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

NCT02517918 | Completed Phase 1 Results DMC

• 1 other identifier: IB 2014-01
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 3

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.

Conditions

Solid Tumor; Osteosarcoma

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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: * Is considered to be at least possibly related to the study treatment * Occurs during the first cycle of treatment * Is unrelated to disease, disease progression, inter-current illness, or concomitant medications * Meets one of the criteria below, graded as outlined or according to NCI CTCAEv4.3: * Grade 4 non-haematological toxicity (not laboratory) * Grade 3 non-haematological toxicity \> 3 days (not laboratory) (except for asthenia, 1rst episode of nausea/vomiting without maximal symptomatic/prophylactic treatment) * Grade ≥ 3 non-hematologic laboratory value if medical intervention is required to treat the patient, or the abnormality leads to hospitalization, or the abnormality persists for \> 1 week * Grade ≥ 3 hematologic toxicity \> 3 days (except for lymphopenia) * Grade 4 lymphopenia * Confirmed febrile neutropenia

  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 : * Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions and also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD * Unevaluable : patients stopped the treatment before tumor assessment.

  6-month non-progression rate as per RECIST v1.1

Secondary Outcomes (6)

• Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per 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.

• 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) 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) 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

  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) as per RECIST v1.1

Study Arms (1)

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).

Drug: Sirolimus combined with CP, MT and ZA

Interventions

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.

Also known as: Endoxan, Methotrexate, Rapamune, Zoledronic acid

Sirolimus combined with CP, MT and ZA

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Institut Bergonié: lead
• Reliable Cancer Therapies: collaborator
• Pfizer: collaborator

Study Sites (3)

Institut Bergonié

Bordeaux, 33076, France

Location

Centre Oscar Lambret

Lille, 59000, France

Location

Centre Léon Bérard

Lyon, 69008, France

Location

Related Publications (1)

• 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.

  PMID: 31401903 DERIVED

MeSH Terms

Conditions

Osteosarcoma

Interventions

Cyclophosphamide; Methotrexate; Sirolimus; Zoledronic Acid

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Macrolides; Lactones; Diphosphonates; Organophosphonates; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Pr Simone Mathoulin-Pelissier
• Organization: Institut Bergonié

S.Mathoulin@bordeaux.unicancer.fr

0556333333

Study Officials

• Maud TOULMONDE, Doctor

  Institut Bergonié

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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) * an expansion cohort once the MTD is established.

Study Record Dates

• First Submitted: February 19, 2015
• First Posted: August 7, 2015
• Study Start: February 1, 2015
• Primary Completion: September 5, 2016
• Study Completion: November 16, 2021
• Last Updated: June 8, 2025
• Results First Posted: June 8, 2025

Record last verified: 2025-06

Locations

FR (3)