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

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ClinicalTrials.gov Identifier: NCT03291080
Recruitment Status : Not yet recruiting
First Posted : September 25, 2017
Last Update Posted : September 25, 2017
Wellcome Trust
UK Department of Health
Information provided by (Responsible Party):
Nova BioPharma Limited

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.

Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: Liquid 13-Cis Retinoic Acid Drug: Extracted capsules 13-CRA Phase 1 Phase 2

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.

The pharmacokinetics of 13-CRA liquid (test product) and 200mg/m2/day 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  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: 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.
Anticipated Study Start Date : January 1, 2018
Estimated Primary Completion Date : August 28, 2019
Estimated Study Completion Date : October 28, 2019

Resource links provided by the National Library of Medicine

U.S. FDA Resources

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 Name: Isotretinoin
Experimental: Capsule
Isotretinoin capsules (13-CRA extracted per standard of care)- reference product.
Drug: Extracted capsules 13-CRA
Extracted capsules 13-CRA
Other Name: Isotretinoin

Primary Outcome Measures :
  1. PK- Relative bioavailability (population pharmacokinetic measures) [ Time Frame: On day 1 and 14 of treatment ]
    Non-linear, mixed effects modelling approach to determine the relative bioavailability and pharmacokinetics of 13-CRA administered as oral liquid and capsule formulations.

Secondary Outcome Measures :
  1. Time to maximum concentration (Tmax) [ Time Frame: On day 1 and 14 of treatment ]
    Pharmacokinetic parameter

  2. Maximum plasma concentration (Cmax) [ Time Frame: On day 1 and 14 of treatment ]
    Pharmacokinetic parameter

  3. Area under plasma concentration time curve (AUC) [ Time Frame: On day 1 and 14 of treatment ]
    Pharmacokinetic parameter

  4. Half-life (t1/2) [ Time Frame: On day 1 and 14 of treatment ]
    Pharmacokinetic parameter

  5. Clearance (CL/F) [ Time Frame: On day 1 and 14 of treatment ]
    To determine clearance pharmacokinetics of 13-CRA

  6. Volume of distribution (V/F) [ Time Frame: On day 1 and 14 of treatment ]
    To determine volume of distribution pharmacokinetics of 13-CRA

Other Outcome Measures:
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Over 2 months treatment and 14 day follow up ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03291080

Contact: Deborah Tweddle, MB ChB, MRCP 44-191-282-4068 deborah.tweddle@ncl.ac.uk

Sponsors and Collaborators
Nova BioPharma Limited
Wellcome Trust
UK Department of Health
Study Director: Hussain Mulla, PhD Nova BioPharma Limited

Responsible Party: Nova BioPharma Limited
ClinicalTrials.gov Identifier: NCT03291080     History of Changes
Other Study ID Numbers: INV500
First Posted: September 25, 2017    Key Record Dates
Last Update Posted: September 25, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents