Aprepitant Vs. Placebo Plus Oral Ondansetron and Dexamethasone for the Prevention of Nausea and Vomiting Associated with Highly Emetogenic Preparative Regimens Prior to Hematopoietic Stem Cell Transplantation: A Prospective, Randomized Double-Blind Phase III Trial.

Both acute and delayed nausea and vomiting are a major problem for patients undergoing highly emetic high dose preparative regimens prior to hematopoietic stem cell transplant (HSCT). Aprepitant (APR) is an NK-1 antagonist FDA approved for the prevention of N/V due to standard dose highly and moderately emetogenic chemotherapy. While several small Phase II studies have suggested its benefit in HSCT, no completed prospective comparisons have been reported. In addition as APR is known to interact with cytochrome P450 isoenzymes involved in the bioactivation of high dose cyclophosphamide, and may interfere with etoposide pharmacokinetics, its impact on regimen related toxicity and long term survival post transplant is unknown.

We performed a randomized (1:1 randomization) blinded Phase III trial to determine the safety and efficacy of APR for N/V due to ablative preparative regimens. Patients received either placebo (PBO) or oral APR 125mg PO day 1 then 80mg daily during and for 3 days after the preparative regimen was completed, in addition to oral ondansetron 8 mg PO q 8hrs + IV dexamethasone daily during and for 1 day after the preparative regimen. Only PRN lorazepam was permitted for nausea. Due to a known drug interaction between APR and dexamethasone, patients also received blinded dexamethasone doses of 10mg on the placebo arm and 7.5mg on the APR arm. Patients were stratified based on gender, and patients with heavy ETOH use were excluded. Clinical evaluations were performed daily during therapy with the primary endpoint being a CR, defined as: no emesis and no or mild nausea [less than grade (gr) 3 using CTC 2.0 criteria]. Other endpoints included; major response (MR): 1 episode of emesis or moderate nausea; minor response (mR): 2–4 episodes of emesis; and failure (F) : >4 episodes of emesis. Major efficacy (ME) = CR + MR. Other analyses performed included subjective nausea based on a 100 mm visual analog scale (VAS) with 0 = no nausea; amount of PRN antiemetics used to control breakthrough N/V and no emesis all days.. Safety analyses performed included time to engraftment, 30 day survival and progression free survival (PFS) and overall survival (OS). The study began 9/20/04 and completed enrollment 7/18/08. The study was powered (90 pts per arm) to detect a difference of 20 % between the two groups with a significance level of 0.05 using a two-sided t-test. The 181 randomized patients were balanced with respect to age, weight, donor source and h/o N/V with prior chemotherapy. Patients received one of 5 ablative prep regimens: CY/TBI/VP16 (36), CY/TBI (79), IV BU/CY (14), PO BU/CY (34), and BCV(16) Two pts never proceeded to transplant so only 179 pts are eligible for analysis. Ten pts (6 APR/4 PBO) failed to complete the study; data were analyzed as intent to treat.

Efficacy: There was a difference in CR rate (primary endpoint) in favor of APR: 81.9% vs 65.8 % for those receiving PBO with 48.9% vs 14.6% respectively meeting this endpoint for the entire study period (p<0.001). In addition, 73.3% of the APR group never experienced a single episode of emesis during the study vs 22.5% of the PBO group (p<0.001). Other response rates were as follows: MR: APR 16% PBO 21.6% (p= 0.011); mR: APR 2.0% PBO 10.3% (p<0.001); F: APR 0.1% PBO 2.2% (p<0.001) ME: APR 97.9% PBO 87.4% (p<0.001). Ave VAS was 16.5 % for the APR group vs 16.9% for the PBO group (0.892). Heartburn was more common in the APR arm (12/90) vs. PBO (6/89) Safety: Days to engraftment for the PBO vs APR groups: ANC: 11.7 vs 11.5d (p = NS), PLT: 14.1 vs 16.4d (p = NS); 30 day survivals were the same for the two groups. The PFS was 28.3 vs 28.6 months for the APR and PBO groups (p=0.8206) and overall survival was identical in the two groups as well (p = 0.5446).

When used daily up to 10 days with ablative preparative regimens, aprepitant significantly improved control of acute and delayed regimen-related N/V with a major impact on emesis rates. It appears safe for this indication with no impact on WBC and PLT engraftment as well as PFS and OS.

Stiff:Merck: Research Funding. Off Label Use: Aprepitant in BMT setting.