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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Solid Tumor, Osteosarcoma

Intervention / Treatment
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* Drug: Sirolimus combined with CP, MT and ZA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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 Exclusion Criteria: 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 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

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus combined with CP, MT and ZA<br>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<br>* 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.<br>* Other names: Endoxan, Methotrexate, Rapamune, Zoledronic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28) of sirolimus when administered in association with CP, MT and ZA |  | During the first cycle (28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose (RP2D) of sirolimus when administered in association with CP, MT and ZA |  | Throughout 6 month the treatment period | 
| Documentation of any observed antitumor activity |  | 6-month objective response rate (ORR) as per RECIST v1.1,best objective response rate (ORR) as per RECIST v1.1,6-month Non-progression rate (NPR) as per RECIST v1.1,1-year Progression-free survival (PFS) as per RECIST v1.1,1-year Overall Survival (OS) | 
| PK measurements expressed as Area Under Curve for CP |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| PK measurements expressed as Area Under Curve for MT |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| PK measurements expressed as Area Under Curve for Sirolimus |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| PK measurements expressed as half-life for CP |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| PK measurements expressed as half-life for MT |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| PK measurements expressed as half-life for Sirolimus |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| PK measurements expressed as concentration peak for CP |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| PK measurements expressed as concentration peak for MT |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| PK measurements expressed as concentration peak for Sirolimus |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| Dose Limiting Toxicities (DLT) of sirolimus when administered in association with CP, MT and ZA |  | During the first cycle (28 days) | 
| Safety profile of sirolimus when administered in association with CP, MT and ZA evaluated by monitoring the AEs through the NCI-CTC v4 |  | Throughout the treatment period | 
| Pharmacokinetics (PK) of sirolimus when administered in association with CP, MT and ZA |  | Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression | 
| Predictive biomarkers (PD) of sirolimus when administered in association with CP, MT and ZA |  | Day 1 of cycle 1, Day 18 of cycle 1, Day 1 of cycle 2, Day 1 of cycle 3, Day 1 cycle 4, Day 1 cycle 6, At progression which can occur at any time during the 6-month period.] | 
| Antitumor activity of sirolimus when administered in association with CP, MT and ZA in terms of 6-month objective response rate (ORR) as per RECIST 1.1 |  | 6-month objective response rate | 
| Antitumor activity of sirolimus when administered in association with CP, MT and ZA in terms of 6 month best objective response rate (ORR) as per RECIST v1.1 |  | best objective response rate (ORR) as per RECIST | 
| Antitumor activity of sirolimus when administered in association with CP, MT and ZA in terms of 6-month Non-progression rate (NPR) as per RECIST 1.1 |  | 6-month Non-progression rate (NPR) as per RECIST | 
| Antitumor activity of sirolimus when administered in association with CP, MT and ZA in terms of 1-year Progression-free survival (PFS) as per RECIST 1.1 |  | 1-year Progression-free survival (PFS) as per RECIST | 
| Antitumor activity of sirolimus when administered in association with CP, MT and ZA in terms of Growth modulation index (GMI) |  | participants will be followed until progression, unexpected average of 4 month | 
| Antitumor activity of sirolimus when administered in association with CP, MT and ZA in terms of 1-year Overall Survival (OS) |  | 1-year Overall Survival (OS) as per RECIST | 
| Exploration of blood cytokines levels (INFγ, TNFα, TGFβ, IL2, 4, 6, 10) (ELISA) |  | Blood samples collected at different time points : Baseline, Day 1 cycle 1, Day 18 cycle 1, Day 1 cycle 2, Day 1 cycle 3, Day 1 Cycle 4, Day 1 Cycle 6 and at progression which can occur at any time during the 6-month period | 
| Exploration of blood VEGF, PIGF and TPS-1 levels (ELISA) |  | Blood samples collected at different time points : Baseline, Day 1 cycle 1, Day 18 cycle 1, Day 1 cycle 2, Day 1 cycle 3, Day 1 Cycle 4, Day 1 Cycle 6 and at progression which can occur at any time during the 6-month period | 
| Exploration of lymphocytes subpopulations monitoring, CD8+, CD4+,Treg ratio (flow cytometry) |  | Blood samples collected at different time points : Baseline, Day 1 cycle 1, Day 18 cycle 1, Day 1 cycle 2, Day 1 cycle 3, Day 1 Cycle 4, Day 1 Cycle 6 and at progression | 
| Exploration of bone biomarkers such as PTH, vitamin D3, osteoclast activator and cytokine mediating Th1 immunity levels) |  | Blood samples collected at different time points : Baseline, Day 1 cycle 1, Day 18 cycle 1, Day 1 cycle 2, Day 1 cycle 3, Day 1 Cycle 4, Day 1 Cycle 6 and at progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumor, Bone metastasis and advanced pretreated osteosarcoma, Phase I trial, Dose escalation and expansion cohort, Biomarkers study