Transcript Stem Cell Mobilization and Collection in Patients With

1
Albumin-Bound Paclitaxel
for the Treatment of
Non-small Cell Lung Cancer
Monotherapy Studies
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Summary of Albumin-Bound Paclitaxel Monotherapy
Studies in Non-small Cell Lung Cancer
Title
Phase
Monotherapy Studies
Phase II study of albumin-bound paclitaxel as first-line treatment in advanced NSCLC1
II
Phase I/II study of albumin-bound paclitaxel as first-line treatment in stage IV NSCLC2
I/II
NSCLC, non-small cell lung cancer
1. Green et al. Ann Oncol. 2006
2. Rizvi et al. J Clin Oncol. 2008
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Albumin-Bound Paclitaxel, a Novel
Cremophor®-free, Albumin-Bound Particle Form
of Paclitaxel for the Treatment of Advanced
Non-Small Cell Lung Cancer
M.R. Green, G.M. Manikhas, S. Orlov, B. Afanasyev,
A.M. Makhson, P. Bhar, M.J. Hawkins
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Study Rationale
• Single agent solvent-based paclitaxel plays a central role in the
treatment of advanced non-small cell lung cancer, but its use is
limited due to poor solubility, toxicity, and long infusion time1-3
• Albumin-bound paclitaxel delivers paclitaxel as a suspension
of albumin particles in saline, which obviates the need for
Cremophor EL solvent and leads to reduced hypersensitivity
and infusion time4
• In a phase III trial, albumin-bound paclitaxel 260 mg/m2 was
superior to paclitaxel 175 mg/m2 q3w for the treatment of
metastatic breast cancer4
• The current study explored the efficacy and safety of single
agent albumin-bound paclitaxel in the treatment of advanced
NSCLC
NSCLC, non-small cell lung cancer;
q3w, every-3-week
1. Socinski et al. The Oncologist. 1999
2.Gelderblom et al. Eur J Cancer. 2001
3. nab-paclitaxel® Prescribing Information 2010
4. Gradishar et al. JCO 2005
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Study Design
• Intravenous albumin-bound paclitaxel 260 mg/m2 over 30
minutes
– Day 1, every-3-week (q3w)
– Until disease progression or unacceptable toxicity
• Primary endpoint:
– Percentage of patients who achieved complete response (CR) or
partial response (PR), based on Response Evaluation Criteria in
Solid Tumors (RECIST)
• Secondary objectives:
–
–
–
–
–
Time to tumor progression (TTP)
Overall survival (OS)
Number of objective responses
Disease control rate (DCR)
Safety/tolerability
NSCLC, non-small cell lung cancer
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Key Eligibility Criteria
• Key inclusion criteria
– Men and non-pregnant women ≥ 18 years of age
– Histologically or cytologically confirmed advanced NSCLC (at
least 1 measurable stage IIIB or IV lesion)
– Evidence of inoperable local recurrence or metastasis, but no
other active malignancy
– No prior therapy for metastatic disease
– Expected survival of > 12 weeks
– Adequate hematologic, hepatic, and renal function
NSCLC, non-small cell lung cancer
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Key Eligibility Criteria
• Key exclusion criteria
– Clinical evidence of brain metastasis
– Serious concurrent illness
– Eastern Cooperative Oncology Group performance status
(ECOG PS) of ≥ 2
– Peripheral neuropathy grade ≥ 2
– Prior radiotherapy
NSCLC, non-small cell lung cancer
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Select Patient Characteristics
• Forty-three patients with previously untreated stage IIIB or IV
NSCLC enrolled at 6 centers in Russia
–
–
–
–
–
–
Median age: 58
All patients eligible and evaluable (treated population)
Age < 65: n = 34 (79%)
Visceral disease: n = 36 (84%)
ECOG PS of 0 or 1: n = 43 (100%)
Total number of lesions
• One: n = 5 (12%)
• Two to 3: n = 13 (30%)
• > 3: n = 25 (58%)
– Two patients (5%) had preexisting sensory neuropathy (grade 1)
NSCLC, non-small cell lung cancer
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Results: Clinical Response
Subgroup/variable (N = 43)
Baseline, n
Responding patients, n
43
7 (16; 5.24-27.31)
Confirmed overall response, n (%)
Carcinoma/adenocarcinoma
Squamous cell carcinoma
Other
43
11
29
3
7 (16%)
1
5
1
Disease control,b n (%)
Carcinoma/adenocarcinoma
Squamous cell carcinoma
Other
43
11
29
3
21 (49%)
5
14
2
Death, n (%)
Carcinoma/adenocarcinoma
Squamous cell carcinoma
Other
43
11
29
3
23 (53%)
5
16
2
ORR, n (%; 95% CI)
Response by histologya
a Other
categories of NSCLC include large-cell carcinoma, undifferentiated NSCLC, and mixed squamous and adenocarcinoma
responders + patients with stable disease ≥ 16 weeks
ORR, overall response rate; CI, confidence interval
b Includes
NSCLC, non-small cell lung cancer
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Results: TTP
Proportion not Progressed
1.00
Albumin-bound
paclitaxel (N = 43)
0.75
0.50
0.25
.0
0
3
6
9
12
15
18
21
24
Months
• Median TTP was 6 months (95% CI: 3.9-6.5, treated population)
• Probability of not having progressed was 50% at 6 months and 13% at 1 year
NSCLC, non-small cell lung cancer; TTP, time
to tumor progression; CI, confidence interval
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Results: OS
1.00
Probability of Survival
Albumin-bound
paclitaxel (N = 43)
0.75
0.50
0.25
0.00
0
3
6
9
12
15
18
21
24
Months
• Median survival was 11 months (95% CI: 9.5-16.2, treated population)
• The probability of surviving 1 year was 45%
NSCLC, non-small cell lung cancer; OS, overall
survival; CI, confidence interval
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Safety
• Ninety-five percent of patients received albumin-bound
paclitaxel at protocol-specified dose
• Ninety-eight percent of cycles were administered at full dose
• Dose reductions occurred in 2 patients (5%)
– Elevated liver function test after cycle 4 (n = 1)
– Peripheral neuropathy after cycle 6 (n = 1)
• Sixty-three percent of patients received at least 6 treatment
cycles
• Two patients (5%) discontinued therapy due to treatmentrelated adverse events
– Grade 3 neuropathy after cycle 7 (n = 1)
– Grade 3 fatigue after cycle 2 (n = 1)
• Patient received 4 additional cycles after onset of fatigue
NSCLC, non-small cell lung cancer
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Safety: Adverse Events
Adverse event
reported in ≥ 10% of
patients
> 1 treatment-related AE
Hematologica
Anemia
Neutropenia
Leukopenia
Thrombocytopenia
Nonhematologic
Alopecia
Sensory neuropathy
Arthralgia
Fatigue
Myalgia
Fever
All grades
(%)
Grade 1
(%)
Grade 2
(%)
Grade 3
(%)
Grade 4
(%)
40 (93)
7 (16)
24 (56)
9 (21)
0
32 (74)
21 (49)
10 (23)
6 (14)
24 (56)
9 (21)
7 (16)
6 (14)
8 (19)
8 (19)
3 (7)
0
0
4 (9)
0
0
0
0
0
0
33 (77)
28 (65)
15 (35)
14 (33)
8 (19)
7 (16)
4 (9)
21 (49)
10 (23)
3 (7)
5 (12)
2 (5)
29 (67)
5 (12)
4 (9)
8 (19)
3 (7)
5 (12)
N/A
2 (5)
1 (2)
3 (7)
0
0
N/A
0
0
0
0
0
Note: If a patient reported the same AE more than once, that patient was counted only once for that AE, using the highest grade
aBased on central laboratory values
AE, adverse event
NSCLC, non-small cell lung cancer
Green et al. Ann Oncol. 2006;17:1263-1268.
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Albumin-Bound Paclitaxel Monotherapy in Advanced
NSCLC
Conclusions
• Single agent albumin-bound paclitaxel has considerable
activity and a favorable therapeutic index when used as a 30min IV infusion at 260 mg/m2 q3w for the treatment of
advanced NSCLC
• The TTP and estimated median OS are closer to those seen
with standard combination paclitaxel-carboplatin therapy than
with paclitaxel alone1
• Testing combinations of albumin-bound paclitaxel plus a
platinum or non-platinum partner as first-line therapy in
patients with advanced NSCLC is warranted
• Given the minimal myelosuppression, use of albumin-bound
paclitaxel may also facilitate administration of full-dose
chemotherapy concurrently with radiation for the management
of patients with stage III NSCLC (such studies are ongoing)
NSCLC, non-small cell lung cancer; IV,
intravenous; TTP, time to tumor progression; OS,
overall survival
Green et al. Ann Oncol. 2006;17:1263-1268.
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Phase I/II Trial of Weekly Intravenous 130-nm
Albumin-Bound Paclitaxel as Initial
Chemotherapy in Patients With Stage IV
Non-small Cell Lung Cancer
N.A. Rizvi, G.J. Riely, C.G. Azzoli, V.A. Miller, K.K. Ng,
J. Fiore, G. Chia, M. Brower, R. Heelan, M.J. Hawkins,
M.G. Kris
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Rationale
• In a phase III trial, albumin-bound paclitaxel 260 mg/m2 was
superior to paclitaxel 175 mg/m2 q3w in the treatment of
metastatic breast cancer1
• In a phase II study, albumin-bound paclitaxel 260 mg/m2
administered q3w to chemotherapy-naïve advanced non-small
cell lung cancer (NSCLC) patients demonstrated an overall
response rate (ORR) of 16%, median time to progression (TTP)
of 6 months, and median overall survival (OS) of 11 months2
q3w, every-3-week
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
1. Gradishar et al, JCO 2005
2. Green et al, Ann Oncol 2006
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Rationale (cont.)
• A phase I trial of albumin-bound paclitaxel administered weekly
was conducted in patients with solid tumors1
– Albumin-bound paclitaxel doses ranged from 80 to 200 mg/m2 and
the maximum-tolerated dose (MTD) was defined as 100 and 150
mg/m2, respectively
– Dose-limiting toxicities (DLTs) included grade 3/4 peripheral
neuropathy
– Partial responses (PR) were observed in 5 patients who had been
previously treated with paclitaxel
• The purpose of this trial was to identify the MTD of albuminbound paclitaxel administered on a weekly schedule in patients
with untreated advanced NSCLC and to determine the safety and
ORR
q3w, every-3-week
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
1. Nyman et al, JCO 2005
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Study Design
• Single-center, open-label, phase I/II trial
• Treatment administered
– Albumin-bound paclitaxel intravenously (IV) over 30 minutes
without premedication
– Days 1, 8, and 15, every 28 days
• Phase I: Dose escalation study to determine MTD
– Planned dose escalation over 4 dose levels
• 100, 125, 150, and 175 mg/m2
• Phase II: 40 patients treated at MTD
– Response Evaluation Criteria In Solid Tumors (RECIST): clinical
responses reviewed with reference radiologist
• Primary endpoints
– ORR, safety
• Secondary endpoints
– TTP, OS
q3w, every-3-week; MTD, maximum tolerated
dose; ORR, overall response rate; TTP, time to
tumor progression; OS, overall survival
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in Stage
IV NSCLC
Patient Eligibility Criteria
• Key inclusion criteria
– Stage IV or recurrent NSCLC
– Patients may have received chemotherapy in the adjuvant or
neoadjuvant setting
– Prior treatment with gefitinib or erlotinib for advanced disease
was allowed
– Laboratory requirements
• Aspartate aminotransferase and alanine aminotransferase ≤ 2.5
times the upper limit of normal range
• Total bilirubin within the normal range
• Creatinine ≤ 1.5 mg/dL
• Absolute neutrophil count ≥ 1.5  109 cells/L
• Platelets ≥ 100  109 cells/L
• Hemoglobin ≥ 9 g/dL
NSCLC, non-small cell lung cancer
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in Stage
IV NSCLC
Patient Eligibility Criteria (cont.)
• Key exclusion criteria
– Prior chemotherapy for advanced NSCLC
– Peripheral neuropathy > grade 1
– Radiotherapy received < 3 weeks before study entry
NSCLC, non-small cell lung cancer
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Results: Phase I
• Dose limiting toxicities
– Dose 100 and 125 mg/m2: none
– Dose 150 mg/m2: 2/6 patients during first cycle
• Febrile neutropenia (n = 1)
• Sensory neuropathy (n = 1)
• Maximum tolerated dose was determined to be 125 mg/m2
• Study expanded to 40 patients in phase II portion
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Select Baseline Patient Characteristics
Baseline characteristic (N = 40)
Median age, years (range)
n (%)
70 (43-84)
Karnovsky performance status, n (%)
90%-100%
70%-80%
10 (25)
30 (75)
Prior chemotherapy, n (%)
Neoadjuvant
Adjuvant
EGFR TKI
3 (8)
6 (15)
5 (13)
Histology, n (%)
Adenocarcinoma
Squamous-cell carcinoma
32 (80)
8 (20)
EGFR TKI, epidermal growth factor receptor tyrosine kinase inhibitor
• Seventy-five percent of patients had performance statuses of 70%-80%
• Eighty percent of patients exhibited non-squamous NSCLC
EGFR TKI—epidermal growth factor tyrosine kinase inhibitor
NSCLC, non-small cell lung cancer
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Results: Phase II
Treatment characteristic (N = 40)
n (%)
Median number of cycles administered (range)
4 (1-14)
ORR (PR + CR), n (%)
95% CI
12 (30)
16-44
SD ≥ 16 weeks, n (%)
8 (20)
Median TTP, months
95% CI
5
3-8
Median OS, months
95% CI
11
(7-NR)
1-year OS, %
41%
ORR, overall response rate; CR, complete response; PR, partial response; CI,
confidence interval; NR, not reached; OS, overall survival; SD, stable disease; TTP,
time to tumor progression
• The ORR of the phase II portion of this study was 30%
• The 1-year survival rate was 41%
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Safety: Hematologic Adverse Events (AEs) Occurring in ≥ 20% of
Patients
Hematologic adverse events occurring
in ≥ 20% of patients (n = 40)
Grade 1, %
Grade 2, %
Grade 3, %
Grade 4, %
Anemia
63
23
8
0
Leukopenia
23
20
20
0
Neutropenia
13
28
15
5
• Grade 4 neutropenia occurred in 2/40 (5%) of patients (the only grade 4 AE)
• Grade 3 hematologic AEs: anemia (8%), leukopenia (20%), and neutropenia
(15%)
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Safety: Non-Hematologic Adverse Events (AEs) Occurring in ≥
20% of Patients
Nonhematologic adverse events
occurring in ≥ 20% of patients (n = 40)
Grade 1,
%
Grade 2,
%
Grade 3,
%
Grade 4,
%
Sensory neuropathy
35
23
15
0
Fatigue
28
30
18
0
Alopecia
10
60
0
0
Constipation
38
20
0
0
Diarrhea
25
10
13
0
Nausea
38
8
0
0
Rash
35
5
0
0
Edema
18
13
0
0
Myalgia
18
10
0
0
Anorexia
18
10
0
0
Rizvi et al. J Clin Onc. 2008; 26: 639-634.
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First-Line Albumin-Bound Paclitaxel Monotherapy in
Stage IV NSCLC
Conclusions
• This study demonstrated encouraging single-agent activity with
weekly albumin-bound paclitaxel 125 mg/m2 on days 1, 8, and
15 every 28 days
• With the reduced risk of hypersensitivity reactions reported
with albumin-bound paclitaxel compared with solvent-based
paclitaxel, albumin-bound paclitaxel may play an important role
in the treatment of NSCLC
• Additional studies to evaluate the safety and efficacy of
albumin-bound paclitaxel in platinum combination studies are
warranted
Rizvi et al. J Clin Onc. 2008; 26: 639-634.