Clinical trial NCT02517918: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Osteosarcoma
Keywords: Advanced solid tumor
Bone metastasis and advanced pretreated osteosarcoma
Phase I trial
Dose escalation and expansion cohort
Biomarkers study
Lead sponsor: Institut Bergonié
Sponsor class: OTHER
Collaborators: name: Reliable Cancer Therapies
name: Pfizer
First posted: 2015-08-07
Enrollment: 23
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model 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)
* an expansion cohort once the MTD is established.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Dose Escalation Part: Number of Dose-Limiting Toxicities (DLTs) at Each Dose Level on Cycle 1
timeFrame: During the first cycle (28 days)
measure: Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, in Terms of 6-month Non-progression Rate
timeFrame: 6-month non-progression rate as per RECIST v1.1
Secondary outcomes:
measure: Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per RECIST v1.1
timeFrame: 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.
measure: Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Progression-free Survival (PFS)
timeFrame: 1-year Progression-free survival (PFS) as per RECIST v1.1
measure: Dose Escalation Part : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS)
timeFrame: 1-year Overall Survival (OS) as per RECIST v1.1
measure: Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, Best Objective Response Rate (ORR) as Per RECIST v1.1
timeFrame: 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.
measure: Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Progression-free Survival (PFS) as Per RECIST v1.1
timeFrame: 1-year Progression-free survival (PFS) as per RECIST v1.1
measure: Expansion Cohort : Antitumor Activity Observed With Sirolimus Combined With CP, MT and ZA, 1-year Overall Survival (OS) as Per RECIST v1.1
timeFrame: 1-year Overall Survival (OS) as per RECIST v1.1
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonié
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
Study officials:
affiliation: Institut Bergonié
name: Maud TOULMONDE, Doctor
role: STUDY_CHAIR
References:
citation: 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.