NEW ANTIEMETIC TREATMENTS

1
NEW ANTIEMETIC TREATMENTS

• Fausto Roila
• Medical Oncology Division, Perugia, Italy

2
ANTIEMETICS OF CHOICE

• Cisplatin
• - acute emesis NK1 5-HT3
  DEX
• - delayed emesis NK1 DEX or
  
• DEX
  MTC or
• DEX
  5-HT3
• Moderately emetogenic chemotherapy
• - acute emesis 5-HT3 DEX
  ?NK1
• - delayed emesis NK1 or DEX

3
A RANDOMIZED, DOUBLE-BLINDED, PILOT TRIAL OF
APREPITANT ADDED TO STANDARD ANTIEMETICS DURING
CONDITIONING THERAPY FOR HEMATOPOIETIC STEM CELL
TRANSPLANT Bubalo
JS, et al. Proc. ASCO 2007 25 520s (abst.
9112)
4
RESULTS (n 30)

• Patients submitted to high dose chemotherapy ?
  TBI
• Antiemetics ondansetron dexamethasone
• - aprepitant 125 mg po on
  day 1 and 80 mg on
• subsequent days (begun
  on day - 7 through
• day 4 alone on days
  1 through 4)
• - placebo
• 
  

5
RESULTS

• 
  ODA OD
• Complete major response 14/15 (93)
  7/15 (47)
• No emesis 10/15
  (67) 5/15 (33)
• Complete response no emesis, mild-moderate
  nausea
• Major response 1- 2 emesis in only 1 day with
  any level nausea or no emesis with severe nausea

6
NEW ANTIEMETICS

• PALONOSETRON
• CASOPITANT
• OLANZAPINE
• MIDAZOLAM
• GABAPENTIN
• GHRELIN

7
PALONOSETRON
8
PALONOSETRON

• - Potent and selective 5-HT3 antagonist with a
  high affinity for 5-HT3 receptors
• - Mean plasma elimination half-life of 40
  hours substantially longer than that of
  ondansetron (4-6 h), granisetron (5-8 h),
  tropisetron (7 h) and dolasetron (7 h)

9
PALONOSETRON

• - Metabolized primarily by CYP2D6 and to a lesser
  extent by CYP3A and CYP1A2
• - No difference in the drugs metabolism between
  poor and extensive metabolisers of CYP2D6
  substrates.
• - Age, hepatic dysfunction or mild-to-moderate
  renal impairment have no clinically significant
  effect on the pharmacokinetics of palonosetron

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PALONOSETRON IN CISPLATIN-TREATED PATIENTS
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EFFICACY, SAFETY AND PHARMACOKINETICS OF
PALONOSETRON IN PATIENTS RECEIVING HIGHLY
EMETOGENIC CISPLATIN-BASED CHEMOTHERAPY A
DOSE-RANGING CLINICAL STUDY
Eisenberg P, et al Ann Oncol 2004
15 330-337
12
RESULTS

• Dose (?g/kg) 0.3 1 3 10
  30 90
• No. pts 29 24
  25 24 46
• Complete response 24 46 40
  50 46
• No vomiting and no rescue therapy on day 1
• 1/3 of pts treated with 3-10 ?g/kg presented a
  complete response on the 7 days after chemotherapy

13
A PHASE III, DOUBLE-BLIND, RANDOMIZED TRIAL OF
PALONOSETRON COMPARED WITH ONDANSETRON IN
PREVENTING CHEMOTHERAPY-INDUCED NAUSEA AND
VOMITING FOLLOWING HIGHLY EMETOGENIC CHEMOTHERAPY
Aapro MS, et
al. Ann Oncol 2006 171441-449
14
RESULTS

• PAL
  PAL OND p
• Dose (mg) 0.25
  0.75 32
• No. of pts 225
  225 223
• C.R. day 1 59.2
  65.5 57.0 n.s.
• C.R. day 2-5 45.3 48.0
  38.9 n.s.
• C.R. day 1-5 40.8 42.2
  33.0 n.s.
• 67 of pts received dexamethasone on day 1
  

15
PALONOSETRON IN PATIENTS SUBMITTED TO MODERATELY
EMETOGENIC CHEMOTHERAPY
16
PALONOSETRON IMPROVES PREVENTION OF
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
FOLLOWING MODERATELY EMETOGENIC CHEMOTHERAPY
RESULTS OF A DOUBLE-BLIND RANDOMIZED PHASE III
TRIAL COMPARING SINGLE DOSES OF PALONOSETRON WITH
ONDANSETRON
Gralla RJ, et al. Ann Oncol 2003 141570-77
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IMPROVED PREVENTION OF MODERATE
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING WITH
PALONOSETRON, A PHARMACOLOGICALLY NOVEL 5-HT3
RECEPTOR ANTAGONIST RESULTS OF A PHASE III
SINGLE-DOSE TRIAL VERSUS DOLASETRON

Eisemberg P, et al. Cancer 2003
98 2473-82
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RESULTS

• PAL PAL OND
  PAL PAL DOL
• Dose (mg) 0.25 0.75 32 0.25
  0.75 100
• No. pts 189 189 185
  189 189 185
• C.R. day 1 81.0 73.5 68.6 63.0
  57.1 52.9
• C.R. day 2-5 74.1 64.6 55.1 54.0
  56.6 38.7
• C.R. day 1-5 69.3 58.7 50.3 46.0
  47.1 34.0
• Statistically significant

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SHORTCOMINGS OF THE STUDIES

• - Less than 5 and 67 of pts, respectively
  submitted to MEC and HEC, received dexamethasone
  on day 1
• - 30-60 of pts pretreated
• - No prophylaxis for delayed emesis
• - Can we conclude that PALO is superior being the
  studies planned as non-inferiority trials?

20
TOLERABILITY

• - Palonosetron is well tolerated
• - Adverse events are similar to the other 5-HT3
  antagonists in particular palonosetron induces
  headache in about 10 and constipation in about
  5 of patients

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CONCLUSIONS

• - Palonosetron in three well conducted
  double-blind studies demonstrated similar
  efficacy than ondansetron in cisplatin-treated
  patients and superior efficacy than ondansetron
  and dolasetron in patients submitted to
  moderately emetogenic chemotherapy.
• - It remains to evaluate palonosetron with
  respect to the other 5-HT3 antagonists when
  combined with dexamethasone (and aprepitant) on
  day 1 and on day 2-5

22
COMBINATION THERAPY FOR CHEMOTHERAPY-INDUCED
NAUSEA AND VOMITING IN PATIENTS RECEIVING
MODERATELY EMETOGENIC CHEMOTHERAPYPALONOSETRON,
DEXAMETHASONE, AND APREPITANT
Grote T, et al. J Support
Oncol 2006 4403-8
23
Palonosetron Aprepitant Dexamethasone
Complete Response (N58)
100
88
78
78
80
60
( of Patients)
40
20
0
Acute 0-24
Delayed 24-120
Overall 0-120
Time (hr)

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PREVENTION OF MODERATELY EMETOGENIC
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING WITH A
1-DAY 3-DRUG ANTIEMETIC REGIMEN PRELIMINARY
REPORT Grunberg
S, et al. Support Care Cancer 2006 14596-7
25
RESULTS (n 15)

• Chemotherapy doxorubicin
  cyclophosphamide
• Antiemetics palonosetron 0.25 mg iv
• aprepitant 285 mg po
• dexamethasone 20 mg po
  
• Day 1 Days 2-5
• Complete response 80 47
• No emesis 100 100
• 
  

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EFFICACY OF A 1-DAY 3-DRUG ANTIEMETIC REGIMEN FOR
PREVENTION OF ACUTE AND DELAYED NAUSEA AND
VOMITING INDUCED BY MODERATELY EMETOGENIC
CHEMOTHERAPY Grunberg SM, et al. Proc. ASCO
2007 25 520s (abstr 9111)
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CASOPITANT
28
CASOPITANT

• - Potent and selective oral NK1 receptor
  antagonist which has shown activity in preventing
  chemotherapy-induced nausea and vomiting in
  preclinical studies
• - Based on phase I positron emission tomography
  study, casopitant doses from 50 - 150 mg result
  in 70 - 95 saturation of NK1 receptors

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MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
ONDANSETRON-CONTROLLED, DOSE-RANGING, PARALLEL
GROUP TRIAL OF THE NEUROKININ-1 RECEPTOR
ANTAGONIST CASOPITANT MESYLATE FOR
CHEMOTHERAPY-INDUCED NAUSEA / VOMITING IN
PATIENTS RECEIVING MODERATELY EMETOGENIC
CHEMOTHERAPY
Arpornwirat W, et al. Proc. ASCO 2006 24471s
(ab.8512)
30
RESULTS (n 719)

• ANTIEMETICS OND 8 mg x 2 day 1-3
• Dex 8 mg x 1 day 1
• CR ()
• - placebo
  70
• - casopitant 50 mg po day 1-3
  81
• - casopitant 100 mg po day 1-3 79
• - casopitant 150 mg po day 1-3
  85
• - casopitant 150 mg day 1
  80
• Ond 16 mg po day 1-3 Dex 8 mg iv day 1
  84
• casopitant 150 mg po day 1-3

p0.0124
31
RANDOMIZED PHASE II TRIAL OF THE NEUROKININ-1
RECEPTOR ANTAGONIST CASOPITANT MESYLATE WITH
ONDANSETRON / DEXAMETHASONE FOR
CHEMOTHERAPY-INDUCED NAUSEA / VOMITING IN
PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY
Rolski J, et al.
Proc. ASCO 2006 24471s (ab.8513)
32
RESULTS (n 493)

• ANTIEMETICS OND 32 mg x 1 day 1
• Dex 8 mg x 1 day 1-4
• CR ()
• - placebo
  60
• - casopitant 50 mg po day 1-3
  76
• - casopitant 100 mg po day 1-3 86
• - casopitant 150 mg po day 1-3
  77
• - casopitant 150 mg day 1
  75
• - aprepitant 125 mg po day 1 and 80 mg day 2-3
  72
• p0.0036

33
OLANZAPINE
34
OLANZAPINE

• Antipsychotic drug that blocks multiple
  neurotransmitters
• - dopamine at D1, D2, D3 and D4 brain
  receptors,
• - serotonin at 5-HT2a, 5-HT2c, 5-HT3 and 5-HT6
• receptors,
• - catecholamines at alpha 1 adrenergic
  receptors
• - histamine at H1 receptors

35
OLANZAPINE

• - Case reports on the use of olanzapine as an
  antiemetic for chronic nausea in advanced cancer
  patients and for opioid-induced nausea
• - In a retrospective chart review of 28 patients
  who received olanzapine on an as-needed basis
  following moderately to highly emetogenic
  chemotherapy, data suggested that olanzapine may
  decrease delayed emesis (Passik SD et al. J Pain
  Symptom Manage 2003 25 485-89)

36
A PHASE I TRIAL OF OLANZAPINE (ZYPREXA) FOR THE
PREVENTION OF DELAYED EMESIS IN CANCER PATIENTS
A HOOSIER ONCOLOGY GROUP STUDY
Passik SD, et al. Cancer
Invest 2004 22383-8
37
RESULTS (n 15)

• Four-cohort dose escalation of 3-6 pts per cohort
• Antiemetics standard premedication olanzapine
  on day -2
• and -1 prior chemotherapy
  and for 8 days after
• Dose the maximum tolerated dose was 5 mg for day
  -2 and
• -1 and 10 mg for day 0 - 7
• Results no vomiting observed in 4/6 pts treated
  with cisplatin
• and 9/9 with moderately emetogenic
  chemotherapy
  

38
A PHASE II TRIAL OF OLANZAPINE FOR THE PREVENTION
OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING A
HOOSIER ONCOLOGY GROUP STUDY
Navari RM, et al. Support Care Cancer
2005 13529-34
39
Phase II trial of olanzapineTreatment
Day 1
Days 2-4
Days -2-1
G
D
O
D
O
O
Ggranisetron Ddexamethasone Oolanzapine
Navari RM et al. Support Care Cancer
200513529-534.
40
Phase II trial of olanzapineComplete Response
Complete Response (CR) no emesis, no rescue
medication.
Navari RM et al. Support Care Cancer
200513529-534.
41
Phase II trial of olanzapineNo nausea
Navari RM et al. Support Care Cancer
200513529-534.
42
CONCLUSIONS

• - In this study it seems that olanzapine is safe
  (no grade 3 or 4 toxicities) and effective in
  controlling acute and delayed chemotherapy-induced
  nausea and vomiting in patients receiving highly
  and moderately emetogenic chemotherapy
• - Limitations of the study small number of
  patients and lack of a control arm and,
  therefore, RCT are necessary to define its role

43
MIDAZOLAM
44
MIDAZOLAM

• - Short-acting benzodiazepine with a rapid onset
  of action which has been demonstrated efficacious
  as antiemetic in postoperative emesis resistant
  to the usual treatments
• - Midazolam decreases dopamine imput at the CTZ
  or dopaminergic neuronal activity and 5-HT
  release by binding to the GABA benzodiazepine
  complex
• - In a phase I study in outpatients submitted to
  chemotherapy the dose for phase II studies was
  0.04 mg/kg (Potanovich LM. J Pain Symptom Manage
  1991 8 519-524)

45
MIDAZOLAM FOR ACUTE EMESIS REFRACTORY TO
DEXAMETHASONE AND GRANISETRON AFTER HIGHLY
EMETOGENIC CHEMOTHERAPY
Mandalà M, et al. Support Care Cancer 2005
13375-80
46
RESULTS (n 30)

• Cisplatin-induced acute emesis refractory
  to granisetron and dexamethasone
• Antiemetics
• Gran 3 mg iv Dex 20 mg iv Midazolam
• 0.04 mg/kg 4-hour c.i.
  during chemotherapy
• Results
• 73 of pts had a reduction of at least one
  grade
• (NCI common toxicity criteria) in
  nausea and vomiting intensity in the subsequent
  courses.
• 6 pts (23) had no acute emesis
  during the second course
  

47
GABAPENTIN
48
GABAPENTIN

• - A ?-aminobutyric acid analogue approved in 1994
  as an anticonvulsant
• - In an anedoctal report, complete resolution of
  chemotherapy-induced nausea was seen in a patient
  with breast cancer, after she was placed on
  gabapentin for the treatment of hot flushes
• - The mitigation of tachykinin neurotransmitter
  activity useful to control both hot flushes and
  emesis has been suggested as possible mechanism
  of action

49
EFFECT OF GABAPENTIN ON NAUSEA INDUCED BY
CHEMOTHERAPY IN PATIENTS WITH BREAST CANCER

Guttuso T, et al. Lancet 2003 3611703-05
50
RESULTS (n 9)

• Patients with moderate nausea after the 1st
  course of adjuvant doxorubicin and
  cyclophosphamide
• Antiemetics
• Ond 16-24 mg iv Dex 20 mg iv ? lorazepam
• 0.5-1 mg iv before chemotherapy
• On course 2nd and 4th gabapentin was
  added
• Results
• 3 pts had complete resolution of nausea during
  gabapentin and 6/9 had at least a 3-point
  reduction (8-point nausea scale) in delayed
  nausea

51
GHRELIN
52
Rudd JA et al. Neuroscience Letters
200639279-85.
53
Is ghrelin involved in antiemesis?

• Ghrelin
• Stimulates gastric motility
• Protects gastric mucosa
• Increases appetite
• Ghrelin receptor mRNA (rats)
• Expression increased in the stomach
  and hypothalamus after cisplatin

Rudd JA et al. Neuroscience Letters
200639279-85.
54
Ghrelin and cisplatin-induced emesis
Rudd JA et al. Neuroscience Letters
200639279-85.