Chemotherapy-Induced Nausea and Vomiting
Conditions
Brief summary
NETU-08-18 is a two-arm clinical study assessing efficacy and safety of a single oral dose of netupitant and palonosetron, two antiemetic drugs, versus oral palonosetron, both given with oral dexamethasone. The objective of the study is to demonstrate that netupitant and palonosetron are more effective than palonosetron alone, to prevent nausea and vomiting induced by moderately emetogenic cancer chemotherapy after administration of repeated cycles of chemotherapy.
Detailed description
NETU-08-18 is a two-arm clinical study assessing efficacy and safety of a single oral dose of netupitant and palonosetron, two antiemetic drugs, versus oral palonosetron, both given with oral dexamethasone. Study is organised in two phases: cycle-1 and a multi-cycle extension. Safety assessment is performed separately in cycle 1 (arm 1 and arm 2) and in multi-cycle extension (arm 3 and arm 4).
Interventions
Sponsors
Parexel
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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Naïve to cytotoxic chemotherapy. Previous biological or hormonal therapy will be permitted. * Scheduled to receive first course of an anthracycline and cyclophosphamide containing moderately emetogenic chemotherapy (MEC) regimen for the treatment of a solid malignant tumor: cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. doxorubicin (more or equal to 40 mg/m2) or cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. epirubicin (more or equal to 60 mg/m2). * If scheduled to receive chemotherapy agents of minimal to low emetogenic potential they could be given on any day. * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. * Female patients of either non-childbearing potential or child-bearing potential with a commitment to use contraceptive methods throughout the clinical trial * Hematologic and metabolic status adequate for receiving a moderately emetogenic regimen based on laboratory criteria (Total Neutrophils,Platelets, Bilirubin, Liver enzymes, Serum Creatinine or Creatinine Clearance) The following inclusion criteria must be checked prior inclusion at each cycle of the Multiple-Cycle Extension: * Participation in the study during the next cycle of chemotherapy is considered appropriate by the investigator Satisfactory study compliance in the preceding cycle of chemotherapy and related study procedures. * Scheduled to receive the same chemotherapy regimen as cycle 1 * Adequate hematologic and metabolic status as defined for cycle 1
Exclusion criteria
* If female, pregnant or lactating. * Current use of illicit drugs or current evidence of alcohol abuse. * Scheduled to receive any highly emetogenic chemotherapy (HEC) from Day 1 to Day 5 or moderately emetogenic chemotherapy (MEC) from Day 2 to Day 5 following the allowed MEC regimen. * Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to Day 1 or between Days 1 to 5 in cycle 1. * Any vomiting, retching, or mild nausea within 24 hours prior to Day 1. * Symptomatic primary or metastatic central nervous system (CNS) malignancy. * Active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcemia, an active infection or any uncontrolled medical condition (other than malignancy) that, in the opinion of the investigator, may confound the results of the study, represent another potential etiology for emesis and nausea (other than chemotherapy-induced nausea and vomiting, CINV) or pose unwarranted risks in administering the study drugs to the patient. * Known hypersensitivity or contraindication to 5-HT3 receptor antagonists or dexamethasone. * Previously received a neurokin-1 (NK1) receptor antagonist * Participation in a clinical trial involving oral netupitant administered in combination with palonosetron. * Any investigational drugs taken within 4 weeks prior to Day 1 of cycle 1, and/or is scheduled to receive any investigational drug during the study. * Systemic corticosteroid therapy at any dose within 72 hours prior to Day 1 of cycle 1. * Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy. * Any medication with known or potential antiemetic activity within 24 hours prior to Day 1 of cycle 1 * Scheduled to receive any strong or moderate inhibitor of cytocrome P450 3A4 (CYP3A4) or its intake within 1 week prior to Day 1. * Scheduled to receive any of the following CYP3A4 substrates: terfenadine, cisapride, astemizole, pimozide. * Scheduled to receive any CYP3A4 inducer or its intake within 4 weeks prior to Day 1. * History or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block. * History of risk factors for Torsade de Point (heart failure, hypokalemia, family history of Long QT Syndrome). * Severe cardiovascular diseases, including myocardial infarction within 3 months prior to Day 1, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic Congestive Heart Failure (CHF) New York Heart Association (NYHA) class III-IV, and severe uncontrolled arterial hypertension. * Any illness or condition that, in the opinion of the investigator, may confound the results of the study or pose unwarranted risks in administering the investigational product to the patient. * Concurrent medical condition that would preclude administration of dexamethasone such as systemic fungal infection or uncontrolled diabetes. The following
