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

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.

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03291080

Acronym

My-CRA

Enrollment

Registered

2017-09-25

Start date

2018-04-17

Completion date

2019-09-12

Last updated

2021-10-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neuroblastoma

Brief summary

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

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.

Interventions

DRUGLiquid 13-Cis Retinoic Acid

Liquid 13-Cis Retinoic Acid

DRUGExtracted capsules 13-CRA

Extracted capsules 13-CRA

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 21 Years

Healthy volunteers

Inclusion criteria

1. Male or female aged from 0 years to \< 21 years of age. 2. Patient with high risk neuroblastoma, or unresectable, unfavourable histology intermediate risk neuroblastoma the latter age ≥ 18 months at diagnosis 3. Patient who is scheduled to receive at least two treatment cycles of 13-CRA. 4. Patient who cannot swallow 13-CRA capsules (i.e. requires extraction of 13-CRA from the capsules). 5. 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). 6. Provision of a single or double lumen central venous catheter for sampling (i.e. already in place). 7. Parent(s)/legal guardian able and willing to provide written informed consent for the patient to take part in the trial. 8. Where applicable, the patient should assent to undergo blood sampling for pharmacokinetic purposes and to allow physiological measurements to be made.

Exclusion criteria

1. 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. 2. 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). 3. Known allergy to 13-CRA or any of the excipients. 4. Inadequate contraception measures in females of childbearing age. 5. Receiving concomitant treatment with tetracyclines. Prior to each cycle: 1. Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. Veno-occlusive disease if present, should be stable or improving. 2. Skin toxicity no greater than CTCAE Grade 1(10) 3. Serum triglycerides \<5.65mmol/L. 4. No haematuria and / or proteinuria on urinalysis. 5. Serum calcium ≤ 2.9mmol/L. 6. 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 7. Patients with a seizure disorder must be well controlled and taking anticonvulsants. CNS toxicity \< grade 2 (CTCAE). Withdrawal Criteria: 1. 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. 2. Request of the patient, for any reason. 3. Discretion of the investigator.

Design outcomes

Primary

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

Secondary

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

Countries

United Kingdom

Participant flow

Participants by arm

Arm	Count
Liquid First Oral liquid formulation of 13-Cis Retinoic Acid (test product) administered in Cycle 1, then 13-CRA extracted capsules (reference product) administered in Cycle 2. The daily dose in each cycle was 200mg per m\^2 (in 2 divided doses), reduced to 160 mg per m\^2 if weight \< 12 kg	11
Extracted Capsule First 13-CRA extracted capsules (reference product) administered in Cycle 1, then oral liquid formulation of 13-Cis Retinoic Acid (test product) administered in Cycle 2. The daily dose in each cycle was 200mg per m\^2 (in 2 divided doses), reduced to 160 mg per m\^2 if weight \< 12 kg	9
Total	20

Baseline characteristics

Characteristic	Total	Extracted Capsule First	Liquid First
Age, Categorical <=18 years	20 Participants	9 Participants	11 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	0 Participants	0 Participants	0 Participants
Height	1.009 Metre STANDARD_DEVIATION 0.163	1.062 Metre STANDARD_DEVIATION 0.21	0.974 Metre STANDARD_DEVIATION 0.113
Race/Ethnicity, Customized Race Asian or Asian British	4 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Race Other	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Race White	15 Participants	7 Participants	8 Participants
Sex: Female, Male Female	5 Participants	1 Participants	4 Participants
Sex: Female, Male Male	15 Participants	8 Participants	7 Participants
Weight	16.3 Kg STANDARD_DEVIATION 6.5	18.96 Kg STANDARD_DEVIATION 9.09	14.66 Kg STANDARD_DEVIATION 3.47

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 20	0 / 20
other Total, other adverse events	18 / 20	15 / 20
serious Total, serious adverse events	10 / 20	5 / 20

Outcome results

Primary

Relative Bioavailability

Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations.