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

Phase 1

Completed

• Conditions: Solid Tumor; Osteosarcoma
• Interventions: Drug: Sirolimus combined with CP, MT and ZA

• Registration Number: NCT02517918
• Lead Sponsor: 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.

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 Timeline

• Study Start: 2015-02
• Study First Submitted: 2015-02-19
• Study First Submitted QC: 2015-08-04
• Study First Posted: 2015-08-07
• Primary Completion: 2016-09-05
• Study Completion: 2021-11-16
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-22
• Last Update Posted: 2022-11-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sirolimus combined with CP, MT and ZA	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).

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28) of sirolimus when administered in association with CP, MT and ZA	During the first cycle (28 days

Secondary Outcome Measures

Name	Time	Method
PK measurements expressed as Area Under Curve for Sirolimus	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	Day 1 of cycle1, Day 18 of cycle1, Day 2 of cycle 2, Day 1 of cycle3, Day 1 of cycle 6, At progression
Recommended phase II dose (RP2D) of sirolimus when administered in association with CP, MT and ZA	Throughout 6 month the treatment period
PK measurements expressed as Area Under Curve for MT	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	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	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	During the first cycle (28 days)
Documentation of any observed antitumor activity	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 concentration peak for CP	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 CP	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	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	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 profile of sirolimus when administered in association with CP, MT and ZA evaluated by monitoring the AEs through the NCI-CTC v4	Throughout the treatment period
Pharmacokinetics (PK) of sirolimus when administered in association with CP, MT and ZA	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	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	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	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	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	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)	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)	1-year Overall Survival (OS) as per RECIST
Exploration of blood cytokines levels (INFγ, TNFα, TGFβ, IL2, 4, 6, 10) (ELISA)	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)	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)	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)	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

Trial Locations

Locations (3)

Centre Léon Bérard; 🇫🇷 Lyon, France

Centre Oscar Lambret; 🇫🇷 Lille, France

Institut Bergonié; 🇫🇷 Bordeaux, France