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

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ClinicalTrials.gov Identifier: NCT02517918
Recruitment Status : Recruiting
First Posted : August 7, 2015
Last Update Posted : September 18, 2018
Sponsor:
Collaborators:
Reliable Cancer Therapies
Pfizer
Information provided by (Responsible Party):
Institut Bergonié

Tracking Information
First Submitted Date  ICMJE February 19, 2015
First Posted Date  ICMJE August 7, 2015
Last Update Posted Date September 18, 2018
Study Start Date  ICMJE February 2015
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 4, 2015)
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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02517918 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 4, 2015)
  • Recommended phase II dose (RP2D) of sirolimus when administered in association with CP, MT and ZA [ Time Frame: Throughout 6 month the treatment period ]
  • 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) ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Dose Limiting Toxicities (DLT) of sirolimus when administered in association with CP, MT and ZA [ Time Frame: 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 [ Time Frame: Throughout the treatment period ]
  • 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 ]
  • 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.] ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Metronomic Chemotherapy in Patients With Advanced Solid Tumor With Bone Metastasis and Advanced Pretreated Osteosarcoma
Official Title  ICMJE 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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Tumor
  • Osteosarcoma
Intervention  ICMJE 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.

Other Name: Endoxan, Methotrexate, Rapamune, Zoledronic acid
Study Arms  ICMJE Experimental: 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).
Intervention: Drug: Sirolimus combined with CP, MT and ZA
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 4, 2015)
26
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2019
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 13 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Maud TOULMONDE, Doctor +33 (0)556333333 m.toulmonde@bordeaux.unicancer.fr
Contact: Simone MATHOULIN-PELISSIER, Professor +33 (0)556333333 s.mathoulin@bordeaux.unicancer.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02517918
Other Study ID Numbers  ICMJE IB 2014-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Institut Bergonié
Study Sponsor  ICMJE Institut Bergonié
Collaborators  ICMJE
  • Reliable Cancer Therapies
  • Pfizer
Investigators  ICMJE
Study Chair: Maud TOULMONDE, Doctor Institut Bergonié
PRS Account Institut Bergonié
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP