Oral Neurokinin-1 Antagonist, Aprepitant, in Combination With Ondansetron and Dexamethasone in Patients Undergoing Autologous Peripheral Blood Stem Cell Transplantation

Condition(s) targeted: Chemotherapy Induced Nausea and Vomiting; Non-Hodgkins Lymphoma; Multiple Myeloma

Intervention: aprepitant (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Washington University School of Medicine

Official(s) and/or principal investigator(s):
John DiPersio, MD,PhD, Study Chair, Affiliation: Washington University School of Medicine

Overall contact:
Kristan Augustin, Pharm.D., Phone: 314-454-8512, Email: kma3852@bjc.org

The purpose of this study is to determine if the use of aprepitant in patients undergoing bone marrow transplants will lead to a reduction in symptoms of nausea and vomiting.

Official title: A Study Evaluating the Efficacy and Safety of the Oral Neurokinin-1 Antagonist, Aprepitant, in Combination With Ondansetron and Dexamethasone in Patients Undergoing Autologous Peripheral Blood Stem Cell Transplantation

Study design: Treatment, Randomized, Single Blind, Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome:

nausea/vomiting as defined below

Emetic control will be defined by the number of emetic episodes (see definitions) occurring within a 24-hour period, or the requirement for rescue medication. Emetic control will be defined as follows:

Complete: no episodes of emesis or nausea in any 24-hour period after administration of study antiemetics, with no rescue antiemetics needed.

Major: One or two episodes of nausea or vomiting, or the need for antiemetic rescue medication.

Minor: Three to five episodes of nausea or vomiting.

Treatment failure: More than five emetic episodes

Emetic episodes will be defined as single vomit or retch, or any number of continuous vomits or retches; distinct episodes must be separated by at least one minute.

Nausea61: A subjective, unobservable phenomenon of an unpleasant sensation in the back of the throat and the epigastrium that may or may not culminate in vomiting.

Vomiting61: The forceful expulsion of the contents of the stomach, duodenum or jejunum through the oral cavity.

Retching61: The unsuccessful attempt to vomit without expelling gastrointestinal contents.

Acute phase62: The first 24 hours after initiation of chemotherapy.

Delayed phase62: Nausea and vomiting occurring 24 hours after initiation of chemotherapy administration. It may begin as early as 16 hours after chemotherapy administration.

Anticipatory CINV62: Nausea and vomiting occurring as a result of a conditioned response from previous chemotherapy treatment.

Breakthrough CINV62: Nausea and vomiting occurring despite preventive therapy.

Refractory CINV62: Nausea and vomiting occurring during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy (or both) has failed in earlier cycles

Objective Measurements

7.3.1.1 Proportion of patients with or without emesis in the acute and delayed phase

7.3.1.2. Number, time to onset, and duration of emetic episodes after chemotherapy administration

7.3.1.3 Need for breakthrough antiemetics

Secondary outcome:

pharmacokinetic parameters as well as Patient Treatment Diary

• Daily while hospitalized, beginning on day 1 of transplant conditioning regimen until count recovery (ANC > 1500 x 2 days) and then weekly until day +30.

• Once discharged, weekly until day + 30 post transplant

• Nausea will be assessed every 24 hours in the patient diary using a 100-mm horizontal visual analog scale

• Patient's number of emetic episodes will be documented

• Record of oral fluid intake

• Quality of life questions pertaining to nausea and vomiting will be assessed

7.3.3 Toxicity Assessment (see Appendix C)

7.3.3.1 Toxicity of the antiemetic regimens will be assessed every 24 hours until count recovery (ANC >1500 x 2 days) and then weekly until day +30.

7.3.3.1.1 Side effects associated with the antiemetics

7.3.3.1.2 Creatinine daily until count recovery (ANC >1500 x 2 days) and then weekly until day +30

7.3.3.1.3 Liver function tests including total bilirubin, AST, ALT, and alkaline phosphatase at least twice weekly until count recovery (ANC >1500 x 2 days) and then weekly until day +30

Detailed description: 1. 1 Chemotherapy Induced Nausea and Vomiting Associated with Bone Marrow Transplantation

Acute and delayed chemotherapy induced emesis remains a persistent problem in the setting of autologous bone marrow transplantation despite premedication with the combination of dexamethasone and serotonin antagonists or metoclopramide. Several factors have been implicated as the cause of emesis, including gastroparesis, central nervous system disease, electrolyte abnormalities, viral infections, reinfusion of bone marrow or peripheral blood stem cells, and the conditioning regimen. The conditioning regimen is often categorized as highly emetogenic, administered on consecutive days, and may contain total body irradiation resulting in several factors associated with nausea and vomiting.

Randomized clinical trials involving serotonin antagonists in the setting of high dose chemotherapy, with or without total body irradiation, followed by transplantation are few. This results in information pertaining to nausea and vomiting being obtained from heterogeneous clinical trials in which the definitions of response, doses of antiemetics, patient characteristics, and risk factors are highly variable. Although serotonin antagonists are known to be safe and effective in preventing emesis associated with high dose chemotherapy, a significant number of patients continue to experience nausea and vomiting. During the conditioning regimen, greater than 50% of the patients experience episodes of emesis despite premedication with a serotonin antagonist. Orchard and colleagues report that in adult and pediatric patients undergoing bone marrow transplantation, the average number of emetic episodes per day are 0. 86 for those receiving dexamethasone and ondansetron and 0. 73 for those receiving dexamethasone and granisetron. Additionally, during administration and within ten days of completion of high dose chemotherapy for transplantation, greater than 80% of the patients complain of nausea or require breakthrough antiemetics with only a modest impact on the frequency and severity of nausea and vomiting. The frequency and severity of nausea and vomiting associated with high dose chemotherapy appears to increase with time and is persistent, lasting throughout the study period or up to 9 days after bone marrow transplant.

1. 2 Neurokinin-1 Antagonists and Chemotherapy Induced Nausea and Vomiting

It has been established that different pathways exist within the body that induce emesis, each relying on a set of different neurotransmitters. Substance P is a neurotransmitter that is located in the neurons innervating the brainstem, the nucleus tractus solitarius, and the area postrema. It acts through the neurokinin-1 (NK-1) pathway and has been implicated in the pathogenesis of emesis. When exogenous substance P was applied to the cells in the nucleus solitarius in ferrets, emesis was induced. Further investigation in ferrets revealed the antiemetic capabilities of the NK-1 antagonists. This data led to the development of a newer class of antiemetics, the NK-1 receptor antagonists which were recently approved by the FDA for prevention of emesis associated with highly emetogenic chemotherapy, including cisplatin.

In vivo, the NK-1 receptor antagonists when compared to a serotonin antagonist, as monotherapy, does not improve the incidence of acute emesis. Additionally, no benefit is observed for preventing acute nausea and vomiting with the combination of a NK-1 receptor antagonist in combination with dexamethasone. However, the real benefit of a NK-1 receptor antagonist appears to be in preventing delayed emesis after administration of cisplatin. When combined with dexamethasone and a serotonin antagonist, the NK-1 receptor antagonist reduced the incidence of delayed emesis after the administration of cisplatin. This combination may provide added benefit in controlling acute and delayed emesis, as well as nausea compared to dual therapy consisting of dexamethasone and a serotonin antagonist.

1. 3 Overview of Aprepitant

Aprepitant (EmendTM, MK-0869, L-754030) is an oral potent and selective NK-1 antagonist which may be effective in preventing chemotherapy induced nausea and vomiting. Although an IV formulation, L-758298, has been included in clinical trials evaluating the safety and efficacy of this compound, a capsule formulation is the proposed formulation to market. In humans, aprepitant capsules have a half life of 9 to 13 hours and a Tmax of 3. 2 to 4. 7 hours. It is metabolized via the CYP3A4 system and is a moderate inhibitor, as well as an inducer of other CYP3A4 substrates. Due to the nature of its metabolism, co-administration of other medications which utilize the CYP3A4 system need to be considered. Several drug interaction studies have been conducted. Diltiazem and ketoconazole both increase the serum concentration of aprepitant, but not above levels shown to be well tolerated. Rifampin significantly reduces the levels of aprepitant found in the blood (AUC reduced approximately 10 fold), resulting in the possibility of reduced efficacy. Warfarin trough concentrations are reduced by approximately 34% when administered with aprepitant, therefore the frequent monitoring of a patient's INR is recommended. There were no significant drug interactions noted with digoxin or ondansetron. Increased AUCs are noted with both methylprednisolone and dexamethasone and dose reduction of these corticosteroids should be considered. Pharmacokinetic data observed in the elderly and in patients with mild or moderate hepatic insufficiency, renal insufficiency, or on hemodialysis did not support the need for dose adjustments in these patient populations. A total of 1377 patients have been included in clinical trials evaluating the safety and efficacy of aprepitant in preventing chemotherapy induced nausea and vomiting. Additionally, it is being evaluated in Phase II and III studies for the treatment of major depressive disorder.

1. 4 Clinical Trials Evaluating the Safety and Efficacy of the Neurokinin-1 Antagonists

Hesketh and colleagues assessed the impact of adding the neurokinin-1 receptor antagonist CJ-11,974 to granisetron and dexamethasone for control of cisplatin induced emesis in a double blind, randomized phase II study. Sixty-one patients were randomized to receive granisetron 10 mcg/kg IV and dexamethasone 20 mg IV thirty minutes prior to cisplatin at a dose of at least 100 mg/m2. In addition, patients were randomized to receive MK-0869 or placebo, 30 minutes prior to and 12 hours after cisplatin and repeated twice daily on days 2 to 5. During days 2 to 5, 42. 9% of the patients receiving study medication had complete control of emesis compared to 30% of the patients receiving placebo. Furthermore, 67. 8% of the study group reported no nausea compared to 36. 6% to placebo. The study drug was well tolerated. More patients receiving the study medication had elevations of blood urea nitrogen compared to placebo, but this was most likely due to age and creatinine clearance abnormalities. The addition of CJ-11,974 to granisetron and dexamethasone compared to placebo appears to significantly reduce the incidence of delayed nausea and vomiting, with relatively minimal toxicity.

A total of 1377 patients have been included in several clinical trials evaluating the safety and efficacy of MK-0869 and its IV prodrug, L-758298. Two clinical trials evaluated L-758298, in chemotherapy naïve patients with various malignancies. The first study (Protocol L758298 004) assessed the efficacy of L-758298 compared to ondansetron 32 mg IV in 53 patients receiving ≥ 50 mg/m2 cisplatin. The dose of L-758298 was increased from 60 mg to 100 mg when less than a complete response was observed in the first 9 patients. Despite inferior control of the acute phase of nausea and vomiting, L-758298 was superior in providing complete control of emesis on days 2 through 7 compared to ondansetron (72% vs. 30%; p=0. 004). A second study compared the combination of L-758298 and dexamethasone (LD) to ondansetron and dexamethasone (OD) in 177 chemotherapy naïve patients receiving ≥ 70 mg/m2 cisplatin (Protocol L-758298 007). Once again in the acute phase, standard therapy consisting of ondansetron and dexamethasone was superior in preventing nausea and vomiting compared to the study medication and dexamethasone (84. 5% vs. 45. 6%). In the delayed phase, L-758298 and dexamethasone were more effective compared to standard therapy (60. 7% vs. 41. 4%). Furthermore, a third group received oral MK-0869 on days 2 through 5 in addition to L-758298 and dexamethasone on day 1. The continued therapy with a NK-1 antagonist was slightly more effective in the delayed phase (LD + MK-0869 66. 1% vs. LD 60. 7% vs. OD 41. 4%).

The above findings established a basis to further evaluate the three different regimens to determine a definitive dose, as well as dosing administration schedule, which would be safe and efficacious in preventing chemotherapy induced emesis. The neurokinin-1 antagonist, morpholine acetal (L-754,030), was evaluated for efficacy and safety by Navari and associates in 159 cisplatin naïve patients with cancer in a multicenter, double-blind, placebo controlled trial. All patients received granisetron 1 mcg/kg IV and dexamethasone 20 mg PO, 30 minutes prior to receiving a dose of 70 mg/m2 or greater of cisplatin. In addition to the granisetron and dexamethasone, patients in group I received on day the NK-1 antagonist on days 1 to 5, group II received the NK-1 antagonist on day 1 and placebo on days 2-5 and group III received placebo on all 5 days. In the acute and delayed phase of emesis, the addition of the neurokinin-1 antagonist significantly reduced the incidence of nausea and vomiting compared to placebo. Acutely, greater than 1 episode of vomiting was observed significantly less in patients receiving the study drug (Groups I and II) compared to the placebo group (Group III) (7% vs. 6% vs. 33%, respectively; p<0. 001). Patients receiving the study drug (Groups I and II) had significantly fewer episodes of emesis during days 2-5 compared to the placebo group with respect to no documented episodes of vomiting (82% vs. 78% vs. 33%, respectively; p<0. 001). Additionally, the patients with complete control of emesis during days 1-5, required significantly less breakthrough medication. The combination of granisetron, dexamethasone and morpholine acetal significantly reduced the incidence of nausea reported on the visual analog scale with minimal or no nausea reported in 49% (group 1), 48 % (group 2) and 25% (group 3) for days 1 to 5 (p<0. 05). Morpholine acetal was well tolerated and no significant differences with respect to adverse events were observed. The addition of this neurokinin-1 antagonist to granisetron and dexamethasone appears to reduce the incidence of chemotherapy induced emesis in both the acute and delayed phase.

Campos and colleagues evaluated the efficacy of the addition of MK-0869 to granisetron and dexamethasone in 351 cisplatin naïve patients with cancer in a randomized, double blind, parallel group multicenter study. All patients receiving cisplatin at a dose of greater than or equal to 70 mg/m2 were randomized to receive granisetron and dexamethasone on the day of chemotherapy (Group I), granisetron, dexamethasone, and MK-0869 on the day of chemotherapy with MK-0869 repeated for 4 days following chemotherapy (Group II), MK-0869 on the day prior to chemotherapy followed by dexamethasone and MK-0869 on the day of chemotherapy with MK-0869 repeated for 4 days following chemotherapy (Group III), or dexamethasone and MK-0869 on the day of chemotherapy with MK-0869 repeated for 4 days following chemotherapy (Group IV). Breakthrough antiemetics were allowed on days 2 to 5 following the administration of cisplatin. The combination of granisetron (day 1), dexamethasone (day 1) and MK-0869 (days 1-5) (Group II) significantly reduced the incidence of acute and delayed emesis and need of breakthrough emesis medication compared to the group which did not receive MK-0869 (Group I).

Treatment Group Without Emesis on Day 1 (%) Without Emesis on Days 2-5 (%) Without emesis or Need for Breakthrough medications (%) Group I 57 29 22 Group II 80* 63* 41** Group III 46 51* 39** Group IV 43 57* 39** * p<0. 01

** p< 0. 05

The study drug, MK-0869, was well tolerated during the study with no difference in the incidence of adverse events amongst the groups except for a higher frequency of diarrhea in patients not receiving granisetron.

A dose ranging study was conducted to determine the optimal dosing regimen of MK-0869 in preventing cisplatin induced induced nausea and vomiting (Protocol MK-0869 040/042). Two fundamental differences were implemented in this study compared to previous clinical trials. A capsule formulation was administered as it had superior bioavailability compared to a tablet formulation and oral dexamethasone 8 mg was administered along with MK-0869 on days 2 through 5. A total of 583 patients received ondansetron 32 mg IV and dexamethasone 20 mg IV on day 1 followed by dexamethasone 8 mg PO on days 2 through 5. In addition to the standard antiemetic therapy, the patients were randomized to receive MK-0869 375 mg PO on day 1 followed by 250 mg PO on days 2 to 5, MK-0869 125 mg PO on day 1 and 80 mg on days 2 to 5, MK-0869 40 mg on day 1 and 25 mg on days 2 to 5, or no MK-0869. Overall, the addition of MK-0869 to standard therapy was superior to standard therapy alone in preventing nausea and vomiting. Additionally, the regimen consisting of 125 mg MK-0869 on day 1 was as effective as 375 mg MK-0869 and superior to the 40 mg regimen in preventing emesis. Thus, the 125/80 mg regimen of MK-0869 is the expected dosing regimen to market.

1. 5 Study Rationale

Currently, the symptomatic success of inpatient and outpatient bone marrow transplant is prohibited by its associated acute and delayed chemotherapy induced nausea and vomiting. Dual therapy with dexamethasone and a serotonin antagonist is frequently insufficient to overcome this problem. Newer agents, such as a neurokinin-1 receptor antagonist, when administered in combination with a corticosteroid and serotonin antagonist, appears to be beneficial in reducing the incidence and severity of acute and delayed emesis associated with moderately and highly emetogenic chemotherapy. Furthermore, the combination of dexamethasone, a serotonin antagonist, and the NK-1 receptor antagonist may reduce the incidence, severity, and frequency of acute and delayed emesis, as well as the need for rescue antiemetics in the setting of high dose chemotherapy followed by bone marrow transplantation.

2. 0 Study Objectives

2. 1 Primary Objectives

2. 1.1 To determine the efficacy of aprepitant in preventing acute and delayed chemotherapy induced nausea and vomiting when administered in combination with intravenous ondansetron and intravenous dexamethasone in the autologous transplant setting.

2. 2 Secondary Objectives

2. 2.1 To measure the severity, frequency, and duration of chemotherapy induced nausea and vomiting in patients receiving aprepitant and compare these results to a control group, not receiving aprepitant.

2. 2.2 To measure the need for breakthrough antiemetics in patients receiving aprepitant and compare these results to the control group.

2. 2.3 To assess the incidence of complications associated with chemotherapy induced nausea and vomiting in patients receiving aprepitant and compare these results to the control group.

2. 2.4 To assess the safety of aprepitant in combination with ondansetron and dexamethasone in the autologous transplant setting.

3. 0 Patient Eligibility Criteria

3. 1 Inclusion Criteria

3. 1.1 Male or female patients 18 years of age or older

3. 1.2. Patients deemed eligible to undergo autologous bone marrow or peripheral stem cell transplant therapy per usual transplant inclusion and exclusion criteria

3. 1.3. Patients with Non-Hodgkins Lymphoma or Multiple Myeloma

3. 1.4. Written informed consent

3. 2 Exclusion Criteria

3. 2.1. Nausea at baseline

3. 2.2. Chronic use of other antiemetic agent(s)

3. 2.3. Gastrointestinal obstruction or active peptic ulcer

3. 2.4. Radiation therapy to pelvis or abdomen within 1 week before or after study day 1

3. 2.5. Allogeneic stem cell transplant recipient

3. 2.6. AST > 3x ULN

3. 2.7. ALT > 3x ULN

3. 2.8. Bili > 3x ULN

3. 2.9. Alk Phos > 3x ULN

3. 2.10. Creatinine >2

3. 2.11. Known hypersensitivity to any component of study regimen

3. 2.12. Pregnant or lactating women

3. 2.13. Participating in a clinical trial which involves other investigational agent(s)

3. 2.14. Patients taking any of the following medications: warfarin, oral contraceptives (except for the administration of stopping menses), tolbutamide, phenytoin, midazolam, ketoconazole, rifampin, paroxetine, and/or diltiazem.

3. 2.15. In reference to the exclusion of patients who report ≥ 5 drinks per day for the last year, we would prefer to collect data on this population. The exclusion criteria will be modified to exclude patients who have a concurrent illness/condition requiring chronic systemic steroid use.

4. 0 Registration

Patients may be enrolled on this study by calling the Siteman Cancer Center Clinical Trials Office at (314) 747-4190.

The following information must be provided:

- Patient's name, date of birth, race, and sex

- Responsible physician

- Diagnosis and date of diagnosis

- Date Informed Consent signed

- Date of Human Studies Committee approval

5. 0 Treatment Plan

Patients will be stratified according to disease and randomized at registration to receive intravenous ondansetron and dexamethasone with or without the addition of oral aprepitant. All chemotherapy premedications will be administered 30 minutes prior to each dose of chemotherapy as written below. All patients will receive dexamethasone 8 mg IV QD for 3 days following the completion of the conditioning regimen.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Male or female patients 18 years of age or older

- Patients deemed eligible to undergo autologous bone marrow or peripheral stem cell

transplant therapy per usual transplant inclusion and exclusion criteria

- Patients with Non-Hodgkins Lymphoma or Multiple Myeloma

- Written informed consent

Exclusion Criteria:

- Nausea at baseline

- Chronic use of other antiemetic agent(s)

- Gastrointestinal obstruction or active peptic ulcer

- Radiation therapy to pelvis or abdomen within 1 week before or after study day 1

- Allogeneic stem cell transplant recipient

- AST > 3x ULN

- ALT > 3x ULN

- Bili > 3x ULN

- Alk Phos > 3x ULN

- Creatinine >2

- Known hypersensitivity to any component of study regimen

- Pregnant or lactating women

- Participating in a clinical trial which involves other investigational agent(s)

- Patients taking any of the following medications: warfarin, oral contraceptives

(except for the administration of stopping menses), tolbutamide, phenytoin, midazolam, ketoconazole, rifampin, paroxetine, and/or diltiazem.

Kristan Augustin, Pharm.D., Phone: 314-454-8512, Email: kma3852@bjc.org

Barnes-Jewish Hosptial/ Siteman Cancer Center/ Washington University, St. Louis, Missouri 63110, United States; Recruiting

Starting date: January 2006
Ending date: January 2008
Last updated: October 25, 2007