nab-Paclitaxel

nab-paclitaxel
in monoterapia
Dati clinici e safety
nab-paclitaxel
in monoterapia
Studi clinici che hanno
portato all’indicazione
Gli studi pre-registrativi nell’ MBC
Phase I1
Dose-finding study
• No steroid premedication
• DLTs at 375 mg/m2: keratitis,
neuropathy-sensory, stomatitis
• MTD: 300 mg/m2
• Linear PK
Phase II2
175 mg/m2
Phase II3
300 mg/m2
• ORR 40%
• First-line response 45%
• Well tolerated without steroids
• 0% grade 3/4 neuropathy
• ORR 48%
• First-line response 64%
• Well tolerated without steroids
• 11% grade 3/4 neuropathy
Pivotal phase III study (n = 460)4
260 mg/m2 NAB-P vs
175 mg/m2 paclitaxel
1. Ibrahim et al. Clin Cancer Res. 2002;8:1038–1044
2. American BioScience, Inc. Data on File
3.Ibrahim et al. J Clin Oncol. 2005;23:6019–6026
4. Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Studi di Fase 1
• Phase I
–MTD, PK, etc.
• Phase II
• Phase III
–Registration RCT
–Other
Studio fase I “DOSE FINDING”
• No premedicazione steroidea
• No reazioni acute di ipersensibilità
• Tossicità Dose-limitanti da taxano a 375
mg/m2 (neuropatia, cheratite, stomatite)
• Dose Massima Tollerata: 300 mg/m2
• Durata infusione tollerabile: 30 minuti
• AUCs lineari nel range di dose clinicamente
rilevante
Phase I and Pharmacokinetic Study of ABI007, a cremophore-free, protein-stabilized,
nanoparticle formulation of paclitaxel
A new paradigm in cancer therapy: the nabTM platform
• Receptor-mediated transport (via gp60) and specific protein (SPARC) binding
in tumour with the goal of improving efficacy and the therapeutic index
• Phase I studies were conducted to determine the safety, MTD and PK profile
of this novel formulation
140
80
NAB-P
Paclitaxel
60
40
20
0
0
20
40
60
80
100
Dose (mg/kg)
50% higher paclitaxel dose
Paclitaxel (nCi/g)
Mortality (%)
100
120
NAB-P (20 mg/kg)
Paclitaxel
(20 mg/kg)
100
80
60
40
0.01
0.1
1
10
100
Hrs
33% higher intra-tumour paclitaxel
Ibrahim et al. Clin Cancer Res. 2002:8;1038–1044
NAB-P was administered safely over 30
minu with no HSR
• 19 patients treated
• No HSRs observed during the infusion period
• Haematological toxicity (characterised by ANC and PLT nadirs) mild and dosedependent
• DLTs (in three of six patients treated at dose level 3): sensory neuropathy (n = 3),
stomatitis (n = 2) and superficial keratopathy (n = 2)
• MTD defined as 300 mg/m2
ANC nadir x 103/mm3 (range)
PLT nadir x 103/mm3 (range)
0
2.229 (1.850–5.040)
204 (174–292)
1
1.845 (0.586–3.729)
197 (118–270)
2
0.960 (0.264–3.680)
200 (105–609)
3
0.966 (0.018–1.804)
173 (25–251)
Dose level
ANC, absolute neutrophil count; DLT, dose-limiting toxicity;
HSR, hypersensitivity reaction; PLT, platelet
Ibrahim et al. Clin Cancer Res. 2002:8;1038–1044
Paclitaxel PK for nab-Paclitaxel are Linear
Paclitaxel
nab-Paclitaxel
Paclitaxel AUC 3 hr1
Mean AUCinf (ng hr/ml)
45 000
Paclitaxel AUC 3 hr2
35 000
Paclitaxel AUC 1 hr3
30 000
y = 3213e0.0095x
40 000
R2 = 0.9328
35 000
y = 3023.2e0.0089x
30 000
R2 = 0.9683
25 000
20 000
15 000
25 000
20 000
15 000
10 000
5000
10 000
0
5000
0
100
AUCinf (ng hr/mL)
50 000
nab-Paclitaxel4
N= 3 6
150
200
Dose (mg/m2)
250
300
51 3
3
12
5
4
75 100 125 150 175 200 225 250 275 300 325 350 375
nab-Paclitaxel dose (mg/m2)
1Kearns.
Pharmacotherapy. 1997;17:105S–109S
2Taxol package insert
3Ross et al. Cancer Chemother Pharm. 2000
4nab-paclitaxel® NDA
Studi di fase II
• Phase I
–MTD, PK, etc.
• Phase II
• Phase III
–Registration RCT
–Other
• nab-paclitaxel 300mg/m2 q 3w
• MBC w measurable disease
• No taxanes within past 6 months
nab-Paclitaxel Phase II Trial: Purpose
• To evaluate the safety and antitumor activity of nabPaclitaxel in MBC patients
• Treatment Regimen
– nab-paclitaxel 300 mg/m2 q3w, no standard pre-medication
• Primary endpoint
– tumor response rate (CR or PR)
• Secondary endpoints
–
–
–
–
TTP
OS
Antitumor activity in anthracycline-naïve vs. anthracycline-exposed patients
Changes in quality of life from baseline
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
Metodi Statistici
• Endpoint primario di efficacia basato su
popolazione ITT
• Criteri Successo / Fallimento
– 30% tasso di risposta (ORR) per nab-paclitaxel in
pazienti pre-trattati con anthracycline
• Tutti i pazienti che ricevevano una dose erano
inclusi in analisi di risposta e tossicità
nab-paclitaxel Trial Fase II
Pazienti
• N = 63 pazienti con malattia misurabile CMM
• Precedente Taxano > 6 mesi
Caratteristiche
– Lesioni Metastatiche > 3
– Polmone / Fegato
– 1a Linea di Terapia per CMM
– Naïve Chemoterapia
– Precedente Anthraciclina
– Precedente Taxano
41%
57%
62%
24%
59%
17%
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
nab-paclitaxel Trial Fase II
Risultati primari
• ORR = 48%
• WHO = criteri RECIST
• 1a Linea = 64%
• Pretrattate con
antracicline = 41%
• 3a Linea = 22%
Risultati secondari
• TTP = 26.6 settimane
• Responders = 48.1
settimane
• OS = 63.6 settimane
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
Treatment-related toxicities
Treatment-related grade 3 and 4 toxicities/AEs (N = 63)
Grade 3
Grade 4
Haematological toxicities
No. (%)
No. (%)
Neutropaenia†
17 (27)
15 (24)
Leucopoenia
12 (19)
3 (5)
Infection with unknown absolute neutrophil count
4 (6)
0 (0)
Febrile neutropaenia
0 (0)
3 (5)
Anaemia
3 (5)
1 (2)
Thrombocytopenia
3 (5)
0 (0)
†N
= 62
Note: if a patient reported the same toxicity more than once, that patient was only counted once for the
summary of that toxicity, using the most severe intensity.
Haematological toxicities were based on laboratory values; others were based on AE reports from the
clinical investigators
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
Treatment-related toxicities (cont.)
Treatment-related grade 3 and 4 toxicities/AEs (N = 63)
Grade 3
Grade 4
No. (%)
No. (%)
Fatigue
8 (13)
0 (0)
Sensory neuropathy
7 (11)
0 (0)
Myalgia
5 (8)
0 (0)
Diarrhoea
3 (5)
0 (0)
Cardiac - ischaemia/infarction
0 (0)
1 (2)
Jaundice
0 (0)
1 (2)
Vomiting
1 (2)
0 (0)
Nausea
1 (2)
0 (0)
Headache
1 (2)
0 (0)
Mucositis
1 (2)
0 (0)
Rash/desquamation
1 (2)
0 (0)
Stomatitis/pharyngitis
1 (2)
0 (0)
Non-haematological toxicities
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
Treatment-related toxicities
Percentage of patients
100
90
Grade 1
80
Grade 2
70
60
50
Grade 3
Grade 4
40
30
20
10
0
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
Treatment-Related Toxicities
• Grade 4 neutropeenia
– Primarily during the first treatment cycle and managed with dose
reductions
• Grade 3 neuropathy
– All occurrences were sensory neuropathy
– Five patients discontinued due to neuropathy (8%)
• Myalgia
– Episodes were worse immediately after dosing and resolved by next
dose (no discontinuation)
• Ocular/visual
– Mostly dry eye and blurred vision (no G3)
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
Conclusioni
• NAB-P demonstrated significant antitumour activity and a favourable safety
profile in patients with MBC
• No premedication, prolonged infusions or special IV infusion sets are
required with NAB-P
• The significant antitumour activity and favourable safety profile of NAB-P
may be related to both
• exploitation of albumin to obtain high intratumoral
concentration via gp60 and SPARC
• the absence of polyethylated castor oil
• The low incidence of neutropaenia makes NAB-P a good candidate for
combination treatment regimens
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
Conclusioni: Review Punti principali:
• Popolazione Eterogenea 63 pazienti con CMM:
(1a - 3a Linea), (Precedentemente trattati
con/senza Anthracicline)
• ORR = 48%: (1a Linea = 64%), (Antrac. = 41%)
• Effetti collaterali: (Grado 4 Neutropenia = 24%),
(NF = 5%), (Grado 3 Neuropatia = 11%)
Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026
Studi di Fase III
• Phase I
• MTD, PK, etc.
• Phase II
• Phase III
–Registration RCT
–Other
CA-O12: nab-paclitaxel Trial Pivotal Fase III
Phase III Trial of Nanoparticle Albumin-bound
Paclitaxel Compared with Polyethylated Castor Oilbased Paclitaxel in Women with Breast Cancer
William J. Gradishar, Sergei Tjulandin, Neville Davidson, Heather
Shaw, Neil Desai, Paul Bhar, Michael Hawkins, and Joyce
O’Shaughnessy
Gradishar et al. J Clin Oncol 23: 7794-7803. Nov 2005.
Phase III Trial of nab-Paclitaxel Compared
with Polyethylated Castor Oil-Based
Paclitaxel in Women with Breast Cancer
NAB-P 260 mg/m2
iv over 30 min q3w
No standard premedication
Randomisation (1:1)
n = 460
Paclitaxel 175 mg/m2
iv over 3 hrs q3w
Standard premedication with
dexamethasone and antihistamines
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Fase III: obiettivi
Goals:
Confrontare l’attività antitumorale di nab-paclitaxel e
paclitaxel convenzionale in
pazienti con carcinoma
mammario metastatico.
Valutare la safety e tollerabilità
di nab-paclitaxel confrontata al
paclitaxel convenzionale.
Endpoints Primari
Objective response rates (ORR)
Tutti I pazienti trattati & 1° linea (analisi
pianificata)
RECIST criteria
Safety e tollerabilità
Endpoints Secondari
Time to tumour progression (TTP)
Overall survival (OS)
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Phase III: inclusion criteria
• Females ≥ 18 yrs of age
• Measurable MBC
• ECOG PS 1 or 2
• Patients stratified for prior anthracycline exposure
• No prior taxane for metastatic disease
• No limit on number of prior therapies in the
metastatic setting
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Select Baseline Characteristics:
Primary Site of Measurable Disease
nab-Paclitaxel
n=229
Paclitaxel
n=225
53
53
Liver
40%
43%
Lung
32%
35%
LN, soft tissue only
16%
13%
Abdominal
4%
3%
Bone involvement
6%
6%
Unknown
1%
0%
Mean Age (yr)
Gradishar et al. J Clin Oncol 23: 7794-7803. Nov 2005.
Demographics:
Terapie precedenti
nab-Paclitaxel
n=229
Paclitaxel
n=225
Anthracycline-adiuvante e/o metastatico
77%
78%
Anthracycline per malattia metastatica
50%
58%
Precedente CT per malattia metastatica:
Nessuna
1 regime
2 regimi
>2 regimi
42%
41%
10%
7%
40%
43%
16%
2%
Gradishar et al. J Clin Oncol 23: 7794-7803. Nov 2005.
Overall Response Rate (RECIST)
Tutti i pazienti
Pazienti 1a linea
nab-paclitaxel
Standard paclitaxel
nab-paclitaxel
Standard paclitaxel
(N = 229)
(N = 225)
(N = 97)
(N = 89)
CR+PR
33%
19%
42%
27%
95% CI
27-39%
14-24%
32-52%
18-36%
P-value*
†Cochran-Mantel-Haenszel
P = 0.001
P = 0.029
test
CR, complete response
PR, partial response
Gradishar WJ et al. J Clin Oncol 2005;23: 7794-7803
Phase III: NAB-P improved ORR independent
of line of therapy and across various
subgroups
60
P = 0.001
P = 0.029
P = 0.006
P = 0.002
P = 0.002
34.1%
33.5%
ORR (± 95% CI)
50
42.3%
40
33.2%
30
20
27.0%
26.5%
18.7%
18.3%
18.7%
13.2%
10
0
NAB-P
Paclitaxel
All
patients
229
225
First-line
therapy
97
89
> First-line
therapy
132
136
Anthracycline
exposed
176
175
Visceral
disease
176
182
Greater ORR was confirmed by an independent review committee
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Phase III: NAB-P was associated with
increased paclitaxel intensity and improved
outcome
• Cross trial comparison (consistent with phase III data)
CALGB 93421
(n = 474)
q3w regimen
(mg/m2)
Pivotal phase III trial2
(n = 454)
Paclitaxel
175
Paclitaxel
210
Paclitaxel
250
NAB-P
260
Paclitaxel
175
23
26
21
33
19
P = 0.001
3.9 mo
(16.8 wks)†
4.1 mo
(17.6 wks)†
4.9 mo
(21.1 wks)†
P = 0.045
23.0 wks
16.9 wks
P = 0.006
Neutropaenia
grade 4 (%)
34
44
53
9
22
P ≤ 0.001
Neuropathy
grade 3 (%)
7
19
32
10
2
P ≤ 0.001
ORR (%)
TTP
†Wks
= mo x 4.3
Cancer and leukaemia group B 9342 data with paclitaxel may
not reflect on the active ingredient per se, but rather on the
increased concentrations of Cremophor® EL implicated
in drug entrapment in micelles and added toxicities
1. Winer et al. J Clin Oncol. 2004;22:2061–2068
2. Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Fase III: nab-paclitaxel prolungato “time to
disease progression” in tutti i pazienti
• Median TTP was significantly longer with NAB-P vs. solvent-based
paclitaxel for all patients (23.0 vs. 16.6 weeks; HR = 0.726; P = 0.002)
1.00
NAB-P (n = 229)
Proportion not progressed
Paclitaxel (n = 224)
P = 0.006
HR = 0.75
0.75
Median = 23.0 wks
(19.4–26.1)
0.50
0.25
Median = 16.9 wks
(15.1–20.9)
0.00
0
8 16 24 32 40 48 56 64 72 80 88 96 104 112 120
Wk
Note: P value from log-rank test
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Phase III: OS in tutti i pazienti
• All patients treated with NAB-P showed a trend for greater median OS vs.
solvent-based paclitaxel (65 vs. 55.7 weeks; P=0.374)
1.00
NAB-P (n = 229)
Paclitaxel (n = 225)
Probability of survival
0.75
Median = 65.0 wks
(52.1–76.9)
P = 0.374
HR = 0.90
0.50
Median = 55.7 wks
(48.0–66.4)
0.25
0.00
0
8 16 24 32 40 48 56 64 72 80 88 96 104112 120 128 136 144
Wk
Note: P value from log-rank test
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Phase III: NAB-P significantly
prolonged OS in > first-line patients
• NAB-P significantly prolonged median OS in patients receiving > first-line
therapy vs. solvent-based paclitaxel (56.4 vs 46.7 weeks; HR=0.73;
P=0.024)
1.00
NAB-P (n = 131)
Probability of survival
Paclitaxel (n = 136)
0.75
Median = 56.4 wks
(45.1–76.9)
P = 0.024
HR = 0.73
0.50
Median = 46.7 wks
(39.0–55.3)
0.25
0.00
0
Note: P value from log-rank test
8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136144
Wk
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Phase III: tossicità ematologiche
nab-paclitaxel ben tollerato
NAB-P
n = 229
Grade
AE (%)
Neutropaenia
Thrombocytopaenia
Anaemia
Febrile neutropaenia
Septic deaths
†Cochran-Mantel-Haenszel
3
25
<1
<1
<1
test based upon all grades
4
9
0
<1
<1
0
Paclitaxel
n = 225
Grade
3
32
<1
0
<1
4
22
0
<1
0
0
P value†
< 0.001
0.290
0.279
0.491
–
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Phase III: NAB-P was associated
with increased sensory neuropathy
NAB-P
n = 229
Grade
AE (%)
Hypersensitivity
Flushing
Sensory
neuropathy
Fatigue
Myalgias
Vomiting
Oedema
†Cochran-Mantel-Haenszel
Paclitaxel
n = 225
Grade
2
<1
<1
3
0
0
4
0
0
2
0
5
3
1
0
4
0
0
P value†
0.150
< 0.001
20
10
0
10
2
0
< 0.001
13
12
4
2
8
7
3
0
<1
0
<1
0
16
15
4
<1
3
2
1
<1
<1
0
0
0
0.062
0.567
0.022
0.851
test based upon all grades
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Phase III: sensory neuropathy following
NAB-P 260 mg/m2 q3w improved rapidly
+
Proportion not resolved
1.00
+
NAB-P (n = 24)
+
0.75
+
0.50
NAB-P median time to resolution to a lesser
grade: 22 days (95% CI: 17–22 days) vs. 79 days
with solvent-based paclitaxel
0.25
0.00
0
10
20
30
40
50
60
70
80
90
100
110
120
130
Days since grade 3 to lower grade
+Censored
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Fase III: neuropatia migliorata rapidamente
nella maggior parte dei pazienti
24 pazienti (10%) con nab-paclitaxel® hanno sviluppato
grado 3 neuropatia:
• 14 / 24 rapido miglioramento con una mediana di 22 giorni
• 71% (10/14) con miglioramento hanno ripreso nab-paclitaxel® ad
una dose ridotta
• solo 3% (6/233) interrotto nab-paclitaxel® a causa della
neuropatia sensoriale
• no neuropatia motoria in entrambi I bracci di trattamento
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Phase III: nab-paclitaxel ben
tollerato in pazienti ≥ 65 aa
• AEs erano simili in pazienti < 65 e ≥ 65 aa in entrambi I gruppi
AE (%)
Neutropenia
Leucopenia
Nausea
Iperglicemia
Flushing
NAB-P
n = 229
23
10
20
0
0
Paclitaxel
n = 225
59
31
38
19
16
NO effetti collaterali addizionali per nab-paclitaxel®
in pazienti 65 aa rispetto a pazienti più giovani
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
Conclusioni
Confronto con solvent-based paclitaxel
- nab-paclitaxel® ha dimostrato un significativamente maggiore tasso di
risposta e prolungato TTP
- nab-paclitaxel® ha prolungato sopravvivenza in pazienti con CMM trattati
come seconda linea
- L’incidenza di grade 4 neutropenia è stata significativamente più bassa per
nab-paclitaxel®
- Maggiore tasso di neuropatia sensoriale grade 3 con nab-paclitaxel® ma
risolta rapidamente con una mediana di 22 giorni verso 79 giorni per solventbased taxano
- no Severe HSRs con nab-paclitaxel® con assenza di premedicazione e più
breve tempo di infusione
HSR, hypersensitivity reaction
Gradishar et al. J Clin Oncol. 2005; 23: 7794–7803
Phase III:
Subgroup Analysis Comparing
nab-paclitaxel® with Paclitaxel in Patients with
MBC Previously Treated with Anthracycline
Davidson et al.
EBCC. 2008. Poster# 569
Phase III: prior anthracycline
patient demographics
Metastatic anthracycline
(n = 245)
Metastatic or adjuvant
anthracycline
(n = 351)
nabpaclitaxel®
(n = 115)
Paclitaxel
(n = 130)
nab-paclitaxel®
(n = 176)
Paclitaxel
(n = 175)
mean
53.3
53.8
52.6
52.8
range
27–79
34–83
27–79
30–83
white
111 (97)
128 (98)
169 (96)
169 (97)
other
4 (3)
2 (2)
7 (4)
6 (3)
109 (95)
127 (98)
165 (94)
172 (98)
2
6 (5)
3 (2)
10 (6)
3 (2)
3
0 (0)
0 (0)
1 (< 1)
0 (0)
Age (yrs)
Race, n (%)
ECOG PS, n (%)
≤1
Davidson et al. EBCC. 2008. Poster# 569
Phase III CA012: nab-paclitaxel significantly
improved ORR by 16% over paclitaxel
Sub-analysis of anthracycline pretreated patients
P = 0.002
nab-paclitaxel
Paclitaxel
ORR (%)
P = 0.01
Davidson et al. EBCC. 2008. Poster# 569
Phase III CA012: nab-paclitaxel had a
significantly longer TTP
compared with paclitaxel
Prior anthracycline in metastatic
setting only
Prior anthracycline
(adjuvant or metastatic setting)
1.00
Proportion not progressed
Proportion not progressed
1.00
P = 0.004
0.75
0.50
0.25
P = 0.011
0.75
nab-paclitaxel
Paclitaxel
0.50
0.25
0.00
0.00
0
16
32
48
64
Wks
80
96
120
0
16
32
48
64
Wks
80
96
120
Davidson et al. EBCC 2008. Poster #569
Phase III CA012: nab-paclitaxel significantly
prolonged OS compared with paclitaxel
Prior anthracycline in metastatic
setting only
B
Prior anthracycline
(adjuvant or metastatic setting)
A
1.00
1.00
P = 0.049
Probability of survival
Probability of survival
P = 0.049
0.75
0.50
0.25
0.75
nab-paclitaxel
Paclitaxel
0.50
0.25
0.00
0.00
0
16 32 48 64 80 96 112 128
Wks
152
0
16 32 48 64 80 96 112 128
Wks
152
Davidson et al. EBCC 2008. Poster #569
CA012: conclusions from subgroup analysis
• This subset analysis evaluating patients previously treated
with anthracycline shows that, compared with
paclitaxel, treatment with nab-paclitaxel®
– significantly improved clinical outcomes in patients with
MBC
• nab-paclitaxel® achieved significantly higher ORRs
• nab-paclitaxel® had a significantly longer TTP
• nab-paclitaxel® significantly prolonged survival benefit
– is effective for the treatment of patients with MBC
nab-paclitaxel
in monoterapia
Altri dati/studi: pazienti
pesantemente trattate con taxani
November 2007
• nab-paclitaxel 100 or 125mg/m2 qw
• MBC w measurable disease
• PD on taxanes or relapse within 12 months
from adjuvant taxanes
nab-Paclitaxel QW Regimen Phase II
Trial in Taxane-Refractory MBC:
Purpose
• To explore whether nab-paclitaxel has antitumor activity in
patients with MBC that had progressed on conventional taxane
therapy
• Primary Endpoint
• Percentage of patients who achieved a confirmed objective, complete,
or partial response
• Secondary Endpoints
•
•
•
•
SD after > 16 weeks
PFS
OS
Safety
Blum et al. Clin Breast Cancer. 2007;7:850–856
nab-Paclitaxel QW Regimen Phase II
Trial in Taxane-Refractory MBC: Trial
Design
• Heavily pre-treated, taxane-refractory patients
PATIENT COHORTS
nab-Paclitaxel 100 mg/m2 qw 3/4
n = 106
nab-Paclitaxel 125 mg/m2 qw 3/4
n = 75
Study initiated at 100 mg/m2 qw 3 of 4 wks. Because minimal toxicities were observed at
this dose and schedule, protocol was amended to include additional cohort of patients to
receive 125 mg/m2 qw 3 of 4 wks. Each cohort was analyzed separately.
Blum et al. Clin Breast Cancer. 2007;7:850–856
nab-Paclitaxel QW Regimen Phase II Trial
in Taxane-Refractory MBC: Select
Demographics and Baseline Characteristics
Median (range) age, yrs
Visceral disease (%)
> 3 metastatic sites (%)
Tumour progression while on taxane therapy
for metastatic disease (%)
Previous taxane therapy on a qw schedule for
metastatic disease (no. of pts)
paclitaxel (%)
docetaxel (%)
paclitaxel/docetaxel (sequential) (%)
Median (range) no. of previous chemotherapy
regimens for metastatic disease
Previous adjuvant chemotherapy (no. of pts)
anthracycline-containing (%)
taxane-containing (%)
100 mg/m2
(n=106)
53 (34–76)
94
65
125 mg/m2
(n=75)
53 (33–74)
89
69
88
89
58
41
40
34
26
44
37
20
3 (0–7)
3 (1–14)
85
75
29
79
56
27
Blum et al. Clin Breast Cancer. 2007;7:850–856
nab-Paclitaxel QW Regimen:
Responses in Taxane-Refractory MBC
n
Antitumour activity
all patients
Prior taxane therapy for
metastatic disease
Docetaxel
Paclitaxel
Docetaxel and Paclitaxel
†Cochran-Mantel-Haenszel
100 mg/m2
Disease
ORR Control
(%)
(%)
n
125 mg/m2
Disease
ORR Control
(%)
(%)
106
14
26
75
16
37
34
30
29
21
13
7
32
30
21
28
20
19
21
20
0
46
45
21
test based upon all grades
Blum et al. Clin Breast Cancer. 2007;7:850–856
nab-Paclitaxel QW Regimen: Similar Survival
Between Patients Who Achieved SD ≥ 16 wks
and Those With a Confirmed Response
Probability of survival (%)
100
Survival curves for the 100 and 125 mg/m2
cohorts combined (n = 181)
Confirmed responders
75
SD ≥ 16 wks
Non-responders
50
25
P = 0.7106
0
0
3
6
9
12
15
18
21
24
27
30
Mo
Blum et al. Clin Breast Cancer. 2007;7:850–856
NAB-P qw regimen: safety
100 mg/m2
NCI CTC toxicity/AE
125 mg/m2
Grade 3
Grade 4
Grade 3
Grade 4
19
<1
33
3
14
4
31
3
fatigue
5
0
12
0
sensory neuropathy
8†
0
19†
0
nausea
diarrhoea
vomiting
alopaecia
4
1
3
0
0
0
0
0
3
5
1
0
0
0
0
0
Haematological toxicities (%)
leucopaenia
neutropaenia (without G-CSF)
Non-haematological toxicities (%)
†41%
of patients treated with NAB-P 100 mg/m2
and 35% of those treated with 125 mg/m2 had pre-existing
grade 1 peripheral neuropathy
G-CSF, granulocyte-colony stimulating factor
NCI CTC, National Cancer Institute common toxicity criteria
Blum et al. Clin Breast Cancer. 2007; 7: 850–856
NAB-P qw regimen: peripheral
neuropathy improved rapidly
• Grade 3 neuropathy
• 100 mg/m2 cohort, nine patients (8%)
• 125 mg/m2 cohort, 14 patients (19%)
• grade 1 pre-existing neuropathy
• three patients in 100 mg/m2 and three patients in 125 mg/m2
• Of the 23 patients with grade 3 PN, 15 (65%)
restarted NAB-P at a lower dose
• patients who continued treatment were able to resume
dosing, typically in 1–2 wks
PN, peripheral neuropathy
Blum et al. Clin Breast Cancer. 2007; 7: 850–856
Conclusions
• QW nab-paclitaxel at 100 mg/m2 and 125 mg/m2 achieved
– Disease control in 26% and 36% of pts, respectively
– PFS of 3.0 mo and 3.5 mo
– OS of 9.2 mo and 9.1 mo
• There was no significant difference in OS between patients who
achieved an objective response and
non-responders who had SD ≥ 16 wks
• nab-Paclitaxel 100 mg/m2 was well tolerated with no HSR and a
low rate of treatment cessation for peripheral neuropathy
• Minimal myelosuppression; grade 4 neutropenia and
leukopaenia occurred in < 5% of patients in both cohorts
Blum et al. Clin Breast Cancer. 2007;7:850–856
nab-paclitaxel
in monoterapia
Altri dati/studi: confronto
verso docetaxel
nab-paclitaxel JCO Editorial
nab-paclitaxel JCO Editoriale
CA-012: nab-paclitaxel vs
Taxol
TAX 311: Taxotere vs Taxol
nab-paclitaxel 260mg/m2 (30min) q 3 wk
DOCETAXEL 100mg/m2 (1h) q 3 wk
No premedicazione
No special tubing
R
PACLITAXEL 175mg/m2 (3h) q 3 wk
Dexametasone 8mg po bid x 5 d
Dal giorno precedente all’ infusione
R
PACLITAXEL 175mg/m2 (3h) q 3 wk
Dexametasone 20mg po 12 & 6 h +
Dexametasone 20mg po 12 & 6 h +
Difenidramine 50mg IV +
Difenidramine 50mg IV +
Cimetidine 300mg or Ranitidine 50mg IV
Cimetidine 300mg or Ranitidine 50mg IV
30-60 min prima dell’ infusione
30-60 min prima dell’ infusione
JCO Editorial: CA-012 vs. TAX 311
• Entrambi i trials mostrano avere simili caratteristiche
di pazienti e malattia
–
–
–
–
Simile numero di pazienti in ogni trial
Mix di pazienti trattati e non trattati per CMM
Precedente trattamento con antracicline
Simili Fattori Prognostici
• Sia nab-paclitaxel che Taxotere confrontati con Taxol
alla dose di 175mg/m2 ogni 3 settimane
nab-paclitaxel JCO Editoriale
Significantly Longer Progression-Free
Survival with nab-Paclitaxel Compared
with Docetaxel as First-Line Therapy for
Metastatic Breast Cancer
W.J. Gradishar, D. Krasnojon, S. Cheporov, A.N.
Makhson, G.M. Manikhas, A. Clawson, P. Bhar
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
Study Objectives
• To obtain comparative safety and preliminary
antitumor response data for:
–
nab-paclitaxel vs docetaxel
– weekly (QW) vs every-3-week (Q3W) nab-paclitaxel
– lower vs higher dose QW nab-paclitaxel
• Design: open-label, randomized, phase II,
multi-center study
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
qw or q3w NAB-P vs q3w
docetaxel: study design
• 302 first-line MBC patients randomised to four arms (300 pts received study drug
and were evaluable)
Comparisons
R
NAB-P vs
docetaxel
(A, B, C vs D)
A
N
D
qw vs q3w NAB-P
(B, C vs A)
Arm A: NAB-P 300 mg/m2 q3w
Arm B: NAB-P 100 mg/m2 3q4w
O
M
Arm C: NAB-P 150 mg/m2 3q4w
I
low- vs high-dose
qw NAB-P
(B vs C)
Arms A, C and D administered at the MTD
3q4w, repeated wkly for 3 wks out of 4
S
E
Arm D: docetaxel 100 mg/m2 q3w
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
qw or q3w nab-paclitaxel vs q3w
docetaxel: obiettivi dello studio
• Ottenere confronto tossicità e dati preliminari di risposta
antitumorale per:
– nab-paclitaxel® vs docetaxel
– qw vs q3w nab-paclitaxel®
– lower- vs higher-dose qw nab-paclitaxel®
• Utilizzare dati di questo trial per disegnare futuri trials con
nab-paclitaxel®
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
qw or q3w nab-paclitaxel vs q3w docetaxel:
analisi finale - status dello studio
nab-paclitaxel®
Terapia in corso (%)
Interrotta (%)
Motivi per interruzione (%)
300 mg/m2
q3w
(n = 76)
4 (5)
72 (95)
Docetaxel
100 mg/m2 150 mg/m2 100 mg/m2
3q4w
3q4w
q3w
(n = 76)
(n = 74)
(n = 76)
6 (8)
14 (19)
3 (4)
70 (92)
60 (81)
71 (96)
PD
37 (51)
48 (69)
33 (55)
27 (38)
tossicità inaccettabile
10 (14)
5 (7)
10 (17)
15 (21)
AEs
decisione investigatore
0
7 (10)
1 (1)
5 (7)
2 (3)
6 (10)
2 (3)
14 (20)
decisione paziente
18 (25)
11 (16)
8 (13)
13 (18)
PD, progressive disease
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
qw or q3w nab-paclitaxel vs q3w docetaxel:
(RECIST) sperimentatore-ORR
100%
90%
80%
B vs D
P = 0.002
ORR
70%
50%
A vs D
NS
40%
46%
60%
C vs D
P < 0.001
74%
63%
39%
30%
20%
10%
0%
300 mg/m2
q3w
(A: n = 76)
A vs B; P = 0.024
A vs C; P = 0.002
B vs C; NS
NS, not significant
100 mg/m2
3q4w
(B: n = 76)
150 mg/m2
3q4w
(C: n = 74)
Docetaxel
100 mg/m2
q3w
(D: n = 74)
nab-paclitaxel®
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
qw or q3w nab-paclitaxel vs q3w docetaxel:
controllo della malattia (ORR + SD > 16 wks)
Disease Control Rate: stable disease for 16 weeks or
confirmed overall PR or CR
P = 0.009
P = 0.017
100
91
% of Patients
90
80
70
83
75
72
68
Independent
*
Investigator
80
69
58
60
50
40
30
20
10
0
300 mg/m2 q3w
A
100 mg/m2 qw 3/4
B
nab-Paclitaxel
* P-Values
150 mg/m2 qw 3/4
C
100 mg/m2 q3w
D
Docetaxel
for Investigator-assessed DCR are not shown
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619
qw or q3w nab-paclitaxel vs q3w docetaxel:
PFS (Investigator Review)
Proportion not progressed
1.00
nab-paclitaxel® 300 mg/m2 q3w (A)
Regimen
nab-paclitaxel® 100 mg/m2 qw (B)
nab-paclitaxel® 150 mg/m2 qw (C)
Docetaxel 100 mg/m2 q3w (D)
0.75
0.50
0.25
Median
PFS (mo)
P value vs
docetaxel
nab-paclitaxel® (A)
300 mg/m2 q3w
10.9
NS
nab-paclitaxel® (B)
100 mg/m2
3q4w
7.5
NS
nab-paclitaxel® (C)
150 mg/m2
3q4w
(n = 74)
14.6
P = 0.012
HR = 0.568
Docetaxel (D)
100 mg/m2 q3w
7.8
NA
0.00
0
3
6
9
12 15 18 21 24
Mo
A vs B; P = 0.076, HR = 0.702
B vs C; P = 0.001; HR = 1.972
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
qw or q3w nab-paclitaxel® vs q3w
docetaxel: tossicità†
nab-paclitaxel®
Docetaxel
300 mg/m2
q3w (n = 76)
100 mg/m2
qw (n = 76)
150 mg/m2
qw (n = 74)
100 mg/m2
q3w (n = 74)
grade 2
17 (22)
11 (14)
19 (26)
14 (19)
grade 3
13 (17)
6 (8)
10 (14)
9 (12)
grade 4
0 (0)
0 (0)
0 (0)
0 (0)
grade 2
17 (22)
5 (7)
15 (20)
12 (16)
grade 3
4 (5)
0 (0)
2 (3)
14 (19)
grade 4
0 (0)
0 (0)
0 (0)
0 (0)
Neuropatia, n (%)
Fatigue, n (%)
† Tossicità
legate al trattamento riportate in ≥ 25% dei pazienti
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
qw or q3w nab-paclitaxel® vs q3w
docetaxel: tossicità†
nab-paclitaxel®
Docetaxel
300 mg/m2
q3w (n = 76)
100 mg/m2
qw (n = 76)
150 mg/m2
qw (n = 74)
100 mg/m2
q3w (n = 74)
grade 2
20 (26)
5 (7)
14 (19)
10 (14)
grade 3
1 (1)
0 (0)
0 (0)
0 (0)
grade 4
0 (0)
0 (0)
0 (0)
0 (0)
grade 2
22 (29)
25 (33)
24 (32)
2 (3)
grade 3
29 (39)
15 (20)
26 (35)
14 (19)
grade 4
4 (5)
4 (5)
7 (9)
54 (75)
1.21 ± 1.00
1.51 ± 0.96
1.11 ± 0.63
0.38 ± 0.34
Artralgia
Neutropenia
Medio nadir ± SD, x 109/l
† Tossicità
legate al trattamento riportate in ≥ 25% dei pazienti
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
qw or q3w nab-paclitaxel® vs q3w docetaxel:
grade 3 neuropatia migliorata più
rapidamente con nab-paclitaxel
• Neuropatia con simile
frequenza in tutti i bracci
di trattamento
Proportion not improved
1.00
nab-paclitaxel® 300 mg/m2 q3w (A)
nab-paclitaxel® 100 mg/m2 qw (B)
nab-paclitaxel® 150 mg/m2 qw (C)
Docetaxel 100 mg/m2 q3w (D)
0.75
• Tempo mediano al
miglioramento
– per nab-paclitaxel® 300
mg/m2,
100 mg/m2, 150 mg/m2 :
22, 22, 19 giorni
0.50
0.25
– vs docetaxel 37 giorni
0.00
0
10
20
30
40
50
60
70
80
90
100
Giorni
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
Conclusioni
• nab-paclitaxel® ha dimostrato migliore tollerabilità ed
efficacia rispetto a docetaxel
• Tutti e tre i bracci di nab-paclitaxel® con più bassi tassi di neutropenia,
neutropenia febbrile e fatigue
• Il braccio più efficace di nab-paclitaxel® basato su
PFS e ORR è risultato 150 mg/m2 qw
• nab-paclitaxel® 150 mg/m2 qw è risultato superiore in maniera
statisticamente significativa in termini di ORR e PFS rispetto a
docetaxel
• nab-paclitaxel® 100 mg/m2 qw è risultato associato con la minore
tossicità
Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619.
Ultimi Aggiornamenti
- Dati di Overall Survival
- Older patients with MBC
Nab- Paclitaxel Versus Docetaxel for the
First-line Treatment of Metastatic Breast
Cancer (MBC): Final Overall Survival (OS)
Analysis of a Randomized Phase 2 Trial
ASCO Breast Symposium, September 8-10 , 2011, California
Abstract # 275
Overall Survival
Median OS
(mo)
AB-Pac
150mg/m2 qw (C)
33.8
AB-Pac
300mg/m2 q3w (A)
27.7
Taxotere
100mg/m2 q3w (D)
26.6
AB-Pac
100mg/m2 qw (B)
22.2
P
HR
Overall:
0.047
C vs B:
0.008
C vs D: -
0.575
0.688
• The 150 mg/m2 qw albumin-bound paclitaxel arm
demonstrated:
• A significantly longer median OS versus the 100
mg/m2 arm
• A longer OS versus docetaxel, although this
difference was not statistically significant
• The OS benefit of the 150 mg/m2 arm was consistent
among patient subgroups:
• Age <65 vs ≥65 years
• Visceral vs non-visceral disease
• No. of visceral lesion sites <5 vs ≥5
• Pre-menopausal vs post-menopausal
ASCO Breast Symposium, Abstract # 275
Overall Efficacy Analyses
A significant (P= .047) treatment effect on OS was observed among the 4
tratment arms
The OS benefit of 150 mg/mq qw nab-paclitaxel arm was consistent with
results observed in investigator-assessed ORR and PFS
ASCO Breast Symposium, Abstract # 275
Conclusion
• Based on event-driven analysis of final OS, the nab-paclitaxel
150 mg/m2 qw 3/4 regimen provided the best clinical benefit
for the forst-line treatment of patients with MBC
• The median OS of 33.8 months compares favorably with
historical values for taxane monotherapy for MBC
• The OS benefit of the 150 mg/mq qw regimen in consistent
with trends seen in investigator-assessed ORR and PFS
• nab.-paclitaxel was generally well tolerated, and the safety
profile is consistent with previous reports
• These results support further eveluation of the 150 mg/mq
qw dosing schedule of nab-paclitaxel in a randomized, phase 3
trial for the first-line treatment on MBC
ASCO Breast Symposium, Abstract # 275
Weekly nab-paclitaxel is safe and
effective in 65 years old patients
with metastatic breast cancer:
A post-hoc analysis
Matti Aapro, Sergei Tjulandin, Paul
Bhar, William Gradishar
Purpose
This post-hoc analysis of 2 studies (Gradishar
W. 2005 and Gradishar W. 2009) investigated
the safety and efficacy of weekly and every-3week (q3w) nanoparticle albumin-bound
paclitaxel (nab-paclitaxel) in older patients
with metastatic breast cancer (MBC)
compared with q3w solvent-based paclitaxel
and docetaxel.
Aapro M et al, The Breast 2011
Patient Population
Among the total treatment population in the 2 studies:
114 (15%) were 65 years old (phase 2, n = 52; phase 3, n = 62)
In the phase 2 study:
33 pt randomized to nab-paclitaxel
19 pt
n= 9
n= 14
n= 10
300 mg/m2 q3w
100 mg/m2 weekly
150 mg/m2 weekly
randomized to docetaxel
In the phase 3 study:
30 pt
32 pt
randomized to nab-paclitaxel
randomized to paclitaxel
Aapro M et al, The Breast 2011
Demographics/Baseline
Characteristics
Aapro M et al, The Breast 2011
Efficacy (1)
In the phase 2 study
ORR
nab-paclitaxel
22%
300 mg/m2 q3w
docetaxel
64%
60%
32%
100 mg/m2 weekly
150 mg/m2 weekly
100 mg/m2 q3w
nab-paclitaxel
27%
260 mg/m2 q3w
paclitaxel
19%
175 mg/m2 q3w
In the phase 3 study
ORR
In the phase 2 study
DCR
nab-paclitaxel
56%
300 mg/m2 q3w
docetaxel
86%
90%
79%
100 mg/m2 weekly
150 mg/m2 weekly
100 mg/m2 q3w
nab-paclitaxel
53 %
260 mg/m2 q3w
paclitaxel
41%
175 mg/m2 q3w
In the phase 3 study
DCR
Aapro M et al, The Breast 2011
Efficacy (2)
In the phase 2 study
PFS
median
nab-paclitaxel
docetaxel
13.8
9.2
18.9
8.5
300 mg/m2 q3w
100 mg/m2 weekly
150 mg/m2 weekly
100 mg/m2 q3w
In the phase 3 study
PFS median
Aapro M et al, The Breast 2011
nab-paclitaxel
5.6
260 mg/m2 q3w
paclitaxel
3.5
175 mg/m2 q3w
Conclusion
Weekly nab-paclitaxel was safe and more efficacious compared
with the q3w schedule and with solvent-based taxanes in older
patients with MBC.
In particular, the 150 mg/m2 weekly for 3 weeks followed by 1
week of rest nab-paclitaxel resulted in 60% ORR and 21 months
of median OS along with no SAEs and no deaths; thus, it may be
the optimal dose of nab-paclitaxel therapy in patients 65 years
old. These findings warrant further examination of weekly nabpaclitaxel in older patients with MBC.
Aapro M et al, The Breast 2011
nab-Paclitaxel
Ongoing Study in MBC
Cooperative Group Trial with
Biomarker Analysis
Tumor biopsy on
accessible tissue
R
A
N
D
O
M
I
Z
E
Paclitaxel 90 mg/m2 qw 3/4
nab-Paclitaxel 150 mg/m2 qw 3/4
Bevacizumab
10 mg/kg q2w
Ixabepilone 16 mg/m2 qw 3/4
Serum for Caveolin-1
Tumor block for SPARC,
tubulin mutations,
Serial serum measurement of caveolin-1
Circulating Tumor Cells
Serial measurement of CTC and CEC
(CTC) and Circulating
Endothelial Cells (CEC)
CALGB and NCCTG, PI: Hope Rugo, Alvino Moreno; N=900