E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced/Metastatic Osteosarcoma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10031294 |
E.1.2 | Term | Osteosarcoma metastatic |
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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 assess the antitumor activity of pemetrexed therapy, as measured by tumor response rate according to RECIST, in patients with advanced/metastatic osteosarcomas.
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E.2.2 | Secondary objectives of the trial |
* To assess the following efficacy variables: - duration of response for responding patients - progression-free survival - time to treatment failure - overall survival time * To examine the toxicity (NCI-CTC, version 3.0) and safety profile of study treatment * Correlation of disease outcome with pharmacogenomic analysis; MTAP gene deletion, FRα and FPGS expression will be correlated with the clinical data to determine the association between these factors and clinical outcome to treatment.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
[1] Histological diagnosis of high grade locally advanced or metastatic osteosarcoma (WHO classification), not amenable to surgery, radiation, or combined modality therapy with curative intent. [2] One prior chemotherapy regimen for advanced disease; neo-adjuvant is not counted towards this requirement. Pemetrexed is considered as second line chemotherapy for advanced/metastatic disease. [3] At least one unidimensionally measurable lesion meeting RECIST criteria (at least 10 mm in longest diameter by spiral computerized tomography [CT] scan, or at least 20 mm by standard techniques). Positron emission tomography [PET] scans and ultrasounds may not be used. At least one measurable lesion outside of the field of any prior radiation therapy (according to RECIST criteria). Prior radiotherapy to a single index lesion is not allowed. Osseous lesions with soft tissue tumor at study entry (excluding completely calcified or necrosed lesion) are considered measurable lesions. [4] Have a performance status of 0, 1, or 2 on the ECOG scale [5] Adequate organ function including the following: Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.0 x 10e9/L, platelets ≥100 x 10e9/L (in case of bone marrow disease: ≥75 x 10e9/L), and hemoglobin ≥9.0g/dL. Hepatic: bilirubin < or = 1.5 times the upper limit of normal (x ULN), alkaline phosphatase (AP), aspartate transaminase (AST), and alanine transaminase (ALT) < or = 3.0 x ULN (AP, AST, and ALT < or = 5 x ULN is acceptable if the liver has tumor involvement). Renal: calculated creatinine clearance (CrCl) ≥45 mL/min based on the standard Cockcroft and Gault formula. [6] Estimated life expectancy of at least 12 weeks. [7] Patient compliance and geographic proximity that allow adequate follow-up. [8] Prior radiation therapy allowed to <25% of the bone marrow. Prior radiotherapy must be completed at least 4 weeks before study enrollment. Patients must have recovered from the acute toxic effects of the treatment prior to study enrollment. [9] Patients must sign an informed consent document. [10] Patients must be at least 18 years of age. [11] Fully recovered from any previous surgery and prior chemotherapy (at least 4 weeks since major surgery or prior myelosuppressive chemotherapy). With the exception of alopecia, patients must have resolution of all acute toxic effects of any prior surgery or chemotherapy to NCI-CTC (Version 3.0) grade ≤ 1. [12] For women: Must be surgically sterile, post-menopausal, or compliant with a medically approved contraceptive regimen (for example, intrauterine device [IUD], birth control pills, or barrier device) during and for 6 months after the treatment period; must have a negative serum or urine pregnancy test within 7 days before study enrollment and must not be breast-feeding. For men: Must be surgically sterile, or compliant with a contraceptive regimen during and for 6 months after the treatment period.
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E.4 | Principal exclusion criteria |
[13] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. [14] Have previously completed or withdrawn from this study or any other study investigating pemetrexed. [15] Inability to comply with protocol or study procedures. [16] Have a serious concomitant systemic disorder (e.g. active infection including HIV) that, in the opinion of the investigator, would compromise the patient’s safety or the patient’s ability to adhere to the protocol. [17] Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV. [18] Have a concurrent serious infection. [19] Have a psychiatric disorder that prevents patients from providing informed consent or following protocol instructions. No other severe medical illness, including psychosis and previous history of severe cardiovascular disease. [20] Have a prior malignancy other than osteosarcoma, carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Patients with a history of low grade (Gleason score < or = 6) localized prostate cancer will be eligible even if diagnosed less than 5 years previously. [21] Have central nervous system (CNS) metastases (unless the patient has completed successful local therapy for CNS metastases and has been off corticosteroids for at least 4 weeks before starting study therapy). A screening computerized tomography (CT) or magnetic resonance imaging (MRI) before enrollment in the absence of a clinical suspicion of brain metastases is not required. [22] Presence of clinically detectable (by physical exam) third-space fluid collections, for example, ascites or pleural effusions that can not be controlled by drainage or other procedures prior to study entry. [23] Significant weight loss (that is ≥20%) over the previous 6 weeks before study entry. [24] Concurrent administration of any other antitumor therapy. [25] Inability to discontinue administration of aspirin at a dose >1.3 g/day or other nonsteroidal anti-inflammatory agents for 2 days before, the day of, and 2 days after the dose of pemetrexed (5 days prior for long-acting agents such as piroxicam). [26] Inability or unwillingness to take folic acid or vitamin B12 supplementation. [27] Inability to take corticosteroids. [28] Pregnant or breast-feeding. [29] Have had a recent (within 30 days of study treatment) or concurrent yellow fever vaccination.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is the tumor response rate. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
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 | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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
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Study closure will occur as soon as 80% events have occurred (80% deaths) or all patients have a last (2-year) follow-up assessment whichever comes first, and until 30 days following discontinuation of study therapy of the last patient. |
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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 | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |