| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| T-cell acute lymphoblastic leukaemia (T-ALL) with bone marrow relapse, relapsed T-cell lymphoblastic lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063621 |
| E.1.2 | Term | Acute lymphoblastic leukaemia recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025245 |
| E.1.2 | Term | Lymphoblastic lymphoma (Precursor T-lymphoblastic lymphoma/leukaemia) recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 and dose-limiting toxicities of nelarabine, etoposide and cyclophosphamide when given in combination to children with T-ALL and bone marrow relapse or T-LL. |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine the second complete remission (CR2) rate after 1 and 2 courses of this therapy in children with T-ALL and bone marrow relapse or T-LL.
2. To determine the percentage of children with T-ALL and first bone marrow relapse that attain a second complete remission (CR2) following nelarabine, etoposide and cyclophosphamide and are able to proceed to HSCT in CR2 within 20 weeks of beginning re-induction chemotherapy.
3. To determine minimal residual disease (MRD) levels at the end of each course of treatment.
UK participants will not contribute to these endpoints:
4. To evaluate the vitamin B12 pathway and metabolites and the potential association of neurotoxicity following nelarabine therapy with alterations in this pathway
5. To determine, in a preliminary manner, whether patients with relapsed T-ALL/LL have a distinct signaling signature that distinguishes malignant cells from normal thymocytes.
6. To evaluate, in a preliminary manner, whether phospho-flow c |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age
Patients must be ≥1 and ≤ 21 years of age at the time of study enrollment.
Diagnosis
Patients to be enrolled in the dose-escalation portion of this study must have T-cell ALL or T-cell lymphoblastic lymphoma in first relapse or must have failed primary induction chemotherapy (IE, never attained a complete remission following an initial course of standard therapy for T-ALL or T-LL).Patients to be enrolled in the cohort expansion portion of this study (ie, those treated at the recommended phase 2 dose) must have T-cell ALL in first relapse or must have failed primary induction chemotherapy (ie, never attained a complete remission following an initial course of standard therapy for T-ALL). T-LL patients are not eligible for the cohort expansion phase.
Patients with T-cell ALL must have (1) greater than 25% blasts in the bone marrow with or without testicular disease, or (2) isolated extramedullary disease such as lymph node or mediastinal involvement. T-ALL patients with extramedullary disease involving only sanctuary sites (ie, testicular relapse) are not eligible.
Patients with T-cell LL or T-ALL followed by isolated extramedullary disease such as lymph node or mediastinal involvement must have disease documented by clinical or radiographic criteria, as well as histologic verification of the malignancy at original diagnosis. Patients with T-cell LL or T-ALL followed by isolated extramedullary disease such as lymph node or mediastinal involvement enrolled in the phase I dose-escalation study are not required to have measurable disease; however, such patients who are enrolled in the phase II cohort expansion at the MTD must have measurable disease so as to be evaluable for response,
Patients may have CNS 1 or CNS 2 disease but not CNS 3.
Performance Level
ECOG 0-2 or Karnofsky ≥ 50% for patients > 16 years of age; Lansky ≥ 50% for patients ≤16 years of age.
Prior Therapy
Patients who are primary induction failures may have had only 1 previous therapeutic attempt.
Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study.
Patients who relapse on therapy other than standard ALL maintenance therapy must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
At least 7 days must have elapsed since the completion of cytotoxic therapy (other than standard ALL maintenance therapy) with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy.
At least 6 weeks must have elapsed since administration of nitrosureas.
At least 12 weeks must have elapsed since administration of craniospinal, hemipelvic or other radiation therapy to more than 25% of the bone marrow containing spaces.
Patients who have previously been treated with nelarabine are eligible, however if they have previously received a regimen of nelarabine, cyclophosphamide and etoposide, they are not eligible.
Patients may be enrolled on study regardless of the timing of prior intrathecal therapy; however, they may not begin treatment on this protocol until a minimum of 7 days has elapsed since prior intrathecal therapy.
Reproductive Function
Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
Female patients with infants must agree not to breastfeed their infants while on this study.
Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.
Renal and Hepatic Function
Patient must have adequate renal and hepatic functions as indicated by the following laboratory values:
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.
Cardiac Function
Adequate cardiac function defined as shortening fraction of ≥ 27% by echocardiogram
Pulmonary Function
Patients must have adequate pulmonary function as defined below:
No evidence of dyspnea at rest;
No exercise intolerance;
A pulse oximetry ≥ 94% at sea level (≥ 90% at altitude ≥ 5000 feet).
Informed Consent
Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent. Age appropriate assent will be obtained per institutional guidelines. |
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| E.4 | Principal exclusion criteria |
Diagnosis
Patients are excluded if they have CNS 3 disease as defined in section 10.2.
Patients with isolated extramedullary disease involving only sanctuary sites (ie, testicular relapse) are excluded; patients with extramedullary disease involving nodal or other nonsanctuary sites are eligible.
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, defined as: conjugated serum bilirubin >1.4 mg/dL AND unexplained weight gain greater than 10% of baseline weight or ascites AND hepatomegaly or right upper quadrant pain without another explanation, OR reversal of portal vein flow on ultrasound, OR pathological confirmation of VOD on liver biopsy.
Prior Therapy
Patients are excluded if they have had
•Previous hematopoietic stem cell transplantation;
•A prior seizure disorder requiring anti-convulsant therapy. For the purposes of this study, this includes any patient that has received any therapy to prevent/treat seizures in the 2 years prior to study enrollment.
Infection Criteria
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.
Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
•Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections is allowed.
Plan to administer non-protocol chemotherapy, radiation therapy, immunotherapy, or any other investigational agents during the study period.
Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Occurrence of dose limiting toxicity during course 1 of NECTAR protocol |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Decisions about dose escalation, de-escalation, and determination of MTD will be based on observationsmade after the first course of therapy.
The MTD is the highest dose level tested at which 0 or 1 of 6 patients experience DLT with at least 2 of 3 or 6 patients encountering DLT at the next higher dose. In the event that no DLT occurs at Dose Level 3, that dose level will be declared the MTD for the purposes of this study. |
|
| E.5.2 | Secondary end point(s) |
1) Second complete remission (CR2) rate after 1 and 2 courses of this therapy in children wiht T-ALL and bone marrow relapse or T-LL
2) Percentage of children with T-ALL and 1st bone marrow relapse that attain CR2
following nelarabine, etoposide and cyclophosphamide and are able to proceed to haematopoietic stem cell transplantation (HSCT) in CR2 within 20 weeks of beginning re-induction chemotherapy.
3) Minimal residual disease (MRD) levels at the end of each course of treatment.
Additional secondary objectives in US study (European centres not participating)
4) Vitamin B12 pathway and metabolites and the potiential association of neurotoxcity following nelarabine therapy with alterations in this pathway.
5) Whether patients with relapsed T-ALL/ LL have a distinct
signalling signature that distinguishes malignant cells from normal thymocytes
6) Whether phospho-flow cytometry can be used to predict clinical responses to nelarabine. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) After 1 and 2 courses of NECTAR protocol
2) Within 30 weeks of beginning reinduction therapy
3) At the end of course 1 and at the end of course 2
Additional secondary objectives in US study (European centres not participating)
4) After Nelarabine therapy
5) At study entry
6) During treatment |
|
| 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) | 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 I in Paediatric patients |
|
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| 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 |
| Australia |
| Canada |
| United States |
|
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 31 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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