DAVINCY trial: optimal Duration of (fos)Aprepitant prophylaxis for nausea and Vomiting INduced by ChemotherapY in children: a double-blind placebo-controlled crossover randomized phase III trial.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prinses Maxima Centrum voor Kinderoncologie B.V.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Diseases [C] - Neoplasms [C04]

Trial duration

21 Dec 2021 → 6 Apr 2026

Decision date (initial)

2024-11-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-517846-32-00

EudraCT number

2021-003311-26

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Pharmacokinetic, Safety

To evaluate the effect of prolonged duration of (fos)aprepitant prophylaxis on the prevention of delayed CINV (complete remission in the 24-72 hours after the final dose of chemotherapy) in children using moderate or highly emetogenic chemotherapy. The current 3-day regimen is followed by placebo and compared to a regimen of (fos)aprepitant prophylaxis during the complete course of chemotherapy (maximum of 8 days) in a double-blind fashion and with a randomized cross-over design in which the patient functions as its own control in 2 similar chemotherapy cycles (of 8 days) (not necessarily consecutive courses).

Secondary objectives 7

1. To evaluate the effect of prolonged duration of (fos)aprepitant prophylaxis on the pre-vention of acute and overall chemotherapy induced nausea and vomiting (CINV) in children.
2. To compare the effect of prolonged duration of (fos)aprepitant prophylaxis regarding the efficacy endpoint of no vomiting, regardless of rescue medication use, in the acute, delayed and overall phases.
3. To assess the safety and tolerability of (fos)aprepitant according to a prolonged dosing regimen.
4. To evaluate the pharmacokinetics of (fos)aprepitant during a prolonged dosing regi-men by constructing a population pharmacokinetics (PK) model.
5. To assess the improvement of complaints of CINV in children during prolonged (fos)aprepitant dosing regimen by using the validated pediatric nausea assessment tool (PeNAT)17 and the Baxter Retching Faces.
6. To determine which of two patient-report nausea assessment tools (PeNAT or BARF) performs better in terms of validity criteria (criterion, construct, and face validity), responsiveness, or feasibility.
7. To assess cost-effectiveness of a prolonged dosing regimen.

Conditions and MedDRA coding

Delayed chemotherapy induced nausea and vomiting (CINV)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Age must be ≥ 6 months to ≤ 18 years at time of study entry.
2. Patients must not receive radiation therapy to the abdomen or pelvis in the week before treatment.
3. Patient must not use benzodiazepines or opioids initiated within 48h before treatment, except for single doses of triazolam, temazepam, or midazolam.
4. Continuation of chronic benzodiazepine or opioid therapy is permitted provided it was initiated ≥48 hours prior to study drug administration.
5. In patients on chronic warfarin, acenocoumarol, tolbutamide or phenytoin (metabolised by CYP2C9) therapy should be monitored closely during treatment with (fos)aprepitant and for 14 days following each course of (fos)aprepitant.
6. A documented malignancy.
7. Patients need to receive moderate or highly emetogenic chemotherapy blocks, or chemotherapy not previously tolerated due to vomiting, for a minimum duration of 4 days.
8. Chemotherapy schedules need to contain two similar courses of chemotherapy, which do not necessarily have to be consecutive courses.
9. No symptomatic primary or metastatic CNS malignancy causing nausea or vomiting.
10. Patients do not receive scheduled blocks of chemotherapy containing corticosteroids as part of anti-tumour treatment during the study period.
11. Patients aged greater than 16y with a Karnofsky score of 60 or more or patients aged 16y or less with a Lansky Play performance score of 60 or more.
12. Patient must have a life expectancy of 3 months or more.
13. Patients must not use antiemetic treatment within 48h before treatment (see appendix B).
14. No use of CYP3A4 substrates/inhibitors within 7 days, or no CYP3A4 inducers within 30 days of treatment (see appendix B).
15. Serum creatinine must be ≤ 1.5 x institutional upper limit of normal (ULN) according to age.
16. AST and ALT must be ≤ 5 x institutional ULN.
17. Total bilirubin must be ≤ 1.5 x institutional ULN
18. No history of QT prolongation.
19. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
20. Female patients with infants must agree not to breastfeed their infants while on this study.
21. Male and female patients of child-bearing potential must agree to use a highly effective method of contraception approved by the investigator during the study, following the CTFG recommendations.
22. Patients have no history of prior grade 3/4 allergic reaction to any of the study drugs.
23. Patients have no underlying gastrointestinal disease that may interfere with the absorption of the medication.

Exclusion criteria 1

1. Only hemato-oncology patients on dexamethasone therapy and symptomatic primary or meta-static CNS malignancy patients causing nausea or vomiting are excluded from study participation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The proportion of patients who achieved complete response (defined as no vomiting, no retching and no use of rescue medication) during the >24-72 hours after the final dose of chemotherapy (delayed phase).

Secondary endpoints 7

1. Proportion of patients who: - achieved complete response during the course of chemotherapy until 24h after the final dose of chemotherapy (acute phase) - achieved complete response during both the acute and delayed phase (overall phase)
2. Time from initiation of emetogenic chemotherapy to: 1. the first vomiting episode 2. the first rescue medication use
3. Safety of prolonged use of (fos)aprepitant (AEs considered related by the investigators).
4. Pharmacokinetic (PK) parameters (i.e. clearance and volume of distribution) and influ-encing PK co-variates as chemotherapeutics.
5. Improvement of CINV complaints according to the Pediatric Nausea Assessment tool (PeNAT) and the Baxter Retching Faces (BARF).
6. Validity, responsiveness and feasibility of PeNAT and BARF.
7. Cost-effectiveness of prolonged (fos)aprepitant dosing regimen.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prinses Maxima Centrum voor Kinderoncologie B.V.

Sponsor organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Address

Heidelberglaan 25

City

Utrecht

Postcode

3584 CS

Country

Netherlands

Scientific contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Dr. E. de Vos- Kerkhof

Public contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

TDC secretary

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications