Baseline Demographics
Ninety-four subjects consented and were randomized to the study. A total of 91 subjects were included in the analysis. Three subjects (two in the autologous and one in the allogeneic HCT subgroup) withdrew from the study before any study drug was provided. Of the 91 subjects analyzed, 45 subjects were in the olanzapine arm and 46 in the placebo arm. Overall, baseline characteristics were similar between both treatment arms (Table 1). In the autologous HCT subgroup (n = 69), 33 (47.8%) subjects were in the olanzapine arm versus 36 (52.2%) in the placebo arm; in the allogeneic HCT subgroup, 12 (54.5%) subjects were in the olanzapine arm versus 10 (45.5%) in the placebo arm (Online Resource). The most common indications for transplant included multiple myeloma (n = 50, 72.5%) in the autologous HCT subgroup and acute myeloid leukemia (n = 10, 45.5%) in the allogeneic HCT subgroup.
Table 1. Baseline demographics of all subjects (N = 91)
|
Olanzapine
(n=45)
|
Placebo
(n=46)
|
Median age, (range)
|
61 (20-75)
|
62 (30-76)
|
Male, n (%)
|
28 (62.2)
|
22 (47.8)
|
ECOG, n (%)
0
1
|
35 (77.8)
10 (22.2)
|
36 (78.3)
10 (21.7)
|
Indication for transplant, n (%)
Multiple myeloma
AML
Non-Hodgkin lymphoma
Hodgkin lymphoma
Myelofibrosis
ALL
CLL
MDS
Othera
|
26 (57.8)
7 (15.6)
4 (8.9)
3 (6.7)
3 (6.7)
1 (2.2)
1 (2.2)
0 (0)
0 (0)
|
24 (52.2)
3 (6.5)
9 (19.6)
3 (6.5)
2 (4.3)
2 (4.3)
0 (0)
2 (4.3)
1 (2.2)
|
Median QTc-F, msec (range)
|
417 (367-462)
|
413 (384-465)
|
Abbreviations: ECOG = Eastern Cooperative Oncology Group; AML = acute myeloid leukemia; MDS = myelodysplastic syndromes; CLL = chronic lymphocytic leukemia; ALL = acute lymphocytic leukemia; MAC = myeloablative conditioning; NMA = nonmyeloablative conditioning; RIC = reduced intensity conditioning; Mel = melphalan
aOther indication for transplant included polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome
Overall Results
Complete response was achieved in 46.7% (21/45) of subjects in the olanzapine arm versus 28.3% (13/46) of placebo (p=0.085) (Figure 2). The median number of rescue antiemetic medications used throughout the study period was significantly lower in the olanzapine arm in comparison to placebo (2 [median IQR 0-4] versus 4 [median IQR 2-11]; p=0.003) (Table 2). Among all patients, minimal nausea was achieved in 55.6% (25/45) of the olanzapine arm versus 32.6% (15/46) of placebo (p=0.04). A significant difference in achieving minimal nausea was also demonstrated in the delayed phase for olanzapine versus placebo (57.8% vs 34.8%, respectively; p=0.04), however, no significant difference was demonstrated in the acute phase (82.2% vs 69.6%, respectively, p=NS). Six subjects had documented emesis, however, did not report higher than a “rarely” and/or “mild” regarding frequency and severity of nausea.
Table 2. CINV outcomes in all subjects (N=91) and by HCT subgroups including autologous HCT (n=69) and allogeneic HCT (n=12)
|
All Subjects
(N=91)
|
Autologous HCT
(n=69)
|
Allogeneic HCT
(n=22)
|
Olanzapine
(n=45)
|
Placebo
(n=46)
|
p
|
Olanzapine
(n=33)
|
Placebo
(n=36)
|
p
|
Olanzapine
(n=12)
|
Placebo
(n=10)
|
p
|
Achieved CR, n (%)
|
21 (46.7)
|
13 (28.3)
|
0.085
|
16 (48.5)
|
12 (33.3)
|
0.23
|
5 (41.7)
|
10 (10)
|
0.16
|
Total number of PRN doses used for N/V throughout the study period, median (IQR)
|
2
(0-4)
|
4
(2-11)
|
0.003
|
2
(0-4)
|
3
(1-9)
|
0.06
|
1.5
(0.5-4)
|
11.5
(6-16)
|
0.011
|
Achieved minimal nausea, n (%)
|
25 (55.6)
|
15 (32.6)
|
0.04
|
19 (57.6)
|
14 (38.9)
|
0.15
|
6 (50)
|
1 (10)
|
0.07
|
Acute phase, n (%)
|
37 (82.2)
|
32 (69.6)
|
0.22
|
28 (84.8)
|
26 (72.2)
|
0.25
|
9 (75)
|
6 (60)
|
0.65
|
Delayed phase, n (%)
|
26 (57.8)
|
16 (34.8)
|
0.04
|
20 (60.6)
|
15 (41.7)
|
0.15
|
6 (50)
|
1 (10)
|
0.07
|
Abbreviations: CR = complete response; PRN = pro re nata; N/V = nausea/vomiting; IQR = interquartile
Autologous HCT Group
Of the 69 subjects who received an autologous HCT, 33 subjects were in the olanzapine arm and 36 in the placebo arm. Most received single agent melphalan conditioning (78.8% for olanzapine and 69.4% for placebo). A non-significant, higher rate of CR was demonstrated in the olanzapine arm in comparison to placebo (48.5% versus 33.3%, respectively; p=0.23). The median use of any rescue antiemetic medications throughout the study period was 2 (median IQR 0-4) doses for olanzapine versus 3 (median IQR 1-9) doses for placebo (p=0.06). Although not statistically significant, there was a numerically higher improvement in achieving minimal nausea overall (57.6% vs 38.9%; p=0.15), in the acute phase (84.8% versus 72.2%; p=0.25), and in the delayed phases (60.6% versus 41.7%; p=0.15).
Allogeneic HCT Group
Twenty-two subjects received an allogeneic HCT, in which 12 subjects were in the olanzapine arm and 10 in the placebo arm. The most common conditioning regimens were reduced intensity including either fludarabine plus busulfan or fludarabine plus melphalan (33.3% for both). A numerically higher but non-significant difference was found for the rate of CR between olanzapine and placebo (41.7% versus 10%, respectively; p=0.16). A significantly lower number of rescue antiemetics were used for breakthrough CINV in the olanzapine arm (1.5 [median IQR 0.5-4]) in comparison to placebo (11.5 [median IQR 6-16]; p=0.011). Minimal nausea was achieved in 50% (n=6) of the olanzapine arm and 10% (n=1) of the placebo (p=0.07); the same rates of minimal nausea existed in the delayed phase. In the acute phase, no significant difference was demonstrated between the two arms (75% vs 60%; p=0.65).
Safety
Subjects who received at least one dose of study drug were included in the safety analyses (n=91). Dose reductions or discontinuation were not required in any of the subjects during study period. The most frequent adverse events reported in at least 10% of subjects were fluid overload (42.2% vs 30.4%), diarrhea (35.6% versus 41.3%), tachycardia (17.8% vs 17.4%), and headache (11.1% versus 23.9%) in the olanzapine and placebo arms, respectively (Table 3). None of these differences were significant. QTc prolongation was not observed post-chemotherapy day 1 or at the end of study period between patients receiving olanzapine and placebo (median QTc-F of 420 msec and 406, respectively). Somnolence was reported in one subject who received an allogeneic HCT in the olanzapine arm. Two subjects in the olanzapine arm had incomplete documentation of somnolence (one in each HCT subgroup).
Table 3. Reported adverse events in all subjects (N=91)
Adverse event
|
Olanzapine
(n=45)
|
Placebo
(n=46)
|
p
|
Electrolyte abnormality
|
4 (8.9)
|
3 (6.5)
|
0.71
|
LFT abnormality
|
5 (11.1)
|
2 (4.3)
|
0.27
|
Coagulation abnormalitya
|
12 (26.7)
|
13 (28.3)
|
1.0
|
Somnolence b
|
1 (2.3)
|
0 (0)
|
0.3
|
Fever
|
1 (2.2)
|
1 (2.2)
|
1.0
|
Headache
|
5 (11.1)
|
11 (23.9)
|
0.17
|
Pain
|
3 (6.7)
|
9 (19.6)
|
0.12
|
Neuropathy
|
1 (2.2)
|
2 (4.3)
|
1.0
|
Diarrhea
|
16 (35.6)
|
19 (41.3)
|
0.67
|
Extrapyramidal symptoms
|
1 (2.2)
|
0 (0)
|
0.49
|
Akathisia
|
0 (0)
|
1 (2.2)
|
1.0
|
Parkinsonism
|
2 (4.4)
|
2 (4.3)
|
1
|
Fluid overload
|
19 (42.2)
|
14 (30.4)
|
0.28
|
Arrhythmia
|
1 (2.2)
|
1 (2.2)
|
1.0
|
Tachycardia
|
8 (17.8)
|
8 (17.4)
|
1.0
|
Bradycardia
|
4 (8.9)
|
1 (2.2)
|
0.2
|
Tachypnea
|
0 (0)
|
1 (2.2)
|
1.0
|
Abbreviations: LFT = liver function test
aCoagulation abnormality included elevated aPTT and/or INR
bSomnolence not fully documented in 2 subjects in the olanzapine arm (1 subject in each HCT subgroup)