Chemotherapy-induced Nausea and Vomiting (CINV)
Conditions
Brief summary
This study is Phase 2 pharmacokinetic (PK) and pharmacodynamic (PD) dose-finding study of oral netupitant administered concomitantly with oral palonosetron in pediatric cancer patients for the prevention of nausea and vomiting associated with emetogenic chemotherapy. Two different netupitant dosages will be tested in patients aged from 3 months to \< 18 years: 1.33 mg/kg up to a maximum of 100 mg, and 4 mg/kg up to a maximum of 300 mg. All netupitant doses in all age classes will be concomitantly administered with palonosetron 20 μg/kg (up to a maximum dose of 1.5 mg) which is the IV palonosetron dose approved by USA FDA for the pediatric population. The primary objective is to investigate the PK/PD relationship between netupitant exposure (AUC, Cmax) and antiemetic efficacy (CR in delayed phase) after a single oral netupitant administration, concomitantly with oral palonosetron in pediatric cancer patients receiving Moderately Emetogenic Chemotherapy (MEC) or Highly Emetogenic Chemotherapy (HEC) cycles. Efficacy parameter to be used in the correlation is the proportion of patients with Complete Response (CR i.e., no emetic episodes and no rescue medication) during (\> 24-120 h after the start of chemotherapy on Day 1). The secondary objectives are to assess the safety and tolerability after single oral administration of netupitant given concomitantly with a single oral administration of palonosetron; to evaluate the pharmacokinetic (AUC, Cmax, tmax and t1/2) of oral palonosetron at the fixed dose of 20 μg/kg in pediatric patients with the concomitant administration of netupitant. A total of 92 pediatric cancer patients receiving either HEC or MEC will be enrolled in the study.
Interventions
DRUGNetupitant
Netupitant 1.33 mg/kg oral suspension up to a maximum of 100 mg
DRUGPalonosetron
Palonosetron 20 μg/kg solution for oral use up to a maximum of 1.5 mg
Sponsors
Helsinn Healthcare SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Signed written informed consent by parent(s)/legal guardians of the pediatric patient in compliance with the local laws and regulations. In addition signed children's assent form according to local requirements. 2. Male or female in- or out-patient from birth to \< 18 years at the time of randomization. 3. Patient weight at least 3.3 kg. 4. Naïve or non-naïve patient with histologically, and/or cytologically (or imaging in the case of brain tumors) confirmed malignant disease. 5. Scheduled and eligible to receive at least one moderately or highly emetogenic chemotherapeutic agent on Day 1 only or for multiple days. 6. For patient aged ≥ 10 years: Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2. 7. For patient aged 2 years with known mild to moderate hepatic impairment: in the Investigator's opinion the impairment does not jeopardize patient's safety during the study. 8. For patient aged 2 years with known mild to moderate renal impairment: in the Investigator's opinion the impairment should not jeopardize patient's safety during the study. 9. For patient with known history or predisposition to cardiac abnormalities: in the Investigator's opinion the history/predisposition should not jeopardize patient's safety during the study. 10. If the patient is female, she shall: a) not have attained menarche yet or b) have attained menarche and have a negative pregnancy test at the screening visit and at Day 1. 11. Male or female fertile patient using reliable contraceptive measures (such measures, for patient and sexual partner, include: implants, injectables, combined oral contraceptives, intrauterine devices, vasectomized/sterilized partner, use of a double-barrier method or sexual abstinence). The patient and his/her parent(s)/legal guardians must be counseled on the importance of avoiding pregnancy before or during the study.
Exclusion criteria
1. The patient and/or parents/caregivers are expected by the Investigator to be non-compliant with the study procedures. 2. Patient has received or is scheduled to receive total body irradiation, total nodal irradiation, upper abdomen radiotherapy, half or upper body irradiation, 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 start of chemotherapy administration on Day 1. 3. Known history of allergy to any component or other contraindications to any Neurokinin-1 (NK1) or 5-hydroxytryptamine 3 (5-HT3) receptor antagonists. 4. Active infection. 5. Uncontrolled medical condition (e.g., uncontrolled insulin dependent diabetes mellitus). 6. Patient suffering from ongoing vomiting from any organic etiology (including patients with history of gastric outlet obstruction or intestinal obstruction due to adhesions or volvulus, patients with a symptomatic central nervous system(CNS) tumor causing nausea and/or vomiting) or patient with hydrocephalus. 7. Patient who experienced any vomiting, retching, or nausea within 24 h prior to the administration of the study drug 8. Patient who received any drug with potential anti-emetic effect within 24 h prior to the start of reference chemotherapy, including but not limited to: NK1- receptor antagonists (e.g., aprepitant or any other new drug of this class); 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, ramosetron); Benzamides (e.g., metoclopramide, alizapride); Phenothiazines (e.g., prochlorperazine, promethazine, perphenazine, fluphenazine, chlorpromazine, thiethylperazine); Benzodiazepines initiated 48 h prior to study drug administration or expected to be received within 120 h following initiation of chemotherapy, except for single doses of midazolam, temazepam or triazolam; Butyrophenones (e.g., droperidol, haloperidol); Anticholinergics (e.g., scopolamine, with the exception of inhaled anticholinergics for respiratory disorders e.g., ipratropium bromide); Antihistamines (e.g., diphenhydramine, cyclizine, hydroxyzine, chlorpheniramine, dimenhydrinate, meclizine); Domperidone; Mirtazapine; Olanzapine; Prescribed cannabinoids (e.g., tetrahydrocannabinol, nabilone); Over the Counter (OTC) antiemetics, OTC cold or OTC allergy medications; Herbal preparations containing ephedra or ginger. 9. Patient who received palonosetron within 1 week prior to administration of study drug. 10. Patient who has been started on systemic corticosteroid therapy within 72 h prior to study drug administration or is planned to receive a corticosteroid as part of the chemotherapy regimen 11. Patient aged \< 6 years who received any investigational drug (defined as a medication with no marketing authorization granted for any age class and any indication) within 90 days prior to Day 1, or patient aged 6 years who received any investigational drug within 30 days prior to Day 1 or is expected to receive investigational drugs prior to study completion. 12. Intake of alcohol, food or beverages (e.g., grapefruit, cranberry, pomegranate and aloe vera juices, German chamomile) known to interfere with either CYP3A4 or CYP2D6 metabolic enzymes within 1 week prior to Day 1 and during the overall study period. 13. Use of any drugs or substances known to be strong or moderate inhibitors of CYP3A4 and CYP2D6 enzymes within 1 week prior to Day 1 or planned to be used during the overall study period. 14. Use of any drugs or substances known to be CYP3A4 substrates with narrow therapeutic range within 1 week prior to Day 1, or planned to be used during the overall study period. 15. Use of any drugs or substances known to be inducers of CYP3A4 enzymes within 4 weeks prior to Day 1 or planned to be used during the overall study period. 16. Lactating female patient. 17. Patient with clinically relevant abnormal laboratory values that in the Investigator's opinion jeopardize the patient's safety during the study. 18. Patient aged \< 2 years with known hepatic impairment (any grade), or patient aged 2 years with known severe hepatic impairment. 19. Patient aged \< 2 years with known renal impairment (any grade), or patient aged 2 years with known severe renal impairment. 20. Enrolment in a previous study with netupitant (either alone or in combination with palonosetron).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | within 168 hours after netupitant administration. A sampling windows approach will be used by collecting a single blood sample from each patient in one of these time windows: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h and from 120 to 168 h. | Mean values of area under the plasma Concentration versus time curve from time zero to infinity (AUC0-inf) of netupitant after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles. AUC estimates are obtained by non-compartmental analysis of population model-predicted individual plasma concentration-time profiles. |
| Maximum Plasma Concentration (Cmax) of Netupitant | within 168 hours after netupitant administration. A sampling windows approach will be used by collecting a single blood sample from each patient in one of these time windows: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h and from 120 to 168 h | Mean values of maximum plasma concentration (Cmax) of netupitant after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles. Cmax estimates are obtained by non-compartmental analysis of population model-predicted individual plasma concentration-time profiles |
| Exposure - Response Analysis for Netupitant | > 24-120 hours after the start of chemotherapy on Day 1 | Exposure - Response analysis for netupitant performed by assessing the relationships between exposure parameters AUC0-inf and Cmax with the primary efficacy endpoint, i.e., the CR in the delayed phase. Graphical exposure-response analysis for netupitant performed by assessing the relationship between individual exposure parameters (AUC0-inf) and Cmax) with the primary efficacy endpoint, i.e the CR in the delayed phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Pediatric Patients With Complete Response During the Delayed Phase | > 24-120 hours after the start of chemotherapy on Day 1 | Percentage of Pediatric Patients with complete response (CR, i.e., no emetic episodes and no rescue medication) during the delayed phase (\> 24 to 120 h after the start of chemotherapy on Day 1) after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles. |
Countries
Russia, Serbia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Netupitant 1.33 mg/kg Plus Palonosetron Single oral dose of Netupitant 1.33 mg/kg up to a maximum of 100 mg (for patients \< 3 months of age the netupitant dose will be 0.8 mg/kg) administered with single oral dose of 20 μg/kg palonosetron up to a maximum of 1.5 mg.
Netupitant: Netupitant 1.33 mg/kg oral suspension up to a maximum of 100 mg
Palonosetron: Palonosetron 20 μg/kg solution for oral use up to a maximum of 1.5 mg | 34 |
| Netupitant 4 mg/kg Plus Palonosetron Single oral dose of Netupitant 4 mg/kg up to a maximum of 300 mg (for patients \< 3 months of age the netupitant dose will be 2.4 mg/kg) administered with single oral dose 20 μg/kg palonosetron up to a maximum of 1.5 mg.
Netupitant: Netupitant 4 mg/kg oral suspension up to a maximum of 300 mg
Palonosetron: Palonosetron 20 μg/kg solution for oral use up to a maximum of 1.5 mg | 32 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Netupitant 1.33 mg/kg Plus Palonosetron | Netupitant 4 mg/kg Plus Palonosetron | Total |
|---|---|---|---|
| Age, Continuous | 6.6 years STANDARD_DEVIATION 6.29 | 5.6 years STANDARD_DEVIATION 5.46 | 6.1 years STANDARD_DEVIATION 5.88 |
| Age, Customized 12 to <18 years | 9 Participants | 7 Participants | 16 Participants |
| Age, Customized 1 to <2 years | 3 Participants | 4 Participants | 7 Participants |
| Age, Customized 1 to <3 months | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized 2 to <5 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Customized 3 to <6 months | 3 Participants | 2 Participants | 5 Participants |
| Age, Customized 5 to <12 years | 8 Participants | 8 Participants | 16 Participants |
| Age, Customized 6 to <12 months | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 31 Participants | 65 Participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Male | 21 Participants | 18 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 32 |
| other Total, other adverse events | 22 / 34 | 22 / 32 |
| serious Total, serious adverse events | 0 / 34 | 3 / 32 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant
Mean values of area under the plasma Concentration versus time curve from time zero to infinity (AUC0-inf) of netupitant after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles. AUC estimates are obtained by non-compartmental analysis of population model-predicted individual plasma concentration-time profiles.
Time frame: within 168 hours after netupitant administration. A sampling windows approach will be used by collecting a single blood sample from each patient in one of these time windows: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h and from 120 to 168 h.
Population: Pediatric patients divided in seven age groups; in netupitant 4 mg/kg arm 1 patient was withdrew from the study after randomization of study drug and was not treated; 1 patient was treated with study drug but did not receive the entire planned dose and was not included in this analysis and one patient received the entire planned dose, but did not have any measurable concentration of netupitant and/or palonosetron.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Netupitant 1.33 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 2 years to <5 years | 3135 ng*hr/mL | Standard Deviation 44 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 3 month to <6 months of age | 3849 ng*hr/mL | Standard Deviation 91.3 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 5 years to <12 years | 2676 ng*hr/mL | Standard Deviation 35 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 1 year to <2 years | 2276 ng*hr/mL | Standard Deviation 29.8 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 12 years to <18 years | 3107 ng*hr/mL | Standard Deviation 54.9 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 1 month to <3 months of age | 4460 ng*hr/mL | — |
| Netupitant 1.33 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 6 month to <1 year of age | 7637 ng*hr/mL | Standard Deviation 113 |
| Netupitant 4 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 12 years to <18 years | 12266 ng*hr/mL | Standard Deviation 26.9 |
| Netupitant 4 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 3 month to <6 months of age | 17340 ng*hr/mL | Standard Deviation 36.4 |
| Netupitant 4 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 6 month to <1 year of age | 8617 ng*hr/mL | Standard Deviation 45.2 |
| Netupitant 4 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 1 year to <2 years | 9886 ng*hr/mL | Standard Deviation 59.6 |
| Netupitant 4 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 2 years to <5 years | 14404 ng*hr/mL | Standard Deviation 131 |
| Netupitant 4 mg/kg Plus Palonosetron | Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Netupitant | patients 5 years to <12 years | 10154 ng*hr/mL | Standard Deviation 70.7 |
Primary
Exposure - Response Analysis for Netupitant
Exposure - Response analysis for netupitant performed by assessing the relationships between exposure parameters AUC0-inf and Cmax with the primary efficacy endpoint, i.e., the CR in the delayed phase. Graphical exposure-response analysis for netupitant performed by assessing the relationship between individual exposure parameters (AUC0-inf) and Cmax) with the primary efficacy endpoint, i.e the CR in the delayed phase.