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, at Cycle 1 | 25-120 hours |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication at Cycle 1 | 0-24 hours |
| Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, at Cycle 1 | 0-120 hours |
Countries
Argentina, Belarus, Brazil, Bulgaria, Croatia, Germany, Hungary, India, Italy, Mexico, Poland, Romania, Russia, Ukraine, United States
Participant flow
Pre-assignment details
1455 patients randomized (ITT population), 1450 received study drug i.e. netupitant/palonosetron combination or palonosetron, both with dexamethasone, in cycle 1 (safety population-cycle 1), 1449 received chemotherapy and study drug (FAS), 1286 received study drug in multi-cycle extension (safety population-multi-cycle extension)
Participants by arm
| Arm | Count |
|---|---|
| Netupitant and Palonosetron Plus Dexamethasone Oral netupitant/palonosetron (300 mg/0.50 mg) hard capsule with oral dexamethasone, both given on Day 1, prior to each scheduled chemotherapy cycle
Netupitant and Palonosetron
Dexamethasone | 725 |
| Palonosetron Plus Dexamethasone Oral palonosetron 0.50 mg (Aloxi) with oral dexamethasone both given on Day 1, prior to each scheduled chemotherapy cycle
Palonosetron
Dexamethasone | 725 |
| Total | 1,450 |
Baseline characteristics
| Characteristic | Netupitant and Palonosetron Plus Dexamethasone | Palonosetron Plus Dexamethasone | Total |
|---|---|---|---|
| Age, Continuous | 53.7 years STANDARD_DEVIATION 10.66 | 54.1 years STANDARD_DEVIATION 10.65 | 53.9 years STANDARD_DEVIATION 10.65 |
| Race/Ethnicity, Customized Asian | 101 participants | 103 participants | 204 participants |
| Race/Ethnicity, Customized Black | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Hispanic | 46 participants | 36 participants | 82 participants |
| Race/Ethnicity, Customized Other | 3 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized White | 574 participants | 579 participants | 1153 participants |
| Sex: Female, Male Female | 711 Participants | 711 Participants | 1422 Participants |
| Sex: Female, Male Male | 14 Participants | 14 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 551 / 725 | 507 / 725 | 533 / 635 | 527 / 651 |
| serious Total, serious adverse events | 13 / 725 | 12 / 725 | 23 / 635 | 15 / 651 |
Outcome results
Primary
Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, at Cycle 1
Time frame: 25-120 hours
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Netupitant and Palonosetron Plus Dexamethasone | Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, at Cycle 1 | 76.9 percentage of responders |
| Palonosetron Plus Dexamethasone | Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, at Cycle 1 | 69.5 percentage of responders |
Comparison: The null hypothesis was rejected if the 2 sided p value from the Cochran Mantel Haenszel test was less than or equal to 0.050 and in the right direction i.e., the Odds Ratio (OR) was in favor of netupitant/palonosetron. Power was 90%.p-value: 0.00195% CI: [1.16, 1.87]Cochran-Mantel-Haenszel
Secondary
Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication at Cycle 1
Time frame: 0-24 hours
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Netupitant and Palonosetron Plus Dexamethasone | Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication at Cycle 1 | 88.4 percentage of responders |
| Palonosetron Plus Dexamethasone | Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication at Cycle 1 | 85.0 percentage of responders |
Comparison: CR in the acute phase was to be tested using the same 2 sided CMH test as for the primary endpoint. netupitant/palonosetron combination was to be considered superior to palonosetron in the acute phase if the 2 sided p value from the CMH was less than or equal to 0.050 and in the right direction.p-value: 0.04795% CI: [1, 1.87]Cochran-Mantel-Haenszel
Secondary
Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, at Cycle 1
Time frame: 0-120 hours
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Netupitant and Palonosetron Plus Dexamethasone | Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, at Cycle 1 | 74.3 percentage of responders |
| Palonosetron Plus Dexamethasone | Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, at Cycle 1 | 66.6 percentage of responders |
Comparison: CR in the overall phase was to be tested using the same 2 sided CMH test as for the primary endpoint. netupitant/palonosetron combination was to be considered superior to palonosetron in the overall phase if the 2 sided p value from the CMH was less than or equal to 0.050 and in the right direction.p-value: 0.00195% CI: [1.17, 1.85]Cochran-Mantel-Haenszel