Optimizing management of chemotherapy-induced neutropenia: the development of once-per-cycle cytokine support

1
Optimizing management of chemotherapy-induced
neutropenia the development of once-per-cycle
cytokine support

• Salvatore Siena
• Divisione di Oncologia Medica FalckOspedale
  Niguarda Ca GrandaDepartment of Oncology and
  HematologyMilan, Italy

2
Filgrastim in the treatment of chemotherapy-induc
ed neutropenia

• Myelosuppression is a major dose-limiting adverse
  effect of chemotherapy
• Filgrastim reduces duration and severity of
  neutropenia and its sequelae
• Serum half-life (3 hours) and neutrophil
  response necessitate daily injections

3
The relative odds of developing febrile
neutropenia in patients receiving filgrastim
prophylaxis compared with those not receiving
prophylaxis
Crawford et al. Trillet-Lenoir et al. Chevailier
et al. Bui et al. Gisselbrecht et al. Fossa et
al. Pettengell et al. Zinzani et al. Total
OR0.381plt0.001
0.01 0.1 1 10
Odds ratio (95 confidence level)
Adapted with permission of Dr G Lyman
Crawford et al. N Engl J Med 199132516470
Trillet-Lenoir et al. Eur J Cancer
199329A31924 Chevalier et al. J Clin Oncol
1995156471 Bui et al. J Clin Oncol
199513262936 Gisselbrecht et al. Leuk
Lymphoma 199725289300 Fossa et al. J Clin
Oncol 19981671624 Pettengel et al. Blood
199214306 Zinzani et al. Blood 19978939749.
4
Rationale for sustained-duration filgrastim

• Polyethylene glycol (PEG)-conjugated proteins
• increased plasma half-life (4662 hours)
• prolonged activity
• Hypothesis a single injection of pegfilgrastim
  per cycle of chemotherapy is as effective as
  daily filgrastim

5
Clinical objective of pegfilgrastimonce-per-cycl
e dosing
6
Pharmacokinetic profile of filgrastim and
pegfilgrastim in healthy volunteers
100 10 1 0.1 0.01
Pegfilgrastim 60 µg/kg (n9) Filgrastim 5 µg/kg
(n8)
Median serumconcentration (µg/L)
0 2 4 6 8 10 12 14
Day
7
Pegylation does not alter the biologic
properties of filgrastim

• Proliferation assays
• similar stimulation of G-CSFdependent cells by
  filgrastim and pegfilgrastim
• Receptor binding
• similar competitive-binding affinity to G-CSF
  receptors on neutrophils

8
Pegylation does not alter the biologic
properties of filgrastim (contd)

• Neutrophil response
• dose-response relationship with respect to
  neutrophil increase
• Neutrophil function studies
• no difference in superoxide release and E. coli
  phagocytosis

9
Healthy volunteer absolute neutrophil count (ANC)
profile following a single dose of pegfilgrastim
60 50 40 30 20 10 0
Pegfilgrastim 30 µg/kg (n8) Pegfilgrastim 60
µg/kg (n8) Pegfilgrastim 100 µg/kg
(n8) Pegfilgrastim 300 µg/kg (n8)
Median ANC (x109/L)
0 2 4 6 8 10 12 14 16
Day
Molineaux G, et al. Exp Hematol 199927172434
10
Pegfilgrastim and peripheral blood CD34 cell
counts in healthy volunteers
160 140 120 100 80 60 40 20 0
Pegfilgrastim 30 µg/kg (n8) Pegfilgrastim 60
µg/kg (n8) Pegfilgrastim 100 µg/kg
(n8) Pegfilgrastim 300 µg/kg (n8)
Mean CD34 cells (x106/L)
0 2 4 6 8 10 12 14
Days after pegfilgrastim
Molineaux G, et al. Exp Hematol 199927172434
11
A single dose of pegfilgrastim is as effective as
daily filgrastim to reduce the duration of
severe, chemotherapy-induced neutropenia

• FA Holmes, SE Jones, J OShaughnessy, et al.
• US Oncology, Dallas, Texas UCLA, Los Angeles,
  California Southwest Oncology Associates,
  Lafayette, Louisiana Eastern Connecticut
  Hematology/Oncology Associates, Norwich,
  Connecticut Northshore University Hospital,
  Manhasset, New York Amgen Inc, Thousand Oaks,
  California

Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
12
Study design

• Day 1 chemotherapy
• doxorubicin 60mg/m2 i.v. bolus
• docetaxel 75mg/m2 i.v. infusion
• Day 2 patients randomized to study drug
• single-dose pegfilgrastim 30 µg/kg/cycle
• single-dose pegfilgrastim 60 µg/kg/cycle
• single-dose pegfilgrastim 100 µg/kg/cycle
• daily filgrastim 5 µg/kg/day

Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
13
Patient eligibility

• High-risk stage II or stage III or IV breast
  cancer
• Women ³18 years old
• ECOG performance status 2
• Prior chemotherapy 1 metastatic regimen
• WBC ³4 x 109/L, platelets ³150 x 109/L

As defined by the investigator
Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
14
First cycle incidence of severe neutropenia is
similar for pegfilgrastim 100 µg/kg and daily
filgrastim
Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
15
ANC profile across chemotherapy cycles is similar
for pegfilgrastim and filgrastim
Pegfilgrastim 100µg/kg (n47) Filgrastim
5µg/kg/day (n25)
Pegfilgrastim 30µg/kg (n19) Pegfilgrastim
60µg/kg (n61)
100 10 1.0 0.1 0.01
Cycle 1 Cycle 2 Cycle 3 Cycle 4
ANC (x109/L)
0 7 14 21 7 14 21 7 14 21 7 14 21
Cycle day
Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
16
Self-regulation clears pegfilgrastim as
neutrophil levels return to normal
1000 100 10 1 0.1 0.01
1000 100 10 1 0.1 0.01
Pegfilgrastim 100µg/kg ANC
Mean pegfilgrastim serumconcentration (ng/mL)
Mean ANC (109/L)
0 3 6 9 12 15 18 21
Cycle 1 day
Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
17
Safety profile

• No apparent differences in adverse events or
  laboratory measures between patients treated with
  chemotherapy supported by once-per-cycle
  pegfilgrastim or daily filgrastim
• Cytokine-related adverse events with ³10
  incidence

Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
18
Laboratory measures with change of WHO toxicity
³2 grades from baseline
Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
19
Median platelet counts acrosschemotherapy cycles
Pegfilgrastim 100µg/kg (n47) Filgrastim
5µg/kg/day (n25)
Pegfilgrastim 30µg/kg (n19) Pegfilgrastim
60µg/kg (n61)
600 500 400 300 200 0
Cycle 1 Cycle 2 Cycle 3 Cycle 4
Platelet count (x109/L)
0 7 14 21 7 14 21 7 14 21 7 14 21
Cycle day
Holmes F, et al. Proc Am Soc Clin Oncol 200019
(Abstract 191)
20
Summary

• Safety and efficacy profiles of
  single-dose-per-cycle pegfilgrastim are similar
  to those of daily filgrastim
• Clearance of pegfilgrastim is self-regulated by
  neutrophils and neutrophil precursors
• pegfilgrastim levels are sustained for the
  duration of neutropenia and then decline rapidly
  with neutrophil recovery
• Based on these phase II data a multinational
  phase III trial is ongoing

21
A randomized, double-blind, phase III study
evaluating fixed-dose once-per-cycle
pegfilgrastim versus daily filgrastim to support
chemotherapy for breast cancer

• M Green, H Koelbl, J Baselga, E Kubista, V
  Guillem, P Gascon, S Siena, R Lalisang, P
  Krippl, M Clemens, V Zani, S Bashir, J Renwick, B
  Liang, M Piccart
• RMH, Melbourne, Australia Univ.-klinikum Halle,
  Halle, Germany H Vall d'Hebron, Barcelona,
  Spain AKH, Wien, Austria IVO, Valencia, Spain
  H Clinic I Prov, Barcelona, Spain Ospedale
  Niguarda Ca' Granda, Milan, Italy AZM,
  Maastricht, Netherlands Univ.-klinikum, Graz,
  Austria KMB, Trier, Germany Amgen Inc, Thousand
  Oaks, CA Institute Jule Bordet, Brussels,
  Belgium

Green M, et al. Proc Am Soc Clin Oncol 200120
(Abstract 90)
22
Phase III trial of fixed-dose, once-per-cycle
pegfilgrastim versus daily filgrastim study
design

• 157 breast cancer patients were treated with four
  cycles of doxorubicin (60 mg/m2) plus docetaxel
  (75 mg/m2)
• To support chemotherapy, patients were randomized
  to receive either
• a single, once-per-chemotherapy cycle
  subcutaneous injection of pegfilgrastim (6 mg)
  followed by daily placebo injections
• or daily subcutaneous filgrastim (5 µg/kg/day)
• 130 patients evaluable (68 pegfilgrastim and 62
  filgrastim)

Green M, et al. Proc Am Soc Clin Oncol 200120
(Abstract 90)
23
Fixed-dose once-per-cycle pegfilgrastrim provides
for effective ANC support

• Mean duration of severe neutropenia in cycle one
  was 1.8 and 1.6 days in the pegfilgrastim and
  filgrastim groups, respectively
• Incidence of febrile neutropenia over all cycles
  was 13 and 20 in the pegfilgrastim and
  filgrastim groups, respectively
• The total chemotherapy dose administered in each
  arm was similar
• Related adverse events were comparable between
  treatment groups, including the incidence,
  duration and severity of bone pain

Green M, et al. Proc Am Soc Clin Oncol 200120
(Abstract 90)
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Conclusions

• Single fixed-dose of pegfilgrastim (6 mg) is
  comparable to multiple daily injections of
  filgrastim
• Body weight does not influence the efficacy and
  safety of pegfilgrastim
• Single-dose pegfilgrastim may have several
  benefits
• greater convenience for patients and healthcare
  providers
• improved patients compliance, avoiding concern
  over missed doses of daily filgrastim
• positive impact on quality of life with less
  disruption to a patients daily routine

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Divisione Oncologia Medica FalckOspedale
Niguarda Ca Granda, Milan
Improving therapeutic outcomes in patients with
cancer

• Toxicity
• new cytokines
• hematopoietic stem cell transplantation
• non-cytotoxic antitumor agents

• Activity
• new modalities with known agents
• new agents
• targeted therapies