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Trial record 5 of 13 for:    "Bone Osteosarcoma" | "Bone Density Conservation Agents"

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

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.

Condition or disease Intervention/treatment Phase
Solid Tumor Osteosarcoma Drug: Sirolimus combined with CP, MT and ZA Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : February 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : October 2019


Arm Intervention/treatment
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).
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




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. Recommended phase II dose (RP2D) of sirolimus when administered in association with CP, MT and ZA [ Time Frame: Throughout 6 month the treatment period ]
  2. 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) ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. Dose Limiting Toxicities (DLT) of sirolimus when administered in association with CP, MT and ZA [ Time Frame: During the first cycle (28 days) ]
  13. 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 ]
  14. 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 ]
  15. 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.] ]
  16. 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 ]
  17. 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 ]
  18. 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 ]
  19. 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 ]
  20. 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 ]
  21. 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 ]
  22. 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 ]
  23. 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 ]
  24. 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 ]
  25. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   13 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02517918


Contacts
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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

Locations
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France
Institut Bergonié Recruiting
Bordeaux, France, 33076
Contact: Maud Toulmonde, Doctor         
Centre Léon Bérard Not yet recruiting
Lyon, France, 69008
Contact: Jean-Yves BLAY, Professor         
Institut Curie Not yet recruiting
Paris Cedex 05, France, 75248
Contact: Sophie PIPERNO-NEUMANN, Doctor         
Institut Gustave Roussy Not yet recruiting
Villejuif Cedex, France, 94805
Contact: Julien DOMONT, Doctor         
Sponsors and Collaborators
Institut Bergonié
Reliable Cancer Therapies
Pfizer
Investigators
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Study Chair: Maud TOULMONDE, Doctor Institut Bergonié

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Responsible Party: Institut Bergonié
ClinicalTrials.gov Identifier: NCT02517918     History of Changes
Other Study ID Numbers: IB 2014-01
First Posted: August 7, 2015    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: September 2018
Keywords provided by Institut Bergonié:
Advanced solid tumor
Bone metastasis and advanced pretreated osteosarcoma
Phase I trial
Dose escalation and expansion cohort
Biomarkers study
Additional relevant MeSH terms:
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Osteosarcoma
Bone Density Conservation Agents
Neoplasm Metastasis
Neoplasms
Neoplastic Processes
Pathologic Processes
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Sarcoma
Zoledronic Acid
Sirolimus
Cyclophosphamide
Methotrexate
Everolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites