E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
relapsed T-ALL, T-NHL |
recidief T-ALL, T-NHL |
|
E.1.1.1 | Medical condition in easily understood language |
T-cell Acute Lymphatic Leukemia, T-cell non-Hodgkin lymphoma |
T-cel leukemie, T-cel non-Hodgkin lymfoom |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024338 |
E.1.2 | Term | Leukemia lymphoblastic acute |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10025321 |
E.1.2 | Term | Lymphomas non-Hodgkin's T-cell |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
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 |
To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of nelarabine, etoposide and cyclophosphamide when given in combination to children with T-ALL and bone marrow relapse or T-LL. |
Het vaststellen van de maximale tolereerbare dosis (MTD) en 'dose-limiting' toxiciteiten (DLTs) van gecombineerde therapie met nelarabine, etoposide en cyclofosfamide aan kinderen met T-ALL en T-NHL, plus de preliminaire anti-leukemische activiteit (expansiecohort) als de juiste dosering bekend is. |
|
E.2.2 | Secondary objectives of the trial |
Secondary endpoints for this study include CR2 and CR2p as defined in section 10.1, and in addition:
• For T-ALL patients achieving CR2, ability to proceed to HSCT within 20 weeks from study entry
• Minimal residual disease (MRD) levels at the end of each course of therapy for T-ALL patients that attain CR2 |
-CR2 en CR2p zoals gedefinieerd in sectie 10.1, en aanvullend:
• Voor alle T-ALL patiënten met een CR2, de haalbaarheid van stamceltransplantatie binnen 20 weken van studie inclusie;
• Minimale rest ziekte (MRD) gehaltes na elke kuur voor T-ALL patiënten met een CR2. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Patients must be ≥1 and <18 years of age at the time of study enrollment (adpated for the NL)
-Patients must have T-cell ALL or T-cell lymphoblastic lymphoma (LL) in first relapse or must have failed primary induction chemotherapy
- ECOG 0-2 or Karnofsky ≥ 50% for patients > 16 years of age; Lansky ≥ 50% for patients ≤16 years of age. (See Appendix II for Performance Scales)
- Adequate renal function defined as serum creatinine ≤ 1.5x upper limit of normal (ULN) for age. If the serum creatinine is above these values, the calculated creatinine clearance or radioisotope GFR must be ≥ 70 mL/min/1.73m2.
- Total bilirubin ≤ 1.5x ULN for age.
- If the total bilirubin is elevated, patient will still be eligible if the conjugated (direct) serum bilirubin ≤ ULN for age.
- ALT ≤ 5x ULN of normal for age.
- Adequate cardiac function defined as shortening fraction of ≥ 27% by echocardiogram or ejection fraction ≥ 45% by gated radionuclide study.
- Patients must have adequate pulmonary function
- All patients and/or their parents or legal guardians must sign a written informed consent. |
- Patiënten in de leeftijd ≥1 en <18 jaar ten tijde van inclusie (aangepast voor NL);
- Patiënten met T-ALL of T-NHL in eerste relapse of refractaire ziekte na primaire inductiebehandeling;
- ECOG 0-2 of Karnofsky ≥50% voor patiënten >16 jaar; Lansky ≥50% voor patiënten ≤16;
- Adequate nierfunctie gedefinieerd als serum creatinine ≤1.5x bovenste normaalwaarde (ULN)voor de leeftijd. Als het serum creatinine hoger is dan moet de bekende klaring GFR ≥ 70 mL/min/1.73m2 zijn.
- Totaal blirubine ≤ 1.5x ULN voor leeftijd;
-Indien het totaal bilirubine verhoogd is, dan is de patiënt nog steed eligible als de geconjugeerde (direkt) biluribne ≤ 1.5x ULN voor leeftijd is;
-ALAT ≤ 5x ULN voor leeftijd;
- Adequate hartfunktie gedefinieerd als een shortening fraction van ≥ 27% middels een echocardiogram of een ejectiefractie ≥ 45%;
- Patiënten moeten een adequate longfunctie hebben;
- Een schriftelijke toestemming van alle patiënten en/of ouders of wettelijke vertegenwoordigers. |
|
E.4 | Principal exclusion criteria |
Patients are excluded if they have CNS 3 disease
- Patients with Down syndrome are excluded.
- Patients with pre-existing Grade 2 (or greater) peripheral motor or sensory neurotoxicity per the CTCAE 3.0 as determined by the treating physician or a neurologist.
- Patients with a history of prior veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) or findings consistent with a diagnosis of VOD/SOS
- Patients are excluded if they have had
-Previous hematopoietic stem cell transplantation;
-Patients with a prior seizure disorder requiring anti-convulsants
- Patients are excluded if they have:
Positive blood culture within 48 hours of study enrollment;
Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection
- Plan to administer non-protocol chemotherapy, radiation therapy, immunotherapy, or any other investigational agents during the study period. |
-Patiënten met CNS 3 ziekte;
- Patiënten met Down syndrome;
- Patiënten met bestaande Graad 2 (of hoger) perifere motorische of sensorische neurotoxiciteit volgens CTCAE v3.0 zoals vastgesteld door de behandelend arts of neurolooog.
- Patiënten met een geschiedenis van veno-occlusive ziekte VOD)/sinusoidale obstructie syndroom (SOS) of bevindingen consistent met de diagnose van VOD/SOS;
-Patiënten die al een hematopoietische stamcel transplantatie hebben ondergaan;
-Patiënten met epilepsie waarvoor anti-convulsiva worden gegeven;
-Patiënten die een positieve bloedkweek hebben binnen 48 uur van inclusie.
-Patiënten met koorts >38.2 binnen 48 uur van inclusie of met klinische tekenen van infectie;
-Patiënten met geplande niet-protocollaire chemotherapie, bestraling, immunotherapie, of elk andere experimentele medicatie tijdens de studieperiode. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
For part I of the study: the recommended phase II dose of nelarabine in combination with cyclophosphamide and etoposide |
Deel 1 van de studie: de aanbevolen dosis van nelarabine in combinatie met cyclofosfamide en etoposide voor het fase 2 deel.
Deel 2: preliminaire activiteit van de combinatie. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Secondary endpoints for this study include CR2 and CR2p as defined in section 10.1, and in addition:
• For T-ALL patients achieving CR2, ability to proceed to HSCT within 20 weeks from study entry
• Minimal residual disease (MRD) levels at the end of each course of therapy for T-ALL patients that attain CR2 |
-CR2 en CR2p zoals gedefinieerd in sectie 10.1, en aanvullend:
• Voor alle T-ALL patiënten met een CR2, de haalbaarheid van stamceltransplantatie binnen 20 weken van studie inclusie;
• Minimale rest ziekte (MRD) gehaltes na elke kuur voor T-ALL patiënten met een CR2. |
|
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 | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
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 |
phase IB study |
fase IB studie |
|
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 | 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 | 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 | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
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
|
LVLS |
Laatste patiënt laatste visite |
|
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 | 4 |
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 | 4 |