Chemotherapy-Induced Nausea and Vomiting
Conditions
Keywords
Prevention of Chemotherapy-Induced Nausea and Vomiting, Palonosetron, Ondansetron, Pediatric
Brief summary
The primary objective is to evaluate the efficacy of two different doses of IV palonosetron in the prevention of chemotherapy induced nausea and vomiting in MEC and HEC patients through 120 hours after start of chemotherapy in single and repeated chemotherapy cycles. The secondary objectives are to evaluate the safety and tolerability of IV palonosetron in pediatric patients and evaluate the pharmacokinetics of IV palonosetron in a subset of pediatric CINV patients.
Detailed description
For neonates (\<28 days, full term) an open-label sub-study will be conducted to assess exposure and tolerability in this age group with escalating doses of palonosetron, starting with 3 mcg/kg to the first three or more neonates included in the study. If this dose is shown to be safe and well tolerated then the following three neonates will be treated with a dose of 10 mcg/kg. If also this dose is safe and well tolerated, then the following three neonates will be treated with a dose of 20 mcg/kg. If this last dose is also shown to be safe and well tolerated, then all the following neonates will be randomized to the main study.
Interventions
DRUGPalonosetron
Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg
DRUGOndansetron
Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg
Sponsors
Helsinn Healthcare SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 16 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent signed 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 * Male or female in- or out-patients from neonates (full term) to \<17 years at the time of randomization * Patient weight at least 3.2 kg * Histologically, and/or cytologically (or imaging in the case of brain tumors) confirmed malignant disease * Naïve or non-naïve to chemotherapy * Scheduled and eligible to receive at least one of the moderately or highly emetogenic chemotherapeutic agents on Study Day 1 * For patients aged ≥ 10 years to \<17 years: ECOG PS ≤ 2 * For patients with known hepatic impairment: in the Investigator's opinion the impairment should not jeopardize patient's safety during the study * For patients with known renal impairment: in the Investigator's opinion the impairment should not jeopardize patient's safety during the study * For patients 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 * For patients with known clinically relevant abnormal laboratory values: in the Investigator's opinion the abnormality should not jeopardize the patient's safety during the study * Fertile patients (male or female) must use reliable contraceptive measures * Female patients who have attained menarche must have a negative pregnancy test at the screening visit (Visit 1) and at study treatment visit (Visit 2)
Exclusion criteria
* Lactating or pregnant female patient * Patient has received total body irradiation, upper abdomen radiotherapy, radiotherapy of the cranium, craniospinal regions or the pelvis within 1 week prior to study entry (screening) * Scheduled to receive concomitant total body irradiation, radiotherapy of the upper abdomen, lower thorax region, or cranium/craniospinal regions up to 24 hours after study drug administration * Known history of allergy to any component or other contraindications to any 5-HT3 receptor antagonists * Active infection * Uncontrolled medical condition * Marked baseline prolongation of QTc interval \[QTcB or QTcF \> 460 msec\] in any of the ECG assessments at screening. For this purpose, assessment will rely on the automatic interpretation by the ECG machine * 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) or patients with hydrocephalus * Patient who experienced any vomiting, retching, or nausea within 24 hours prior to the administration of the study drug * Patient who received any drug with potential anti-emetic effect within 24 hours prior to administration of study treatment, including but not limited to: * NK1- receptor antagonists (e.g. aprepitant) * 5-HT3 antagonists (e.g., ondansetron, granisetron, dolasetron); * Phenothiazines (e.g., perphenazine, prochlorperazine, promethazine, fluphenazine, chlorpromazine, thiethylperazine); * Butyrophenones (e.g., droperidol, haloperidol); * Benzamides (e.g., metoclopramide, alizapride); * Corticosteroids (e.g., prednisone, methylprednisolone; except inhaled steroids for respiratory disorders and topical steroids for skin disease with doses of ≤ 10 mg of prednisone daily or its equivalent); Corticosteroids foreseen in the chemotherapy regimen or to reduce intracranial pressure are allowed. According to the guidelines1,2, patients will receive also dexamethasone as a co-medication in accordance with standard clinical practice and if deemed appropriate by the Investigator. * Dimenhydrinate; Hydroxyzine; Domperidone; Lorazepam; Cyclizine; Cannabinoids; Scopolamine; Trimethobenzamide HCl; Meclizine hydrochloride; Pseudoephedrine HCl; * Over the Counter (OTC) antiemetics, OTC cold or OTC allergy medications; * Herbal preparations containing ephedra or ginger. * Patient aged ≤ 6 years who received any investigational drug (defined as a medication with no marketing authorization granted for any age group 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 * Patient who participated in any previous trial with palonosetron
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1 | 0 to 24 hours after T0 | Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from 0 to 24 hours (acute phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle. Time 0 (T0) is defined as the time when the patient starts the first cycle of chemotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1 | from >24 to 120 hours (delayed phase) after T0 | Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from \>24 to 120 hours (delayed phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle. |
Countries
Argentina, Austria, Bulgaria, Chile, Czechia, Estonia, France, Germany, Hungary, Peru, Poland, Romania, Russia, Serbia, Ukraine, United States
Participant flow
Pre-assignment details
A total of 502 patients were enrolled and randomly assigned to treatment. Study drug was not administered to 8 randomized patients, of these patients 2 had also an adverse event and were counted under this category in overall study statement. Therefore 494 patients did receive the study drug and are part of the analysis for the safety population.
Participants by arm
| Arm | Count |
|---|---|
| Palonosetron 10 mcg/kg Palonosetron and placebo to Ondansetron
Intervention:
Drug: Palonosetron
Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg
Placebo to Ondansetron | 166 |
| Palonosetron 20 mcg/kg Palonosetron and placebo to Ondansetron
Intervention:
Drug: Palonosetron
Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg
Placebo to Ondansetron | 165 |
| Ondansetron Ondansetron and placebo to Palonosetron
Drug:
Comparator: Ondansetron
Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg
Placebo to Palonosetron | 162 |
| Total | 493 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 2 |
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | Not eligible for subsequent cycles | 1 | 2 | 0 |
| Overall Study | Patients not treated | 2 | 3 | 1 |
| Overall Study | Withdrawal of consent | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Ondansetron | Palonosetron 20 mcg/kg | Palonosetron 10 mcg/kg |
|---|---|---|---|---|
| Age, Customized 12 to <17 years | 150 participants | 49 participants | 50 participants | 51 participants |
| Age, Customized 2 to <6 years | 162 participants | 54 participants | 54 participants | 54 participants |
| Age, Customized <2 years | 45 participants | 15 participants | 15 participants | 15 participants |
| Age, Customized 6 to <12 years | 136 participants | 44 participants | 46 participants | 46 participants |
| Emetogenicity of chemotherapy in Cycle 1 HEC | 154 participants | 51 participants | 49 participants | 54 participants |
| Emetogenicity of chemotherapy in Cycle 1 MEC | 339 participants | 111 participants | 116 participants | 112 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 64 Participants | 12 Participants | 26 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 429 Participants | 150 Participants | 139 Participants | 140 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 19 Participants | 3 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 469 Participants | 159 Participants | 154 Participants | 156 Participants |
| Sex: Female, Male Female | 262 Participants | 98 Participants | 76 Participants | 88 Participants |
| Sex: Female, Male Male | 231 Participants | 64 Participants | 89 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 143 / 167 | 130 / 163 | 145 / 164 |
| serious Total, serious adverse events | 68 / 167 | 62 / 163 | 70 / 164 |
Outcome results
Primary
Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1
Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from 0 to 24 hours (acute phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle. Time 0 (T0) is defined as the time when the patient starts the first cycle of chemotherapy.
Time frame: 0 to 24 hours after T0
Population: Full Analysis Set (FAS) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palonosetron 10 mcg/kg | Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1 | 54.2 percentage of patients |
| Palonosetron 20 mcg/kg | Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1 | 59.4 percentage of patients |
| Ondansetron | Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1 | 58.6 percentage of patients |
Comparison: The stratum adjusted Mantel-Haenszel method was used to compute the confidence interval (CI) of the difference in proportion. If the lower bound of the 97.5% CI of either the difference (CR0-24h palonosetron 20 mcg/kg - CR0-24h ondansetron) or the difference (CR0-24h palonosetron 10 mcg/kg - CR0-24h ondansetron) was strictly superior to the non-inferiority margin (δ=-0.15) then the null hypothesis (H0) was rejected. A power of 80% was used for sample size computation.97.5% CI: [-11.7, 12.4]
Comparison: The stratum adjusted Mantel-Haenszel method was used to compute the confidence interval (CI) of the difference in proportion. If the lower bound of the 97.5% CI of either the difference (CR0-24h palonosetron 20 mcg/kg - CR0-24h ondansetron) or the difference (CR0-24h palonosetron 10 mcg/kg - CR0-24h ondansetron) was strictly superior to the non-inferiority margin (δ=-0.15) then the null hypothesis (H0) was rejected. A power of 80% was used for sample size computation.97.5% CI: [-16.4, 7.6]
Secondary
Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1
Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from \>24 to 120 hours (delayed phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle.
Time frame: from >24 to 120 hours (delayed phase) after T0
Population: Full Analysis Set (FAS) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Palonosetron 10 mcg/kg | Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1 | 28.9 percentage of patients |
| Palonosetron 20 mcg/kg | Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1 | 38.8 percentage of patients |
| Ondansetron | Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1 | 28.4 percentage of patients |