A randomized, open label, parallel-group, phase 3 study to investigate the efficacy and tolerability of palonosetron, dexamethasone, aprepitant plus Olanzapine versus palonosetron, dexamethasone and aprepitant alone in patients receiving high moderately emetogenic chemotherapeutic (MEC) regimens (OMEC study)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 560
- 试验地点
- 1
- 主要终点
- Objectives The primary objective is to compare an antiemetic regimen consisting of aprepitant, palonosetron, dexamethasone and olanzapine (active arm) and a regimen consisting of aprepitant, palonosetron, and dexamethasone, (control arm) with respect to complete response (CR); the proportion of subjects with no vomiting, no significant nausea (scored as 5 on a scale of 1-100) and no use of rescue medications during pre-specified high MEC protocols for 1 cycle of chemotherapy
研究概览
简要总结
Study rationale
Chemotherapy induced nausea and vomiting (CINV) are unpleasant and worrisome side effects associated with the administration of chemotherapy. Improved control of emesis positively
impacts quality of life in patients receiving chemotherapy and lack of adequate control also reflects adversely on quality of life (1). While current antiemetic regimens have markedly reduced the incidences of vomiting across chemotherapy regimens, control of nausea has not been as effective with lesser importance also having been given to this equally important and distressing side effect(2,3).
The term ‘Moderately emetogenic chemotherapy (MEC)’ is a mixed bag of regimens with varying incidences of CINV (30%-90%) with currently used antiemetic regimens. The currently approved antiemetic regimen for MEC is the combination of a 5 HT3 antagonist and dexamethasone, with the exception of regimens using carboplatin AUC >4, where the addition of a neurokinin (NK)1-receptor antagonist (RA) is recommended(4,5). Besides Carboplatin, other chemotherapeutic agents which may be considered to have high to moderate emetogenic potential include Irinotecan and Irinotecan based combination regimens(6).
The addition of NK1-RA antagonists has improved complete response rates in HEC and MEC regimens - however, 20% - 38% of patients still do not achieve complete response (CR)(7,8). Beyond not achieving CR, a majority of the seminal clinical trials have not concentrated on control of nausea. While acute, and to a certain extent delayed vomiting control rates have improved, control of nausea still remains low. The lack of control of nausea is one of the major reasons for a lag between control of vomiting and CR rates for nausea and vomiting.
Olanzapine is one of the recommended drugs for use in highly emetogenic chemotherapy (HEC) regimens (9,10). Known as an atypical antipsychotic agent of the thiobenzo-diazepine class, olanzapine was approved by the USA FDA (Food and Drug Administration) for the treatment of the manifestations of psychotic disorders in 1996. Olanzapine blocks multiple neurotransmitter receptors including dopaminergic D1, D2, D3, D4 brain receptors, serotonergic 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamine alpha1 adrenergic receptors, acetylcholine muscarinic receptors, and histamine H1 receptors. Moreover, olanzapine may reduce opioid requirements in cancer patients with uncontrolled pain, cognitive impairment, or anxiety. Due to the broad and potent inhibitory activity of olanzapine at multiple receptors involved in the nausea and vomiting pathways, this agent is an effective treatment as well as prophylaxis for CINV. It is also a significant inhibitory effect on nausea from available data. Besides its efficacy in CINV, it is also a low cost medication with a tolerable safety profile. Side effects may include mild short-term sedation, as well as weight gain and an increased risk of diabetes mellitus with prolonged use (>6 months). The efficacy of Olanzapine has been shown in small Phase 2 and retrospective studies when used as an additional antiemetic in MEC(11–13). However, there is no phase 3 study examining the role of olanzapine in MEC.
The purpose of this study is therefore to investigate in a randomized manner, if the addition of Olanzapine to the combination of a 5-HT3-RA (palonosetron) plus a corticosteroid (dexamethasone) and NK1-RA improves the antiemetic efficacy in patients receiving specific ‘high’ MEC regimens.
The assessment of quality of life in cancer patients as per patient reported outcomes of a treatment sometimes differ in comparison with the clinical objective outcome. Keeping this in mind, we will also investigate the patient reported outcomes with respect to nausea and vomiting. As part of this, the Functional Living-Index Emesis (FLIE) questionnaire will be used as part of the study.
primary hypothesis The addition of Olanzapine to palonosetron, dexamethasone and aprepitant combination will increase the CR rates [(the proportion of subjects with no vomiting, no significant nausea (scored as < 5 on a scale of 1-100) and no use of rescue medications] during high MEC regimens.
