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Division of Hematology/Oncology, Department of Medicine [U. V., M. H.], and Department of Biostatistics [W. D.], Wayne State University, and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan 48201; University of Colorado Health and Science Center, Denver, Colorado [M. G., A. K.]; Fox Chase Cancer Center, Philadelphia, Pennsylvania [G. H.]; and National Cancer Institute, Bethesda, Maryland [J. W.]
ABSTRACT
Dolastatin-10 is a natural, cytotoxic peptide with microtubule-inhibitory and apoptotic effects. It has demonstrated in vitro and in vivo efficacy in the DU-145 human prostate cancer model. A Phase II clinical trial was designed in patients with hormone-refractory prostate cancer. Dolastatin-10 was administered at a dose of 400 µg/m2 i.v. every 3 weeks. Dose escalation to 450 µg/m2 was permitted. Toxicity evaluation was conducted every 2 weeks, and assessment of response was done at the end of every two cycles. Sixteen patients were enrolled between October 1998 to December 1999. The median age was 71 years (range, 59–79 years). Median prostate-specific antigen value was 108 ng/ml (range, 15.3–1672 ng/ml). Of the 15 eligible patients, 7 were Caucasian and 8 were African-American. Eight patients had bone-only metastases, and seven had measurable disease with or without bone metastases. A total of 56 cycles have been administered. Only 2 patients required dose adjustment because of toxicity, and in 5 patients, dose escalation was feasible to 450 µg/m2. The major toxicities observed were grade 3 and 4 neutropenia in 8 patients and grade 3 neuropathy in 1 patient. All 15 patients are evaluable for response. Three patients demonstrated stable disease; 2 of these had bone disease, and 1 had nodal metastasis. All others had disease progression. Dolastatin-10 is very well tolerated in this elderly, pretreated population but lacks significant clinical activity as a single agent.
INTRODUCTION
In the year 2000, it is estimated that 180,400 men will be diagnosed with prostate cancer, and 31,900 men will die of the disease (1) . The vast majority of these deaths are secondary to metastatic disease for which androgen deprivation continues to be the therapeutic standard. Historically, a variety of agents have been evaluated in HRPC3 with objective response rates of <10%. Recognizing the morbid course of HRPC, studies have evaluated the palliative effects of chemotherapy. The demonstration of a palliative benefit led to the approval of mitoxantrone and prednisone as standard treatment for symptomatic disease (2, 3, 4) . Several estramustine-based combinations using either etoposide, vinblastine, or the taxanes have elicited higher response rates (30–50%) in Phase II trials (5, 6, 7, 8) . The impact of some of these combinations on overall survival is currently being evaluated in randomized trials.
Dolastatins are natural cytotoxic pseudopeptides extracted
from the marine shell-less mollusk Dolabela auricularia.
These compounds were first isolated by Pettit et al.
(9)
. The dolastatin family has demonstrated
antineoplastic, bactericidal, and fungicidal properties (10
, 11)
. Within the family, dolastatin-10 and dolastatin-15 exhibit
the most promising antiproliferative actions, and synthetic analogues
of these are currently under evaluation in clinical trials. These
antimitotic agents exhibit inhibition of microtubule assembly and
induction of apoptosis in numerous malignant cell lines
(12)
. In vitro growth inhibition and in
vivo efficacy were demonstrated against small lung cell cancer
cell lines (13
, 14)
. Turner et al.
(15)
studied the effects of dolastatin-10 on the DU-145
human prostate cancer cell lines. Complete growth inhibition was
observed in vitro at concentrations of 1
nM. Cell cycle arrest in
G2-M phase and 
-tubulin depolymerization
correlated with the growth inhibition. Similar results were observed in
the PC3 and LNCaP human prostate cancer cell lines (15)
.
In vivo efficacy was demonstrated at a 5-µg dose of
dolostatin-10 administered i.p. every 4 days in athymic mice.
Dolastatin-10 decreased the number and size of tumors on the diaphragms
of mice and prevented invasion of the musculature, as compared with the
prostate tumors implanted in mouse controls (15)
. The
modulation of apoptotic pathways by bcl-2 phosphorylation was shown on
immunoblot analysis (13
, 14)
. Bcl-2 is expressed in
65% of HRPC specimens and appears to play a role in development of
resistance to therapy (16
, 17)
. These promising
preclinical results, together with the properties of microtubule
inhibition, bcl-2 phosphorylation, and apoptosis induction, led to this
Phase II clinical trial of dolostatin-10 in HRPC.
PATIENTS AND METHODS
Patient Eligibility.
Patients with metastatic (D1 or D2) HRPC were eligible for
this study. Documentation of clinical or PSA progression during
administration of hormone therapy was required. All patients were
required to have had primary gonadal suppression with or without
antiandrogens. Patients with elevated PSA had to demonstrate a rising
trend with three successive elevations at a minimum interval of 2
weeks. For patients lacking measurable disease, the minimum PSA value
for enrollment on the study was 10 ng/ml. No prior chemotherapy was
permitted. A maximum of three prior hormonal manipulations were
permitted, with antiandrogen withdrawal considered as one manipulation.
Patients had to be off flutamide and any other hormones, including
steroids for at least 4 weeks and off bicalutamide for at least 6
weeks. No prior treatment with strontium-89 or other therapeutic
radioisotope was allowed. A minimum of 4 weeks since prior radiation
therapy was required. Good performance status (0–2 by Southwest
Oncology Group criteria) was necessary, with adequate bone marrow,
hepatic, and renal function (absolute neutrophil count
1500/mm3, hemoglobin 8 g/dl, platelet count
>100,000/mm3, serum bilirubin 
2 mg/dl, and
serum creatinine 1.5 mg/dl). Continuation of GNRH agonist was
permitted. Patients with a prior malignancy other than nonmelanoma skin
cancers had to be disease free for 5 years. A signed informed consent
was obtained from every individual enrolled in the protocol.
Treatment Plan.
Dolastatin-10 was administered at a starting dose of 400
µg/m2
by i.v. bolus every 3 weeks. There was a
provision for dose escalation to 450 µg/m2
after two cycles if grade one toxicity was observed. Dose
reduction was required for absolute neutrophil count nadir
500/mm3 or platelet nadir
50,000/mm3. At the time of each scheduled
treatment, dolastatin-10 was administered only if absolute neutrophil
count 1000/mm3, and if the platelet count was
100,000/mm3. Otherwise, treatment was held
until hematological recovery to these minimum levels, and subsequent
cycles were started at a dose reduction. A one level, dose reduction
was necessary for grade 2 neuropathy (dose, 300
µg/m2
), and a two-level dose decrease was
required for grade 3 or 4 neuropathy (dose, 225
µg/m2
). Other nonhematological toxicities were
managed at the discretion of the treating physician and did not mandate
specific dose adjustments.
Evaluation and Response.
Patients were evaluated weekly for toxicity. Measurable
disease was assessed, and bone scans were repeated every three cycles.
Patients were taken off protocol if there was disease progression,
treatment delay of >4 weeks, administration of any other antitumor
therapy, or patient refusal. The National Cancer Institute common
toxicity criteria version 2.0 were used to grade toxicity. Measurable
disease response was assessed using standard criteria for solid tumors
(18)
. Bone metastases were considered nonevaluable
disease, and its status did not affect response assessment, except in
the determination of complete response (must be absent) or progressive
disease (new lesions). Complete clinical response was defined as
disappearance of all measurable and evaluable disease for a minimum of
4 weeks, no new lesions, and normalization of PSA (4 ng/ml). PSA was
measured prior to each cycle every 3 weeks and every 2 weeks as
necessary to document a response. A "PSA partial response" for
patients with metastatic bone disease and PSA-only progression was
defined as 50% reduction in PSA sustained for three successive
determinations performed 2 weeks apart. PSA progression was defined as
two values at least 2 weeks apart with 50% increase over nadir PSA.
Patients who did not meet the above criteria of response and
progression were considered to have stable disease. The time to
treatment failure was calculated from the date of registration to date
of progressive disease or to date off treatment because of toxicity,
refusal, or death. Response rate assessment and toxicity evaluation
were the primary end points of the study. Time to treatment failure and
overall survival were secondary end points. A two-stage study design
was used with provisions for early stopping for demonstrated efficacy
or the lack thereof. Fifteen patients were to be enrolled initially,
and if 1 response was observed, then the study would be terminated.
If >5 responses were observed, then the regimen would be pursued
further in a larger study. If two to four responses occurred, then an
additional 15 patients were to be accrued.
RESULTS
Patient Characteristics.
Sixteen patients were registered between October 1998 and
December 1999. One patient was deemed ineligible because of PSA
elevation alone in the absence of detectable metastases. Patient
characteristics are summarized in Table 1
. The median age of the patients was 71
years (range, 59–79 years). Median baseline PSA was 108 ng/ml
(15.3–1672 ng/ml). The majority of the patients (75%) had three prior
hormonal interventions. All patients had progressed on primary gonadal
suppression. Four patients had orchiectomy, and 10 patients continued
to be on a GNRH agonist. One patient was off the GNRH agonist because
of progression while on therapy and had subsequently received
ketaconazole and hydrocortisone with documented disease progression.
Seven patients had prior radiation therapy (three, definitive to the
prostate, and four, palliative).
|
A comprehensive list of toxicities is included in Table 2
. Although the major toxicity observed
was grade 3 and 4 neutropenia in 50% of the patients, no hospital
admissions were necessary for febrile neutropenia. Only two patients
had severe neutropenia in the first two courses. Grade 3 neuropathy was
noted in one patient. There were no treatment-related deaths.
|
. All other patients
had disease progression. Median follow-up duration at the time of this
report is 10 months (range, 4–15 months). Six patients have died, and
median survival has not been reached. The patients with stable disease
are alive at 5, 7, and 12 months since starting dolastatin-10.
|
Traditional guidelines for pursuing new agents in clinical
oncology have required the demonstration of clinical activity in Phase
II settings. However, there are several examples in prostate cancer
where two single agents, individually having minimal impact, have been
combined to produce significant antitumor effects. Single-agent trials
involving vinblastine, paclitaxel, and etoposide each demonstrated low
activity (19, 20, 21)
, whereas combinations of each of these
drugs with estramustine, a drug with microtubule-inhibiting properties,
resulted in significant antitumor activity (5
, 6 , 22
, 23
;
Table 3
).
|
Phase I trials of dolastatin-10 in a variety of advanced solid tumors have shown minimal myelosuppressive effects (31 , 32) . There was no relation between hematological toxicity and systemic exposure to dolastatin-10 in one of these trials (32) . Our experience in this trial confirms that grade 4 neutropenia of brief duration was observed in one-third of patients with no episodes of febrile neutropenia at the recommended Phase II dose. Also, no cases of severe thrombocytopenia or anemia were seen, and the incidence of neuropathy was low.
Despite the lack of significant clinical activity in an advanced metastatic prostate cancer population, the mechanism of action and favorable toxicity profile of dolastatin-10, coupled with ease of administration, make it a potentially attractive agent in a combination chemotherapy development strategy. The observation of stable disease in 3 of 15 patients may warrant further evaluation of this agent. Treatment of patients in earlier stages and treatment of asymptomatic prostate cancer patients with relatively lower tumor burden may be worthy of investigation.
ACKNOWLEDGMENTS
We extend our thanks to the Investigational Drug Branch of the National Cancer Institute for providing the dolastatin-10 used in this study.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Presented in part at the American Association of
Cancer Research meeting in April 2000. 
2 To whom requests for reprints should be
addressed, at 5 Hudson, Harper Hospital, 3990 John R. Road, Detroit, MI
48201. Phone: (313) 745-2357; Fax: (313) 993-0559; E-mail: hussainm{at}karmanos.org
3 The abbreviations are: HRPC,
hormone-refractory prostate cancer; PSA, prostate-specific antigen;
GNRH, gonadotrophin releasing hormone.
Received 5/18/00; revised 8/14/00; accepted 9/ 1/00.
REFERENCES
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