Download Phase II study of mitoxantrone and ketoconazole for hormone

2459
Phase II Study of Mitoxantrone and Ketoconazole for
Hormone-Refractory Prostate Cancer
John Eklund, M.D.1,2
Mark Kozloff, M.D.3,4
Joy Vlamakis, M.D.3
Alexander Starr, M.D.3
Margaret Mariott, M.D.3
Lilia Gallot, M.D.1,2
Borko Jovanovic, M.D.5
Lawrence Schilder, M.D.6
Erwin Robin, M.D.7
Michael Pins, M.D.8
Raymond C. Bergan, M.D.1,2
BACKGROUND. Doxorubicin plus ketoconazole has exhibited significant activity in
patients with advanced prostate cancer. However, overall and cardiac-specific
toxicity was reported to be high. Mitoxantrone has activity similar to that of
doxorubicin, is less cardiotoxic, and is widely used to treat prostate cancer. The
current study sought to evaluate the toxicity and activity of mitoxantrone plus
ketoconazole in a cohort of patients with hormone-refractory prostate cancer.
6
Silver Cross Hospital, Joliet, Illinois.
7
Munster Community Hospital, Munster, Indiana.
METHODS. Progression after medical or surgical castration and, for those patients
receiving antiandrogens, progression after withdrawal was required, as was objective evidence of metastasis, castrate levels of testosterone, an Eastern Cooperative
Oncology Group (ECOG) performance status of 0 to 2, and intact cardiac function.
After enrollment onto a multicenter local consortium study, subjects were treated
with mitoxantrone at a dose of 12 mg/m2 intravenously every 3 weeks plus
continuous oral ketoconazole at a dose of 400 mg 3 times daily and ascorbic acid
at a dose of 250 mg. Replacement doses of hydrocortisone were given.
RESULTS. For 40 enrolled subjects, the median prostate-specific antigen and ECOG
performance status were 68 and 1, respectively, 53% had Gleason scores of 8 to 10,
and all had metastasis. Predominant Grade 3/4 toxicities were: neutropenia in 13%,
neutropenic fever in 10%, and anemia in 13%. Of 37 evaluable patients, 8%
achieved a complete remission (CR) and 62% achieved a partial remission (PR), for
a CR plus PR rate of 70%. For soft tissue and bone disease, overall response rates
were 13% and 8%, respectively. The median progression-free survival and overall
survival were 10 months and 18 months, respectively.
CONCLUSIONS. Mitoxantrone plus ketoconazole is well tolerated, is active in hormone-refractory prostate cancer, and should be studied further. Cancer 2006;106:
2459 – 65. © 2006 American Cancer Society.
Department of Pathology, Division of Hematology/Oncology, Northwestern University Medical
School, Chicago, Illinois.
KEYWORDS: prostate cancer, chemotherapy, metastasis, hormone refractory,
Phase II.
1
Department of Medicine, Division of Hematology/
Oncology, Northwestern University Medical School,
Chicago, Illinois.
2
Robert H. Lurie Cancer Center of Northwestern
University, Chicago, Illinois.
3
Ingalls Hospital, Harvey, Illinois.
4
Cook County Hospital, Chicago, Illinois.
5
Department of Prevention, Division of Hematology/Oncology, Northwestern University Medical
School, Chicago, Illinois.
8
P
Supported by Specialized Program of Research
Excellence (SPORE) grant CA90386 from the National Cancer Institute, National Institutes of
Health, by the Department of Health and Human
Services, and by Immunex Corp.
Address for reprints: Raymond C. Bergan, M.D.,
Division of Hematology/Oncology, Northwestern
University, McGaw #2301, 240 East Huron St.,
Chicago, IL 60611-3008; Fax: (312) 503-4744;
E-mail: [email protected]
Received December 8, 2005; revision received
January 5, 2006; accepted February 13, 2006.
rostate cancer was expected to be diagnosed in approximately
232,090 men in the U.S. in 2005, and will result in death in
approximately 30,350.1 Treatment options for metastatic prostate
cancer remain limited, with disease progression being inevitable after
initial hormone therapy.2 Once hormones have failed, combination
chemotherapy is typically employed. A variety of taxane-based regimens have been tested in hormone-refractory prostate cancer, yielding response rates between 38% to 69%,3–12 or 48% to 50% when
tested in multicenter trials.9,10 As responses to taxane-based regimens
have appeared to exceed those typically associated with mitoxantrone
plus prednisone, taxane-based therapy has been widely used in the
community, typically as a first-line therapy. Two recent Phase III trials
have compared docetaxel-based therapies with mitoxantrone plus
prednisone, and both have demonstrated the superiority of docetaxel,
© 2006 American Cancer Society
DOI 10.1002/cncr.21880
Published online 13 April 2006 in Wiley InterScience (www.interscience.wiley.com).
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CANCER June 1, 2006 / Volume 106 / Number 11
in terms of response and survival.9,10 Therefore, increased use of taxane-based regimens as initial therapy is expected. Alternatives that are nontaxane-based
and have comparable activities do not exist.
At a time when nontaxane-based regimens were
associated with response rates of 30% to 40%, Sella et
al.13 reported that the combination of doxorubicin
plus ketoconazole was associated with a response rate
of 55% in a hormone-refractory cohort. In addition,
objective responses were observed in 7 of 12 patients
(58%) with measurable soft tissue disease. However,
toxicity was high, with 45% of patients requiring hospitalization for treatment-related complications, 29%
experiencing Grade 3/4 neutropenia, and 5% experiencing sudden cardiac death.
Single-agent ketoconazole has been shown in a
number of studies to have activity in prostate cancer.14 –20 Whereas the mechanism(s) by which ketoconazole exerts anticancer activity is not clear, inhibition of adrenal androgen synthesis,21 as well as
nonhormone-dependent effects,22 have both been implicated. In a cohort of patients with hormone-refractory prostate cancer, responses to single-agent ketoconazole ranged from 11% to 65%.
Mitoxantrone has a planar polycyclic aromatic
ring structure, similar to that of doxorubicin and other
anthracyclines, and therefore can intercalate into DNA
in a similar fashion and has a similar spectrum of
activity, but does not lead to the production of quinone-type free radicals, which are believed to be responsible for cardiac toxicity, and has less cardiac
toxicity than doxorubicin.23,24 Mitoxantrone has been
widely used, in combination with prednisone, for the
treatment of hormone-refractory prostate cancer.25
Because mitoxantrone has a spectrum of activity similar to that of doxorubicin, but is less toxic, it was
hypothesized that mitoxantrone plus ketoconazole
would be active in men with hormone-refractory prostate cancer, and would be tolerable in an older cohort.
The current study was designed to test this hypothesis.
MATERIALS AND METHODS
Patient Eligibility
Subjects were entered into an Institutional Review
Board-approved protocol. Participating institutions
constituted a local consortium and included Ingalls,
Silver Cross, Munster Community, and Cook County
Hospitals, as well as the Northwestern University-associated hospitals, Northwestern Memorial Hospital,
and Jessie Brown Veterans Administration Medical
Center. Subjects were eligible for study if they had
histologically confirmed adenocarcinoma of the prostate, objective evidence of metastases (as measured by
bone scan, computed tomography [CT], and/or phys-
ical examination), had disease progression after hormonal therapy, and had castrate levels of testosterone.
Those whose only evidence of disease progression was
prostate-specific antigen (PSA) elevation must have
had prior objective evidence of metastasis. Participants must have been off all forms of active therapy
for at least 1 month before study entry (exclusive of
luteinizing hormone-releasing hormone agonist treatment, which was continued). Prior therapy with either
mitoxantrone or ketoconazole was not allowed. Those
receiving androgen receptor-blocking agents must
have had confirmed disease progression after withdrawal.
Additional requirements included: an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, a life expectancy ⬎3 months, a baseline
cardiac ejection fraction of ⱖ55% (measured by either
echocardiogram or multiple gated acquisition
[MUGA] scan), and intact liver (bilirubin ⱕ1.5 mg/dL,
transaminases ⱕ4 times the upper limit of normal),
bone marrow (platelet count ⱖ100,000 per mm3 and
an absolute neutrophil count ⬎1500 per mm3) and
renal (creatinine ⱕ2.5 mg/dL) function. Patients with
active peptic ulcer disease or clinically significant
heart disease were excluded. No concurrent use of
proton pump inhibitors, H2 blockers, or antacids was
permitted. People who were taking terfenadine or
astemizole also were excluded.
Evaluations
Pretreatment evaluation included a medical history,
physical examination, serum PSA level, serum testosterone level, complete blood count (CBC) with differential, electrolytes, liver function tests, an electrocardiogram, and a MUGA scan (or echocardiogram).
Additional studies to define the extent of disease consisted of a CT scan of the abdomen and pelvis, a bone
scan, a chest radiograph, and additional radiographic
studies as clinically indicated. All participants provided both written and verbal informed consent.
While on study, subjects were followed with a
weekly CBC and differential. History and physical examination, PSA, and serum electrolytes were repeated
before each cycle. Individuals were completely restaged after every 3 cycles. For those in whom mitoxantrone was discontinued because continued treatment would exceed a cumulative dose of 140 mg/m2
and were being maintained on ketoconazole only, history and physical examination, PSA, CBC with differential, and serum electrolytes were repeated monthly,
whereas restaging studies were repeated every 3
months. Toxicity was assessed and scored at each
scheduled clinic visit, or sooner if clinically indicated,
Mitoxantrone and Ketoconazole in Prostate CA/Eklund et al.
using the National Cancer Institute Common Toxicity
Criteria (version 2.0).
Response Criteria
PSA Working Group consensus criteria were used to
define response and progression for PSA,26 whereas
non-PSA responses were defined as previously described.27 Specifically, a complete response (CR) required resolution of all clinical and radiographic evidence of disease and normalization of PSA for a
duration of at least 6 weeks (2 cycles of therapy). A
partial response (PR) required a ⬎50 percent reduction in the sum of the products of the perpendicular
dimensions of all soft tissue lesions, a decline in baseline PSA of ⬎50% (maintained for at least 1 month), or
the resolution of ⱖ1 lesions on bone scan, without the
appearance of new lesions. Progressive disease (PD)
was scored if there was a ⬎25% increase in the sum of
the products of the perpendicular dimensions of all
measurable soft tissue lesions, the appearance of new
soft tissue or bone lesions, or if there was a ⬎50%
increase in PSA from nadir value. To be scored PD
based on PSA criteria alone, a confirmatory PSA was
required 2 weeks after the initial PSA that was ⬎50%
over the nadir value. Once confirmed, the time of the
first PSA value that was 50% elevated was used as the
time of progression. Patients who experienced a decline in ECOG performance status, the onset of intractable pain, renal obstruction, or spinal cord compression due to prostate cancer were also considered to
have PD. Patients who had improvement in ⱖ1 parameter while meeting the criteria for PD by another
parameter were scored as having PD. Patients who did
not meet the criteria for PR and did not experience PD
were scored as having stable disease (SD).
Treatment
Treatment consisted of mitoxantrone at a dose of 12
mg/m2 given intravenously every 3 weeks, up to a
maximum cumulative dose of 140 mg/m2. Concomitant with mitoxantrone, the following oral drugs were
administered on a continuous basis: ketoconazole at a
dose of 400 mg 3 times daily (either 1 hour before, or
2 hours after meals), ascorbic acid at a dose of 250 mg
given 3 times daily (given with ketoconazole), and
replacement doses of hydrocortisone (20 mg in the
morning and 10 mg in the evening). Treatment was
discontinued in the face of PD and/or for Grade 3/4
nonhematologic toxicity. Individuals who received
maximum cumulative doses of mitoxantrone, but had
not experienced PD, continued to receive ketoconazole, ascorbic acid, and replacement doses of hydrocortisone.
If on the day of treatment platelets were below
2461
100,000/mm3, granulocytes were below 1000/mm3, or
ⱖGrade 3 toxicity was present, treatment was held for
1 week. Treatment could be held for up to 2 weeks and
if by that time counts did not recover, or toxicity
decreased to below Grade 3, no further mitoxantrone
was administered. For those experiencing recovery,
and for those who experienced Grade 3 nonhematologic toxicity during the cycle, subsequent doses of
mitoxantrone were reduced by 20%. Ketoconazole was
held for toxicity of ⱖGrade 3, and was reinitiated with
a one-third dose reduction once toxicity decreased to
below Grade 2. For either drug, if toxicity persisted
after 2 dose reductions, or if at any time the patient
developed Grade 4 nonhematologic toxicity, treatment was withdrawn.
Statistical Methods
All patients entered into the study were formally registered and all registered patients were included in the
final data analysis. To ensure the accuracy of data, a
subset of charts was periodically reviewed by a dedicated independent Quality Control Manager according to guidelines established under the Northwestern
University Data Safety and Monitoring Plan, which
has been reviewed and approved by the National Cancer Institute.
The study was designed as a Phase II trial. Based
on previous results of the use of doxorubicin plus
ketoconazole,13 a response rate of 40% for the current
study was considered to be too low to be of further
interest. A scheme for the optimal 2-stage design of a
Phase II trial is presented by Simon.28 Using the Simon
method, 18 patients would be enrolled initially. If ⱕ7
responses were achieved among the first 18 patients,
the trial would be terminated. Otherwise, up to an
additional 28 patients would be entered, for a total of
46. Among these 46 patients the regimen would not be
recommended for further study if ⱕ22 total responses
were observed. The probability of early termination of
this study if the true response rate was 40% would be
.56. The type 2 and type 1 error rates were both set at
10%.
Because of the 2-stage design, determination of
the 2-sided confidence limits for the proportion with
SD or response was determined by a method taking
this design into consideration.29 Survival and time to
PD were calculated from on-study date until date of
progression, death, or last follow-up. The KaplanMeier method was used to calculate the probability of
survival or progression-free survival (PFS) as a function of time.30
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CANCER June 1, 2006 / Volume 106 / Number 11
TABLE 1
Baseline Characteristics of Patients
Characteristic
Age, y
Median
Range
ECOG performance status
Median
0
1
2
Unknown
Site of disease
Osseous
Soft tissue
Lymph nodes
Lung
Laboratory values
Hemoglobin, mg/dL
Median
Range
PSA, ng/mL
Median
Range
Gleason score
2-4
5-7
8-10
Unknown
Prior treatment
Local therapy
Surgery
External radiation
Seed implantation
Therapy for metastatic disease
Hormone therapy
Primary
Secondary
ⱖ3 prior therapies
Chemotherapy
External radiation
Systemic radiopharmaceuticals
TABLE 2
Adverse Events While Receiving Treatment
No. of Patients
Percent*
71
50-85
—
—
1
13
14
1
12
—
33
35
3
30
34
85
10
2
25
5
12.6
9.9-15.3
—
—
68
18.2-1400
—
—
0
7
21
12
0
18
53
30
7
7
1
18
18
3
40
20
4
2
6
2
100
50
10
5
15
5
ECOG: Eastern Cooperative Oncology Group; PSA: prostate-specific antigen.
* Based on 40 patients.
RESULTS
Patient Characteristics
Between March 1998 and May 2002, 40 patients were
enrolled in the study. The median age of participants
was 71 years (range, 50-85 years), the median ECOG
performance status was 1 (range, 0-2), and the median
PSA at baseline was 68 ng/mL (range, 18-1400 ng/mL)
(Table 1). Fifty-three percent of patients had Gleason
scores between 8 and 10, osseous disease was present
in 85%, and 40% had soft tissue metastasis. All participants had objective evidence of metastasis, all had
failed primary hormone therapy, all had castrate levels
of testosterone, and 50% had received ⱖ1 additional
No. (percent)*
Toxicity†
Grades 3-4
Grades 1-2
Leukopenia
Anemia
Neutropenia
Neutropenic fever
Atrial arrhythmia
Deep venous thrombosis
Edema
Fatigue
Thrombocytopenia
Hyperglycemia
Pain
Pulmonary
Syncope
Alopecia
Anorexia/weight loss
Coagulopathy
Depression
Diarrhea
Dizziness
Hypertension
Hypokalemia
Infection
Insomnia
Malaise
Nail changes
Nausea/vomiting
Neurologic
Other gastrointestinal
Rash
Renal
Xerostomia
6 (19)
4 (13)
4 (13)
3 (10)
2 (6)
2 (6)
2 (6)
2 (6)
2 (6)
1 (3)
1 (3)
1 (3)
1 (3)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
13 (42)
17 (55)
10 (32)
3 (10)
2 (6)
2 (6)
12 (39)
16 (52)
12 (39)
3 (10)
18 (58)
6 (19)
1 (3)
5 (16)
9 (29)
1 (3)
2 (6)
2 (6)
5 (16)
3 (10)
1 (3)
8 (26)
3 (10)
2 (6)
4 (13)
16 (52)
2 (6)
5 (16)
4 (13)
5 (16)
1 (3)
* Of 31 patients evaluable for toxicity.
†
Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (vesion 2.0).
systemic treatment regimens after failing primary hormonal therapy. Of the 2 patients who had received
prior chemotherapy, it was taxane-based in both instances.
A total of 266 cycles of mitoxantrone were administered. The average number of cycles per subject was
7 (range, 0-11 cycles). The mean dose of mitoxantrone
administered for the first cycle was 11 mg/m2 (range,
0-12 mg/m2).
Toxicity
Toxicity data were available for 31 patients (Table 2).
The predominant Grade 3/4 toxicity associated with
treatment was bone marrow suppression, with 13% of
individuals experiencing neutropenia and 10% neutropenic fever. Other Grade 3/4 toxicities were less
common and of unclear relation to treatment. Two
Mitoxantrone and Ketoconazole in Prostate CA/Eklund et al.
2463
patients had atrial dysrhythmia, 1 had syncope, and 1
discontinued treatment when he developed idiopathic
thrombocytopenia purpura. Of lower-grade toxicities,
edema was relatively common, but there were no episodes of congestive heart failure reported. Nausea/
vomiting was associated with ketoconazole administration and was noted in 52%, was primarily Grade 1,
and was generally responsive to treatment with antiemetics. Pain, anemia, and fatigue were also common.
Response and Survival
Of 40 patients enrolled, 37 were evaluable for response. One person refused therapy after being registered for the study, 1 had a massive stroke after 2
cycles and died shortly thereafter, and 1 person withdrew from study after 1 cycle because of gastrointestinal bleeding (the latter 2 in the face of normal platelets). There was no evidence of PD in any of these 3
cases.
Three patients (8%) achieved CR and 23 patients
(62%) achieved a PR, giving a CR plus PR rate of 70%.
For those with Gleason scores of 8, 9, and 10 disease,
the CR, PR, and overall response rates were 10%, 70%,
and 80%, respectively. All 3 of those patients achieving
CR had pretreatment measurable soft tissue metastases, as well as elevated PSA, whereas 2 patients also
had bone metastases. Four patients (11%) in the study
had SD. Seven patients (19%) had PD. The overall
response rate for bone disease was 8% (all CRs),
whereas that for soft tissue was 13%. The median PFS
and overall survival was 10 months and 18 months,
respectively (Fig. 1).
DISCUSSION
Therapeutic options for men with hormone-refractory
prostate cancer are limited. Because the combination
of doxorubicin plus ketoconazole has been reported to
have high activity, but high toxicity, and because mitoxantrone has a similar activity spectrum to doxorubicin, it was hypothesized that mitoxantrone plus ketoconazole would have high activity and low toxicity
in a cohort with hormone-refractory prostate cancer.
Findings from the current study directly support this
hypothesis.
It is important to note that high response rates
were attained even though a high proportion of participants had high-grade prostate cancer (i.e., a Gleason score of 8-10). A high Gleason score is known to be
a poor prognostic indicator for individuals with metastatic disease.31 Because the goal of 22 responding
patients was reached well before the planned maximum cap of 46, the study was terminated at 37 evaluable patients. If accrual had continued up to 46 patients, the worst-case scenario (no additional
FIGURE 1. Progression-free survival (A) and overall survival (B) curves for
men with hormone-refractory prostate cancer treated with mitoxantrone and
ketoconazole.
responses) and best-case scenario would have given
overall response rates of 57% and 76%, respectively.
Given the nature of the cohort, interest in further
investigation would still remain even under the worstcase scenario. Although the current study represents a
single report, the findings of which should be confirmed separately, it is important to note that it is in
fact a multiinstitution study in which 5 separate institutions and 6 separate hospital systems participated.
Both ketoconazole and mitoxantrone have activity
in prostate cancer. Mitoxantrone, even when combined with steroids, is reported to have low activity in
prostate cancer.9,10,25,32 Ketoconazole has been exten-
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CANCER June 1, 2006 / Volume 106 / Number 11
sively evaluated in patients with advanced prostate
cancer, with widely varying response rates.14 –20,33,34 In
more recent trials,16 –20 in which PSA was used as an
endpoint, response rates were higher, and ranged
from 27% to 63%. Whereas the 63% response rate
noted in 1 previous study16 approximates the 70%
response rate seen in the current study, the same
investigators recently reported a response rate of 27%
in a trial that targeted a cohort of patients at an early
stage of hormone independence.19 Higher response
rates in an earlier cohort would have been expected.
Again, it is also important to note that relatively high
response rates were observed in the current study,
despite the fact that a high percentage of participants
had high-grade disease. Therefore, although the combination of mitoxantrone plus ketoconazole needs to
be studied further, existing data support the notion
that there is an added benefit to combining these 2
agents. It also should be noted that epirubicin has an
activity spectrum similar to that of doxorubicin and
can be well tolerated and active in hormone-refractory
prostate cancer,35,36 and therefore also may be suitable in combination with ketoconazole.
To our knowledge, until recently, no regimen had
been shown to improve survival in men with hormone-refractory prostate cancer. Two recent reports
demonstrate that docetaxel-based regimens improve
survival, at least as compared with mitoxantrone plus
prednisone (MP). Tannock et al.10 demonstrated that
docetaxel plus prednisone gave superior responses
and longer survival than did MP. Petrylak et al.9 reported a similar superiority with docetaxel plus estramustine. Before these reports, taxane-based regimens
were widely used for hormone-refractory prostate
cancer, even as first-line therapy.3–12 The use of taxane-based regimens is now expected to increase significantly. The results of the current study demonstrate that mitoxantrone plus ketoconazole has
activity that appears to be similar to that of taxanebased regimens.
The combination of mitoxantrone plus ketoconazole is a well-tolerated regimen with significant activity for men with histologically aggressive, hormonerefractory prostate cancer. This combination warrants
further study in men with prostate cancer. In particular, its activity in a hormone-refractory cohort should
be independently confirmed.
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