Oral Liquid 13-cis-retinoic Acid (13-CRA)

Study Overview
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Brief Summary
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An open label, randomised, multiple dose, cross-over relative bioavailability and pharmacokinetics trial of a novel oral liquid and capsule formulations of 13-CRA administered to patients from 0 months - < 21 years.

Detailed Description
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All patients requiring at least two cycles of 13-CRA therapy will be eligible for recruitment into the trial. 13-CRA will be prescribed to patients according to local treatment protocols at each clinical site. The dose administered will be 200mg/m2/day for both test and reference product. Patients with a body weight of ≤12kg will receive a dose of 160 mg/m2/day. The pharmacokinetics of 13-CRA liquid (test product) and extracted from capsule (reference product) will be evaluated over two months. Prior to the initiation of 13-CRA treatment as part of the trial, patients will be randomised to receive either liquid or capsule formulation in My-CRA month 1. The patients will then cross-over to the alternative formulation in My-CRA month 2. The patients on the trial who require further treatment will revert to standard therapy i.e. 13-CRA extracted from capsules according to local practice.

Official Title
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Relative Bioavailability and Comparative Pharmacokinetics of 13-CRA Oral Liquid and Extracted Capsule Formulations: a Randomised, Open Label, Multi-dose, Cross-over Clinical Trial in Patients Requiring Treatment Cycles of 13-CRA.

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: Liquid 13-Cis Retinoic Acid
* Drug: Extracted capsules 13-CRA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged from 0 years to < 21 years of age. Patient with high risk neuroblastoma, or unresectable, unfavourable histology intermediate risk neuroblastoma the latter age ≥ 18 months at diagnosis Patient who is scheduled to receive at least two treatment cycles of 13-CRA. Patient who cannot swallow 13-CRA capsules (i.e. requires extraction of 13-CRA from the capsules). Negative pregnancy test for females of child-bearing potential before initiation of treatment, and sexually active patients and partners agreeing to undertake adequate contraceptive measures (see section 4.5). Provision of a single or double lumen central venous catheter for sampling (i.e. already in place). Parent(s)/legal guardian able and willing to provide written informed consent for the patient to take part in the trial. Where applicable, the patient should assent to undergo blood sampling for pharmacokinetic purposes and to allow physiological measurements to be made. Exclusion Criteria: Any clinically significant medical condition or abnormality, which, in the opinion of the investigator, might compromise the safety of the patient or which might interfere with the trial. Diagnosis of high-risk neuroblastoma (HRNBL) which is currently being treated on the SIOPEN HRNBL trial (patients who have exited this trial will be eligible). Known allergy to 13-CRA or any of the excipients. Inadequate contraception measures in females of childbearing age. Receiving concomitant treatment with tetracyclines. Prior to each cycle: Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. Veno-occlusive disease if present, should be stable or improving. Skin toxicity no greater than CTCAE Grade 1(10) Serum triglycerides <5.65mmol/L. No haematuria and / or proteinuria on urinalysis. Serum calcium ≤ 2.9mmol/L. Serum creatinine based on age / gender as follows: Age Maximum Serum Creatinine µmol/L Male Female 1 month to < 6 months 35 35 6 months to < 1 year 44 44 1 to < 2 years 53 53 2 to < 6 years 70 70 6 to < 10 years 88 88 10 to < 13 years 106 106 13 to < 16 years 132 124 ≥ 16 years 150 124 Patients with a seizure disorder must be well controlled and taking anticonvulsants. CNS toxicity < grade 2 (CTCAE). Withdrawal Criteria: Positive pregnancy test - pregnancy testing will be undertaken before treatment commences and routinely before each course of treatment in females of childbearing potential. If a patient is found to be pregnant during the trial, the next course of treatment will not be given until the pregnancy has been discussed with the treating clinician, and the patient will be withdrawn from the trial whether or not treatment is continued. Request of the patient, for any reason. Discretion of the investigator.

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liquid<br>Oral liquid formulation of 13-Cis Retinoic Acid - test product. | Drug: Liquid 13-Cis Retinoic Acid<br>* Liquid 13-Cis Retinoic Acid<br>* Other names: Isotretinoin;|
| Experimental: Capsule<br>Isotretinoin capsules (13-CRA extracted per standard of care)- reference product. | Drug: Extracted capsules 13-CRA<br>* Extracted capsules 13-CRA<br>* Other names: Isotretinoin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Bioavailability | Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations. | On day 1 and 14 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) | Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation | On day 1 and 14 of treatment | 
| Time to Maximum Concentration (Tmax) | Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation | On day 1 and 14 of treatment | 
| Area Under Plasma Concentration Time Curve (AUC) Metabolite | Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation- metabolite 4-oxo-13-cisRA | On day 1 and 14 of treatment | 
| Cmax (ng/mL)- Metabolite | Pharmacokinetic parameter for metabolite 4-oxo-13-cisRA PK | On day 1 and 14 of treatment | 
| T Max of Metabolite | T max for metabolite -4-oxo-13-cisRA PK | On day 1 and 14 of treatment |