Clinical Trials /

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

NCT02517918

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) followed by an expansion cohort once the Maximum Tolerated Dose (MTD) is established.

Related Conditions:
  • Malignant Solid Tumor
  • Osteosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Metronomic Chemotherapy in Patients With Advanced Solid Tumor With Bone Metastasis and Advanced Pretreated Osteosarcoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: IB 2014-01
  • NCT ID: NCT02517918

Conditions

  • Solid Tumor
  • Osteosarcoma

Interventions

DrugSynonymsArms
Sirolimus combined with CP, MT and ZAEndoxan, Methotrexate, Rapamune, Zoledronic acidSirolimus combined with CP, MT and ZA

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
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).
  • Sirolimus combined with CP, MT and ZA

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:13 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Institut Bergonié

Trial Keywords

  • Advanced solid tumor
  • Bone metastasis and advanced pretreated osteosarcoma
  • Phase I trial
  • Dose escalation and expansion cohort
  • Biomarkers study

Last Updated

February 5, 2020