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Dysesthesia | Nervous system disorders | Version 4.0 (CTCAE) | Systematic Assessment |
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| Dysgeusia | Nervous system disorders | Version 4.0 (CTCAE) | Systematic Assessment |
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| Neuralgia | Nervous system disorders | Version 4.0 (CTCAE) | Systematic Assessment |
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| Paresthesia | Nervous system disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Chronic kidney disease | Renal and urinary disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Hoarseness | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Pleuritic pain | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Sinus disorder | Respiratory, thoracic and mediastinal disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Erythema multiforme | Skin and subcutaneous tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Nail loss | Skin and subcutaneous tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Rash maculo-papular | Skin and subcutaneous tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Skin hypopigmentation | Skin and subcutaneous tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Skin ulceration | Skin and subcutaneous tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| Superior vena cava syndrome | Vascular disorders | Version 4.0 (CTCAE) | Systematic Assessment |
|
| WORSENING OF GENERAL STATUS | General disorders | Version 4.0 (CTCAE) | Systematic Assessment | General disorders and administration site conditions - Other, specify |
|
| INFLAMMATORY SYNDROM | General disorders | Version 4.0 (CTCAE) | Systematic Assessment | General disorders and administration site conditions - Other, specify |
|
| HOT FLUSHES | General disorders | Version 4.0 (CTCAE) | Systematic Assessment | General disorders and administration site conditions - Other, specify |
|
| POLYDYPSIA | General disorders | Version 4.0 (CTCAE) | Systematic Assessment | General disorders and administration site conditions - Other, specify |
|
| ALTERATION OF GENERAL STATUS | General disorders | Version 4.0 (CTCAE) | Systematic Assessment | General disorders and administration site conditions - Other, specify |
|
| LDH INCREASED | Investigations | Version 4.0 (CTCAE) | Systematic Assessment | Investigations - Other, specify |
|
| CRP INCREASED | Investigations | Version 4.0 (CTCAE) | Systematic Assessment | Investigations - Other, specify |
|
| IRON DEFICIENCY | Metabolism and nutrition disorders | Version 4.0 (CTCAE) | Systematic Assessment | Metabolism and nutrition disorders - Other, specify |
|
| SUBCUTANEOUS NODULE | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Version 4.0 (CTCAE) | Systematic Assessment | Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify |
|
| DYSURIA | Renal and urinary disorders | Version 4.0 (CTCAE) | Systematic Assessment | Renal and urinary disorders - Other, specify |
|
| NOCTURIA | Renal and urinary disorders | Version 4.0 (CTCAE) | Systematic Assessment | Renal and urinary disorders - Other, specify |
|
| URINARY DISORDERS | Renal and urinary disorders | Version 4.0 (CTCAE) | Systematic Assessment | Renal and urinary disorders - Other, specify |
|
| POLYURIA | Renal and urinary disorders | Version 4.0 (CTCAE) | Systematic Assessment | Renal and urinary disorders - Other, specify |
|
| VAGINAL ULCERATION | Reproductive system and breast disorders | Version 4.0 (CTCAE) | Systematic Assessment | Reproductive system and breast disorders - Other, specify |
|
| ESCHAR OF THE SACRUM | Skin and subcutaneous tissue disorders | Version 4.0 (CTCAE) | Systematic Assessment | Skin and subcutaneous tissue disorders - Other, specify |
|
Not provided
Not provided
Not provided
| D009369 | Neoplasms |
| D012509 | Sarcoma |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D000630 | Aminopterin |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D018942 | Macrolides |
| D007783 | Lactones |
| D004164 | Diphosphonates |
| D063065 | Organophosphonates |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| Title | Measurements |
|---|---|
|
| Progression |
|
| Unevaluable according to RECIST v1.1 |
|
| Stable disease |
|
| Progression |
|
| Inevaluable for response |
|
| Title | Measurements |
|---|---|
|
| Progression |
|
| Inevaluable for response |
|