Download Final results of a phase II study of nab

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Breast Cancer Res Treat (2010) 123:427–435
DOI 10.1007/s10549-010-1002-0
CLINICAL TRIAL
Final results of a phase II study of nab-paclitaxel, bevacizumab,
and gemcitabine as first-line therapy for patients
with HER2-negative metastatic breast cancer
•
TA
B
Received: 11 June 2010 / Accepted: 15 June 2010 / Published online: 29 June 2010
Ó Springer Science+Business Media, LLC. 2010
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Christopher Lobo • Gilberto Lopes • Odalys Baez • Aurelio Castrellon
Annapoorna Ferrell • Connie Higgins • Erin Hurley • Judith Hurley •
Isildinha Reis • Stephen Richman • Pearl Seo • Orlando Silva •
Joyce Slingerland • Keleni Tukia • Catherine Welsh • Stefan Glück
(CR) and partial (PR) response rates, clinical benefit
(ORR ? stable disease), overall survival (OS), and safety.
Thirty patients were enrolled. One patient was ineligible
and was not included in analysis. Median PFS was
10.4 months (95% CI: 5.6–15.2 months). ORR was 75.9%,
comprising eight (27.6%) CRs and 14 (48.3%) PRs; five
patients had stable disease (SD) and two patients (6.9%)
had progressive disease (PD) as their best response. The
clinical benefit rate was 93.1% (27/29) in the overall group
and 84.6% in the triple-negative cohort (11/13). The
18-month survival rate was 77.2% (95% CI: 51.1–90.5%).
Eight (27.6%) patients experienced grade 3 or 4 toxicity:
grade 4 neutropenic fever (n = 1) and grade 3 infection
(n = 6), leukopenia, thrombocytopenia, peripheral neuropathy, seizure, shortness of breath, hematuria, and cardiac tamponade (one each). First-line therapy with nab-P,
B, and G demonstrated a median PFS of 10.4 months and a
75.9% ORR with acceptable toxicity; this novel combination warrants investigation in a randomized study.
PR
IN
Abstract In order to examine the efficacy and safety of
nanoparticle albumin-bound paclitaxel (nab-P) in combination with bevacizumab (B) and gemcitabine (G) for the
first-line treatment of patients with HER2-negative metastatic breast cancer (MBC). In this single-center, openlabel phase II trial, patients with HER2-negative MBC
received gemcitabine 1500 mg/m2, nab-paclitaxel 150 mg/m2,
and bevacizumab 10 mg/kg (each administered intravenously) on days 1 and 15 of a 28-day cycle. The primary
end point was progression free survival (PFS); secondary
end points were overall response rate (ORR), complete
Christopher Lobo and Gilberto Lopes contributed equally to the
design and conduction of this trial and should be considered first
authors.
Declaration: Presented in part (Interim Analysis) at the ASCO Annual
Meeting 2008, Abstract 1089 and at the ESMO Conference 2008,
Abstract 152P. Final results presented at EBCC 2010.
O
T
C. Lobo
Florida Cancer Specialists and Research Institute, Gainesville,
FL, USA
N
G. Lopes
The Johns Hopkins Singapore International Medical Centre,
Singapore, Singapore
Keywords HER2-negative metastatic breast cancer First-line therapy Nab-paclitaxel Bevacizumab Gemcitabine
G. Lopes
The Johns Hopkins University School of Medicine, Baltimore,
MD, USA
Introduction
O. Baez A. Castrellon A. Ferrell C. Higgins E. Hurley J. Hurley I. Reis S. Richman P. Seo O. Silva J. Slingerland K. Tukia C. Welsh S. Glück (&)
Division of Hematology/Oncology, Department of Medicine,
Sylvester Comprehensive Cancer Center, Braman Family Breast
Cancer Institute Miller School of Medicine in Miami,
The University of Miami, 1475 NW 12 Avenue, SCCC,
Suite 3510 (D8-4), Miami, FL 33136, USA
e-mail: [email protected]
An American Cancer Society statistic estimates that
192,370 new cases of invasive breast cancer will be diagnosed in the year 2009 in the United States [1]. Only 6% of
these new cases of breast cancer will be metastatic; however, it is estimated that 30% of early stage patients will
develop MBC [2]. Currently, the estimated 5-year survival
rate for patients with metastases is 27%, with a median
survival of 2–3 years [1, 3]. The incurability of MBC is
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Breast Cancer Res Treat (2010) 123:427–435
LE
combining the three agents could potentially lead to a
further improvement in efficacy. In addition, the greater
efficacy and better tolerability of nab-P compared to cbP
suggests that replacing cbP with nab-P may lead to further
improvements of PFS and ORR. Preliminary data from our
pilot study involving heavily pre-treated women with MBC
demonstrated the feasibility of uniting nab-P, B, and G
[11]. The combination was well tolerated, and objective
responses were noted [11]. In this phase II study, we
examined the efficacy and safety of this novel triplet
combination (2-week schedule of nab-P, G, and B) in the
first-line MBC setting.
Patients and methods
This open-label, single-center phase II trial enrolled 30
patients with HER2/neu negative MBC at University of
Miami (UM), Sylvester Comprehensive Cancer Center
(SCCC)/Braman Family Breast Cancer Institute (BFBCI)
and Jackson Memorial Hospital (JMH). The SCCC was the
sponsor of this study and determined the study design,
reporting, and conduct. The study was approved by the UM
Institutional Review Board, and all patients provided
written informed consent. This study was partially funded
by the manufacturing companies, and all three drugs were
provided.
N
O
T
PR
IN
TA
B
well documented and researched; palliative chemotherapy
options are numerous, with diverse regimens based on class
of drug, number of agents, dosage, and schedule. Eventually, all MBC patients will develop refractory disease.
Therefore, more efficacious, less toxic first-line therapy
options for MBC are needed.
Since the early 1970s, chemotherapeutic treatments for
MBC have been assessed, including anthracyclines and
taxanes, in the first-line setting. Cremophor-based paclitaxel (cbP) is one of the taxanes active in MBC, and
nanoparticles albumin-bound paclitaxel (nab-P) has
recently been shown to improve overall response rates
(ORR) and time to tumor progression (TTP) when compared to cbP in patients with MBC [4]. Nab-P was designed
to prevent the adverse events associated with polyethyoxylated castor oil. Nab-P is indicated for the treatment of
MBC after failure of polychemotherapy (e.g., anthracycline) or relapse within 6 months of adjuvant therapy. A
phase III trial confirmed the superior efficacy and reduced
toxicity associated with nab-P versus cbP in patients with
MBC [4]. The efficacy and safety of nab-P in the first-line
setting were compared with those of another taxane,
docetaxel, in a phase II study. Weekly nab-P revealed a
significantly longer progression-free survival (PFS) than
docetaxel (12.9 vs. 7.5 months, respectively) with less
grade 3 and 4 toxicities in patients with MBC, and first-line
therapy [5].
CbP and gemcitabine (G) are FDA approved as a doublet regimen in the first-line treatment of MBC, after failure of an anthracycline. A phase II trial by Tomao et al.[6]
illustrated that the combination of cbP and G was well
tolerated on a biweekly basis, resulting in an ORR of 64%
in patients with previous anthracycline exposure. In 2008, a
phase III study of advanced breast cancer confirmed the
improved activity of G with cbP when compared to cbP
monotherapy; this combination resulted in a median overall
survival (OS) of 18.6 months compared with 15.8 months,
respectively [7].
Another regimen that has been indicated for the use in
HER2-negative patients with untreated metastatic disease
is cbP together with the anti-vascular endothelial growth
factor monoclonal antibody, bevacizumab (B). A phase III
trial of B ? cbP compared with cbP alone demonstrated
significantly improved PFS (11.8 vs. 5.9 months, respectively); however, there was not a significant improvement
in OS with B [8, 9]. Preliminary data have suggested a
prolongation of PFS and an adequate safety profile with the
addition of B to nab-P [10].
The objective of exploring various polychemotherapy
regimens involving cytotoxic and biologic agents is to
prolong PFS and OS. The doublet regimens G ? cbP and
B ? cbP have demonstrated improved efficacy compared
with any of these agents as monotherapy, suggesting that
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Patient selection
Male and nonpregnant female patients who were
C18 years of age, with measurable (by response evaluation
criteria in solid tumors, RECIST) HER2/neu non-overexpressing or non-amplified (by FISH) MBC were eligible
for this study. Patients were required to have a life
expectancy greater than 3 months, with an ECOG performance status of 0 or 1. Eligibility criteria included treatment-naı̈ve, newly diagnosed MBC or patients with
metastasis diagnosed C6 months after completing primary
systemic treatment in the neoadjuvant or adjuvant setting.
Patients with estrogen receptor-positive breast cancer who
progressed on prior endocrine treatment in the adjuvant
and/or palliative settings were eligible. Good end-organ
function was required as follows: neutrophils, 1.5 9 109/L
or greater; platelets, 100 9 109/L or greater; hemoglobin,
C9.0 g/dL; serum creatinine, B1.5 mg/dL; bilirubin,
Bupper limit of normal; ALT/AST, B2.5 times the upper
limit of the normal range except when caused by metastatic
disease; urine protein/creatinine (UPC) ratio \1.0 at
screening. Patients had to comply with all trial requirements; specifically, birth control measures were mandatory
for all patients capable of reproduction.
Breast Cancer Res Treat (2010) 123:427–435
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Study size, endpoints, and statistical analysis
LE
The primary endpoint of the trial was PFS. The sample size
of 30 patients, which was chosen on the basis of expected
1-year accrual for this single institution trial, provides good
precision in estimating the 1-year PFS rate. More specifically, with 30 patients the maximum standard error for oneyear PFS is 9.1% based on Peto’s method assuming no
losses to follow up [12].
The PFS was defined as the time from the first treatment
date to the earliest date of documented progression measured by CT scans or date of death due to any cause.
Secondary endpoint included ORR, OS, and safety. OS was
determined from the date of enrollment to the date of
death; event-free patients were censored at last contact.
The baseline characteristics were summarized using
descriptive statistics, and adverse events were characterized by type, grade, and attribution to treatment.
The Kaplan–Meier method was used to estimate median
PFS and median OS. The rates of PFS and OS were
summarized by point estimates and 95% confidence intervals (CI) at selected times: 6, 12, 18, and 24 months following initiation of treatment. As much as possible,
considering the sample size limitations, Cox proportional
hazards regression was used to determine whether PFS and
OS were affected by response to treatment, age at diagnosis, race/ethnicity, and hormonal receptor status [12].
TA
B
Patients with any exposure to G or other chemotherapy
within one month of enrollment were excluded. In addition,
the presence of active central nervous system metastases or
simultaneous malignancies (excluding inactive skin nonmelanoma or inactive cervical cancer) disqualified patients
from participation. Pre-existing conditions excluded
patients from enrollment, including: gastrointestinal
bleeding in the previous 3 months, inadequately controlled
hypertension, grade 1? peripheral neuropathy, known
AIDS or HIV positive serology, unstable angina, congestive heart failure NYHA grade 2?, history of myocardial
infarction or stroke within the last 6 months, significant
peripheral vascular disease, and a history of an abdominal
fistula within 6 months of enrollment.
Treatment protocol
O
T
PR
IN
Patients received treatment with G 1500 mg/m2 intravenously (IV) over 30 min, followed by nab-P 150 mg/m2 IV
over 30 min, and then with B 10 mg/kg IV over 30 min on
days 1 and 15 of a 28-day cycle. All dose reductions followed the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE) (version 3.0)
for hematologic and nonhematologic toxicity. Chemotherapy, including bevacizumab, was continued until disease
progression, excessive toxicity, or withdrawal of consent.
Bevacizumab was not continued alone in the advent of
unacceptable toxicity induced by the cytotoxic drugs.
Supportive care with granulocyte colony-stimulating factor
(G-CSF) was administered when necessary. Premedication
with antiemetic and steroid agents was dispensed according
to institutional standards. Early stopping rules were in
place for unacceptable toxicity and/or lack of efficacy.
Assessments
N
Initial patient evaluations included a full medical history
and a complete physical examination. Baseline-computed
tomography (CT) scans with contrast of the head, chest,
abdomen, and pelvis were obtained, and follow-up scans
were repeated every two cycles. Tumor response was
confirmed according to RECIST. Laboratory samples were
collected before treatment, including complete blood count
with differential and platelet count, glucose, BUN, creatinine, uric acid, bilirubin, alkaline phosphatase, SGOT,
electrolytes, urine pregnancy test, and protein/creatinine
ratio on spot urinalysis. All adverse events and laboratory
values were classified according to the NCI CTCAE version 3.0.
Results
Patient characteristics
Thirty patients were enrolled between July 2007 and September 2008. Subsequently, one patient, having received
one dose of treatment before evidence of active brain
metastases, was disqualified from the trial. The median age
of these 29 patients (28 females and 1 male) was 54
(Table 1). The majority of patients were Hispanic (58.6%),
and the remainders were African American (27.6%), nonHispanic Caucasian (10.3%), and Asian (3.4%). All the
patients had stage IV breast cancer; the most common sites
of metastases were the liver, bone, and lung (34.5% of
patients each), and 17.5% of patients had lymph node
involvement. Other sites of metastasis included the chest
wall (6.9%), brain (3.4%), and gastrohepatic ligament
(3.4%).
All patients who received C1 cycle of the study treatment and met the study criteria were evaluated for efficacy
and toxicity (N = 29). The median number of treatment
cycles received was 6.5 (range 1.5–23), and one patient
remained on study (Table 1).
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Table 1 Patient Demographics and Disease Characteristics
Table 1 continued
Characteristic
Characteristic
N (%), unless
otherwise
specified
Median age, y (range)
53.8 (34–69)
[5–10
Mean (std)
52.3 (9.2)
[10
Sex:
Female
28 (96.6)
Male
1 (3.4)
17 (58.6)
ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor-2
Non-Hispanic
12 (41.4)
Efficacy
White
20 (69.0)
Black
8 (27.6)
Asian
1 (3.4)
Stage at Initial Diagnosis
Stage 0
1 (3.4)
Stage I–II
12 (41.4)
Stage III
2 (6.9)
Stage IV
14 (48.3)
Prior systemic therapy
Adjuvant chemotherapy naı̈ve
18 (62.1)
11 (37.9)
Adjuvant or palliative endocrine therapy exposure
No. Visceral Sites
0
17 (58.6)
12 (41.4)
9 (31.0)
PR
18 (62.1)
2 (6.9)
Bone
Liver
Lung
Lymph nodes
10 (34.5)
10 (34.5)
10 (34.5)
5 (17.2)
2 (6.9)
Brain
1 (3.4)
O
T
Chest wall
Gastrohepatic ligament
ER status
1 (3.4)
13 (44.8)
Positive
16 (55.2)
N
Negative
R status
Negative
19 (65.5)
Positive
7 (24.1)
Unknown
3 (10.3)
HER2 status
Negative
Triple-negative
29 (100)
13 (44.8)
1.00
1.5
1 (3.4)
2–5
8 (27.6)
Month
PFS (%)
95% CI
6
64.5
(44.0 -- 79.1)
12
43.0
(24.7 -- 60.1)
18
18.8
(6.6 -- 35.8)
Median 10.4 months (95%CI: 5.6 to 15.2)
23 events in 29 patients
0.75
0.50
0.25
0.00
At risk
29
18
0
Treatment cycles
123
Proportion progression-free
Adjuvant or palliative endocrine therapy naı̈ve
IN
Adjuvant chemotherapy exposure
In this study, the median PFS was 10.4 months (95% CI:
5.6–15.2) (Fig. 1). The ORR was 75.9%. Eight patients
(27.6%) achieved a complete response (CR); while 14
patients (48.3%) had a partial response (PR); 5 (17.2%)
stable disease (SD); and 2 (6.9%) had progressive disease
(PD) as their best response to treatment (Table 2). The
clinical benefit rate (CBR) (ORR ?SD) for this triplet
regimen is 93.1% (95% CI:77–99). In addition, the 18month OS rate was 77.2% (95% CI:51.1–90.5%) (Fig. 2).
Notably, among the patients in this study with triplenegative (TN) disease (i.e., negative for human epidermal
growth factor receptor 2 (HER2), estrogen receptor (ER)
and progesterone receptor (PR)) (13 [44.8%]), 5 (38.4%)
had CR, 4 (30.7%) patients had PR, and 2 (6.9%) patients
had SD as their best response. 2 (6.9%) patients had PD. At
18-months, the PFS rate was 10.6% in this subgroup (95%
CI: 0.6–36.8) and 25.0% in patients with tumor receptor
positivity (95% CI: 7.8–47.2) (Fig. 3). The CBR for triplenegative patients was 84.6%. The 18-month OS rate in this
subgroup was 82.5% (95% CI: 46.1–95.3%).
In the univariate Cox Regression analysis only two
prognostic factors associated with tumor response were
significant for effect on PFS (CR vs. Other and CR/PR vs.
Other) (Table 3).
TA
B
Race
2
5 (17.2)
6.5 (1.5–23)
LE
Hispanic or Latino
Location of metastases
15 (51.7)
Median (range)
Ethnicity
1
N (%), unless
otherwise
specified
6
12
4
12
18
Months
Fig. 1 Kaplan–Meier plot for Progression Free Survival
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Breast Cancer Res Treat (2010) 123:427–435
431
Table 2 Best response to treatment
Best response
Patients, no. (%) (N = 29)
95% CI
Complete response (CR)
8 (27.6)
13–47
Partial response (PR)
14 (48.3)
5 (17.2)
a
Stable disease (SD)
Table 3 Cox Regression Analysis: univariate effect of prognostic
factors for PFS
Prognostic factor
Hazard Ratio (95% CI)
P value
29–68
Age: 1-year increment
1.02 (0.97, 1.07)
0.43
6–36
Age: 10-year increment
1.20 (0.76, 1.90)
0.43
1.61 (0.65, 3.96)
0.301
2 (6.9)
0.8–23
Clinical Benefit Rate
27 (93.1)
77–99
Race: White vs. Other
0.68 (0.28, 1.63)
0.389
–
Ethnicity: Hispanic vs. NH
0.60 (0.26, 1.38)
0.228
ER: Positive vs. negative
0.85 (0.37, 1.96)
0.707
(CR ? PR ? SD)
a
–
\30% reduction according to RECIST
0.574
1.17 (0.51, 2.69)
0.707
Response: CR vs. Other
0.12 (0.03, 0.54)
0.006
Response: CR/PR vs. Other
0.34 (0.13, 0.89)
0.027
0.75
Month
OS (%)
95% CI
6
92.9
(74.3 -- 98.2)
12
84.9
(64.5 -- 94.1)
18
77.2
(51.1 -- 90.5)
61.7
(25.4 -- 84.4)
0.50
24
6 events in 29 patients
0.25
0.00
At risk
29
0
25
6
18
9
12
18
24
Months
portAcath infections (6.9%) and abscess, fever/sepsis, breast
abscess, hematuria, leukopenia, peripheral neuropathy,
seizure/syncope, shortness of breath, cardiac tamponade,
thrombocytopenia, and UTI (3.4% each). There was only
one case of grade 4 toxicity, neutropenic fever. This patient
was hospitalized for neutropenic fever, hematuria, and
thrombocytopenia. There were a total of ten hospitalizations on trial and no toxicity-related deaths.
IN
Fig. 2 Kaplan–Meier plot for overall survival
Discussion
0.75
0.50
ER+
TN
0.25
10
8
7
5
O
T
At risk
16
13
PR
1.00
Proportion progression-free
1.31 (0.51, 3.35)
TN: TN vs. Other
TA
B
Proportion surviving
1.00
PR: Positive vs. Other
LE
Progressive disease
Age: [ 50 vs. B 50
0.00
0
6
12
18
24
Months
N
Fig. 3 Kaplan–Meier plot for PFS comparison for triple-negative
patients and non-triple-negative patients (log-rank P = 0.707)
Toxicity
Safety analysis included all the 29 eligible patients. The
most common grade 1 and grade 2 toxicities were alopecia
(65.5%), fatigue (37.9%), bone pain (31%), nausea (31%),
and skin rash/lesions (27.6%) (Table 4). There were also
three cases (10.3%) of neutropenia, which were all grade 2.
Eight (27.6%) patients experienced grade 3 or 4 toxicity
potentially related to the study treatment, including
This single-center, open-label, phase II study is the first to
investigate the combination of nab-P, B and G as first-line
therapy for patients with MBC. The trial accrued 30
patients with recently diagnosed HER2-negative metastatic
disease over a 15-month period. The rationale for this
novel treatment regimen was based on prior success with
the single-agent use of each of these agents, as well as their
combinations as doublet therapy. We hypothesized that
response rates after treatment with this triplet combination
would be higher than those currently found in MBC. We
also recognized the potential for improvement in toxicity
management; our dosage schedule would allow chemotherapy infusions to be given on day 1 and day 15, while
omitting the standard Day 8 dose. The 2 week interval
period would allow for toxicity recovery, in an attempt to
prevent treatment delays.
In this study, treatment with the triplet nab-P, B, and G
resulted in a very low incidence of severe adverse events.
One patient had grade 4 toxicity (neutropenic fever) which
resolved on therapy after two weeks of hospitalization. In
addition, the reported incidence of hematologic toxicity
was low. Compared with a study using single-agent docetaxel (100 mg/m2) in patients with MBC, the incidence of
neutropenia was lower in this study using the triplet
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Table 4 Adverse events
Toxicity
Any Grade,
no. (%)
Grade 1,
no. (%)
Grade 2,
no. (%)
Grade 3,
no. (%)
Grade 4,
no. (%)
Neutropenia
3 (10.3)
–
3 (10.3)
Leukopenia
2 (6.9)
–
1 (3.4)
Thrombocytopenia
2 (6.9)
1 (3.4)
–
Anemia
1 (3.4)
1 (3.4)
–
Alopecia
19 (65.5)
3 (10.3)
Fatigue
11 (37.9)
6 (20.7)
Bone pain
9 (31.0)
2 (6.9)
7 (24.1)
–
–
Nausea
9 (31.0)
1 (3.4)
8 (27.6)
–
–
Skin rash/lesion
8 (27.6)
2 (6.9)
6 (20.7)
–
–
Hand/Foot syndrome
7 (24.1)
7 (24.1)
–
–
Headache
7 (24.1)
2 (6.9)
5 (17.2)
–
Epistaxis
6 (20.7)
TA
B
Hematologic
–
1 (3.4)
1 (3.4)
–
–
–
–
–
16 (55.2)
–
–
5 (17.2)
–
–
4 (13.8)
Insomnia
4 (13.8)
Anxiety
3 (10.3)
Hypertension
3 (10.3)
PortAcath infection
3 (10.3)
Abscess
2 (6.9)
Amenorrhea
Blurred vision
2 (6.9)
2 (6.9)
Cough
2 (6.9)
Depression
2 (6.9)
Dysgeusia
Flu-like symptoms
Loss of appetite
Lymphedema
Oral infection
Rhinorrhea
Skin discoloration
–
–
5 (17.2)
4 (13.8)
–
–
–
4 (13.8)
–
–
–
3 (10.3)
–
–
–
3 (10.3)
–
–
1 (3.4)
2 (6.9)
–
1 (3.4)
1 (3.4)
2 (6.9)
2 (6.9)
–
–
–
–
1 (3.4)
1 (3.4)
–
–
1 (3.4)
1 (3.4)
–
–
–
–
–
–
–
–
2 (6.9)
2 (6.9)
1 (3.4)
–
1 (3.4)
1 (3.4)
–
–
–
2 (6.9)
–
–
–
–
2 (6.9)
–
2 (6.9)
–
–
2 (6.9)
–
2 (6.9)
–
–
2 (6.9)
–
2 (6.9)
–
–
2 (6.9)
–
2 (6.9)
–
–
2 (6.9)
–
1 (3.4)
–
2 (6.9)
O
T
Shortness of breath
2 (6.9)
IN
6 (20.7)
Diarrhea
4 (13.8)
PR
Peripheral neuropathy
–
LE
Nonhematologic
2 (6.9)
–
–
–
Weight loss
2 (6.9)
Acute renal insufficiency
1 (3.4)
–
Breast abscess
1 (3.4)
–
Chest pain
1 (3.4)
–
1 (3.4)
–
–
Conjunctivitis
Constipation
1 (3.4)
1 (3.4)
–
–
1 (3.4)
1 (3.4)
–
–
–
–
1 (3.4)
–
–
N
1 (3.4)
1 (3.4)
Epigastric pain
1 (3.4)
–
Fever/sepsis
1 (3.4)
–
Heartburn
1 (3.4)
–
Heat intolerance
1 (3.4)
1 (3.4)
1 (3.4)
–
–
1 (3.4)
–
–
–
–
1 (3.4)
–
1 (3.4)
–
–
–
–
–
–
Hematuria
1 (3.4)
–
Hot flashes
1 (3.4)
–
1 (3.4)
–
–
Jaundice
1 (3.4)
–
1 (3.4)
–
–
Mucositis
1 (3.4)
–
–
123
1 (3.4)
–
1 (3.4)
–
1 (3.4)
–
Breast Cancer Res Treat (2010) 123:427–435
433
Table 4 continued
Toxicity
Any Grade,
no. (%)
Grade 1,
no. (%)
Grade 2,
no. (%)
–
Grade 3,
no. (%)
Grade 4,
no. (%)
Neutropenic fever
1 (3.4)
–
Painful edema
1 (3.4)
–
1 (3.4)
–
–
Pedal edema
1 (3.4)
–
1 (3.4)
–
–
Pelvic pain
1 (3.4)
Pericardial effusion
1 (3.4)
1 (3.4)
–
–
–
1 (3.4)
1 (3.4)
–
–
–
–
Pharyngitis
1 (3.4)
–
1 (3.4)
–
–
Reflux
1 (3.4)
–
1 (3.4)
–
–
1 (3.4)
–
1 (3.4)
Scotoma
1 (3.4)
–
1 (3.4)
Seizure/syncope
1 (3.4)
–
Tachycardia
1 (3.4)
–
Tamponade
1 (3.4)
–
Thrombus
1 (3.4)
–
Tricuspid regurg
1 (3.4)
Upper respiratory infection
1 (3.4)
UTI
1 (3.4)
Vomiting
1 (3.4)
–
1 (3.4)
–
–
–
LE
Regurgition (valve)
1 (3.4)
–
1 (3.4)
–
TA
B
1 (3.4)
–
–
–
–
–
–
–
1 (3.4)
–
–
–
1 (3.4)
–
–
–
–
–
–
–
–
treatment failure were greater in the doxorubicin and cbP
combination arm; however, there was no significant difference in OS between arms and toxicity that proved to be
unacceptably high with simultaneous combination treatment [15]. Therefore, most medical oncologists in this
country have embraced the sequential single-agent
approach.
O’Shaughnessy et al. and later, Albain et al. showed that
the addition of either capecitabine or G to a taxane led to
improvements not only in response rates, but also in TTP
and OS (a formal cross-over was not allowed in either
study) [7, 16]. In addition, in 2005, Miller et al.[17] demonstrated that the addition of B to capecitabine significantly
increased response rates. However, this did not translate to
longer PFS.
Another important change in the treatment of MBC was
the introduction of nab-P to the treatment armamentarium.
The relatively toxic side effects of cbP require the
administration of steroids and H1 and H2 antagonist premedication, as well as a lengthy infusion time. The
improved efficacy and reduced toxicity of nab-P over cbP
have been demonstrated [4, 18]. Nab-P in combination
with B has been recently tested in a multi-arm phase II
study; the longest reported TTP occurred in arm C, which
randomized patients to receive 130 mg/m2 of nab-P weekly
with 10 mg/kg B q 2 weeks [13]. The TTP for this triplet
regime is only minimally higher (10.4 months), but the
aforementioned reduction in neurotoxicity is notable.
The promising results from these studies, combined with
the convenience of delivering chemotherapy every two
N
O
T
PR
IN
regimen (all grades, 100 vs. 10.3%, respectively) [5]. The
incidence of neurotoxicity in this study is also noticeably
less than other studies using nab-P in combination for
HER2-negative MBC; Conlin et al. reported greater than
50% incidence of sensory neuropathy grade C2 in all the 3
arms of nab-P and B combination therapy (Arm
A = 260 mg/m2 of nab-P ? 15 mg/kg B q 3 weeks; Arm
B = 260 mg/m2 of nab-P ? 10 mg/kg B q 2 weeks; and
Arm C = 130 mg/m2 of nab-P q 1 week ? 10 mg/kg B q
2 weeks) compared to 20.7% incidence of peripheral
neuropathy grade C2 with this triplet combination. This
reduction in neurotoxicity can be partially attributed to the
use of lower infusion dose of nab-P in our study (in terms
of comparison to Arms A and B) and extended time
between doses (in terms of comparison to Arm C) [13].
Similar to other chemotherapy, the most common adverse
events included alopecia (65.5%), fatigue (37.9%), and
nausea (31.0%); these events were limited to grades 1 and
2. All grade 3 and 4 toxicities were treated during hospitalization (N = 10), and all symptoms were resolved
(mean 7.6 days, range 3–14 days).
Combining chemotherapeutic agents in an effort to
increase efficacy with MBC is not a novel approach. In the
early stages of treating breast cancer, cyclophosphamide,
methotrexate, and 5-fluorouracil and later, anthracycline
combinations, were developed for use in MBC [14]. It was
not until Sledge et al. published a landmark study comparing cbP and doxorubicin as single agents, and with the
combination of both agents, that the treatment of MBC
changed in North America [15]. The ORR and time-to-
1 (3.4)
1 (3.4)
123
434
Breast Cancer Res Treat (2010) 123:427–435
LE
An additional benefit of our patient demographic is our
large proportion of often under-represented minority
groups (Table 1). The unequal representation of minority
adults in cancer clinical trials has been documented [22].
An analysis of trial enrollment across ethnic groups from
2000 to 2002 found that blacks and Hispanics were significantly less likely than Non-Hispanic whites to participate in NCI-sponsored cooperative group studies
(P \ 0.001); in breast cancer trials specifically the estimated enrollment fractions (the number of trial enrollees
divided by the estimated number of the U.S. cancer cases
per subgroup) for white, Hispanic, Black, Asian/Pacific
Islander, and American Indian were 3.3, 2.4, 2.5, 3, 1, and
4.5%, respectively [23]. The patient demographic at JMH
and SCCC embodies a large number of minorities that are
indicative of Miami’s diverse population of inhabitants.
Therefore, the patients included in our phase II trial provide an opportunity to analyze a novel regimen across the
racial and cultural spectrum.
The limitations of the study include the small patient
population (29 evaluable patients) and its single-center
study design. Of note, patients were accrued in two different hospitals (JMH and UM/SCCC). However, the
promising results and convenient dose schedule from this
single-center (albeit two hospitals) phase II study indicate
that this novel triplet combination of cytotoxic and biologic
agents (nab-P, B and G) should be further investigated in a
larger, randomized controlled trial.
N
O
T
PR
IN
TA
B
weeks, led to the concept for our combination of two
cytotoxic agents and one biologic agent. We examined the
feasibility of this combination in a pilot study in heavily
pretreated patients with MBC; at the time of first evaluation
two patients had a PR and four patients had SD [11].
Standard response rates observed with combination
regimen including cbP have published values of 36.9% and
41.4% [7, 8]. With the addition of biologic agents, particularly trastuzumab in patients with HER2-positive disease,
response rates have increased to values over 50% [19]. This
study suggests that this triplet combination is notably
efficacious; the median PFS in our study was 10.4 months
(95% CI: 5.6–15.2 months), and the 18-month survival rate
was 77.2% (95% CI: 51.1–90.5%). ORR was 75.9% (out of
29 evaluable patients), with SD reported in an additional
17.2%, for a CBR of 93.1%. The ORR compares very
favorably to the ORR achieved in previous trials using
doublet combinations, either cbP ? G (41.1%)7 or
cbP ? B (36.9% in all the patients or 49.2% in the subgroup of patients with measurable disease at baseline) [8].
All participants in our trial had HER2-negative disease;
response rates achieved in similar cohorts published previously were between 36.9% and 48.9% (as measured by
the independent review facility) [8, 9]. The E-2100 study,
had doubled previously reported ORR observed with cbP
monotherapy, by adding B (21.2 vs. 36.9%, respectively);
our confirmed ORR of 75.9% has greatly improved upon
these previous trials [8, 9]. Although one cannot rely on
cross-trial comparisons, the 27.6% CR and 48.3% PR
observed in this trial seem to be exceptional. Another
investigation using this triplet regimen is underway; a
phase II study is recruiting MBC patients for treatment
with nab-P, G, and B on an alternative schedule (day 1 and
8, q 21 days) [20].
Historically, the MBC patient population has been
challenging to treat; therapeutic responses are fleeting, and
the 5-year survival rate is very low. In addition, treatment
options for patients with TN disease are greatly needed. A
large percentage of the patients in this study were TN
(44.8%). Within this patient subgroup, 38.4% (5/13) had
CR as their best response, and the CBR was exceptionally
high at 84.6%. Surprisingly, there was also no significant
difference when comparing PFS (P = 0.707) and OS
(P = 0.548) between TN patients and patients with hormone receptor-positive disease (Fig. 3). In a phase II study
examining the combination of capecitabine and B, in a set
of HER2-negative MBC patients, the ER-negative subgroup had a median TTP of 4.0 months (95% CI: 3.0–4.9),
while the ER-positive subgroup had a median of
8.9 months (95% CI: 7.5–13.6) [21]. The greater treatment
activity confirmed in the hormonal receptor-positive group
is a common observation; in this respect, the response to
our study in both subgroups is clinically relevant.
123
Acknowledgments We appreciate the efforts of Emilio Weiss, the
Research Pharmacist. We would like to thank Lilly USA, Genentech,
Inc., and Abraxis BioScience for their financial support and drug
supply.
Conflict of interest Statement Stefan Glück received research
funding from Lilly USA, Genentech, Inc., and Abraxis BioScience.
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