| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced solid tumor with bone metastasis and advanced pretreated osteosarcoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced solid tumor with bone metastasis and advanced pretreated osteosarcoma. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the recommended phase II dose, the maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28), the safety profile, and the Dose Limiting Toxicities (DLT) of sirolimus when prescribed in combination with Metronomic cyclophosphamide (CP), methotrexate (MT) and zoledronic acid (ZA) in patients with solid tumor with bone metastasis and advanced pretreated osteosarcoma. |
|
| E.2.2 | Secondary objectives of the trial |
· To describe the pharmacokinetics (PK) of sirolimus, CP, MT given together,
· To better assess the safety profile of sirolimus when administered in
association with CP, MT and ZA (NCI-CTC v4),
· To document any antitumor activity observed with sirolimus combined with CP,
MT and ZA, in OSS patients, in terms of
o 6-month objective response rate (ORR) as per RECIST 1.1
o best objective response rate (ORR) as per RECIST 1.1
o 6-month Non-progression rate (NPR) as per RECIST 1.1
o 1-year Progression-free survival (PFS) as per RECIST 1.1
o Growth modulation index (GMI)
o 1-year Overall Survival (OS)
· To explore Pharmacodynamics (PD) and mechanisms of action of CP + MT +
ZA + sirolimus as well as potential predictive biomarkers. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Pharmacokinetic, pharmacodynamic and biomarkers studies. |
|
| E.3 | Principal inclusion criteria |
1. Histology:
- Advanced solid tumor with radiologically proven bone metastasis, all tumor types (dose escalation part)
- Patients with osteogenic osteosarcoma (dose escalation part and expansion cohort) histologically confirmed by central review (Pr. Coindre team), except if the diagnosis was already confirmed by the RRePS Network,
2. Metastatic or unresectable locally advanced disease,
3. Age > 18 years for patients with solid tumor and ≥ 13 years for patients with osteosarcoma,
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 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. Previous use of > 1 conventional agent(s), and for patients with osteosarcoma previous use of conventional agents including anthracyclines, platinum salts, ifosfamide and/or methotrexate (neoadjuvant/adjuvant setting included),
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:
a. Haemoglobin ≥ 10 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); leucocytes ≥ 3 x 109/l, absolute neutrophil count (ANC) ≥ 1.5 x 109/l, and platelet count ≥ 120 x 109/l.
b. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5 x upper limit of normality (ULN)
c. Total bilirubin ≤ 1.5 x ULN
d. Calculated creatinine clearance (CrCl) > 40 ml/min/1.73 m2 (according to MDRD formula)
e. Creatine phosphokinase (CPK) ≤2.5 x ULN
f. 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 (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4),
12. Patients with a French social security in compliance with the French law relating to biomedical research (Article L.1121-11 of French Public Health Code).
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. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier.
|
|
| E.4 | Principal 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 (CNS),
4. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding,
5. Patients receiving any substances that are inhibitors or inducers of CYP450 3A4 (non-exhaustive list on Appendix 3),
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 (Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1, rabies, BCG, and typhoid vaccine. However, if seasonally indicated, it is advised to give seasonal flu vaccine as recommended, > 15 days before C1J1.). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose escalation part :
· Toxicity as graded using the common toxicity criteria from the NCI v4.03.
· Incidence rate of DLT at each dose level on cycle 1
Expansion cohort :
Antitumor activity observed with sirolimus combined with CP, MT and ZA, in OSS patients, in terms of 6-month non-progression rate, defined as the rate of complete or partial response and stable disease at 6 months using RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Dose escalation part :
· PK measurements expressed as AUC, half-life and concentration peak for CP,
MT and sirolimus
· Antitumor activity observed with sirolimus combined with CP, MT and ZA, in terms of
o 6-month objective response rate , defined as the rate of complete or partial response at 6 months confirmed ≥ 4 weeks after initial documentation, as determined by investigator review of tumor assessments using RECIST v1.1
o Best objective response rate, defined as the rate of complete or partial response confirmed ≥ 4 weeks after initial documentation, as determined by investigator review of tumor assessments using RECIST v1.1
o 6-month Non-progression rate (NPR) defined as the percentage of patients with CR, PR or stable disease (SD) according to RECIST v1.1
o 1-year Progression-free survival (PFS), PFS is defined as the time from study treatment initiation to the first occurrence of disease progression, as determined by investigator review of tumor assessments using RECIST v1.1, or death from any cause during the study (i.e., within 30 days after the last dose of study treatment).
o Growth modulation index (GMI) GMI will be defined for each patient as the ratio of its PFS on sirolimus + CP/MTX/ZA treatment to its PFS on a previous line of therapy. This method accounts for inter-patient variability, the patient serving as his/her own control and implies by the natural history of the disease that the PFS tends to become shorter in successive lines of therapy. Von Hoff suggested that an anti-cancer agent should be considered effective if the GMI is greater than 1.3 [2]
o 1-year Overall Survival (OS), OS isdefined as the time from first infusion to death (of any cause)
Expansion cohort :
· Same as for the dose escalation cohort. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation and expansion cohort |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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