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Clinical Trials |
Vancouver Cancer Centre, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 4E6 Canada [K. N. C., M. E. G., R. K., N. M., C. B., D. E. L. d. M., S. D.]; The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, V6H 3Z6 Canada [K. N. C., M. E. G.]; and Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229 [A. W. T.]
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ABSTRACT |
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Design: Twenty-six patients with HRPC were treated at seven dose levels receiving Genasense at a dose ranging from 0.6 to 5.0 mg/kg/day and mitoxantrone from 4 mg/m2 to 12 mg/m2. Genasense was administered as a 14-day i.v. continuous infusion every 28 days with mitoxantrone given as an i.v. bolus on day 8.
Results: No dose-limiting toxicities were observed. Hematological toxicities were transient and included neutropenia, thrombocytopenia, and lymphopenia. Nonhematological toxicities included fatigue, fever, nausea, arthralgias, myalgias, and transient elevations in serum creatinine, none of which were severe. Two patients had >50% reductions in prostate-specific antigen. One patient, who received six cycles of Genasense at 1.2 mg/kg/day and a low dose (4 mg/m2) of mitoxantrone, also had symptomatic improvement in bone pain. Peripheral blood lymphocyte Bcl-2 protein expression decreased in five of five patients given Genasense at 5mg/kg/day (mean change from baseline, -12.8%; SD, 16.4%) as assessed by flow cytometry. Serum concentrations of Genasense given at doses of 3 mg/kg/day and greater, exceeded 1 µg/ml.
Conclusions: Genasense and mitoxantrone are well tolerated in combination, and mitoxantrone can be delivered at a standard dose with biologically active doses of Genasense without significant additional toxicity. This observation allays concerns about trials that combine Genasense with full doses of other cytotoxic agents seeking greater evidence of activity.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 months in the metastatic setting (2)
. A rising PSA3
, and recurrence of symptoms herald the development of androgen independence. At this point, standard treatment options are limited, consisting of palliative radiotherapy or chemotherapy (3)
. Mitoxantrone has been approved by the United States Food and Drug Administration (FDA) for use in HRPC based on two randomized controlled trials demonstrating an improved palliative response rate as compared with corticosteroids alone (4
, 5)
. The objective and PSA response rates with mitoxantrone were low, and there was no survival benefit seen with chemotherapy (4
, 5)
, emphasizing the need for more effective treatment for this disease. The bcl-2 gene is the prototype of a novel class of oncogenes that contributes to neoplastic progression by enhancing tumor cell survival through the inhibition of apoptosis (6) . Bcl-2 belongs to a growing family of apoptosis-regulatory gene products that act as either death antagonists or death agonists. The selective and competitive dimerization between pairs of these antagonists and agonists determines how a cell responds to an apoptotic signal (7) such as with chemotherapy. Furthermore, several lines of evidence have implicated overexpression of Bcl-2 with treatment resistance (8 , 9) . In prostate cancer, Bcl-2 has been found to be overexpressed in the majority of clinical samples of androgen-independent disease (10 , 11) , and experimental and clinical studies report that increased expression of Bcl-2 confers, or is associated with, the development of androgen independence and treatment resistance (12, 13, 14, 15) . Thus, Bcl-2 is an attractive target to improve the efficacy of treatment of patients with prostate cancer by enhancing chemotherapy-induced apoptosis.
Genasense (Genta Inc., Berkeley Heights, NJ) is an 18-mer phosphorothioate antisense oligonucleotide complementary to the first six codons of the initiating sequence of the human bcl-2 mRNA. Antisense oligonucleotides are chemically modified strands of DNA that form RNA-DNA duplexes by Watson-Crick binding, resulting in RNase H-mediated cleavage of the target mRNA, thereby inhibiting gene expression (16)
. In preclinical prostate cancer models, Genasense and bcl-2 antisense oligonucleotides have shown significant activity in inhibiting expression of Bcl-2, delaying time to the development of androgen independence, and enhancing the effects of chemotherapy by increased apoptosis (17, 18, 19, 20, 21)
. A Phase I study of single-agent Genasense in patients with lymphoma reported dose-limiting toxicities of thrombocytopenia, hypotension, fever, and asthenia with a MTD of 147.2 mg/m2/day (4.1 mg/kg/day) given for 14 days by a continuous s.c. infusion (22)
. A Phase I/II trial of Genasense in combination with dacarbazine in patients with melanoma has shown promising activity and a Phase III multicenter trial is under way.
In this study, we sought to evaluate the combination of Genasense and mitoxantrone in patients with HRPC to define quantitatively and qualitatively the toxicities, MTD, and pharmacokinetic and biological effect, and to determine preliminary antitumor activity. Genasense was given as a 14-day CIVI with mitoxantrone delivered on day 8 to theoretically allow sufficient time for Bcl-2 expression to decrease. Dose escalation of both mitoxantrone and Genasense was performed, based on the risk of possible additive or synergistic toxicity from Bcl-2 inhibition in normal tissues.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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20 that was rising after discontinuation of peripheral antiandrogen, defined as at least two consecutive increases not less than 2 weeks apart. The most recent PSA assessment must have been done 
14 days before study entry. Therapies with leuteinizing hormone-releasing hormone agonists were to be continued for the duration of study treatment in those patients not surgically castrated. Patients were required to have radiological or clinical evidence of metastatic disease documented within 14 days before enrollment. Eligibility criteria also included ECOG performance status of 0 or 1; life expectancy of 12 or more weeks; and age 18 years. Prior chemotherapy or strontium was not permitted. External beam radiation was permitted if a minimum of 4 weeks had elapsed since the last dose before enrollment to the trial. Adequate hematopoietic (absolute granulocytes count, 1.5 x 109/liter and a platelet count, 100 x 109/liter), hepatic (bilirubin, 2 x upper limits of normal) and renal (serum creatinine, 2 x upper normal limit) function and normal coagulation parameters (partial thromboplastin time, international normalized ratio) were also required. Patients with a known bleeding disorder, on anticoagulant therapy, or with significant cardiac dysfunction were excluded. All of the patients gave written informed consent, and the protocol was approved by the institutional review board of the University of British Columbia.
This trial was designed as an open-label, nonrandomized, Phase I dose-finding study of Genasense given as a CIVI on days 1 through 14, in combination with mitoxantrone given on day 8 in a 28-day treatment cycle. The MTD of Genasense administered s.c. in advanced lymphoma patients was 4 mg/kg/day for 14 days, which resulted in blood levels in the range of 0.96–6.67 µg/ml. Because experimental animal data had indicated a 60% bioavailability of Genasense for s.c. versus i.v. administration, the MTD of 4 mg/kg/day by a s.c. route would extrapolate to an MTD of 2.4 mg/kg/day when administered i.v. The starting dose of Genasense, therefore, was 25% of the predicted MTD, or 0.6 mg/kg/day. The starting dose of mitoxantrone was 4 mg/m2, one-third the standard dose used in HRPC. Mitoxantrone was given i.v. on day 8. One patient was to be treated at each dose level until National Cancer Institute of Canada common toxicity criteria (NCIC CTC) toxicity 2 (except alopecia) was observed, at which point, a minimum of three patients would be entered to additional dose levels. DLT was defined as any NCIC CTC grade 3 or 4 nonhematological toxicity (except nausea or vomiting), or hematological toxicity defined as any grade 4 thrombocytopenia, or neutropenia defined as grade 4 toxicity lasting for >5 days duration, or febrile neutropenia. DLT was defined on the first cycle only. If one patient at any level experienced DLT, additional patients were entered at that level to a maximum of six patients. If two patients experienced DLT, then accrual would stop at that level, and the next lower dose level would be declared the MTD. Additional patients would be entered at the MTD level to reach six patients if necessary to further characterize the toxicities at that level.
Genasense was supplied by Genta Incorporated (Berkeley Heights, NJ) and provided as a sterile concentrated solution containing the drug substance in sterile isotonic normal saline (pH 5.5–8). Each vial contained 300 mg of Genasense in 10 ml of solution for a concentration of 30 mg/ml. Infusion pump cassettes were filled with the total dose of Genasense concentrate to be delivered over 7 days diluted with sterile normal saline (0.9% Sodium Chloride Injection USP) delivered via a portable volumetric infusion pump through a central venous catheter.
Pretreatment investigations included history and physical exams, complete blood count, differential WBC count, partial thromboplastin time, INR, bilirubin, serum creatinine, total protein, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, PSA, and testosterone. Baseline studies also included an assessment of left ventricular function, bone scan, chest X-ray, and computed tomography scan of abdomen and pelvis. During protocol therapy, histories that included performance status and physical exams were conducted weekly. Hematology (CBC, WBC differential, platelets) was performed twice weekly for two cycles then on day 1 and 8 of subsequent cycles. Biochemistry (bilirubin, creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase) and PSA were performed on day 1 of each cycle. Imaging studies and left ventricular function were assessed every three cycles. Standard WHO criteria were used to assess measurable disease response (23) . PSA response was defined as a greater than 50% decrease from baseline maintained for at least 4 weeks. Treatment failure was defined as new or worsening disease symptoms requiring change in management, fall in ECOG performance status by 2 levels, new or objective progressive disease, and/or continued rise in PSA for 12 weeks in asymptomatic patients.
Lymphocytes from peripheral blood were collected from patients enrolled on dose levels 6 and 7 on days 1 (pretreatment), 5, and 8 (premitoxantrone). Bcl-2 protein level was assessed using quantitative fluorescence cytometry as described previously (24) . This method correlates well with Western blot analysis of Bcl-2 and allows comparisons of values expressed as molecules of equivalent soluble fluorochrome.
Plasma samples from patients on dose levels 6 and 7 (mitoxantrone dose of 12 mg/m2) were collected for Genasense and mitoxantrone pharmacokinetic studies. For Genasense, plasma samples were obtained on days 1 (predose, 1 h, 2 h, 4 h, 6 h), 2, 3, 4, 8, and 15. Plasma concentrations of Genasense were assayed by anion exchange high-performance liquid chromatography as described previously (25) . Genasense steady state concentration (Css) in patient samples was determined from the average Genasense plasma concentration achieved at steady state after continuous drug infusion. For mitoxantrone, plasma samples were obtained on day 8 before the infusion, then after the infusion at 0.5, 1, 1.5, 2, 3, 6, 8, 24, and 48 h. Mitoxantrone was extracted from 0.10 ml of patient serum and spiked serum standards with 0.1% ammonium hydroxide in methanol using Oasis HLB Extraction Cartridges (Waters Ltd., Milford, MA), dried, and resuspended in an equal volume of mobile phase. Quantitation was carried out by high-performance liquid chromatography using an Alliance 2690 system with a PhotoDiode Array detector, extracted wavelength 658 nm, and a Millennium Chromatography Workstation (all Waters Ltd., Milford, MA). The column was a Symmetry C18, 3.9 mm x 150 mm (Waters) and the mobile phase was isocratic aqueous 18 mM formate buffer (pH 2.7) containing 34 mM hexane sulfonic acid (71%) and acetonitrile (29%) with a flow rate of 1 ml/min and injection volume of 0.05 ml. System suitability was checked by resolution of mitoxantrone from USP mitoxantrone-related compound. The assay was found to be reproducible and precise with a linear range of 1–1000 ng/ml The mitoxantrone plasma concentration versus time data sets were fitted to two-compartment model using WinNONLIN version 1.5 pharmacokinetic software (Pharsight Corp., Mountainview, CA). Pharmacokinetic parameters, i.e., AUC, peak plasma concentration (Cp), volume of distribution (V), plasma clearance (Cl) and half life (t1/2) were calculated from model parameters using standard pharmacokinetic equations.
Student’s t test was used to measure statistical significance between means of two treatment groups. Statistical significance was set at P < 0.05. Survival was calculated from the time of first treatment until death from any cause or last follow-up visit. Time-to-event analysis was done by the Kaplan-Meier method. Statistical analysis was performed using SPSS v9.0 for Windows.
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RESULTS |
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.
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. The median number of cycles administered was three (range, 1–8). Six patients were entered at the last planned dose level.
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. Thrombocytopenia or neutropenia was not observed in any patient during the first 7 days of Genasense infusion on cycle 1. Patient 1 developed grade 2 neutropenia with a nadir by day 22 (14 days after mitoxantrone at 4 mg/m2), and recurred but did not worsen with subsequent cycles. Grade 3 or 4 neutropenia occurred by day 15–22 in four of four patients and two of six patients at dose levels 6 and 7, respectively. Thrombocytopenia greater than grade 1 was not seen in any patient during the first cycle of treatment. Patient 23 developed grade 2 thrombocytopenia (64 x 109/liter) on cycle 9 but was coincident with a documented central venous catheter infection and bacteremia. Lymphopenia was observed at all of the dose levels, which worsened by grade as dose increased. Decreases in lymphocytes were noted to occur within the 1st week, with a nadir by days 10–15. Grade 3 lymphopenia occurred in three of four patients and four of six patients on dose levels 6 and 7, respectively, but was not clinically significant in any patient.
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. First cycle grade 2 toxicities included elevations in creatinine in one patient each at dose levels 6 and 7. Both resolved and the patient on dose level 7 received a second cycle without incident. Grade 1 and 2 fevers were also observed at dose level 7 after initiation of Genasense but were transient and resolved within 24 h despite continuation of the infusion. Grade 1 arthralgias and myalgias during the Genasense infusion occurred in patients at several dose levels and did not appear dose related. Three patients had asymptomatic declines of 10–20% in cardiac left ventricular ejection fraction after three cycles, and in one patient after six cycles; however, all of the patients’ ejection fractions remained greater than 50%. Serious adverse events related to protocol therapy included a catheter-related thrombosis and a catheter-related bacteremia.
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. One patient received Genasense at 1.2 mg/kg/day and a low dose of mitoxantrone (4 mg/m2) and also had symptomatic improvement in bone pain, receiving a total of six cycles before symptomatic and biochemical progression. The other patient received Genasense at 5 mg/kg/day and mitoxantrone at 12 mg/m2 and received a total of eight complete cycles before discontinuing therapy because of catheter-related bacteremia. One patient had a PSA reduction of 25–50%, and five others had stable biochemical disease. Seven patients had measurable disease, and, of these, one had a partial response. Kaplan-Meier estimate of median overall survival was 18.7 months (95% confidence interval, 10.85–26.51).
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. The mean percentage change from baseline (± SD) of Bcl-2 protein at dose level 6 and 7 were +11.6 ± 24.4% and -12.8 ± 16.4%, respectively (P = 0.11).
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. Mean AUC at dose levels 6 and 7 were 328.9 ± 52.6 ng·h/ml and 579.6 ± 172.7 ng·h/ml, respectively (P = 0.008). At dose levels 6 and 7, mean Cp were 77.8 ± 11.0 liters/h and 38.4 ± 11.51 liters/h, respectively (P = 0.0003).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lymphopenia has been noted in other trials with Genasense (22 , 27) . This is consistent with an antisense effect, because mature lymphocytes seem to be dependent on Bcl-2 for survival (29) . As in previous studies, the lymphopenia observed here was not of clinical significance with no increased occurrence of opportunistic infections. Significant thrombocytopenia, which was a DLT observed in a previous Phase I trial of Genasense as a single agent (22) , was not seen in this study. Most toxicities that have been observed in other studies using antisense oligonucleotides have been non-sequence specific and have been attributed to the phosphorothioate backbone of these molecules (22 , 27 , 28 , 30, 31, 32) . Non-sequence specific toxicities have included fatigue and fever, which occurred in this study. Other reported toxicities with phosphorothioate oligonucleotides, such as elevations in transaminases, hyperglycemia, and alterations in coagulation parameters, were not observed in the present study.
We attempted to assess the biological effects of Genasense on its molecular target, Bcl-2. Ideally, an evaluation of a target effect should be made from neoplastic tissue; however with prostate cancer, patients present predominantly with bone-only disease and rarely present with nodal or visceral metastases, which would be easily amenable to repeated biopsy. Therefore, in this trial, we evaluated Bcl-2 expression in PBLs before and during the Genasense infusion, using a quantitative flow cytometric method as a possible surrogate tissue marker of biological activity. From our results, although minor changes did occur in the Bcl-2 expression that appeared dose related, an antisense effect could not be reliably described as being observed in the patient lymphocyte samples. Other investigators have recently found that Western analysis may be more sensitive in detecting decreases in PBL Bcl-2 expression than flow cytometry techniques (33) . Further validation of tests for markers of target effect, accounting for normal baseline variation and indicating what constitutes a biologically meaningful decrease, and whether a surrogate tissue marker consistently reflects target tissue effect based on preclinical models, is required for future studies before they can be used as evidence of biological activity.
