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

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.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: Liquid 13-Cis Retinoic Acid; Drug: Extracted capsules 13-CRA

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Birmingham, United Kingdom
    • Bruce Morland
  • Bristol, United Kingdom
    • Dr Antony Ng
  • Cambridge, United Kingdom
    • Dr Amos Burke
  • Edinburgh, United Kingdom
    • Mark Brougham
  • Leeds, United Kingdom
    • Dr Martin Elliott
  • London, United Kingdom
    • Dr Guiseppe Barone
  • Manchester, United Kingdom
    • Dr Guy Makin
  • Nottingham, United Kingdom
    • Dr Madhumita Dandapani
  • Oxford, United Kingdom
    • Kate Wheeler
  • Sutton, United Kingdom
    • Sucheta Vaidya

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nova Laboratories Limited
• Investigators: Study Director: Hussain Mulla, PhD, Nova Laboratories Limited

Publications and helpful links

General Publications

• Veal GJ, Tweddle DA, Visser J, Errington J, Buck H, Marange J, Moss J, Joseph S, Mulla H. Pharmacokinetics and Safety of a Novel Oral Liquid Formulation of 13-cis Retinoic Acid in Children with Neuroblastoma: A Randomized Crossover Clinical Trial. Cancers (Basel). 2021 Apr 14;13(8):1868. doi: 10.3390/cancers13081868.

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2018
• Primary Completion (Actual): September 12, 2019
• Study Completion (Actual): September 12, 2019

Study Registration Dates

• First Submitted: July 19, 2017
• First Submitted That Met QC Criteria: September 19, 2017
• First Posted (Actual): September 25, 2017

Study Record Updates

• Last Update Posted (Actual): October 19, 2021
• Last Update Submitted That Met QC Criteria: September 22, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Antineoplastic Agents; Dermatologic Agents; Keratolytic Agents; Tretinoin; Isotretinoin
• Other Study ID Numbers: INV500

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No