An open-label, pharmacokinetic, safety, and efficacy study (Part I, single cycle) and double-blind, efficacy, non inferiority, and safety study of IV NEPA (Part II, repeated cycles) versus active comparator in the prevention of CINV in paediatric cancer patients undergoing single-day HEC and multi-day HEC.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Helsinn Healthcare S.A.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

6 May 2025 → ongoing

Decision date (initial)

2025-04-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Helsinn Healthcare SA

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

Part I:
Cohort 1: To confirm by netupitant PK assessment that a single dose of 3.13 mg/kg IV fosnetupitant (for patients aged ≥3 months up to <18 years - to a maximum of 235 mg fosnetupitant for patients weighing ≥75 kg) or 1.88 mg/kg IV fosnetupitant (for patients <3 months) as IV NEPA provides the expected netupitant exposure observed in previous single-dose oral NEPA studies in paediatric cancer patients receiving 4 mg/kg or 2.4 mg/kg oral netupitant, respectively, with single-day chemotherapy and in adult population following 235 mg IV fosnetupitant (IV NEPA).

Part I:
Cohort 2: To assess the safety and tolerability of IV NEPA infusion after repeated administration (Days 1, 3 and Days 1, 3, 5).

Part II:
To demonstrate the non-inferiority of IV NEPA (fosnetupitant + palonosetron) in Cycle 1 versus IV fosaprepitant + IV ondansetron in the prevention of CINV in the delayed (>24-120 h) phase of emesis in paediatric cancer patients aged between ≥6 months and <18 years receiving multi-day HEC.

Secondary objectives 9

1. Part I: Cohort 1: To assess the safety and tolerability of IV NEPA infusion after single (Day 1) administration. Comparison to IV fosaprepitant/IV ondansetron will be considered for patients aged ≥6 months receiving the Reference Treatment.
2. Part I: Cohort 1 and Cohort 2 (separately): To assess the PK profile of fosnetupitant, netupitant, netupitant metabolites, and palonosetron in the paediatric population following single and repeated dosing of IV NEPA.
3. Part I, Cohort 1 and Cohort 2 (separately): To investigate the PK/PD correlation between netupitant exposure from IV NEPA and antiemetic efficacy in paediatric cancer patients. Efficacy parameters to be used in the correlation are the proportion of patients with CR (i.e., no emetic episodes and no rescue medication) during the acute phase of emesis (CR 0-24 h), during the delayed phase of emesis (CR >24-120 h), and during the overall phase of emesis (CR 0-120 h).
4. Part I: Cohort 1: To assess the efficacy of IV NEPA infusion after single (Day 1) administration in the prevention of acute, delayed, and overall CINV, versus IV fosaprepitant + IV ondansetron, following single-day HEC in patients aged ≥6 months to <18 years.
5. Part I: Cohort 2: To evaluate the efficacy of repeated dosing of IV NEPA in the prevention of acute, delayed, and overall CINV in patients aged between 0 months (newborns) to <18 years following multi-day HEC.
6. Part II: To assess the efficacy of IV NEPA versus IV fosaprepitant + IV ondansetron for the prevention of CINV in Cycle 1 during the acute (0-24 h) and overall (0-120 h) phases, and during the time periods 0-168 h (for all patients) and 0-216 h (only for patients receiving emetogenic chemotherapy after Day 3) after the start of chemotherapy on Day 1 in patients aged between ≥6 months and <18 years receiving multi-day HEC
7. Part II: To assess the efficacy of IV NEPA versus IV fosaprepitant + IV ondansetron for the prevention of CINV in repeated cycles (Cycle 2 onwards) during the acute (0-24 h), delayed (>24-120 h), and overall (0–120 h) phases, and during the time periods 0-168 h (for all patients) and 0-216 h (only for patients receiving emetogenic chemotherapy after Day 3) after the start of chemotherapy on Day 1 of the respective cycle in patients aged between ≥6 months and <18 years receiving multi-day HEC.
8. Part II: To characterize the PK profile of fosnetupitant, netupitant and its metabolites, and palonosetron by a population PK approach and to evaluate the extent of their accumulation following multiple IV NEPA administrations in repeated cycles.
9. Part II: To assess the safety and tolerability in Cycle 1 and repeated cycles of repeated administration of IV NEPA in the prevention of emesis from multi-day HEC in paediatric cancer patients aged between ≥6 months to <18 years.

Conditions and MedDRA coding

Chemotherapy-induced nausea and vomiting

Study design 2 periods

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001198-PIP03-17

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Part I: Cohort 1: Patient < 6 months weighing at least 4 kg or patient ≥ 6 months weighing at least 6 kg. Cohort 2: Patient weighing at least 4 kg.
2. Part I: Cohort 1: Patient scheduled and eligible to receive at least 1 cycle of single-day HEC. Cohort 2: Patient scheduled and eligible to receive at least 1 cycle of multi-day HEC.
3. Part II: Patient weight at least 6 kg.
4. Part II: Patient scheduled and eligible to receive repeated cycles of multi-day HEC.
5. Part I and Part II: Patient with a predicted life expectancy ≥3 months according to Investigator’s opinion.
6. Part I and Part II: For patients aged ≥10 years: Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2.
7. Part I and Part II: For patient with known hepatic impairment: the patient may be enrolled provided the serum ALT and AST are ≤2.5 ULN, the total bilirubin is ≤1.5 ULN, and in the Investigator’s opinion the impairment is not expected to jeopardize the patient’s safety during the study.
8. Part I and Part II: For patient with known renal impairment: the patient may be enrolled provided the estimated glomerular filtration rate (eGFR) is ≥70 mL/min/1.73m2 (≥50 mL/min/1.73m2 for children <3 months old) (the eGFR should be calculated using the modified Schwartz equation) and in the Investigator’s opinion the impairment is not expected to jeopardize the patient’s safety during the study.
9. Part I and Part II: For patient with known history or predisposition to cardiac abnormalities: as per the Investigator’s opinion, the history/predisposition should not jeopardize patient’s safety during the study.
10. Part I and Part II: Patient with non-clinically significant abnormal laboratory values or with clinically relevant abnormal laboratory values may be enrolled if in the Investigator’s opinion the patient’s safety is not expected to be jeopardized.