研究设计
- 研究类型
- Interventional
- 分配方式
- Stratified block randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 19.00 Year(s) 至 90.00 Year(s)（—）
- 性别
- All
入选标准
- •1.Patients has a confirmed diagnosis of one of the cancers mentioned previously and is receiving one of the mentioned chemotherapy protocols mentioned previously.
- •2.The patient understands the nature and purpose of this study and the study procedures and has signed informed consent.
- •3.The patient is aged > 18 years.
- •4.Patients should be chemotherapy naïve.
- •5.The patient has a WHO Performance Status of ≤
- •6.Hematologic and metabolic status must be adequate for receiving planned chemotherapy, and meet the following criteria: Total neutrophils ≥ 1500/mm3 Platelets ≥ 100,000/mm3 Bilirubin ≤ 1.5 x ULN (Upper Limits of Normal) Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3 x ULN GFR ≥ 50 ml/min
- •The patient is able to read, understand, and complete questionnaires and daily components of the Patient Diary for each study cycle.
- •For patients of childbearing potential, urine human chorionic gonadotropin (hCG) (urine dipstick pregnancy test) or blood hCG results must be negative at screening.
- •Has a normal baseline ECG with no QTc prolongation.
排除标准
- •1.The patient is unable to read, understand, and complete the forms required for the study.
- •2.The patient is pregnant or lactating.
- •3.The patient has experienced emesis (i.e., vomiting and/or retching) or clinically significant nausea (defined as nausea graded as moderate or severe) in the 24 hours preceding the first dose of study medication.
- •4.The patient has a history active peptic ulcer disease, significant or symptomatic, acute or subacute gastrointestinal obstruction, increased intracranial pressure,severe cognitive impairment, known central nervous system disease (e.g. brain metastases/ a seizure disorder).
- •hypercalcemia, or any uncontrolled medical condition (other than malignancy) which in the opinion of the Investigator may confound the results of the study, represent another potential etiology for emesis and nausea (other than CINV) or pose an unwarranted risk to the patient.
- •The patient has a known hypersensitivity or contraindication to palonosetron, another 5-HT3 receptor antagonist, dexamethasone, aprepitant or olanzapine 7.The patient has received an investigational drug in the previous 6 months or is scheduled to receive any investigational drug other than fosaprepitant dimeglumine during the study period 8.The patient has taken/received any medication of moderate or high emetogenic potential within the 48 hours prior to the first dose of study medications.
- •Opiate drugs for cancer pain will be permitted if the patient has been on a stable dose and has not experienced emesis or clinically significant nausea from the narcotics in the 24 hours preceding the first dose of study medication.
- •9.The patient has taken/received any medication with known or potential antiemetic activity within the 24-hour period prior to receiving study drugs.
- •This is inclusive of, but not limited to 5 HT3 antagonists, metoclopramide, benzodiazepines, phenothiazines, haloperidol, oral or intravenous steroids, antihistamines, domperidone, olanzapine, antipsychotics.
- •10.Patient on antipsychotics or being planned to receive any of the antiphychotics, amifostine in last 3 months.
- •11.Patient has received concurrent abdominal radiotherapy in last 3 months or being planned to receive the same.
- •12.Patient is receieving or will likey to receive concurrent use of quinolone antibiotic therapy.
- •13.Patient with the history of chronic alcoholism.
- •14.Patient with cardiac arrhythmia, uncontrolled/ controlled heart failure, or acute coronary event or uncontrolled diabetes mellitus within the previous 6 months.
- •15.Has taken drugs which may influence medications used in the study, e.g. CYP inducers or inhibitors.
- •This will have to be evaluated for and decision taken by PI.
结局指标
主要结局
Objectives The primary objective is to compare an antiemetic regimen consisting of aprepitant, palonosetron, dexamethasone and olanzapine (active arm) and a regimen consisting of aprepitant, palonosetron, and dexamethasone, (control arm) with respect to complete response (CR); the proportion of subjects with no vomiting, no significant nausea (scored as 5 on a scale of 1-100) and no use of rescue medications during pre-specified high MEC protocols for 1 cycle of chemotherapy
时间窗: 42 months
次要结局
- 1.To compare the olanzapine containing regimen to the control arm with respect to no emesis rates(2.to compare the olanzapine containing regimen to the control arm with respect to proportion of patients with no significant nausea 3.olanzapine containing regimen to the control arm with respect to CR rates 4.FLIE questionnaire 5.tolerance and side effects with both regimens)