Chemotherapy-induced Nausea and Vomiting
Conditions
Brief summary
Multicenter, randomized, double-blind, double-dummy, parallel group, stratified study assessing the safety and describing the efficacy of a single dose of intravenous (IV) fosnetupitant/palonosetron (260 mg/0.25 mg) infusion \[test\] versus oral netupitant/palonosetron (300 mg/0.5 mg) combination \[control\]; each administered with oral dexamethasone prior to initial and repeated cycles of AC chemotherapy in female breast cancer patients.
Interventions
DRUGfosnetupitant/ palonosetron
intravenous fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed-dose combination
oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination
DRUGdexamethasone
Oral dexamethasone (12 mg)
Sponsors
Emerald Clinical Inc.
The Physicians' Services Incorporated Foundation
Helsinn Healthcare SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cycle 1: The following inclusion criteria must be checked prior to inclusion at Cycle 1: 1. Patient read, understood and signed the written informed consent before any study related activity, agreeing to participate in the study and to comply with study requirements. 2. Female patient of at least 8 years of age. 3. Histologically or cytologically confirmed breast cancer, including recurrent or metastatic. 4. Naïve to moderately or highly emetogenic antineoplastic agents. 5. Scheduled to receive at least 4 consecutive cycles of an AC combination regimen. Notes: 1. additional not emetogenic, minimally or low emetogenic antineoplastic agents are permitted at any time after start of AC combination on Day 1. 2. additional highly or moderately emetogenic antineoplastic agents are only allowed on Day 1 after the start of AC combination, provided their administration is completed within 6 hours from the start of the AC combination administration. 6. ECOG Performance Status of 0 or 1. 7. Patient shall be: a) of non-childbearing potential or b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test within 24 hours prior to dose of investigational product. Notes: 1. Female patients of non-childberaring potential are defined as being in post-menopausal state since at least 1 year; or having documented surgical sterilization or hysterectomy at least 3 months before study participation. 2. Reliable contraceptive measures include implants, injectables, combined oral contraceptives, intrauterine devices, vasectomized partner or complete (long term) sexual abstinence; 8. Hematologic and metabolic status adequate for receiving a cycle of AC chemotherapy based on investigator's assessment. 9. If the patient has a known hepatic or renal impairment, she may be enrolled in the study at the discretion of the Investigator. 10. Able to read, understand, follow the study procedure and complete the patient diary. All inclusion criteria will be checked at screening visit (Visit 1 of Cycle 1); inclusion criteria 7 will be re-checked at Day 1 (Visit 2). Cycles 2 to 4: The following inclusion criteria must be checked prior to inclusion at each repeated cycle: 1. Participation in the study during the next cycle of chemotherapy is considered appropriate by the Investigator and does not pose unwarranted risk to the patient. 2. Scheduled to receive an AC chemotherapy regimen or AC chemotherapy together with other chemotherapies as defined in Inclusion criterion #5 for Cycle 1. 3. Patient shall be: a) of non-childbearing potential or b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test within 24 hours prior to dosing of investigational product. 4. Adequate hematologic and metabolic status for receiving a cycle of AC chemotherapy according to the Investigator's opinion. All inclusion criteria will be checked at screening visit (Visit 1); inclusion criterion #3 will be re-checked at Day 1 (Visit 2).
Exclusion criteria
Cycle 1: The following
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Study-Drug-Related TEAEs Reported for ≥2% of Patients in Either Treatment Group Throughout the Study | At the end of Cycle 4 (each cycle is 21 days) |
| Number of Participants With Treatment-emergent AEs at Cycle 1 | At the end of Cycle 1 (each cycle is 21 days) |
| Number of Participants With Treatment-emergent AEs All Cycles | At the end of Cycle 4 (each cycle is 21 days) |
| Number of Participants With Severe (i.e., CTCAE Grade ≥3) TEAEs Reported for ≥2% of Patients in Either Treatment Group and Overall Throughout the Study | At the end of Cycle 4 (each cycle is 21 days) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response in Cycle 1 During the Acute Phase | 24 hours after the start of AC chemotherapy administration | defined as no emetic episodes \[vomit or retch\] and no rescue medication |
| Complete Response in Cycle 1 During the Delayed Phase | 120 hour after the start of AC chemotherapy administration | defined as no emetic episodes \[vomit or retch\] and no rescue medication |
| Complete Response in Cycle 1 During the Overall Phase | 0-120 hours after the start of AC chemotherapy | defined as no emetic episodes \[vomit or retch\] and no rescue medication |
| Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1 | cycle 1 | Percentage (including two-sided 95% CI using Wilson score method) of patients with NIDL based on FLIE scores (overall, by domain, and by individual item) are summarized by treatment group. NIDL was defined as a score greater than 108 points, 54 points, and 6 points for total FLIE score, domain score, and single item score, respectively. Differences between treatment groups for total FLIE score and domain scores (nausea and vomiting) were presented with two-sided 95% CIs using the CMH method adjusted for region and age class strata and also using Newcombe-Wilson's method without strata adjustment. No Impact on Daily Life (NIDL) Based on Functional Living Index-Emesis (FLIE) Scores. The FLIE is a nausea and vomiting specific self report instrument comprised of two domains (nausea and vomiting) with nine identical items in each domain |
Countries
Georgia, United States
Participant flow
Pre-assignment details
202 patients were randomized to IV NEPA and 202 patients were randomized to Oral NEPA. Two randomized patients (Patient IDs 211003 and 213001) in the IV NEPA group did not receive any active study drug or AC chemotherapy.
Participants by arm
| Arm | Count |
|---|---|
| Test Group intravenous fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed-dose combination, administered as a 30-minute infusion of a 50 mL solution, on Day 1 of each cycle.
Oral dexamethasone will be administered on Day 1 of each cycle (12 mg)
fosnetupitant/ palonosetron: intravenous fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed-dose combination
dexamethasone: Oral dexamethasone (12 mg) | 200 |
| Control Group oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination on Day 1 of each cycle.
Oral dexamethasone will be administered on Day 1 of each cycle (12 mg)
netupitant/palonosetron: oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination
dexamethasone: Oral dexamethasone (12 mg) | 202 |
| Total | 402 |
Baseline characteristics
| Characteristic | Test Group | Total | Control Group |
|---|---|---|---|
| Age, Continuous | 55.6 years STANDARD_DEVIATION 9.94 | 55.4 years STANDARD_DEVIATION 9.82 | 55.2 years STANDARD_DEVIATION 9.73 |
| Age, Customized <55 years | 89 Participants | 180 Participants | 91 Participants |
| Age, Customized >55 years | 111 Participants | 222 Participants | 111 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 15 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 192 Participants | 381 Participants | 189 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 6 Participants | 5 Participants |
| Fertility Status of childbearing potential | 59 Participants | 111 Participants | 52 Participants |
| Fertility Status post menopausal | 120 Participants | 248 Participants | 128 Participants |
| Fertility Status surgically sterile | 21 Participants | 43 Participants | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 13 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 9 Participants | 5 Participants |
| Race (NIH/OMB) White | 189 Participants | 375 Participants | 186 Participants |
| Region of Enrollment Georgia | 27 participants | 60 participants | 33 participants |
| Region of Enrollment Russia | 89 participants | 181 participants | 92 participants |
| Region of Enrollment Ukraine | 43 participants | 79 participants | 36 participants |
| Region of Enrollment United States | 41 participants | 82 participants | 41 participants |
| Sex: Female, Male Female | 200 Participants | 402 Participants | 202 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 200 | 0 / 202 |
| other Total, other adverse events | 184 / 200 | 187 / 202 |
| serious Total, serious adverse events | 5 / 200 | 4 / 202 |
Outcome results
Primary
Number of Participants With Severe (i.e., CTCAE Grade ≥3) TEAEs Reported for ≥2% of Patients in Either Treatment Group and Overall Throughout the Study
Time frame: At the end of Cycle 4 (each cycle is 21 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test Group | Number of Participants With Severe (i.e., CTCAE Grade ≥3) TEAEs Reported for ≥2% of Patients in Either Treatment Group and Overall Throughout the Study | 37 Participants |
| Control Group | Number of Participants With Severe (i.e., CTCAE Grade ≥3) TEAEs Reported for ≥2% of Patients in Either Treatment Group and Overall Throughout the Study | 29 Participants |
Primary
Number of Participants With Study-Drug-Related TEAEs Reported for ≥2% of Patients in Either Treatment Group Throughout the Study
Time frame: At the end of Cycle 4 (each cycle is 21 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test Group | Number of Participants With Study-Drug-Related TEAEs Reported for ≥2% of Patients in Either Treatment Group Throughout the Study | 16 Participants |
| Control Group | Number of Participants With Study-Drug-Related TEAEs Reported for ≥2% of Patients in Either Treatment Group Throughout the Study | 22 Participants |
Primary
Number of Participants With Treatment-emergent AEs All Cycles
Time frame: At the end of Cycle 4 (each cycle is 21 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test Group | Number of Participants With Treatment-emergent AEs All Cycles | 184 Participants |
| Control Group | Number of Participants With Treatment-emergent AEs All Cycles | 187 Participants |
Primary
Number of Participants With Treatment-emergent AEs at Cycle 1
Time frame: At the end of Cycle 1 (each cycle is 21 days)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test Group | Number of Participants With Treatment-emergent AEs at Cycle 1 | 121 Participants |
| Control Group | Number of Participants With Treatment-emergent AEs at Cycle 1 | 122 Participants |
Secondary
Complete Response in Cycle 1 During the Acute Phase
defined as no emetic episodes \[vomit or retch\] and no rescue medication
Time frame: 24 hours after the start of AC chemotherapy administration
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test Group | Complete Response in Cycle 1 During the Acute Phase | 173 Participants |
| Control Group | Complete Response in Cycle 1 During the Acute Phase | 179 Participants |
Secondary
Complete Response in Cycle 1 During the Delayed Phase
defined as no emetic episodes \[vomit or retch\] and no rescue medication
Time frame: 120 hour after the start of AC chemotherapy administration
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test Group | Complete Response in Cycle 1 During the Delayed Phase | 151 Participants |
| Control Group | Complete Response in Cycle 1 During the Delayed Phase | 159 Participants |
Secondary
Complete Response in Cycle 1 During the Overall Phase
defined as no emetic episodes \[vomit or retch\] and no rescue medication
Time frame: 0-120 hours after the start of AC chemotherapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test Group | Complete Response in Cycle 1 During the Overall Phase | 146 Participants |
| Control Group | Complete Response in Cycle 1 During the Overall Phase | 156 Participants |
Secondary
Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1
Percentage (including two-sided 95% CI using Wilson score method) of patients with NIDL based on FLIE scores (overall, by domain, and by individual item) are summarized by treatment group. NIDL was defined as a score greater than 108 points, 54 points, and 6 points for total FLIE score, domain score, and single item score, respectively. Differences between treatment groups for total FLIE score and domain scores (nausea and vomiting) were presented with two-sided 95% CIs using the CMH method adjusted for region and age class strata and also using Newcombe-Wilson's method without strata adjustment. No Impact on Daily Life (NIDL) Based on Functional Living Index-Emesis (FLIE) Scores. The FLIE is a nausea and vomiting specific self report instrument comprised of two domains (nausea and vomiting) with nine identical items in each domain
Time frame: cycle 1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Test Group | Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1 | total score | 74.0 percentage of participants |
| Test Group | Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1 | Nausea domain score | 67.5 percentage of participants |
| Test Group | Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1 | Vomiting domain score | 87.5 percentage of participants |
| Control Group | Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1 | total score | 78.7 percentage of participants |
| Control Group | Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1 | Nausea domain score | 68.3 percentage of participants |
| Control Group | Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1 | Vomiting domain score | 90.6 percentage of participants |