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490 Cancer Biology & Therapy 2007; Vol. 6 Issue 4
Research Paper
A Phase II Study of Ixabepilone (BMS-247550) in Metastatic Renal-Cell
Carcinoma
Edwin M. Posadas1
Samir Undevia1
Elizabeth Manchen1
James L. Wade1
A. Dimitrios Colevas2
Theodore Karrison1
Everett E. Vokes1
Walter M. Stadler1
1University of Chicago Phase II Consortium; Chicago, Illinois USA
2National Cancer Institute; Cancer Therapeutics Evaluation Program;
Bethesda, Maryland USA
*Correspondence to: Edwin Melencio Posadas; University of Chicago; Medicine-
Section of Hematology/Oncology; 5841 S. Maryland Ave, MC 2115; Chicago,
Illinois 60637 USA; Tel.: 773.834.5137; Fax: 773.702.3163; Email: eposadas@
medicine.bsd.uchicago.edu
Original manuscript submitted: 11/13/06
Manuscript accepted: 01/08/07
Previously published online as a Cancer Biology & Therapy E-publication:
http://www.landesbioscience.com/journals/cc/abstract.php?id=3831
KEy WorDS
renal cell carcinoma, ixabepilone, chemo‑
therapy, clinical trial, microtubule inhibitor
AbbrEViATionS
RCC renal cell carcinoma
IRB institutional review board
ULN upper limit of normal
SD stable disease
OR overall responses
TTP time to progression
CR complete response
PR partial response
ACKnoWLEDgEMEnTS
The authors wish to thank the Ms. Katherine
Nichols, Ms. Rebecca Exiner, and Dr. Antonio
Fojo for their contributions to this project.
AbSTrACT
Introduction: Ixabepilone (BMS‑247550) is a semi‑synthetic analog of epothilone B
that has been characterized as a microtubule stabilizing agent with a mechanism of
action distinct from taxanes. Suggestion of activity in renal cell carcinoma (RCC) has
been seen in early clinical studies.
Methods: Eligible patients had metastatic RCC as well as ECOG performance status
0–2 and normal organ function. Patients received ixabepilone at a dose of 40 mg/m2
intravenously over three hours every 21 days. There was no restriction on RCC histol‑
ogy or prior treatment type, but prior treatment with tubule inhibitors was not allowed.
The primary endpoint was RECIST defined response and radiographic evaluations
were performed every three cycles. Toxicity evaluations utilized CTCAE v3.0 and were
performed every cycle. Using a Simon two‑stage optimal design with a = 0.1, b = 0.1,
a null hypothesized response rate of 0.05 and an alternative response rate of 0.2, an
initial 12 patients were to be accrued with full accrual of 37 patients if at least one
response were observed.
Results: A median of five cycles were administered. No objective responses were
observed in the first 12 evaluable patients, and six patients showed stable disease for
more than 18 weeks on therapy. Median time to progression among those with objective
progression was nine weeks. One patient experienced grade 4 anemia and lymphope‑
nia. Grade 3 adverse events included lymphopenia, neutropenia, leukopenia, diarrhea,
and infection. Common grade 2 toxicities included alopecia, fatigue and anemia.
Conclusion: Ixabepilone administered at a dose of 40 mg/m2 every 21 days should
not be advanced for further study in metastatic RCC. Given previous results, however,
other dosing schedules may be worthy of further investigation.
inTroDUCTion
According to the NCI SEER database the rate of renal cell carcinoma (RCC) has
been increasing at a rate of about 2 percent per year for the past 65 years.1 The five‑year
survival rate for metastatic RCC is estimated to be less than 10%.2 While the introduc‑
tion of oral tyrosine kinase inhibitor therapy has represented a significant advance for the
field, few long‑term complete responses have been reported at this time.3,4 Thus, there is
a continued need for improved therapeutic strategies.
Ixabepilone is a semi‑synthetic analog of epothilone B that functions as a microtubule
stabilizing agent.5 Preclinical studies suggested broad activity in a variety of tumor types
including taxane‑resistant tumors. Phase I clinical studies evaluated a number of different
doses and schedules. The dose schedules evaluated in phase II studies were 6 mg/m2
qd x 5 repeated every 21 days,6‑9 20 mg/m2 day 1, 8, and 15 q28 days6,10,11 and 35–50
mg/m2 q3weeks.12‑19 Dose limiting toxicities were myelosuppression and peripheral
neuropathy. Some studies suggested that the neuropathy was most closely correlated
with Cmax.
20 Investigators thus explored a daily times five schedule, and found that the
maximum tolerated dose was 6 mg/m2 with neutropenia as the dose limiting toxicity.21
Neuropathy and all other non‑hematologic toxicities were grade 2 or less at this dosing
schedule.21 A dose of 6 mg/m2 over one hour daily for 5 days every 21 days was thus
evaluated in phase II studies.21 Preliminary reports of a phase II study in RCC using this
dosing schedule suggested anti‑tumor activity with 4 of 39 patients experiencing objective
response and an additional five patients experiencing tumor shrinkage not sufficient for an
objective response.9 This dosing schedule is however somewhat awkward for patients and
providers and thus the alternative schedule of 40 mg /m2 every 21 days was investigated
here in a similar RCC population.
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Ixabepilone in Metastatic Renal Cell Carcinoma
PATiEnTS AnD METhoDS
Objectives. The primary objective of this trial was to determine
the objective response (OR) rate (defined as the sum of complete and
partial responses) of metastatic renal cell carcinoma to ixabepilone
therapy when dosed at 40 mg/m2 every 21 days. Secondary objectives
included measurement of progression‑free survival (PFS, or time to
disease progression (TTP) and overall survival (OS) rates in patients
treated with ixabepilone as well as characterization of drug‑related
toxicity.
This study was approved by the institutional review board (IRB)
of University of Chicago and the IRB of each participating center.
Written informed consent was obtained from patients before enroll‑
ment.
Patient enrollment and study design. All patients had evidence
of metastatic RCC, histologically confirmed, with measurable
disease by RECIST definition.22 No prior therapy with microtu‑
bule inhibitors was allowed (vinca alkaloids, taxanes, epothilones).
Eastern Cooperative Oncology Group Performance Status of two or
better was required. Patients were required to have normal organ and
bone marrow function: WBC ≥ 3000/mL, absolute neutrophil count
≥1500/mL, platelets >100,000/mL, total bilirubin ≤1.5 x institutional
upper limit of normal (ULN), AST and ALT ≤2.5 x ULN, creati‑
nine ≤1.5 x ULN or glomerular filtration rate ≥50 ml/min/1.73 m2.
Patients were excluded for CNS metastases, preexistent neuropathy
grade 1 or higher, anti‑retroviral therapy for HIV or uncontrolled
intercurrent illness.
Treatment plan. Patients received ixabepilone 40 mg/m2 by
intravenous infusion over three hours on day 1 of each 21‑day
cycle. Premedication for hypersensitivity included diphenhydramide
50 mg IV and rantidine 50 mg IV or famotidine 20 mg IV given
30–60 minutes prior to ixabepilone. A physician examined each
patient prior to every administered dose. CT scans of the chest,
abdomen, and pelvis were obtained every three cycles (nine weeks).
Patients with a CR, PR, or SD were allowed to continue treatment.
Toxicity and response monitoring. NCI Common Terminology
Criteria for Adverse Events v3.0 (CTCAE v3.0)23 were used to
grade treatment‑related toxicities. Radiographs were evaluated by
the Response Evaluation Criteria In Solid Tumors (RECIST).22
In brief, a CR represented a disappearance of all target lesions.
A PR represented decrease of at least 30% in the sum of the longest
diameter (LD) of the target lesions taking the baseline sum LD as
a reference. Progressive disease (PD) was defined as a 20% increase
in the sum of the LD taking the smallest LD sum as recorded since
treated started OR the appearance of one of more new lesions. Stable
disease (SD) was defined as insufficient change to qualify for either
PR or PD taking the smallest sum LD since treatment started as a
reference. Measurable disease was defined as lesions that were at least
20 mm in largest dimension on CT, MRI, or x‑ray or at least 10 mm
on spiral CT. Time to progression (TTP) was defined as the interval
between the date of the start of treatment and the date of disease
progression.
Dose modifications. Doses were reduced to 30 mg/m2 (dose level
(DL) ‑1) or 20 mg/m2 (DL‑2) based upon the worst toxicity in a
given cycle. Doses were reduced by 1 level for grade 4 neutropenia
lasting more than seven days, grade 3 or greater neutropenia with
fever, grade 4 thrombocytopenia, or grade 3 thrombocytopenia with
bleeding requiring transfusion. Additional non‑hematologic dose
modifications were made in the event of a greater than one week
delay in treatment due to toxicity, grade 3 nausea or vomiting despite
maximal prophylaxis, grade 3 diarrhea, grade 2 neuropathy lasting
more than seven days, or grade 3 neuropathy. If more than two dose
reductions were required, the patient was taken off study.
Statistical considerations. This study was conducted using a
Simon two‑stage optimal design24 with an alpha level of 0.1 and
power of 0.9. Sample size was based upon the null hypothesis that the
response rate in advanced RCC was <5% with the alternative hypoth‑
esis that the response rate would be 20% or greater. A first interim
analysis was planned after the first 12 patients. If one responder was
identified, the study would continue to 37 patients.
rESULTS
Patient enrollment. A total of 13 patients were enrolled on study
between September 2005 and July 2006 through the University of
Chicago phase II consortium. Patient characteristics are listed in
Table 1. One patient was excluded from response analysis as he was
lost to follow‑up within three weeks of initiating therapy.
Response and toxicity. Patients received between 1 and 12 cycles
of ixabepilone (median five cycles). At the time of this report, only
one patient remains on active treatment. There were no CRs or PRs
noted in the 12 evaluable patients.
Median time on study and median TTP was 16 weeks (range 2–
38) with a median of five cycles administered. Six patients exhibited
disease stability (SD) for more than 18 weeks on therapy. Four of
these patients had clear cell histologies; the remaining two were
papillary and chromophobe. Of further note four of these patients
had SD in excess of 60 weeks (three clear cell, one chormophobe).
Table 1 Patient characteristics (n = 12)
Category Value (range)
Median age (years) 62 (43–76)
Gender
Male 9
Female 3
Race
White 12
Black 0
ECOG PS
0 5
1 7
2 0
Histology
Clear cell 5
Papillary 2
Chromophobe 1
Collecting duct 1
Sarcomatoid 3
Number of previous systemic rx 1 (0 ‑6)
Nephrectomy 4
IL‑2 2
IFN 1
chemotherapy 3
TKI 3
MSKCC Risk Group26
0 2
1 8
≥2 2
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Ixabepilone in Metastatic Renal Cell Carcinoma
492 Cancer Biology & Therapy 2007; Vol. 6 Issue 4
Prior treatment history did not predict response to ixabepilone.
Two patients had been treated with sorafenib prior to ixabepilone
without significant benefit. These patients also did not respond to
ixabepilone: one showing PD at the nine week assessment, the other
unable to tolerate more than two weeks of therapy. Of the four
patient who exhibited stable disease in excess of 30 weeks. All were
relatively treatment naïve and none had nephrectomies.
Five patients died within six months of study discontinuation due
to disease progression. Two of these patients had clear cell histology;
one had collecting duct histology. The remaining two exhibited a
mixture of clear cell and papillary or clear cell and sarcomatoid.
These were considered poor risk candidates by MSKCC risk factors:
one patient exhibited two MSKCC risk factors and died one month
after treatment cessation; the remainder one each. The patient with
collecting duct pathology died two months after treatment cessation.
Toxicity data is summarized in Table 2. Two patients discontinued
treatment due to adverse events (neuropathy and pleural effusion)
and were designated SD. One patient with rapidly progressive disease
experienced two grade 4 hematologic adverse events: decrease in
hemoglobin and lymphopenia. Grade 3 hematologic events included
lymphopenia, neutropenia, leukopenia (patient’s baseline was grade
2); non‑hematologic included diarrhea, and infection. One patient
with a grade 2 alkaline phosphatase rose to a grade 3 during study
without clinical sequelae. Grade 2 toxicities affecting more than
onepatient included alopecia, fatigue, neuropathy, and anemia.
DiSCUSSion
Ixabepilone is a novel anti‑cancer agent that is classified as a
microtubule stabilizing agent. Current studies suggest that it may be
effective even in taxane‑resistant tumors despite related mechanism
of action. Ixabepilone has now shown evidence of clinical activity in
a number of tumor models including breast,7,8 prostate,12,13,25 head
and neck,6 pancreas,16 gastric17 and kidney cancers.9
The initial studies with ixabepilone in RCC, using a daily times
five dosing schedule, showed promising clinical activity with an
objective response rate of 10% in addition to disease stabilization for
several others.9 Our study was unable to verify these observations.
Importantly the confidence interval on the response rate for this
small study overlaps the response rate observed in the NCI study,
and it is therefore not clear whether the results seen here reflect
a true difference based on drug dose and schedule. There are a
number of further discrepancies between this study and the NCI
series. For example, there was a disproportionate number of non‑
clear cell histology (esp. sarcomatoid) patients in the current study
population. Furthermore, the large number of patients expiring soon
after treatment termination, suggests that an especially poor prognosis
cohort was enrolled. The majority of patients on this study exhibited
at least one Memorial‑Sloan Kettering risk factor suggesting a median
survival of 11.9 months with a 1‑year survival estimation of 49%.26
This is important to note as both series allowed for ECOG PS 0‑2
and the majority of patients in both series was PS 1.
Given the debut of several new anticancer agents to the arma‑
mentarium in renal cell carcinoma, the outcome of stable disease has
is recognized as clinically beneficial provided that no unacceptable
toxicities persist. This has become particularly important with tyro‑
sine kinase inhibitors and other signal transduction inhibitors such
as sorafenib and sunitinib as these are thought be more cytostatic
than cytotoxic. The published phase II study with sorafenib showed
a response rate of 4% after the 12 week lead in phase, but more
notably showed an extension of progression free survival from 6 to
24 weeks in the randomized cohort from the randomized discon‑
tinuation study.27 The most recent analysis of the sorafenib phase III
study has shown 1 CR with a PR rate of 10% and SD of 74%.28 The
sunitinib phase III study showed a progression free survival of 47.3
weeks compared to 24.9 weeks with interferon‑alpha with an objec‑
tive response rate of 35.7%.29 Thus, at this dose and schedule, the
performance of ixabepilone does not meet currently held standards
of performance.
The toxicity profile of the two dosing schedules (6 mg/m2 for five
days versus 40 mg/m2 every 21 days) in this population also appear
to be very different. Other phase II studies at this dose (40 mg/m2
q21 days) showed similar toxicity patterns with more than 10% of
patients experiencing significant fatigue and neuropathy12‑14,18,19
compared to relatively low rates in studies dosed at 6 mg/m2 x 5
days.8,9 These findings are consistent with the original phase I studies
with ixabepilone where neutropenia was the dose limiting toxicity
with high rates of fatigue and neuropathy also seen.20
At the outset of this study, plans were made to pursue Von
Hippel‑Lindau (VHL) mutation analysis given initial reports that
mutation may be linked to response.30 Given the absence of response,
however, such a hypothesis would not be assessable in this population
and after consultation with the NCI, this aspect of the study was
abandoned. It is important, however, to note that the frequency of
VHL mutation in non‑clear cell cancers is less well defined and thus
may potentially contribute to the lack of response seen in this study
population.
In conclusion, ixabepilone administered at 40 mg/m2 every
three weeks appears more toxic than a daily x 5 dosing regimen and
no responses were observed in 12 patients with metastatic RCC.
This dose and schedule of ixabepilone is thus not recommended
for further study in RCC. Other dosing schedules, given previous
reports, may be worthy of further investigation.
Table 2 Most severe toxicity per patient attributed
to ixabepilone (n = 12)
Toxicity grade 4 grade 3 grade 2
Lymphopenia 1 3 2
Anemia 1 0 4
Neutropenia 0 1 1
Leukopenia 0 1 1
Thrombocytopenia 0 0 1
Diarrhea 0 1 1
Alkaline phosphatase increase 0 1 0
Infection 0 1 0
Alopecia 0 0 3
Fatigue 0 0 2
Peripheral neuropathy, sensory 0 0 2
Anorexia 0 0 1
Constipation 0 0 1
Depression 0 0 1
Dysguesia 0 0 1
Hyperglycemia 0 0 1
Injection site reaction 0 0 1
Nausea 0 0 1
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Ixabepilone in Metastatic Renal Cell Carcinoma
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