It can be speculated that a more pronounced target down-regulation was not observed because lymphopenia occurred in most patients, and the antisense effect on Bcl-2 may have been missed because of a shift in the population of lymphocytes. Assuming that the effect of the antisense molecule is likely heterogeneous within a cell population, those lymphocytes that were affected had a decrease in Bcl-2 expression, underwent apoptosis, were cleared from the circulation, and, thus, could not be identified. Another possibility is that a significant antisense effect may be occurring only within neoplastic tissues and not within normal tissues as has been observed in some animal models (21) . Lack of a greater observed biological effect might also be attributable to low intracellular uptake of the oligonucleotide. Lipid carriers are necessary for efficient uptake of antisense oligonucleotides in vitro (17, 18, 19, 20, 21) ; however, in in vivo models, this has not been necessary (17, 18, 19, 20, 21) , and previously reported clinical trials using Genasense at similar dosing have documented decreases in Bcl-2 expression in neoplastic tissue (22 , 27) .
Some differences in the pharmacokinetic parameters of mitoxantrone were apparent at the higher dose of Genasense characterized by an increase in AUC and a decrease in plasma clearance. Alterations in the serum and tissue pharmacokinetics of an anthracycline when delivered in combination with Genasense have also been observed in preclinical models (34) ; however, the mechanisms for these changes are not understood. Increased toxicity attributable to mitoxantrone was not observed between the dose levels despite the change in mean AUC. Furthermore, large interpatient variability in the pharmacokinetic parameters of mitoxantrone has also been previously reported (35) , and, therefore, the differences seen here are likely attributable to chance alone from the small sample size.
Determining activity was not a primary end point in this study, but preliminary data here does not suggest a synergistic therapeutic effect of combining Genasense with mitoxantrone in patients with metastatic HRPC. Although we were initially encouraged by one patient having had a dramatic PSA response after one cycle of Genasense and low-dose mitoxantrone, this effect was not observed in any other patient on the study except for one treated at the standard dose of mitoxantrone. Mitoxantrone was selected as the chemotherapeutic agent in this trial because it is considered a standard chemotherapy for HRPC. It may, however, be difficult to enhance the activity of a drug with low objective activity used for primarily palliative purposes (4 , 5) . Another possible explanation for the lack of a more pronounced clinical effect is that, for the reasons presented above, we did not sample patient tumors to assess for baseline overexpression of Bcl-2, and it is conceivable that only cancers that overexpress Bcl-2 are amenable to chemosensitization with Genasense. In vitro data however, suggests that this might not be the case and that an antisense effect can still be seen in cells that have either higher or lower expression of Bcl-2 (36) . The median overall survival of the group was 18.7 months, which is significantly longer than the survival for patients with metastatic HRPC reported from randomized trials (4 , 5) . This certainly reflects patient selection, emphasizing that caution must be used when extrapolating survival data from early-phase clinical trials.
Recent published studies report that antimicrotubule regimens, most notably docetaxel, may have significantly more activity in prostate cancer, with response rates in the range of 30% for objective disease and 50% for PSA response in Phase II trials (37) . A mechanism of action of antimicrotubule agents may be through the phosphorylation and, hence, the inactivation of Bcl-2 (38) , and, therefore, the combination of Genasense with an antimicrotubule agent may be a more promising regimen for synergistic activity, as demonstrated in prostate xenograft studies (20 , 21) . Clinical trials that use this combination in HRPC are currently underway at our center and elsewhere.
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FOOTNOTES |
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1 Supported in part by Genta Incorporated. 
2 To whom requests for reprints should be addressed, at Vancouver Cancer Centre, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, Canada, V5Z 4E6. Phone: (604) 877-6000; Fax: (604) 877-0585; E-mail: kchi{at}bccancer.bc.ca
3 The abbreviations used are: PSA, prostate-specific antigen; HRPC, hormone-refractory prostate cancer; ECOG, Eastern Cooperative Oncology Group; MTD, maximum tolerated dose; CIVI, continuous i.v. infusion; DLT, dose-limiting toxicity; AUC, area under the curve.
Received 7/ 6/01; revised 9/18/01; accepted 9/19/01.
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