| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Neuroblastoma is a malignant (cancerous) tumour that develops from precursor cells in adrenal or autonomic nervous system tissues. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029260 |
| E.1.2 | Term | Neuroblastoma |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To find a tolerable treatment schedule of ch14.18/CHO antibody given as a continuous intravenous (through a vein) infusion combined with subcutaneous aldesleukin (IL-2) (given as a needle under the skin) and 13-cis-retinoic acid (isotretinoin), where pain is reduced whilst maintaining immunomodulatory efficacy (ability to successfuly alter or regulate immune functions).
To characterise dose limiting toxicities (side effects that could limit the dose a patient can withstand) and to determine a recommended Phase III dose for further studies in children and adolescents with high risk neuroblastoma.
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| E.2.2 | Secondary objectives of the trial |
To assess pain intensity and pain relief by appropriate medication with a validated self-report tool to be completed by the patient and/or their parent/guardian.
To validate during the first course, the correlation between activated natural killer (NK) cells and ch14.18/CHO level with antibody-dependent cell-mediated cytotoxicity (ADCC) by using mononuclear cells (MNC) and serum from patients on day 15.
To determine ability to successfully alter or regulate immune functions resulting from the combined treatment of ch14.18/CHO and s.c. aldesleukin (IL-2) by repeated analysis of NK cell activation, soluble IL-2 receptor, ADCC, complement-dependent cytotoxicity (CDC) and anti-idiotype response (the human antiglobulin antibodies HAMA and HACA).
To determine the pharmacokinetics of ch14.18/CHO.
To evaluate anti-tumour responses resulting from this treatment regimen through clinical assessments in patients with measurable disease.
To confirm the results of the chosen ch14.18/C |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a) At study entry patients must be > 1 year but <= 21 years of age.
NOTE: Patients >21 years but <=45 years of age, fulfilling the remaining criteria, may be enrolled in the study. These patients will be analysed separately and will not be included in the dose finding schedule algorithm. The purpose for inclusion of the older patients is to enable the collection of tolerability data.
b) Patients must be diagnosed with neuroblastoma according to the INSS criteria.
c) Must have received at least one previous high dose treatment followed by stem cell rescue after conventional therapy.
d) Must fulfil one of the following criteria:
• Patients with stage 4 neuroblastoma either:
o on the current high-risk SIOPEN trial (HR-NBL-1/SIOPEN) either with primary refractory disease having had two or more front-line treatments or patients ineligible for the R2 randomisation due to major delays after completed high-dose treatments or
o Standard high-risk front-line treatment (other than HR-NBL (1.5)/SIOPEN) consisting of intensive induction, followed by high-dose treatment with stem cell rescue.
• Treated and responding relapse after primary stage 4 disease, without signs of progression at study entry
• Treated and responding disseminated neuroblastoma relapse after having received ASCT without signs of progression at study entry.
e) Patients must have a performance status greater or equal 70% (Lansky Score or Karnofsky)
f) Patients must have an estimated life expectancy of at least 12 weeks.
g) Patients must consent to the placement of a central venous line, if one has not already been placed.
h) Patients must be off any standard or experimental treatments for at least two weeks prior to study entry and be fully recovered from the short term major toxic effects.
i) Patients must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery.
j) At least 4 weeks after major surgery (e.g. laporotomy or thoracotomy) and fully recovered from any post-surgical complications.
k) HIV and Hepatitis B negative.
l) Females of childbearing potential must have a negative pregnancy test within 7 days prior to enrolment onto the study. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
m) Patients may have had prior CNS metastasis providing the following criteria are all met:
a. the patient’s CNS disease has been previously treated,
b. the patient’s CNS disease has been clinically stable for four weeks prior to starting this study (assessment must be made clinically and by CT or MRI scan),
c. the patient is off steroids for CNS disease for four weeks prior to starting on study and during the course of the study.
n) Patients with seizure disorders may be enrolled if on anticonvulsants and are well controlled.
o) All patients and/or their parents or legal guardians must sign a written informed consent.
p) All institutional and national requirements for human studies must be met.
q) Laboratory Testing
• Patients should have a shortening fraction of >=30 % by Echocardiogram.
• Patients should have FEV1 and FVC >60% of the predicted by pulmonary function tests. Children unable to do PFTs should have no dyspnoea at rest and a pulse oximetry >94% on room air. All patients must have adequate bone marrow function as defined by ANC >1 10^9/L, platelets >=50 10^9/L and haemoglobin > 9.0 g/dL.Patients must have adequate liver function, as defined by an ALT or AST < 5 x normal and a total bilirubin < 1.0 mg/dL.
• Patients must have adequate renal function, as defined by a serum creatinine <1.5 mg/dL or a creatinine clearance or radioisotope GFR of > 60 mL/minute/1.73m2
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| E.4 | Principal exclusion criteria |
a) Patients with progressive disease.
b) Patients who have previously received treatment with ch14.18/SP2/0 and/or
ch14.18/CHO.
c) Platelet transfusion dependent.
d) Patients with significant intercurrent illnesses and/or any of the following:
- Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance.
- Patients with significant psychiatric disabilities or uncontrolled seizure disorders.
- Patients with active infections.
- Patients with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade >2) are ineligible.
- Patients with clinically significant, symptomatic, pleural or pericardial effusions or ascites.
e) Patients who require, or are likely to require, corticosteroid or other immunosuppressive drugs.
f) Concurrent treatment with any non-trial anticancer therapies.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For the evaluation of the primary endpoints only the first course will be taken into account for the dose schedule finding algorithm.
A) Pain-toxicity endpoint: i.v. morphine free ch14.18/CHO infusion schedule after the first 5 days during the first cycle in ≥ 80% of patients.
B) Efficacy endpoint: On day 15 of the first cycle in ≥ 80% of patients:
- an increase of 500% and/or an absolute minimum increase to ≥100 cells/mcL of the CD16/CD56 positive activated NK cells, AND
- a measurable ch14.18/CHO level of at least 1 µg/ml.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluation of the primary endpoints is carried out after patients have received their first cycle. A cohort of 10 patients will be evaluated at each dose level until acceptable efficacy and toxicity is found, thereby indicating a suitable dose schedule. |
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| E.5.2 | Secondary end point(s) |
• ADCC and activated NK cell concentrations above baseline levels in ≥ 80% of patients.
• Appearance of soluble IL-2 receptor and CDC.
• Detection of anti-idiotype response by appearance of HAMA and HACA.
• Increase of absolute lymphocyte counts by 50% over baseline.
• Increase of absolute NK cell numbers >1000 cells/mcL in ≥80% of patients.
• Ch14.18/CHO concentrations.
• Anti-tumour response in patients with measureable disease (bone marrow, skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site) as measured by immunocytology, MIBG, CT and/or MRI.
• Confirmation of the primary and secondary endpoints in the expansion cohort .
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Each treatment level will have a cohort of 10 patients. The secondary endpoints will be assessed after each cohort to provide additional information as to the best dose schedule. Confirmation of these end points in the expansion cohort will be done after an additional 20 patients have been recruited to the proposed best dose schedule. |
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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 | Yes |
| 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 |
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| 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) | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Austria |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| United Kingdom |
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| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 28 |
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