Research Article
Controversies Regarding the Optimal Dose of Nab-Paclitaxel Combined With Gemcitabine in a Phase 1 Trial of Patients with Metastatic Breast Cancer
Iwai M1, Sato K2*, Fuchikami H2, Mizuno Y2, Matsumoto H3, Ikehara Y4, Mase T5, Kawamoto S6, Shimoyama R7 and Shinozaki N8
1Department of Pharmacy, Tokyo-West Tokushukai Hospital, Japan
2Department of Breast Oncology, Tokyo-West Tokushukai Hospital, Japan
3Department of Surgery, Hanyu General Hospital, Japan
4Department of Surgery, Chubu Tokushukai Hospital, Japan
5Department of Department of Breast and Endocrine Surgery, Ogaki Tokushukai Hospital, Japan
6Department of Surgery, Fukuoka Tokushukai Hospital, Japan
7Department of Surgery, Shonan Kamakura General Hospital, Japan
8Department of Surgery, Shonan Fujisawa Tokushukai Hospital, Japan
*Corresponding author: Kazuhiko Sato, Department of Breast Oncology, Tokyo-West Tokushukai Hospital, 3-1-1 Matsubara, Akishima, Tokyo 196-0003, Japan
Published: 06 Sep, 2016
Cite this article as: Iwai M, Sato K, Fuchikami H, Mizuno
Y, Matsumoto H, Ikehara Y, et al.
Controversies Regarding the Optimal
Dose of Nab-Paclitaxel Combined
With Gemcitabine in a Phase 1 Trial of
Patients with Metastatic Breast Cancer.
Clin Oncol. 2016; 1: 1070.
Abstract
Nano-particle albumin-bound paclitaxel (nab-paclitaxel) has shown significantly higher response rates and time to progression than has solvent-based paclitaxel in patients with metastatic breast cancer. The potential advantages of nab-paclitaxel led us to investigate the combination of nabpaclitaxel and gemcitabine instead of already proven combination regimens of paclitaxel with gemcitabine. Therefore, an open-label, multicenter, phase I trial was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of combination therapy with nabpaclitaxel and gemcitabine in patients with metastatic or recurrent breast cancer. Nab-paclitaxel was administered intravenously on day 1, and gemcitabine was administered intravenously on days 1 and 8 of a 21-day cycle. Nab-paclitaxel was administered at a starting dose of 220 mg/m2 (Level 1) and escalated to 260 mg/m2 (Levels 2-3), and gemcitabine was administered at a starting dose of 1,000 mg/m2 (Levels 1-2) and escalated to 1,250 mg/m2 (Level 3) by using a traditional 3 + 3 dose-escalation scheme in cohorts of three patients. Three patients were treated in Level 1 and no dose-limiting toxicities (DLT) occurred. In Level 2, additional patients were needed because one DLT was observed in 3 cohort patients. This study was ultimately terminated before defining the RD for two reasons: slow accrual and the results of a similar phase I study were reported by another study group. However, the result was different from ours. Although our study could not determine the MTD and RD, it illustrates that novel approaches should be considered to improve the efficiency of clinical studies.
Introduction
Breast cancer is the most frequent malignancy in women, with an estimated 89,400 new
diagnoses in 2015. The disease is the fifth leading cause of cancer deaths in women, and an estimated
13,800 women in Japan died in 2015 [1]. Although often curable when localized to the breast and
local lymph nodes, if the disease becomes metastatic, it is usually not curable. Therefore, treatment
objectives for metastatic breast cancer (MBC) are to prolong survival and improve quality of life [2].
Chemotherapies for patients with MBC have undergone remarkable development in recent
years; however, conventional anthracycline and taxane-containing regimens continue to be
important in this treatment. For cases of human epidermal growth factor receptor type 2 (HER2)-
negative breast cancer, the treatment options are limited relative to those for HER2-positive cases
and development of highly efficacious therapy is needed.
It is thought that combining taxanes with other agents may enhance treatment efficacy and
produce more favorable safety profiles. Gemcitabine is a pyrimidine nucleotide antimetabolite that
is phosphorylated intracellularly to active triphosphate, which inhibits DNA replication and RNA
synthesis. Gemcitabine and paclitaxel are two agents with unique
mechanisms of action, non-cross-resistance, and the potential for
synergistic antitumor activity. Given these mechanisms, gemcitabine
and paclitaxel (GT) combination chemotherapy was examined. A
phase III study of GT combination chemotherapy demonstrated
superior antitumor activity in anthracycline-pretreated patients
with MBC who showed an overall survival (OS) of 18.6 months;
by comparison, the OS for paclitaxel alone was 15.8 months [3].
The response rate (RR) was better for GT (RR 41.4%; 7.9% showed
complete responses (CR)) than for paclitaxel alone (RR 26.2%; 4.6%
showed CR).
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is
a solvent-free formulation in which paclitaxel is delivered as a
suspension of albumin nanoparticles (average size, 130 nm), which
eliminates the need for premedication or special infusion sets and
allows an infusion to be safely given over 30 min. Additionally, the
albumin-bound nanoparticle was designed to preferentially deliver
paclitaxel to tumors by biologically interacting with albumin receptors
that mediate drug transport [4]. Nab-paclitaxel was compared
directly with solvent-based paclitaxel in a randomized phase III trial
in 454 women with MBC [5]. In this study, nab-paclitaxel 260 mg/
m2 administered every 3 weeks showed significantly higher response
rates and time to progression and a decreased incidence of grade 4
neutropenia relative to those for solvent-based paclitaxel 175 mg/m2
administered every 3 weeks. The proven efficacy of GT combination
and the potential advantages of nab-paclitaxel led us to investigate
the combination of nab-paclitaxel and gemcitabine. Therefore,
we conducted a phase I trial of nab-paclitaxel in combination with
gemcitabine for patients with metastatic or recurrent breast cancer.
Methods
Patient eligibility
Patients who met the following major criteria were considered
eligible to participate in the study: women with histologically
confirmed breast cancer who were aged 20-75 years; patients with
inoperable metastatic or recurrent breast cancer; patients with
HER2-negativity demonstrated by immunohistochemical analysis
or fluorescence in situ hybridization; patients previously treated with
single-regimen or no chemotherapy for MBC; an Eastern Cooperative
Oncology Group performance status of 0 or 1; patients for whom each
laboratory test value within 14 days before enrollment was within
the following ranges: white blood cell count ≥4,000/mm3, absolute
neutrophil count (ANC) ≥ 2,000 /mm3, hemoglobin concentration
≥9.0 g/dL, platelet count ≥100,000 /mm3, total bilirubin ≤1.5 mg/dL,
serum aspartate aminotransferase (AST) concentration ≤2.5 × the
upper limit of normal (ULN), serum alanine aminotransferase (ALT)
concentration ≤2.5 × the ULN, and serum creatinine ≤1.5 mg/dL.
However, patients with tumor progression during or within 6
months after the last dose of pre- or postoperative chemotherapy were
excluded from the study. Patients with grade ≥1 peripheral neuropathy
before enrollment were also excluded. Disease measurable by using
the Response Evaluation Criteria in Solid Tumors (RECIST) version
1.1 was not required. The study was approved by the Institutional
Review Board of all participating institutions, and all patients gave
informed written consent before entry into the trial.
Study design
An open-label, multicenter, phase I trial was conducted through
the Tokushukai Group to determine the maximum tolerated dose
(MTD) and recommended dose (RD) of combination therapy
with nab-paclitaxel and gemcitabine in patients with metastatic or
recurrent breast cancer. Secondary objectives were to determine the
RR, safety, and safe dose for phase II evaluation.
Nab-paclitaxel was administered intravenously over 30 minutes
before gemcitabine on day 1, and gemcitabine was administered
intravenously over 30 minutes on days 1 and 8 of a 21-day cycle until
the occurrence of disease progression or development of intolerable
toxicities. Prophylactic antiemetics (including corticosteroids)
and growth factors for hematologic toxicity were permitted. Nabpaclitaxel
was administered at a starting dose of 220 mg/m2 (Level
1) and escalated to 260 mg/m2 (Levels 2-3), and gemcitabine was
administered at a starting dose of 1,000 mg/m2 (Levels 1-2) and
escalated to 1,250 mg/m2 (Level 3) by using a traditional 3 + 3 doseescalation
scheme in cohorts of 3 patients. Three to 6 patients were
enrolled at each dose level. Toxicities were graded according to the
Common Terminology Criteria for Adverse Events version 4.0. If no
dose-limiting toxicity (DLT) was observed for the first 3 patients at a
given dose level, escalation proceeded to the next dose level. Initially,
only the first cycle was used to determine the DLT. After the first DLT,
≤3 more patients were enrolled at that same dose level. Escalation
continued only if DLT was limited to 1 of 6 patients. Escalation halted
if DLT occurred in ≥2 patients. When DLT was observed in ≥2 of 6
patients at any level, that level was considered to be an MTD, and the
dose level immediately below that level was defined as an RD. There
was no interpatient dose escalation.
DLT was defined as grade 4 thrombocytopenia, grade 3
thrombocytopenia requiring platelet transfusion, grade 4 neutropenia
lasting for >4 days, grade 3 or 4 febrile neutropenia (FN), a >7-day
delay on day 8 caused by an ANC of <1,000/mm3 or a platelet count
of <70,000/mm3, grade 3 or 4 peripheral neuropathy, grade 3 or 4
non-hematologic toxicity (with the exception of nausea, vomiting, or
anorexia), or other adverse events that led to a ≥21-day delay in the
start of Cycle 2.
Results
From August 2011 to March 2016, 7 patients were enrolled. The
patient characteristics are listed in Table 1. The median age was 64
years (range, 46-72 years), and all patients had histologically negative
HER2 status. Most patients had received previous hormonal therapy,
and no patient had received any previous chemotherapy for MBC.
The dose levels studied are summarized in Table 2. Three patients
were treated at Level 1 (nab-paclitaxel 220 mg/m2, gemcitabine 1,000
mg/m2) and no DLT occurred. In Level 2 (nab-paclitaxel 260 mg/m2,
gemcitabine 1,000 mg/m2), additional patients were needed because 1
DLT (grade 3 AST increase) was observed in 3 cohort patients. Then,
1 additional patient was treated without DLT; however, the study was
ultimately terminated because of slow accrual. Therefore, the MTD
could not be determined in this study.
All 7 subjects were evaluable for adverse events. Table 3
presents the number of adverse events that were determined to
be clinically relevant by the investigator at each dose level. The
hematological toxicities with high incidence were neutropenia (86%;
n = 6), leukopenia (71%; n = 5), and anemia (71%; n = 5). The nonhematological
toxicities with high incidence included AST increase
(100%; n = 7), ALT increase (86%; n = 6), peripheral neuropathy
(86%; n = 6), and alopecia (86%; n = 6). The most commonly
reported Grade 3 or 4 toxicity related to therapy was neutropenia.
Three patients were taken off the study because of treatment delay
due to neutropenia and required dose reduction in 1 patient. Of the
6 patients who developed peripheral neuropathy, 2 were taken off the
study because of continuation of Grade 2 toxicities. The most frequent
toxicities were increases in AST/ALT; although most patients were
manageable, 1 patient developed DLT.
Of the 7 patients enrolled in the study, 3 patients in Level 1 were
evaluable for response by RECIST version 1.1. In Level 2, 1 patient
had no measurable lesion, and 3 patients were taken off the study
prior to first restaging analysis. The reasons for withdrawal were
occurrence of DLT in Cycle 1in 1 patient and delayed treatment due
to neutropenia in Cycle 2 in 2 patients. The responses in the 3 patients
included partial response in 1 patient and stable disease in 2 patients
(Table 2).
Discussion
Combination chemotherapy represents a treatment choice that
has been prescribed for increased efficacy. Although the utility of
combination chemotherapy or sequential single-agent treatment
is controversial [6], patients with MBC who receive combination
chemotherapy have improved progression-free and overall survival
rates [7-8], and some have long-term remissions [9]. In this way,
most patients with MBC treated with systemic therapies have only
temporary responses to treatment, but some patients show CR
following initial treatment. Greenberg et al. reported that of all
patients who achieve CR, approximately 18% remain disease-free for
>5 years following treatment with doxorubicin and alkylating-agentbased
regimens; >10% remain disease-free for periods >20 years
[10]. These data show that a small percentage of patients achieve
long-term remissions with standard chemotherapy regimens and a
small percentage of patients with MBC can achieve very long-term
unmaintained CR with systemic therapy. Therefore, combination
chemotherapies as attempts to achieve CR have been expected for
use in trials to show improvement in OS. Therefore, this phase I
multicenter trial was undertaken to identify the MTD and RD for
phase II evaluation of nab-paclitaxel and gemcitabine combination
in patients eligible to receive first- or second-line chemotherapy for
MBC and to assess the safety and overall RR for this combination
in patients with MBC. In a phase III trial, a combination of GT for
first-line treatment of anthracycline-pretreated, taxane-naïve, MBC
patients was associated with an RR of 41.4% and time to progression
(TTP) of 6.14 months [3]. The GT regimen was associated with a longer
TTP, an OS advantage, and a manageable toxicity profile relative to
those for three times weekly paclitaxel alone. In this trial, FN was
reported in 5.0% of patients on GT. In contrast, no FN occurred in the
patients who received nab-paclitaxel and gemcitabine combination in
our study. However, grade 3 to 4 neutropenia was more commonly
observed in our study (86% nab-paclitaxel and gemcitabine, 47.9%
GT). The incidences of grade 2 peripheral neuropathy were higher in
our study (57% nab-paclitaxel and gemcitabine, 24.5% GT); however,
grade 3 to 4 peripheral neuropathy was lower for this treatment in our
study than for GT (0% vs. 8.4%). The incidences of increases in grades
≥2 of AST/ALT were also higher in our study.
This study was ultimately terminated before defining the RD
for 2 reasons. First, accrual was very slow because this combination
chemotherapy with possible toxicities was not attractive for patients.
Second, the results of a similar phase I study were reported by
another study group [11]. However, Yoshitomi et al. reported that
DLTs did not occur in any cohorts and the RD was 1,250 mg/m2 for
gemcitabine and 260 mg/m2 for nab-paclitaxel; nevertheless, these
results differed from those in our study. In this study, dose settings
were different from our study; nab-paclitaxel had been started from
a lower dose. Furthermore, in a randomized phase II clinical study,
the median progression-free survival and RR of weekly nab-paclitaxel
was 12.9 months and 49%, respectively, which suggested that weekly
nab-paclitaxel might be superior to triweekly administration [12].
In first-in-human clinical trials that include new combination
chemotherapies, a dose-escalation study design is often used. The
most commonly used dose-escalation study design is the traditional
3 + 3 design, which guides “up-and-down” decisions, using the
modified Fibonacci mathematical series to determine the amount
of dose increase for cohorts of sequentially enrolled patients. This
traditional 3 + 3 design belongs to rule-based methods, which use
pre-specified rules based on actual observations of target events
as DLT from the clinical data to assign patients to dose levels and
determine the MTD or RD for a phase II trial [13]. The principle
for dose escalation in phase I trials is to avoid exposing too many
patients to subtherapeutic doses while maintaining safety and rapid
accrual. The main advantages of the traditional 3 + 3 design are that it
is simple to implement, does not require special software, and is safe.
In addition, accrual of 3 patients per dose level provides additional
information about pharmacokinetic interpatient variability. However,
a disadvantage of this design is that it involves an excessive number of
escalation steps, which results in a large proportion of patients who
are treated at subtherapeutic doses while few patients actually receive
doses at or near the RD for phase II trials.
Generally, accrual of patients with MBC to early-phase trials
is particularly low, despite data suggest that patients with MBC
enrolling in phase I trials may have improved survival outcomes [14].
Poor accrual may be a critical barrier to progress in clinical studies.
This phase I study could not determine the MTD and RD, which
illustrates that novel approaches are needed to improve the efficiency
of clinical studies.
Acknowledgments
The authors would like to thank Enago (www.enago.jp) for the English language review.
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