Time frame: > 24-120 hours after the start of chemotherapy on Day 1
Population: All pediatric patients with exposures parameters and CR data in the delayed phase
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Netupitant 1.33 mg/kg Plus Palonosetron | Exposure - Response Analysis for Netupitant | number of participants with CR in delayed phase | 45 Participants |
| Netupitant 1.33 mg/kg Plus Palonosetron | Exposure - Response Analysis for Netupitant | number of participants with no CR in delayed phase | 19 Participants |
Comparison: The population consist of all patients having CR in the delayed phase and AUC0-inf and Cmax, there is no comparison between the two dose groups.p-value: 0.55loess (Local regression or polynomial)
Comparison: The population consist of all patients having CR in the delayed phase and AUC0-inf and Cmax, there is no comparison between the two dose groups.p-value: 0.75loess (Local regression or polynomial)
Primary
Maximum Plasma Concentration (Cmax) of Netupitant
Mean values of maximum plasma concentration (Cmax) of netupitant after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles. Cmax estimates are obtained by non-compartmental analysis of population model-predicted individual plasma concentration-time profiles
Time frame: within 168 hours after netupitant administration. A sampling windows approach will be used by collecting a single blood sample from each patient in one of these time windows: from 2 to 8 h, from 24 to 48 h, from 72 to 96 h and from 120 to 168 h
Population: Pediatric patients divided in seven age groups; in netupitant 4 mg/kg arm 1 patient was withdrew from the study after randomization of study drug and was not treated; 1 patient was treated with study drug but did not receive the entire planned dose and was not included in this analysis and one patient received the entire planned dose, but did not have any measurable concentration of netupitant and/or palonosetron.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Netupitant 1.33 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 2 years to <5 years | 74.0 ng/mL | Standard Deviation 32.3 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 3 months to <6 months | 76.0 ng/mL | Standard Deviation 27.1 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 5 years to <12 years | 67.9 ng/mL | Standard Deviation 32.1 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 1 year to <2 years | 69.5 ng/mL | Standard Deviation 19.3 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 12 years to <18 years | 76.8 ng/mL | Standard Deviation 27.3 |
| Netupitant 1.33 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 1 month to <3 months | 60.8 ng/mL | — |
| Netupitant 1.33 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 6 months to <12 months | 133 ng/mL | Standard Deviation 71.7 |
| Netupitant 4 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 12 years to <18 years | 274 ng/mL | Standard Deviation 15.6 |
| Netupitant 4 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 3 months to <6 months | 233 ng/mL | Standard Deviation 4.25 |
| Netupitant 4 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 6 months to <12 months | 255 ng/mL | Standard Deviation 31.2 |
| Netupitant 4 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 1 year to <2 years | 275 ng/mL | Standard Deviation 38.2 |
| Netupitant 4 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 2 years to <5 years | 266 ng/mL | Standard Deviation 55 |
| Netupitant 4 mg/kg Plus Palonosetron | Maximum Plasma Concentration (Cmax) of Netupitant | 5 years to <12 years | 213 ng/mL | Standard Deviation 20.1 |
Secondary
Percentage of Pediatric Patients With Complete Response During the Delayed Phase
Percentage of Pediatric Patients with complete response (CR, i.e., no emetic episodes and no rescue medication) during the delayed phase (\> 24 to 120 h after the start of chemotherapy on Day 1) after a single oral netupitant administration, concomitantly with oral palonosetron, in pediatric cancer patients receiving HEC or MEC cycles.
Time frame: > 24-120 hours after the start of chemotherapy on Day 1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Netupitant 1.33 mg/kg Plus Palonosetron | Percentage of Pediatric Patients With Complete Response During the Delayed Phase | 24 Participants |
| Netupitant 4 mg/kg Plus Palonosetron | Percentage of Pediatric Patients With Complete Response During the Delayed Phase | 22 Participants |