Efficacy and Safety Addition of Low Dose Olanzapine to the Standard Prophylaxis of Nausea and Vomiting Induced by Highly-emetogenic Chemotherapy in Children and Adolescents (OZONE-V)
Overview
- Phase
- Phase 3
- Enrollment
- 210
- Locations
- 1
- Primary Endpoint
- Complete control of vomiting
Overview
Brief Summary
Chemotherapy-induced nausea and vomiting continues to be a significant problem in children and adolescents. Standard antiemetic therapy, including a 5-HT3 antagonist, aprepitant, and a corticosteroid, achieves complete control in less than 50% of patients. Studies have shown that the addition of large doses of olanzapine improves control, including in children and adolescents. However, olanzapine has not yet been included in standard recommendations in the pediatric population. Studies in adults indicate that the dose of the drug can be halved without loss of effectiveness and with a decrease in toxicity. This open-label, randomized, phase III trial evaluates the efficacy and safety of adding low-dose olanzapine to standard prevention of nausea and vomiting induced by highly emetogenic chemotherapy in children and adolescents.
Detailed Description
After signing informed consent, eligible patients are randomized with stratification (previously received or not received high emetogenic therapy; regimens with and without cisplatin) to receive the first cycle of highly emetogenic chemotherapy with standard prophylaxis (5-HT3 receptor antagonist, dexamethasone, aprepitant) with or without addition of 0.07 mg/kg olanzapine (rounded to multiples of 2.5 mg, maximum 5 mg). During chemotherapy and 120 hours after its completion, patients are assessed for the presence and absence, as well as the severity of CINV, the need for "rescue" therapy, and the development of adverse events. In the future, patients undergo a similar course of highly emetogenic chemotherapy with a change in the antiemetic prophylaxis option - crossover (patients who received an olanzapine regimen as antiemetic prophylaxis after the first cycle of chemotherapy receive treatment without it, patients who received prophylaxis without olanzapine receive a second cycle of therapy with olanzapine). After this cycle, the presence and absence, as well as the severity of CINV, the need for salvage therapy, the development of adverse events are assessed and, additionally, at the end of the cycle, patients are asked about the preferred option for further antiemetic prophylaxis (the regimen with olanzapine, no olanzapine, or no preferences).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 5 Years to 18 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age from 5 to 18 years.
- •Body weight ≥ 30 kg.
- •Confirmed diagnosis of malignancy.
- •Planned at least 2 cycles of highly emetogenic chemotherapy according to the Pediatric Ontario Cancer Group (POGO) emetogenicity classification.
- •ECOG status \<
- •Adequate function of internal organs (bilirubin \< 1.5 upper limit of normal (ULN), ALT and AST \<2.5 ULN, creatinine \< 1.5 ULN).
- •Ability to swallow study drug.
- •The presence of a written voluntary informed consent of the patient and / or his legal representative.
Exclusion Criteria
- •Treatment with olanzapine or another antipsychotic drug within the last 30 days.
- •Planned use of antibiotics from the group of fluoroquinolones or other drugs that have drug interactions with olanzapine and other drugs used in the study (amifostin, citalopram, CYP1A2 inducers or inhibitors).
- •The presence of intensive CINV against the background of a previous similar cycle of chemotherapy, which does not allow prescribing standard antiemetic prophylaxis upon inclusion in the study.
- •The presence of a convulsive syndrome.
- •Hypersensitivity to olanzapine or other drugs used in the study.
- •Uncontrolled arterial hypertension or cardiovascular disorders, uncontrolled diabetes mellitus, or other diseases and conditions that, in the opinion of the physician, preclude study therapy.
- •The presence of other factors (other than ongoing highly emetogenic therapy) that can cause the development of CINV (radiotherapy to the abdominal cavity or pelvis 1 week or less before inclusion in the study, obstruction of the gastrointestinal tract, uncontrolled intracranial hypertension, etc.).
- •Severe CINV of any intensity 24 hours or less before the first dose of chemotherapy.
- •Pregnancy or breastfeeding.
- •Planned use of systemic glucocorticosteroids at the time of inclusion in the study.
Arms & Interventions
Control group
- Weight category 30-40 kg will receive: dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (80 mg)
- Weight category > 40 kg will receive:
dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (125 mg) Note: aprepitant at a dose of 80 mg/day. applied for another 2 days, regardless of the number of days of chemotherapy.
Intervention: Ondansetron (Drug)
Control group
- Weight category 30-40 kg will receive: dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (80 mg)
- Weight category > 40 kg will receive:
dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (125 mg) Note: aprepitant at a dose of 80 mg/day. applied for another 2 days, regardless of the number of days of chemotherapy.
Intervention: Dexamethasone (Drug)
Control group
- Weight category 30-40 kg will receive: dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (80 mg)
- Weight category > 40 kg will receive:
dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (125 mg) Note: aprepitant at a dose of 80 mg/day. applied for another 2 days, regardless of the number of days of chemotherapy.
Intervention: Aprepitant (Drug)
Olanzapine
- Weight category 30-40 kg will receive:
dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (80 mg), olanzapine (2.5 mg) 2. Weight category > 40 kg will receive: dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (125 mg), olanzapine (2.5 mg for <55 kg, 5 mg for >55 kg) Note: aprepitant at a dose of 80 mg/day. applied for another 2 days, regardless of the number of days of chemotherapy.
Intervention: Ondansetron (Drug)
Olanzapine
- Weight category 30-40 kg will receive:
dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (80 mg), olanzapine (2.5 mg) 2. Weight category > 40 kg will receive: dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (125 mg), olanzapine (2.5 mg for <55 kg, 5 mg for >55 kg) Note: aprepitant at a dose of 80 mg/day. applied for another 2 days, regardless of the number of days of chemotherapy.
Intervention: Dexamethasone (Drug)
Olanzapine
- Weight category 30-40 kg will receive:
dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (80 mg), olanzapine (2.5 mg) 2. Weight category > 40 kg will receive: dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (125 mg), olanzapine (2.5 mg for <55 kg, 5 mg for >55 kg) Note: aprepitant at a dose of 80 mg/day. applied for another 2 days, regardless of the number of days of chemotherapy.
Intervention: Aprepitant (Drug)
Olanzapine
- Weight category 30-40 kg will receive:
dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (80 mg), olanzapine (2.5 mg) 2. Weight category > 40 kg will receive: dexamethasone (5 mg/m2), ondansetron (0.15 mg/kg), aprepitant (125 mg), olanzapine (2.5 mg for <55 kg, 5 mg for >55 kg) Note: aprepitant at a dose of 80 mg/day. applied for another 2 days, regardless of the number of days of chemotherapy.
Intervention: Olanzapine (Drug)
Outcomes
Primary Outcomes
Complete control of vomiting
Time Frame: up to 21 days
proportion of patients who did not have episodes of vomiting and/or use of additional antiemetic drugs (rescue therapy) during the chemotherapy cycle and within 120 hours after its completion
Patient preference
Time Frame: up to 42 days
Proportion of patients who, after crossover, chose to continue treatment with an experimental regimen including olanzapine
Adverce events
Time Frame: up to 42 days
Percentage of patients with grade 3-4 adverse events according to CTCAE v. 5.0. \[Time frame: day(s) of chemotherapy administration and 120 hours after chemotherapy administration\]
Secondary Outcomes
- Complete control of acute vomiting(up to 21 days)
- Complete control of chemotherapy-induced nausea and vomiting (CINV)(up to 21 days)