APF530 or Aloxi (Palonosetron Hydrochloride) Combined With Dexamethasone in Preventing Nausea and Vomiting in Patients Receiving Chemotherapy for Cancer

Study Overview
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Brief Summary
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This randomized phase III trial is studying APF530 and dexamethasone to see how well they work compared with palonosetron and dexamethasone in preventing nausea and vomiting in patients receiving chemotherapy for cancer.

Detailed Description
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OBJECTIVES: Primary Compare the overall activity and effects of APF530 versus palonosetron hydrochloride in combination with dexamethasone for prophylaxis of acute- or delayed-onset, chemotherapy-induced nausea and vomiting in patients undergoing moderately or highly emetogenic chemotherapy for cancer. Secondary Evaluate the safety, tolerability, and efficacy of APF530, in terms of prevention of acute- and delayed-onset nausea and vomiting, in these patients. Gather the pharmacokinetics of APF530 in a subset of patients during chemotherapy course 1. Gather ECG data (using 24-hour Holter monitoring) in a subset of patients during chemotherapy course 1. OUTLINE: This is a randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Patients are stratified according to emetogenicity of scheduled chemotherapy (moderate-risk [level 3 or 4] vs high-risk [level 5]). Patients are randomized to 1 of 3 treatment arms (I, II, and III). Patients who are randomized to receive palonosetron hydrochloride during chemotherapy course 1 (arm I) are then re-randomized to 1 of 2 treatment arms (II and III) after chemotherapy course 1 to receive treatment during chemotherapy courses 2-4. Patients receive palonosetron hydrochloride or APF530 and/or placebo 30-60 minutes before the start of chemotherapy. Patients receive dexamethasone 30-90 minutes before the start of chemotherapy. Arm I: Patients receive palonosetron hydrochloride IV, placebo subcutaneously (SC), and dexamethasone IV on day 1 of chemotherapy course 1. Patients in the high-risk (level 5) stratum also receive oral dexamethasone on days 2-4 of all treatment courses. Arm II: Patients receive APF530 SC, placebo IV, and dexamethasone IV on day 1 of chemotherapy course 1. Patients then receive APF530 SC and dexamethasone IV on day 1 of chemotherapy courses 2-4. Patients in the high-risk (level 5) stratum also receive oral dexamethasone as in arm I. Arm III: Patients receive APF530 SC at a higher dose, placebo IV, and dexamethasone IV on day 1 of chemotherapy course 1. Patients then receive APF530 SC (at the same higher dose) and dexamethasone IV on day 1 of chemotherapy courses 2-4. Patients in the high-risk (level 5) stratum also receive oral dexamethasone as in arm I. A subset of patients undergo blood collection periodically during study for analysis of plasma APF530 concentration. Quality of life is assessed on day 5 after completion of chemotherapy course 1. After completion of study treatment, patients are followed at approximately 30 days.

Official Title
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A Pivotal Phase 3 Observer-Blind, Randomized Clinical Trial of the Efficacy and Safety of APF530 Compared to Aloxi For The Prevention of Acute-Onset and Delayed-Onset Chemotherapy-Induced Nausea and Vomiting Following The Administration of Either Moderately or Highly Emetogenic Chemotherapy Regimens

Conditions
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Nausea and Vomiting, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: APF530
* Drug: dexamethasone
* Drug: Palonosetron Hydrochloride
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed malignant disease No head and neck cancer or upper gastrointestinal cancer Scheduled to receive a single day of moderately or highly emetogenic chemotherapy regimen (for ≤ 4 courses) Chemotherapy administration ≤ 4 hours Duration of each course ≤ 28 days Causing nausea and vomiting in 30-100% of patients if untreated according to Hesketh algorithm Must be able to receive standardized doses of dexamethasone for the prevention of emesis during study treatment No greater than mild nausea or any vomiting within 24 hours before beginning study treatment PATIENT CHARACTERISTICS: ECOG performance status 0-2 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No known allergy or hypersensitivity to other selective 5-HT3 receptor antagonists or local anesthetics QTc interval ≤ 500 ms No cardiac abnormality predisposing the patient to arrhythmia No psychological problem that, in the opinion of the investigator, is severe enough to preclude study participation No recent history (i.e., ≤ 1 year) of alcohol or drug abuse No concurrent condition that, in the opinion of the investigator, could affect assessment of study medication or interfere with the nausea/vomiting response (e.g., severe renal or hepatic impairment) PRIOR CONCURRENT THERAPY: See Disease Characteristics No radiotherapy 7 days prior to, during, and 5 days after completion of study treatment More than 7 days since prior chemotherapy More than 7 days since prior and no concurrent prohibited medications (e.g., CYP3A4 inhibitors or other antiemetic medications) More than 7 days since prior antinausea medications More than 30 days since prior treatment on an investigational trial No other concurrent corticosteroids or dexamethasone at a different dose than study treatment No concurrent use of APF530, palonosetron hydrochloride, or aprepitant as rescue medications

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>Patients receive palonosetron hydrochloride IV, placebo subcutaneously (SC), and dexamethasone IV on day 1 of chemotherapy course 1. Patients in the high-risk (level 5) stratum also receive oral dexamethasone on days 2-4 of all treatment courses. | Drug: dexamethasone<br>* Given IV and orally<br>Drug: Palonosetron Hydrochloride<br>* Given IV<br>Other: placebo<br>* Given subcutanously or IV<br>|
| Experimental: Arm II<br>Patients receive APF530 SC, placebo IV, and dexamethasone IV on day 1 of chemotherapy course 1. Patients then receive APF530 SC and dexamethasone IV on day 1 of chemotherapy courses 2-4. Patients in the high-risk (level 5) stratum also receive oral dexamethasone as in arm I. | Drug: APF530<br>* Given subcutanously<br>Drug: dexamethasone<br>* Given IV and orally<br>Other: placebo<br>* Given subcutanously or IV<br>|
| Experimental: Arm III<br>Patients receive APF530 SC at a higher dose, placebo IV, and dexamethasone IV on day 1 of chemotherapy course 1. Patients then receive APF530 SC (at the same higher dose) and dexamethasone IV on day 1 of chemotherapy courses 2-4. Patients in the high-risk (level 5) stratum also receive oral dexamethasone as in arm I. | Drug: APF530<br>* Given subcutanously<br>Drug: dexamethasone<br>* Given IV and orally<br>Other: placebo<br>* Given subcutanously or IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Complete Response (CR) During Acute Phase (0-24 Hours) After Administration of Chemotherapy Course 1 | Complete Response is defined as no emetic episodes and no use of rescue medications | 0-24 Hours | 
| Proportion of Patients With CR During Delayed-onset Phase (24-120 Hours) After Administration of Chemotherapy Course 1 | Complete Response is defined as no emetic episodes and no use of rescue medications | 24-120 Hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Complete Control During the Acute Phase (0-24 Hours), Delayed-onset Phase (24-120 Hours), and During Chemotherapy Course 1 | Complete control is defined as complete response with no more than mild nausea. | 0-120 Hours | 
| Proportion of Patients With Total Response During the Acute Phase, Delayed-onset Phase, and During Chemotherapy Course 1 | TR during acute phase is defined as Complete Response with no nausea during 0 to 24 hours following the administration of chemotherapy in Cycle 1. TR during delayed-onset phase is defined as Complete Response with no nausea during >24 to 120 hours following the administration of chemotherapy in Cycle 1. TR during overall risk period is defined as Complete Response with no nausea during 0 to 120 hours following the administration of chemotherapy in Cycle 1. | 0-120 Hours | 
| Number of Emetic Episodes | Number of Emetic Episodes - days 1-5 | Days 1-5 | 
| Time to First Treatment Failure | Proportions of subjects event free at 24, 48, 72, 96, and 120 hours after chemotherapy administration | 0-120 Hours | 
| First and Overall Use of Rescue Medication |  | 0-120 Hours | 
| Severity of Nausea Daily and During Chemotherapy Course 1 (0-120 Hours) | Maximum severity of nausea, days 1-5 | 0-120 Hours | 
| Sustainability of Antiemetic Effect of APF530 Over Multiple Chemotherapy Courses | Sustainability of Overall Complete Response (CR 0-120 hrs) Over Two, Three, and Four Cycles Complete Response is defined as no emetic episodes and no use of rescue medications | 0-120 Hours | 
| Quality of Life and the Impact of Nausea and Vomiting on Day 5 | Functional Living Index | 5 days | 
| Patient's Global Satisfaction With Antiemetic Therapy During Acute Phase and Chemotherapy Course 1 | Subject who were very satisfied on Day 1 | 0- 24 Hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nausea and vomiting, unspecified adult solid tumor, protocol specific