E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
T-cell or B-cell precursor (BCP) acute lymphoblastic leukaemia (T-ALL or BCP-ALL) or T-cell Non Hodgkin’s lymphoma (T-NHL) |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000844 |
E.1.2 | Term | Acute lymphoblastic leukaemia |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10025321 |
E.1.2 | Term | Lymphomas non-Hodgkin's T-cell |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the proposed intravenous and oral forodesine doses in children with relapsed or refractory T-cell or B-cell precursor (BCP) acute lymphoblastic leukaemia (T-ALL or BCP-ALL) or T-cell Non-Hodgkin’s Lymphoma (T-NHL)
2. Attempt to assess the oral bioavailability of forodesine and the level of accumulation after repeated oral and intravenous dosing
3. Attempt to assess whether twice daily dosing alters the oral bioavailability of forodesine compared with once daily dosing |
|
E.2.2 | Secondary objectives of the trial |
1. Evaluate the safety of six different dose schedules of forodesine in paediatric subjects
2. Collect preliminary efficacy data on forodesine in children with relapsed or refractory haematological malignancies at six different dose schedules
3. Collect preliminary data on the penetration and efficacy of forodesine in the cerebrospinal fluid (CSF). |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects who are to be included in the study, are those who meet all of the following criteria: 1. Males and females aged ≥ 2 years to ≤ 18 years
2. Males and females ≥ 13 kg
3. Unequivocal histological diagnosis of T-ALL, BCP-ALL or T-NHL (World Health Organisation [WHO] classification) at initial diagnosis
4. T-ALL or T-NHL subjects: a. 1st relapse after HSCT, or b. ≥2 relapses, or c. newly diagnosed subjects who are refractory to 1 standard induction chemotherapy regimen, or d. 1st relapse subjects who are refractory to 1 standard induction chemotherapy regimen
BCP-ALL subjects: a. ≥ 2 relapses, or b. newly diagnosed subjects who are refractory to 2 standard induction chemotherapy regimens, or c. 1st relapse subjects who are refractory to 2 standard induction chemotherapy regimens
Note: Relapse is defined as ≥ 25% marrow blasts or reappearance of any nodal lesion(s) after documented complete response (CR).
Two regimens can be defined as either two different treatment regimens or the same treatment regimen given to a subject who has relapsed after a durable response to the first treatment. A previous regimen can include a HSCT.
5. KPS or LPS (as appropriate for subject’s age) scores ≥60
6. Anticipated life expectancy of at least 6 weeks
7. Adequate kidney and liver function in the opinion of the Investigator and the Medical Monitor e.g. creatinine levels ≤ 2.0 times upper limit of normal, liver function tests (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] ≤ 3 times upper limit of normal and total bilirubin ≤ 5 times upper limit of normal
8. Female subjects of childbearing potential (i.e. have reached the age of menarche) must have a negative urine pregnancy test recorded prior to the first dose of study medication, be non-lactating, and be willing to use adequate and highly effective method of contraception throughout the study and for one month after the last dose of study medication, if sexually active. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (hormonal), sexual abstinence or vasectomised partner
9. Sexually active male subjects must be willing and able to use a barrier form of contraception (i.e. condoms) or sexual abstinence throughout the study and for one month after the last dose of study medication
10. Signed informed consent form and assent if appropriate according to local laws and regulations prior to start of any study specific procedures |
|
E.4 | Principal exclusion criteria |
Subjects who are to be excluded from the study are those who meet any of the following criteria:
1. Subjects with clinical evidence of active symptomatic CNS disease or isolated CNS disease.
2. Prior treatment with any antileukaemic agent, chemotherapy or leukophoresis treatment within 7 days (within 4–5 days for 6-mercaptopurine [MP] and within 2 days for low-dose methotrexate) prior to study entry. Corticosteroid use will not be excluded.
3. Concurrent treatment with other anticancer agents (with the exception of CNS therapy, see Section 9.5.9.2 of the protocol).
4. Subjects with a history of HIV and/or HTLV-1 infection Note: HIV and HTLV-1 testing will be performed at the Screening Visit for subjects who have not been tested within 3 months of screening. Results for HIV and HTLV-1 infection do not need to be available prior to initiation of treatment due to the aggressive nature of the disease. Subjects with a positive result will be evaluated on a case by case basis.
5. Subjects with known active HBV, HCV, CMV and/or EBV infection Note: HBV, HCV, CMV and EBV testing will be performed at the Screening Visit for subjects who have not been tested within 3 months of screening. Results for HBV, HCV, CMV and EBV do not need to be available prior to initiation of treatment due to the aggressive nature of the disease. Subjects with active disease will be evaluated on a case by case basis.
6. Subjects with active serious infection.
7. Females who are pregnant (positive β-hCG test) or lactating.
8. Lack of full recovery from adverse drug reactions due to prior therapy, independent of when that therapy was given.
9. Subjects who have chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the product; however, study drug administration via nasogastric or gastrostomy tube is allowed
10. Any history of hypersensitivity or intolerance to any component of the study medication.
11. Subjects who have received an investigational medicinal product in a clinical study within 30 days of study entry (defined as the start of the Screening Period). Current participation in another clinical trial is not permitted unless the sole purpose of the trial is for long term follow up/survival data.
12. Previous enrolment in this clinical study.
13. Rapidly progressive disease with compromised organ function judged to be life-threatening by the investigator. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of the proposed study is to provide adequate PK/PD data for the development of the intravenous and oral formulation in paediatric use i.e. to determine the optimal dose for a future Phase II/III study and to demonstrate safety of forodesine in paediatric patients.
Preliminary efficacy data on forodesine in children with relapsed or refractory haematological malignancies at six different dose schedules will also be assessed. |
|
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 | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
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 | 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 | No |
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 |
Different dosages of the same formulation will be compared. |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 | 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 | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |