A phase II trial of netupitant/palonosetron for prevention of chemotherapy-induced nausea/vomiting in patients receiving BEAM prior to hematopoietic cell transplantation

Objective: The purpose of this study was to investigate the efficacy and safety of netupitant/palonosetron (NEPA) for the prevention of chemotherapy-induced nausea and vomiting (CINV) for hematopoietic cell transplantation (HCT) patients receiving BEAM therapy. Study Design: This phase II, prospective, intention-to-treat, single-center, single-arm study involved 43 adult patients who received NEPA and dexamethasone for the prevention of CINV due to BEAM conditioning chemotherapy. An interim analysis, performed after 13 patients, determined utility versus futility, and supported continuation to full enrollment. Descriptive statistics were used to report complete response (CR), complete protection, incidence of emesis, and administration of rescue agents. A Kaplan–Meier curve depicted time to first emesis and first rescue medication. Patients self-reported levels of daily nausea descriptively via a CINV Questionnaire. Results: By study end, 13 of 43 patients achieved a CR with an average of 10.6 emesis-free days (SD 0.95) over the 11-day observation period, with no emetic events in any patient during the acute/chemotherapy phase. Nausea was well-controlled throughout the acute therapy phase (Day 1–6) and increased during the delayed phase (Day 7–11) with a peak mean level of 2.79/10 at Day 10. Aside from lower grade (≤2), headaches, constipation, and diarrhea were the most widely reported adverse effects. Conclusion: The combination of NEPA and dexamethasone is safe and effective for the prevention of CINV in patients receiving BEAM conditioning therapy prior to HCT. The regimen demonstrated greater effectiveness in the acute phase versus the delayed phase, with low levels of nausea throughout the study period and complete emesis prevention during chemotherapy.


Introduction
Chemotherapy-induced nausea and vomiting (CINV) prevention in hematopoietic cell transplantation (HCT) populations undergoing highly emetogenic chemotherapy (HEC) is an area of open research as newer neurokinin-1 receptor antagonists (NK-1 RAs) have not yet been integrated into all practice guidelines.Additionally, consideration of CINV in this population has only recently been addressed by evidence-based guidelines such as the American Society of Clinical Oncology (ASCO) and Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO). 1,2Highly emetogenic pre-HCT conditioning regimens are reported to have up to 90% frequency of emesis, impacting patient quality of life (QOL). 3][6] A common regimen used for CINV prevention in HCT patients includes the prophylactic use of a serotonin receptor antagonist (5-HT3 RA), an NK-1 RA, and dexamethasone, a regimen that aligns with the strongest recommendations provided in the updated 2020 ASCO guidelines. 1,6etupitant/palonosetron (NEPA) is a fixed-dose combination antiemetic consisting of an NK-1 RA, netupitant, and a 5-HT3 RA, palonosetron.Netupitant, along with other NK-1 RAs, has shown significant in vitro and in vivo activity against substance P and subsequent efficacy in preventing nausea and vomiting in the postchemotherapeutic phase. 7The additive inhibition of 5-HT3 by palonosetron provides a synergistic action against vomiting; palonosetron is unique in that it also interferes with 5-HT3/NK-1 communication channels and, concomitant with netupitant, promotes the internalization of NK-1 receptors. 8ulti-day emetogenic chemotherapy regimens developed for HCT (e.g., BEAM therapy-carmustine, etoposide, cytarabine, and melphalan) have received more attention in guideline recommendations for CINV in recent years as management of CINV from HCT-related conditioning regimens continues to be a poorly studied area with unmet patient needs.The ASCO Antiemetic Update (2020) strongly recommends patients undergoing high-dose chemotherapy prior to HCT should receive dexamethasone, a 5-HT3 RA, and an NK-1 RA with an additional weak recommendation that olanzapine be added on the basis of low-quality evidence. 1][11] At the time this trial began, the use of NEPA for the prevention of CINV in multi-day regimens and specifically in patients undergoing BEAM conditioning therapy prior to HCT had not been investigated.It represents a different challenge from conventional multi-day chemotherapy in that not only is it 6 days in length but has high emesis risk agents on the first and last days of the regimen.

Design
This phase II, investigator-initiated, single-center clinical trial was conducted at Oregon Health & Science University, in Portland, Oregon.The study design and all procedures were approved by the OHSU Institutional Review Board.Prior to treatment, all patients provided written informed consent.The rationale of the study was to determine the safety and efficacy of NEPA during the acute and delayed CINV phases surrounding BEAM therapy.

Patient population
Adult patients (≥18 years) met inclusion criteria if they were undergoing autologous HCT with the BEAM conditioning regimen, had an Eastern Cooperative Oncology Group performance status ≤2, had swallowing capability, and were able to understand, willingly consent, and sign documentation expressing their consent to participate in the study.Inpatient and outpatient clinic patients were eligible for inclusion in the study.
Exclusion criteria included subjects with known allergies or hypersensitivities to any study drugs, exposure to other investigational agents (last 30 days), prior emesis or antiemetic use within 48 h from start of HCT conditioning, previous use of NK-1 antagonists within 14 days from start of the BEAM regimen, significant renal or liver dysfunction, concurrent illness requiring systemic corticosteroids, medical history of gastrointestinal malabsorption issues or anticipatory nausea and vomiting, strong CYP3A4-inhibitor or -inducer drug exposure within 7 days of study commencement, benzodiazepine use on a regular basis, use of QT-prolonging medications, or presence of medical/family history of QT prolongation at time of enrollment.A full list of exclusions can be viewed in the Supplementary Information.

Treatment description
Patients received the study drug, NEPA, 60 min (±30 min) prior to chemotherapy on Days −6, −4, and −1.The dose of NEPA was standardized at 300 mg/0.5 mg by mouth with no dose modifications.Given the discordant half-lives of palonosetron (∼40 h) and netupitant (∼80 h), the midregimen NEPA dose on Day −4 was added to ensure adequate serotonin blockade. 12Additionally, dexamethasone 12 mg by mouth was given 60 min (±30 min) prior to chemotherapy on Day −6 and 8 mg by mouth was given once daily on Days −5 through −1.The study dose of dexamethasone is equivalent to the 20 mg/day standard due to the drug interaction between netupitant and dexamethasone; the systemic exposure of dexamethasone increases two-fold when used concomitantly with NEPA.Of note, at the time of study design development, olanzapine was not a first-line recommendation and was thus not included as part of prophylaxis. 13Rescue antiemetics were permitted for breakthrough nausea or vomiting, with the choice of rescue agent determined by the provider.Patients were not given additional 5-HT3 RA as rescue medications until after Day 0. All outside medications that interact with NEPA were prohibited during the study; all study treatments, concomitant medications, or previously received medications (within 15 days) were recorded.

Assessments
Patients were assessed daily beginning with the date of first NEPA administration through Day +4 of the study period.To assess nausea, a self-reported QOL/nausea assessment form (CINV Questionnaire; Appendix 2) was completed daily.In both the clinic and inpatient setting, each day's assessment form was provided by health care personnel and collected after patient documentation.The CINV Questionnaire included the incidence of nausea and vomiting, the degree of nausea experienced (1-10; Table 1) and information on meal consumption.Additionally, emetic episodes (including emesis and retching) were also charted by the patient's nurse and verified with the patient; maximum incidence of emesis was reported if irreconcilable discordance between reports was present.

Response definitions
Potential responses ranged from treatment failure (TF) to complete response (CR).In subjects receiving 6 days of chemotherapy and 4 days of observation after cell infusion, TF was defined as >2 episodes of emesis within any one day of the conditioning regimen or 2 emetic episodes on ≥3 days of the conditioning regimen.Minor response was defined by 1-2 episodes of emesis for 1-3 days with any degree of nausea.Partial response was defined by ≤2 episodes of emesis within any one day of the conditioning regimen or <2 episodes of emesis on >3 days of the conditioning regimen.Complete response was defined by lack of emesis, presence of mild to moderate nausea, and no reported need for rescue therapy.Of note, this definition is similar to that for "complete protection" (CP) or "complete control" (CC) used in other related studies; however, we have redefined CP in our study as the absence of emesis, nausea, and need for rescue medications. 14,15Patients not completing the 11-day observation period would be excluded from the CR calculation.Major response (MR) was defined as 1-2 episodes of emesis within one day only in addition to any degree of nausea or a lack of emesis with severe nausea.All of these definitions refer to events occurring during the 11-day observation period.Emesis occurring within 2 h of administration of DMSO-containing stem cell infusions is excluded from response definitions.

Objectives
The primary objective of this study was to investigate the efficacy of NEPA for the prevention of CINV during and after the BEAM conditioning regimen.This objective was assessed through measuring response rates to therapy for hours 0-264 which encompasses the 6-day chemotherapy period and the 5-day post-chemotherapy period.To determine the action of NEPA through the phases of therapy, the response was also analyzed during the acute phase (0-144 h) and delayed phase (145-264 h), to assess whether differential benefit was experienced during the two segments of the observation period.

Statistical methods
The study followed an intention-to-treat analysis.To determine utility or futility of the study, Stage 1 of the study enrolled 13 patients, with a subsequent enrollment of 30 patients in Stage 2 after an interim analysis.The study stopping rule for lack of benefit was if ≤3 patients had a CR after enrollment of 13 patients.This outcome was not observed, and the study proceeded to full enrollment.A sample size of 43 total subjects was necessary to achieve 80% power with a historical CR rate of 20% in accordance with standard of care and a desired NEPA response rate of 40%.Of note, the definition of CR has evolved over time.The aforementioned historical CR rate is a conservative estimate and reflects the accepted CR rate over time despite slight definition variations of CR applied in historical studies.
For each time phase, the proportion of patients with CR and CP and the incidence of emetic episodes and rescue agents taken were reported descriptively.Additionally, mean and median levels of nausea per day and median time to a heightened level of nausea (per CINV Questionnaire report) were also reported descriptively.Kaplan-Meier curves were used to show time to first emesis and time to first rescue.

Safety
Adverse events and toxicities were presented descriptively and categorized per the National Cancer Institute Common Toxicity Criteria (NCI CTCAE v.4.03) with a focus on the incidence of Grade 3 events or higher.

Patient characteristics
The study enrolled 43 patients undergoing BEAM therapy in preparation for HCT.All patients had a variant of lymphoma without sufficient sample size for comparison between groups.The majority of the study patients were male, and the most common indication for HCT was Hodgkin lymphoma or diffuses large B-cell lymphoma (Table 2).

Efficacy
After receiving NEPA, the average number of emesis-free days was 10.6 (SD 0.95) out of 11.Forty-two patients completed the acute and delayed phases of the study with one patient with limited evaluability due to early death unrelated to NEPA.Of patients completing the overall study, 13 (30.9%)achieved a CR, 25 (59.5%)achieved an MR, and 3 (7.1%)achieved CP, while 1 (2.4%) patient experienced TF as defined in the study protocol (Figure 1).With respect to emesis, NEPA prevented vomiting in 100% of patients within the acute phase and 81% within the delayed phase (Figure 2).Treatment efficacy can be further extrapolated from time to first rescue medication, which was primarily prochlorperazine.Per a Kaplan-Meier time analysis, the median time to rescue in the acute phase occurred after 3 days, with 14% of patients receiving a rescue medication by that time point (Figure 3(a)).Rescue medication use markedly increased beginning on the last day of chemotherapy (Day −1) with 44% of patients requiring rescue medication.Overall, the mean time to first rescue medication between both phases was 5.9 days (Figure 3(b)).By Day +4, only 16% of patients were free from rescue.

Quality of life results
Prospectively collected, self-reported levels of nausea were low during the acute phase of BEAM therapy, with average levels of 0.7/10 over Days −6 through −1 (Figure 4).
Incidence of nausea during the acute phase was similar between women (n = 9/16; 56.25%) and men (n = 15/27; 55.55%).Levels of nausea steadily increased during the delayed phase with mean self-reported levels peaking at 2.79/10 by Day +3.Rates of nausea during the delayed stages trended higher among females, with occurrence rates reaching 93% (n = 14/15) versus only 74% (n = 20/ 27) in males, indicating a potential reduction in effect over time respective to the male group.Dietary consumption was maintained throughout the study period with the majority of individuals reporting normal to increased dietary intake on Days −6 to +1 with the beginning of a decreasing trend on Day +2 (Supplemental Figure 1).

Discussion
Patients receiving moderately and highly emetogenic, multi-day chemotherapy regimens are at significant risk of experiencing CINV.Successful management of CINV remains a challenge for HCT patients in particular, with emetic side-effects persisting despite current treatment strategies which limit HCT as an outpatient therapy.The current study assessed the role of NEPA in combination with dexamethasone for the prevention of CINV for HCT patients receiving BEAM therapy.The regimen of NEPA administered prior to chemotherapy on Day −6, −4, and −1 with daily dexamethasone is in accordance with current NCCN guidelines. 9Although NCCN Guidelines now recommend the addition of olanzapine to provide a four-drug regimen for HEC chemotherapy, this recommendation is derived from a non-HCT population study where patients underwent single-day HEC, which is incongruent with the context of our study. 16In a phase III trial comparing fosaprepitant, ondansetron, and dexamethasone with and without olanzapine for the prevention of CINV in HCT patients (26.5-29.4% received BEAM), a significant improvement in CR (defined by no emesis and no more than minimal nausea) and rates of nausea were seen in the olanzapine group. 17Additionally, the complete side effect profile of olanzapine in this setting is unclear as formal sedation assessments were omitted from the study design.Although cross-comparison with our study is not feasible due to differences in study design and response definitions, the efficacy of a 3-drug regimen (NEPA and dexamethasone) demonstrated herein suggests that patient exposure to additional drug therapy may be unwarranted.
The results of this investigation indicate that NEPA evokes an overall MR and CR in 60% and 31% of patients, respectively, with CP from emesis within the acute phase, low levels of self-reported nausea (with a mean peak of 2.79/10 on Day +3), and a relatively low incidence of emesis in the delayed phase (19%).These findings suggest that NEPA, in combination with dexamethasone, is effective for preventing CINV in the setting of highly emetogenic therapy.
Investigations introducing aprepitant, the first approved NK-1 RA, indicated safety and some efficacy of the regimen-particularly within the acute phase.Deauna-Limayo et al. investigated the multi-day use of aprepitant, dexamethasone, and palonosetron for HCT patients undergoing either BEAM or melphalan treatment. 15They found that only one patient in the acute and delayed phase achieved a CR (as defined by no emetic episodes or rescue medications received).The investigators also assessed CC which they defined as a CR plus a Nausea Visual Score ≤2.5/10; they found a 56% rate of CC in the acute phase, followed by a decrease to only 33% in the delayed phase.They concluded that the triple therapy was safe in this population but that further evaluations were needed.
Examining the safety and efficacy of antiemetic medications can be challenging as patient response can be influenced by a number of clinical and patient-specific factors, one of them being gender. 18As discussed in the Supplementary Information, rates of CINV are significantly higher in females compared to males.In our study, differences in rates of CR among females and males under 55 years were 11% and 18.3%, respectively; for males and females 55 years and older, the CR differences were 15% and 11.7%, respectively.
Commonly reported (10-37%) side effects of 5-HT3 RAs and corticosteroid combination regimens include headache, diarrhea, and constipation. 19,20Similarly, this study reports diarrhea and constipation rates of 42% and 56%, respectively.As headache incidence with NEPA has been extensively reported, only headaches above Grade 2 were reported within the current study and none met these criteria. 14,21,22Furthermore, while recent guideline recommendations (NCCN, ASCO)-that were published post-initiation of our study-are inconsistent on whether a four-drug regimen with olanzapine is needed for HCT patients, the threedrug regimen described herein still demonstrates the efficacy for HCT patients undergoing multi-day chemotherapy without subjecting patients to additional olanzapine-related sedation. 1,9However, recent reports of olanzapine-induced reductions in delayed-phase CINV warrant additional studies to combine NEPA and olanzapine to test whether delayedphase efficacy benefits would counterbalance sedating adverse effects. 17,23polito et al. studied NEPA in 70 multiple myeloma patients after treatment with the two-day high-dose melphalan regimen. 24The investigators defined CR as the absence of emesis and rescue medications post-infusion for 120 h.They found a CR rate of 83% (66/80 procedures), with a large percentage of patients (98%) reporting lack of emesis and nausea with a significant percentage of patients free from nausea (78%) during the acute phase.In alignment with the present study, Apolito et al. also found a substantially lower success rate in preventing nausea in the delayed phase, with a steep decline to only 39%.As discussed in the Supplementary Information, a common confounder in the assessment of antiemetic agents in the delayed phase is the distinction between the effect of irreversible chemotherapy toxicity versus the potentially reversible activity of substance P and less often, 5-HT3. 25o further investigate this concern, we incorporated patient diet tolerance into our daily assessment and found that a small percent of patients reported decreased meal consumption at a steady rate as they progressed through Day +1 to Day +4 of the delayed phase.If delayed nausea is a result of fullness secondary to GI dysmotility, increased doses or duration of NEPA or other antiemetics may not be effective in resolving nausea in this setting.Additionally, this may support the use of shorter follow-up periods as to avoid linking antiemetic efficacy or lack thereof with irreversible nausea in the setting of GI toxicity.
A similar study using NEPA for CINV prevention in autologous HCT patients undergoing BEAM therapy was recently reported and is notable for excluding the use of dexamethasone. 26Di Renzo et al. found that the use of NEPA alone was well-tolerated and resulted in a CR, as defined by lack of emesis and need for rescue medication, of 87% during the overall phase (Days −6 to +1).Additionally, they noted an acute phase CR response (Days −6 to −1) of nearly 89%, and delayed-phase CR response of over 98%.Subsequently, the investigators implied that dexamethasone may be excluded as a part of future CINV regimens but it is pertinent to note that Di Renzo et al. did not incorporate nausea incidence into the CR definition, potentially confounding the absentee effect of dexamethasone and making their results less comparable to the present trial.More importantly, the majority (56.1%) of patients in this study received fotemustine, etoposide, cytarabine, and melphalan, which contain moderately emetogenic fotemustine in place of highly emetogenic carmustine; only 28% of patients received BEAM as a conditioning regimen.This reduced emetogenic potential as well as a shorter observation period of 8 versus 11 days may be significant confounders in the interpretation of this study.
Compared to previous studies, the present study is conservative in expressing the overall efficacy of NEPA as nausea is included in the CR definition.As nausea compromises the patient QOL, excluding it from the primary outcome could provide a disservice to our patients.Although necessary, this inclusion of nausea prevents direct comparisons of the lower CR (31%) reported herein to similar studies by Di Renzo, Apolito, and Deauna-Limyao, as emesis alone is a less-sensitive outcome measure than emesis and nausea together. 15,24,26Despite these differences, the results of this study are valuable in assessing real-world targets for patients suffering from CINV and the investigators herein encourage subsequent studies to integrate a similar assessment of nausea into primary study objectives to further serve this patient population.
In addition to the variances between this trial and other similar trials already discussed, this study has limitations that should be considered when interpreting these results.Although powered for this sample size, it is an uncontrolled phase II study and result interpretation would have benefited from a comparison group.These results would be best validated by a randomized, controlled phase III trial.Additionally, the patient population was predominately male (63%) and results in females may not be fully characterized by these data.Finally, this is the first study using three doses of NEPA in this proximity, and there may be side effects that are not fully appreciated that were not seen in this trial.
Given the efficacy of the NEPA regimen described herein during the chemotherapy delivery period, this may be a particularly attractive prospect for outpatient delivery of the BEAM regimen which encompassed 55.8% of our patients. 9Although the cost of NEPA is initially higher, it can be offset by savings through decreased inpatient hospital day use as described in the Supplementary Information. 12,27,28For patients receiving highly emetogenic BEAM therapy in the setting of autologous HCT, the use of NEPA and dexamethasone is efficacious and safe in preventing CINV, with a greater effect during the acute response period with no observed vomiting episodes during chemotherapy administration days.The results of this investigation indicate that NEPA evokes an overall MR and CR in 60% and 31% of patients, respectively, with CP from emesis within the acute phase, low levels of selfreported nausea (with a mean peak of 2.79/10 on Day +3), and a relatively low incidence of emesis in the delayed phase (19%).These findings suggest that NEPA, in combination with dexamethasone, is effective for preventing CINV in the setting of highly emetogenic therapy.Complete lack of emesis during the chemotherapy delivery phase is a departure from our current experience with ondansetron, dexamethasone, and aprepitant-our institution's standard emetic prevention for the BEAM regimen.

Conclusion
The combination of NEPA and dexamethasone is safe and effective for the prevention of CINV in patients receiving BEAM conditioning therapy prior to HCT.The regimen demonstrated greater effectiveness in the acute phase versus the delayed phase, with low levels of nausea throughout the study period and complete emesis prevention during chemotherapy.

Figure 1 .
Figure 1.The percentage of patients achieving each response definition ‡ within the overall study period (0-264 h): Complete protection (CP), major response (MR), complete response (CR), and treatment failure (TF) ‡Complete protection (CP): The complete absence of emesis, no nausea, and no rescue therapy in subjects who have received all 6 days of chemotherapy and 5 days of observation.Major Response (MR): One or two episodes of emesis on only one day with any level of nausea or no emesis with severe nausea.Complete Response (CR): The complete absence of emesis, mild to moderate nausea, and no rescue therapy in subjects who have received all 6 days of chemotherapy and 5 days of observation.Treatment Failure (TF): More than 2 episodes of emesis on any one day of the conditioning regimen or 2 emetic episodes on >3 days of the conditioning regimen.

Figure 2 .
Figure 2. The percentage of patients that experienced vomiting within the acute phase (0-144 h) and the delayed phase (145-264 h).

Figure 3 .
Figure 3. (a) A cumulative incidence curve that represents the percentage of patients that received rescue medications within the acute phase (0-144 h) and the delayed phase (145-264 h).(b) A cumulative incidence curve that represents the percentage of patients that received rescue medications within the overall study period (0-264 h).

Figure 4 .
Figure 4.The mean (a) and median (b) level of nausea (1-10) reported by patients daily throughout the overall study period (Day −6 to Day +4); BEAM conditioning therapy spanned the days (Day −6 to Day −1) leading up to hematopoietic cell transplantation (HCT) (Day 0).
Auto: autologous stem cell transplant; BMI: body mass index; BSA: body surface area.