Exclusion criteria 7

1. Part I and Part II: Patient has received or is scheduled to receive total body irradiation; total nodal irradiation; upper abdomen radiotherapy; half or upper body irradiation; or radiotherapy of the cranium, craniospinal regions, head and neck, lower thorax region, or the pelvis within 1 week prior to study entry (Day 1) or within 120 h after last study drug administration.
2. Part I and Part II: Any illness or condition that, in the opinion of the Investigator, may pose unwarranted risks in administering the investigational product to the patient.
3. Part I and Part II: Uncontrolled medical condition (e.g., uncontrolled insulin-dependent diabetes mellitus).
4. Part I and Part II: Patient experiencing ongoing vomiting from any organic aetiology (including patients with history of gastric outlet obstruction or intestinal obstruction due to adhesions or volvulus), or patient with hydrocephalus.
5. Part I and Part II: Use of any drugs or substances known to interfere with CYP3A4 or CYP2D6 enzymes within 1 week prior to Day 1
6. Part I and Part II: Marked baseline prolongation of QTc interval (QTcF>460 millisecond [msec]). At the discretion of the investigator, criterion may be based on automatic interpretation of results.
7. Part II: Patient planned to receive multi-day HEC with cycle duration of less than 20 days (less than 20 days between 2 consecutive cycles’ Days 1).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part I: Cohort 1: Netupitant exposure parameters maximum concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable timepoint (AUClast) and to infinity (AUCinf).
2. Part I: Cohort 2: Safety parameters (monitoring of AEs, physical examination, vital signs, clinical laboratory tests [haematology, serum chemistry and urinalysis], and 12-lead ECG) following repeated IV NEPA administration (Days 1, 3 and Days 1, 3, 5) to paediatric cancer patients receiving multi-day HEC treatment.
3. Part II: Proportion of patients with CR (i.e., no emetic episodes and no rescue medication) during the delayed (>24-120 h) phase of emesis after start of chemotherapy administration in Cycle 1.

Secondary endpoints 8

1. Part I: Cohort 1: Physical examination, vital signs, clinical laboratory tests (haematology, serum chemistry and urinalysis), 12-lead ECG, and AEs.
2. Part I: Cohort I: - Other PK parameters for netupitant: tmax, (λz, t1/2, AUC0-48), AUC0-120 SD, CL/F, and Vz/F. PK parameters for netupitant metabolites M1, M2, and M3: Cmax, tmax, AUClast, AUC0-48, AUC0-120 SD, AUCinf, λz, t1/2, CL/F, and Vz/F. - PK parameters for fosnetupitant and palonosetron: Cmax, tmax, AUClast, AUC0-48, AUCinf, λz, t1/2, CL, and Vz.
3. Part I: Cohort 1 and Cohort 2: Population PK analysis using samples of patients from both Cohorts and all Age Groups to characterise PK values for fosnetupitant, netupitant, netupitant metabolites M1, M2, and M3, and palonosetron in paediatric patients upon single and multiple IV NEPA administration.
4. Part I: Cohort 1 and Cohort 2: PK/PD correlations between netupitant and palonosetron exposure parameters and antiemetic efficacy parameters (CR).
5. Part I: Cohort 1 and Cohort 2: Efficacy parameters, such as Proportion of patients with CR, Proportion of patients with no emetic episodes, Proportion of patients with no rescue medication, and Time to treatment failure
6. Part II: in Cycle 1 and repeated Cycles: Efficacy parameters, such as Proportion of patients with CR during the acute delayed and overall phase of emesis, Proportion of patients with no emetic episodes, Proportion of patients with no vomiting, Proportion of patients with no rescue medication, Proportion of patients with no nausea and no use of rescue medication, and Time to treatment failure
7. Part II: in Cycle 1 and repeated Cycles: Population PK for fosnetupitant, netupitant, netupitant metabolites, and palonosetron will be evaluated using pooled plasma concentration-time data from Study Part I and Part II.
8. Part II: in Cycle 1 and repeated Cycles: Physical examination, vital signs, clinical laboratory tests (haematology, serum chemistry and urinalysis), 12-lead ECG, and AEs.

Investigational products

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

Test 2

Comparator 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Helsinn Healthcare S.A.

Sponsor organisation

Helsinn Healthcare S.A.

Address

Via Pian Scairolo 9

City

Pazzallo

Postcode

6912

Country

Switzerland

Scientific contact point

Organisation

Helsinn Healthcare S.A.

Contact name

Head of Clinical Affairs

Public contact point

Organisation

Helsinn Healthcare S.A.

Contact name

Head of Clinical Affairs

Third parties 6

Sponsor responsibilities

Contact point sponsor

Helsinn Healthcare S.A.

Article 77 implementation

Helsinn Healthcare S.A.

Locations

3 EU/EEA countries · 14 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 47 files

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

Application history

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