E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent or refractory rhabdomyosarcoma |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039027 |
E.1.2 | Term | Rhabdomyosarcoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 evaluate the efficacy of the combination of temozolomide with vincristine and irinotecan in children and adult patients with refractory or relapsed rhabdomyosarcoma as assessed by confirmed objective tumor response |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety, tolerability and efficacy of VIT and VI alone as assessed by: duration of response, time to tumor progression, time to treatment failure, overall survival and adverse event profile
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
TUMOR CHARACTERISTICS :
• Histologically or cytologically confirmed diagnosis of rhabdomyosarcoma (RMS) (new biopsy recommended)
• Any Relapsed / progressive disease (in patients who have already presented a response to chemotherapy)
OR
Refractory disease (defined as progression after receiving chemotherapy without prior response)
• Patients must have measurable disease defined as lesions that can be measured in 3 dimensions by medical imaging techniques such as CT or MRI. Ascites, pleural fluid, bone marrow disease alone, and lesions seen on Tc scintigraphy or PET scan only are not considered measurable for these patients
PATIENT CHARACTERISTICS :
• Age > 6 months and < or = 50 years
• Karnofsky performance status (PS) (for patients > 12 years of age) OR Lansky Play Score for patients ≤ 12 years of age) 0-100%
• Life expectancy ≥ 12 weeks
• Adequate bone marrow function : Absolute neutrophil count ≥ 1000/mm3, Platelet count ≥ 100,000/mm3 (transfusion independent), Hemoglobin ≥ 8.5 g/dl (transfusion allowed)
• In case of bone marrow disease: Absolute neutrophil count ≥ 500/mm3, Platelet count ≥ 75,000/mm3
• Adequate renal function : Serum creatinine < 1.5 X ULN for age. If serum creatinine > 1.5 ULN, creatinine clearance (or radioisotope GFR) must be >70 ml/min/1.73 m²
• Adequate hepatic function : Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, except if the patient is known to have Gilbert’s syndrome. ALT and AST < 2.5 times ULN for age
• Negative pregnancy test in females with childbearing potential
• Fertile patients must use effective contraception
• No active > grade 2 diarrhea or uncontrolled infection
• No other malignancy, including secondary malignancy
• Patient affiliated with a health insurance system. Applicable for French patients only
• Written informed consent of patient and/or parents/guardians
PRIOR or CONCURRENT THERAPY :
• More than 3 weeks since prior radiation therapy to the site of any progressive lesion that will be identified as a target lesion to measure tumor response
• At least 3 weeks since prior myelosuppressive therapy (6 weeks for nitrosourea. 2 weeks for vincristine, vinblastine, vinorelbine or low dose cyclophosphamide)
• No concurrent enzyme-inducing anticonvulsants (EIAC), including phenytoin, phenobarbital or carbamazepine
• No concurrent administration of any of the following: rifampicin, voriconazole, itraconazole, ketoconazole, aprepitant, St John’s Wort
• No prior irinotecan or temozolomide administration
• Prior vincristine administration allowed
• Concurrent palliative radiation therapy to sites allowed other than the main measurable target
• Prior allo- or autologous SCT allowed |
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E.4 | Principal exclusion criteria |
• Concomitant anti-cancer treatment
• Pregnancy or breast feeding
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
• Neuromuscular disorders (e.g. Charcot-Marie Tooth disease)
• Uncontrolled intercurrent illness or active infection
• Unavailable for medical follow-up (geographic, social or psychological reasons) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy
The primary efficacy endpoint is the objective response (OR), defined as a documented complete (CR) or partial (PR) volume tumor response after two cycles of treatment in each treatment group.
Any CR or PR should be confirmed not less than 4 weeks later, except when early local treatment is performed or a second-line treatment is administered before confirmation at 4 weeks.
Responses will be assessed by CT or MRI (3D measurements and tumor volume). An external review committee will review all observations to validate response.
Continuing response/stable disease should be confirmed every two cycles until tumor progression or study discontinuation. Further assessment may be performed every 3-4 months. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 2 cycles of 21 days |
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E.5.2 | Secondary end point(s) |
Toxicity
The safety profile will be evaluated in each treatment group. Clinical and laboratory toxicities/symptoms will be graded according to NCI-Common Terminology Criteria AE v4.0 (NCI-CTC). Adverse events which are also reported according to the NCI-CTC will be graded as mild, moderate, severe, or life threatening.
- The secondary efficacy variables are the duration of response, the time to treatment failure, the time to progressive disease and overall survival in each treatment group. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | No |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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 |
Vincristine and Irinotecan (VI) alone compared to VI with Temodal (VIT) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
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
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |