A New Formulation of Calcitriol (DN-101) for High-Dose Pulse Administration in Prostate Cancer Therapy

OPTIMIZING TREATMENT FOR ADVANCED PROSTATE CANCER A New Formulation of Calcitriol (DN-101) for High-Dose Pulse Administration in Prostate Cancer Therapy William David Henner, MD, PhD,* Tomasz M. Beer, MD† *Novacea, Inc., South San Francisco, CA; †Oregon Health & Science University, Portland, OR Although the antineoplastic activity of calcitriol in prostate cancer has been known for many years, the agent’s use in oncology has been prevented because of the occurrence of hypercalcemia with daily administration. High-dose pulse administration of calcitriol has the potential to improve the therapeutic index of calcitriol. Results of a phase II study of calcitriol and docetaxel (Taxotere®) suggest that this combination may have utility in androgen-independent prostate cancer (AIPC). DN-101, a high-dose (15 µg) formulation of calcitriol suitable for use in oncology, is now being tested in a randomized trial (AIPC Study of Calcitriol Enhancing Taxotere). This formulation of calcitriol could become an important new tool for improving the efficacy of docetaxel in the treatment of AIPC and would join the ranks of other nuclear receptor ligands in cancer treatment. Investigations of DN-101 in the treatment of a broad range of tumor types and in combination with a variety of agents are an exciting new area of research. [Rev Urol. 2003;5(suppl 3):S38–S44] © 2003 MedReviews, LLC Key words: Calcitriol • Androgen-independent prostate cancer • Hypercalcemia • High-dose pulse administration • Docetaxel he growth of many human malignancies is regulated by nuclear receptors. Nuclear receptor ligands or their antagonists have become very useful in the treatment of a number of human malignancies. Classes of anticancer agents that work directly or indirectly through interactions with nuclear receptors include the glucocorticoids, selective estrogen receptor modulators, gonadotropin- T S38 VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY DN-101 for HDPA in Prostate Cancer Therapy releasing hormone agonists and antagonists, antiandrogens, and retinoids. Calcitriol is a ligand for the vitamin D receptor (a nuclear receptor) and a new formulation of calcitriol (DN-101) is under active investigation for the therapy of human tumors. Synthesis of Endogenous Calcitriol The vitamin D receptor (VDR) is a nuclear receptor for which calcitriol (1,25-dihydroxycholecalciferol) is the principal biologically active ligand. Calcitriol is a steroid hormone synthesized from dietary precursors. In the skin and in the presence of potential of VDR ligands to treat cancer has long been established. Abe and colleagues2 showed that mouse myeloid leukemia cells have VDRs and that vitamin D exposure can produce terminal differentiation. VDR expression occurs in a wide range of neoplasms, and the antiproliferative action of VDR ligands has been demonstrated in many common human malignancies, including cancers of the prostate, breast, colon, and lung. In prostate cancer, preclinical activity of calcitriol or its analogs has been presented for both in vitro and in vivo models.3–5 In both tissue culture and whole animal models, the antineoplastic Although calcitriol’s best-characterized role is in calcium homeostasis, its role as a mediator of cell growth, immunoregulation, and differentiation has been increasingly recognized. antineoplastic activity to hypercalcemia, hypercalcemia has continued to limit the clinical utility of vitamin D analogs. To date none of these agents have been approved for the therapy of human malignancies. Clinical Trials of Daily Calcitriol in Prostate Cancer Based on the preclinical evidence for antineoplastic activity of calcitriol in prostate cancer, Osborn and coworkers7 studied the effect of doses of calcitriol of up to 1.5 µg/day. Dose escalation was limited by hypercalcemia in 11 of 14 patients. In this study, 2 of 14 patients had decreases in prostatespecific antigen (PSA), although no patient had a confirmed PSA response by standard criteria.8 In a study of patients with a rising PSA after definitive local therapy for prostate cancer, Gross and colleagues9 treated 7 patients with daily calcitriol. Although 6 of 7 patients appeared to have a slowing in the rate of PSA rise in this study, therapy was limited by the predictable development of hypercalcemia. Although neither of these studies determined the physiologic levels of calcitriol achieved, previous work indicates that these daily doses could not have achieved more than modest increases above normal physiologic concentrations without the rapid development of unacceptable hypercalcemia. ultraviolet light, dietary 7-dehydrocholesterol is converted to vitamin D3. Subsequent hydroxylation of vitamin D3 at the 25 position by the liver and at the 1 position by the kidney converts vitamin D3 to the biologically active form, 1,25dihydroxycholecalciferol (calcitriol). The concentration of calcitriol in the blood is an important determinant of calcium metabolism and blood calcium levels. Because of its prominent role in calcium homeostasis, the synthesis of calcitriol is tightly regulated. activity of VDR ligands requires substantially supraphysiologic calcitriol levels. Physiologic levels of calcitriol in humans vary, but are generally reported in the range of 0.05–0.16 nM. In the case of prostate cancer cell lines, growth inhibition generally occurs at levels of ≥ 1 nM, at least six- to 20-fold higher than physiologic concentrations. Prolonged continuous exposure to supraphysiologic levels of calcitriol leads to hypercalcemia and hypercalcemia-related toxicities, such as renal dysfunction. Anticancer Activity of Calcitriol and Analogs Calcitriol Analogs High-Dose Pulse Administration of Calcitriol In attempts to reduce the hypercalcemia associated with VDR ligands and thereby improve the therapeutic index of these compounds, a large number of analogs of calcitriol have been synthesized and tested for both hypercalcemia and antineoplastic activity.6 Although preclinical studies have suggested some of these agents might have an improved ratio of In 2001, we reported the results of a phase I dose-escalation study of calcitriol conducted at Oregon Health & Science University (OHSU) in patients with advanced malignancies.10 In this study, the interval between calcitriol administration was increased to 1 week to test the hypothesis that an increased dosing interval would allow markedly supraphysiologic and poten- Although calcitriol’s best-characterized role is in calcium homeostasis, its role as a mediator of cell growth, immunoregulation, and differentiation has been increasingly recognized.1 VDRs are present in many different tissues, and radioactive vitamin D localizes in many tissues not associated with calcium metabolism. The VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S39 DN-101 for HDPA in Prostate Cancer Therapy continued tially therapeutic concentrations of calcitriol to be achieved while mitigating the hypercalcemic side effects of this agent. If the antineoplastic effects of calcitriol could be produced with a brief exposure to high concentrations, whereas the development Phase II Trial of Weekly Calcitriol as Initial Therapy for Patients with a Rising PSA as Evidence for the Recurrence of Prostate Cancer In our next study, 22 patients who had a recurrence of prostate cancer, as evidenced by a rising PSA despite If the antineoplastic effects of calcitriol could be produced with a brief exposure to high concentrations, whereas the development of hypercalcemia required more prolonged exposure, then a high-dose pulse administration regimen might improve the therapeutic index of calcitriol. of hypercalcemia required more prolonged exposure, then a highdose pulse administration (HDPA) regimen might improve the therapeutic index of calcitriol. In the OSHU study, patients were instructed to limit calcium intake and increase fluid intake. Dose escalation began at 0.06 µg/kg weekly and escalated to 2.8 µg/kg using a commercially available formulation (Rocaltrol®; Roche Pharmaceuticals, Nutley, NJ) containing 0.5 µg calcitriol per capsule. No grade 3 toxicities were encountered; therefore, a maximum tolerated dose was not defined. Hypercalcemia was not a clinically significant problem with this regimen as no hypercalcemia > grade 1 was encountered and no patient required intervention, dose reduction, or dose interruption for hypercalcemia. The study was terminated because of the excessive number of Rocaltrol capsules required at the maximum dose tested. A dose of 2.8 µg/kg requires 392 capsules (0.5 µg each) for a 70 kg person. In addition, although potentially therapeutic levels of serum calcitriol of 3.7–6.0 nM were achieved, serum levels of calcitriol did not increase beyond a dose of ~0.5 µg/kg Rocaltrol. These results suggested that absorption of calcitriol in the Rocaltrol formulation was saturated at any dose beyond the 0.5 µg/kg level. S40 VOL. 5 SUPPL. 3 2003 definitive local therapy for prostate cancer, and who had not yet received hormonal therapy for recurrent disease, were treated with calcitriol (Rocaltrol, 0.5 µg capsules) on an HDPA schedule (weekly at 0.5 µg/kg).11 Patients received calcitriol until a fourfold increase in PSA or This study was an open-label, single-arm, single-institution study, and only limited conclusions regarding efficacy can be reached. No patient had a PSA response as defined by a 50% reduction in PSA confirmed 4 weeks later. Three patients had confirmed reductions in PSA ranging from 10%–47%. Among patients without a PSA reduction, no patient had a decrease in the PSA doubling time (PSADT) and three patients had a statistically increased PSADT, as compared with their PSADT prior to starting therapy. The median PSADT increased from 7.8 months to 10.3 months (P = .03 by Wilcoxon signed rank test) for the entire study patient population. This study indicated that relatively long-term HDPA of calcitriol on this dose and weekly schedule can be administered safely. The study provided preliminary evidence for One study provided preliminary evidence for efficacy of HDPA calcitriol in slowing PSA progression. other evidence of disease progression was demonstrated. With a median duration of treatment of 10 months, this therapy was well-tolerated. No hypercalcemia, symptomatic renal calculi, or any other ≥ grade 3 toxicity was observed. efficacy of HDPA calcitriol in slowing PSA progression. Calcitriol levels that could be achieved in this study were limited by the absorption maximum observed with Rocaltrol. Whether increased efficacy can be obtained with a formulation of cal- Table 1 Combined Calcitriol and Docetaxel versus Docetaxel Monotherapy Endpoint PSA response (%) PSA progression-free survival (mo) Tumor response in measurable disease (%) Median survival (mo) Weekly HDPA calcitriol and docetaxel 81 11.4 Docetaxel monotherapy (range) 42 (35–46) 5 (4.6–5.1) 53 28 (17–40) 19.5 (ongoing) 9.2 (9–9.4) From Beer et al.5 HDPA, high-dose pulse administration; PSA, prostate-specific antigen. REVIEWS IN UROLOGY DN-101 for HDPA in Prostate Cancer Therapy 0.75 Probability Phase II Trial of Weekly Calcitriol and Docetaxel in Patients with AIPC Most commonly, antineoplastic drugs are used in combination to treat human malignancies. Combination therapy can be particularly efficacious when the two agents have a synergistic cytotoxic effect on the malignant cells and when the side-effect profile of the two agents is non-overlapping. The combination of calcitriol and docetaxel (Taxotere®, Aventis Pharmaceuticals, Bridgewater, NJ) for the treatment of AIPC is particularly attractive because preclinical studies indicate that calcitriol enhances the antineoplastic activity of taxanes in prostate cancer models. A number of phase II clinical trials of docetaxel monotherapy in AIPC have already been conducted, demonstrating a 42% PSA response rate overall.12–15 In addition, the side-effect profile of HDPA calcitriol is very favorable, with no apparent overlap in toxicity with docetaxel. In this study, the patients were pretreated with calcitriol the day before docetaxel administration. The rationale for this sequence was that pretreatment would allow time for VDRmediated changes in pro-apoptotic proteins to occur prior to exposure of the prostate cancer cells to the cytotoxic agent docetaxel. In this single-center, single-arm, open-label phase II trial, 37 chemotherapy-naïve patients with metastatic AIPC and fulfilling standard criteria for failure of hormonal therapy8 were treated with oral calcitriol (0.5 µg/kg) on day 1, followed by docetaxel (36 mg/m2) on day 2.5 Treatment was 1.00 0.50 0.25 0.00 0 3 6 9 12 15 18 21 4/34 7/29 5/21 3/14 0/3 (number of events/patients at risk) 0/2 24 Months 2/37 Figure 1. Kaplan-Meier probability of disease progression over time. Reprinted with permission from Beer et al.5 1.00 0.75 Probability citriol that allows greater absorption remains to be determined. A randomized controlled trial would be necessary to confirm these results and to determine if HDPA of calcitriol produces a meaningful delay in disease progression. 0.50 0.25 0.00 0 3 6 9 12 15 18 21 24 Months 1/37 1/36 1/35 1/34 5/29 2/14 (number of events/patients at risk) 1/6 Figure 2. Kaplan-Meier probability of overall survival over time. Reprinted with permission from Beer et al.5 administered for 6 consecutive weeks and repeated on an 8-week cycle. The study was powered to detect an increase in the PSA response rate to 65% from the historical control rate of 45% in this patient population. Treatment-related toxicity was generally similar to that expected with single-agent docetaxel. There was one treatment-related death from pneumonia. Hypercalcemia was observed in three patients: grade 1 (> upper limit normal-11.5 mg/dL) in two patients and grade 2 (11.6–12.5 mg/dL) in one patient. The single patient who developed grade 2 hypercalcemia had mistakenly ingested a full dose of calcitriol for 2 days, instead of the specified 1 day. No patient required intervention or dose delay for hypercalcemia or renal dysfunction. This study met the primary end- VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S41 DN-101 for HDPA in Prostate Cancer Therapy continued Plasma calcitriol concentration, pg/mL 1400 Patient 1 1200 Patient 2 Patient 3 1000 Patient 4 Patient 5 800 600 400 200 0 0 10 20 30 40 50 60 Time following dosing, hr Figure 3. Adjusted plasma calcitriol concentrations in five patients receiving Rocaltrol without docetaxel. Levels are adjusted by subtracting the pretreatment concentration from all time points. Plasma calcitriol concentration, pg/mL 1400 Patient 1 1200 Patient 2 Patient 3 1000 Patient 4 Patient 5 800 600 400 200 0 0 10 20 30 40 50 60 Time following dosing, hr Figure 4. Adjusted plasma calcitriol concentrations in the same five patients receiving Rocaltrol with docetaxel. Levels are adjusted by subtracting the pretreatment concentration from all time points. point of PSA response. Thirty of 37 patients achieved a confirmed PSA response of > 50% (81%, 95% CI, 68%-94%). Fifty-nine percent of patients achieved a confirmed > 75% S42 VOL. 5 SUPPL. 3 2003 reduction in PSA. Results for the secondary endpoints of median time to progression, objective response rate (in patients with measurable disease), median survival, and 1-year survival REVIEWS IN UROLOGY are shown in Table 1. Where results are available for comparison, the results of this study compare favorably with those reported for prior studies of docetaxel as monotherapy in AIPC. Likewise, the Kaplan-Meier estimates of time to tumor progression (Figure 1) and overall survival (Figure 2) were also encouraging. To determine whether or not calcitriol altered the pharmacokinetics of docetaxel, the pharmacokinetics of each agent were compared when used alone and when the agents were administered in combination in five patients in the phase II trial. Although there is considerable intrapatient and interpatient variability in absorption of this formulation of calcitriol (Rocaltrol 0.5 µg capsules), the pharmacokinetic parameters for calcitriol were unaffected by combination with docetaxel (Figures 3 and 4). Likewise, the population pharmacokinetic parameters of docetaxel were unaffected by prior administration of calcitriol (Figures 5 and 6). This analysis, although limited by small sample size, suggests that the improved efficacy results observed with the combination are unlikely to be due to an interaction of calcitriol and docetaxel that leads to altered pharmacokinetics. Although the results of the phase II study of calcitriol and docetaxel in AIPC were encouraging, these results need to be confirmed in a rigorously controlled trial. Phase I Trial of DN-101, a New High-Dose Formulation of Calcitriol for Oncology The OHSU phase II study utilized a currently marketed formulation of calcitriol (Rocaltrol, 0.5 µg capsules). However, there are several limitations to a wider use of this formulation for HDPA in oncology. First, the dose used (0.5 µg/kg) requires ingestion of a very large number of capsules (eg, 70 capsules for a 70-kg person), DN-101 for HDPA in Prostate Cancer Therapy Figure 5. All plasma docetaxel concentrations in five patients receiving docetaxel alone. Docetaxel concentration, nM 10000 1000 100 10 1 0 4 8 12 16 20 24 Time following dosing, hr Figure 6. All plasma docetaxel concentrations in the same five patients receiving docetaxel after calcitriol. Docetaxel concentration, nM 10000 1000 100 10 1 0 4 8 12 16 20 24 Time following dosing, hr Men with AIPC Continue androgen deprivation R A N D O M I Z E Docetaxel (36 mg/m2) weekly + DN-101 (45 µg) Docetaxel (36 mg/m2) weekly + placebo 232 patients at up to 60 sites Endpoints: PSA response (primary), tumor response, survival. Figure 7. Schema for ASCENT clinical trial. AIPC, androgen-independent prostate cancer; PSA, prostate-specific antigen. a requirement that is certainly inconvenient and may result in noncompliance. Second, at high doses, absorption of calcitriol from this formulation varies from patient to patient and reaches an absorption maximum at ~0.5 µg/kg. For these reasons, Novacea has developed DN101, a high-dose (15 µg) capsule of calcitriol suitable for use in oncology. The safety, tolerability, and pharmacokinetics of DN-101 are currently being studied in a phase I trial in patients with advanced malignancies. Although dose escalation with DN-101 continues, early results indicate that the new formulation of calcitriol as DN-101 allows much higher peak levels of calcitriol (Cmax) and exposure to calcitriol (AUC) to be achieved than with the currently marketed formulations. The ASCENT Clinical Trial The goal of ASCENT (AIPC Study of Calcitriol Enhancing Taxotere) is to confirm the results of the phase II study of calcitriol and docetaxel conducted at OHSU in patients with AIPC, using the DN-101 formulation of calcitriol. The study is a randomized, placebo-controlled, double-blind study of the weekly combination of DN-101 (45 µg on day 1) and docetaxel (36 mg/m2 on day 2) versus weekly docetaxel monotherapy, for three weeks of a four week cycle, in patients with AIPC (Figure 7). The primary endpoint of the study is PSA response. ASCENT is designed to have 80% power to detect a 20% absolute improvement in the PSA response rate (eg, from 45% to 65%) with a 0.05 significance level. Patients will also be followed for secondary endpoints of time to progression, objective response rate, skeletal-related events, and overall survival. This study is under way and will enroll 232 patients at 60 sites in the United States and Canada. VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S43 DN-101 for HDPA in Prostate Cancer Therapy continued References 1. Holick MF. Noncalcemic actions of 1,25-dihydroxyvitamin D3 and clinical applications. Bone. 1995;17:107S–111S. Abe E, Miyaura C, Sakagami H. Differentiation of rat myc leukemia cells induced by 1,25dihydroxyvitamin D3. Proc Natl Acad Sci USA. 1981;78:4990–4994. Brown AJ. Mechanisms for the selective actions of vitamin D analogues. Curr Pharm Des. 2000;6:701–716. van den Bemd GJ, Pols HA, van Leeuwen JP. Anti-tumor effects of 1,25-dihydroxyvitamin D3 and vitamin D analogs. Curr Pharm Des. 2000;6:717–732. Beer TM, Eilers KM, Garzotto M, et al. Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol. 2003; 21:123–128. Bouillon R, Verstuyf A, Verlinden L, et al. 2. 3. 4. 5. 6. 7. 8. 9. 10. Non-hypercalcemic pharmacological aspects of vitamin D analogs. Biochem Pharmacol. 1995;50:577–583. Osborn JL, Schwartz GG, Smith DC, et al. 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Main Points • Calcitriol is a ligand for the vitamin D receptor (a nuclear receptor) and a new formulation of calcitriol (DN-101) is under active investigation for the therapy of human tumors. • Prolonged continuous exposure to supraphysiologic levels of calcitriol leads to hypercalcemia and hypercalcemia-related toxicities, such as renal dysfunction. • With a median duration of treatment of 10 months, high-dose pulse administration (HDPA) of calcitriol was well tolerated. No hypercalcemia, symptomatic renal calculi, or any other grade 3 toxicity was observed. • A number of phase II clinical trials of docetaxel monotherapy in androgen-independent prostate cancer (AIPC) have already been conducted, demonstrating an overall 42% prostate-specific antigen (PSA) response rate. In addition, the side-effect profile of HDPA calcitriol is very favorable, with no apparent overlap in toxicity with docetaxel. • In the first phase II trial of docetaxel plus calcitriol, 30 of 37 patients achieved > 50% PSA reduction and 59% of patients achieved > 75% PSA reduction. • Although there is considerable intrapatient and interpatient variability in absorption of oral calcitriol (0.5 µg capsules), the pharmacokinetic parameters for calcitriol were unaffected by combination with docetaxel. Likewise, the population pharmacokinetic parameters of docetaxel were unaffected by prior administration of calcitriol. • Because oral calcitriol therapy requires ingestion of a very large number of capsules (eg, 70 capsules for a 70-kg person), the inconvenience may result in noncompliance. In addition, at high doses, absorption of calcitriol from this formulation varies from patient to patient and reaches an absorption maximum at ~0.5 µg/kg. For these reasons, Novacea has developed DN-101, a high-dose (15 µg) capsule of calcitriol suitable for use in oncology. • The goal of ASCENT (AIPC Study of Calcitriol Enhancing Taxotere) is to confirm the results of the phase II study of calcitriol and docetaxel in patients with AIPC, using the DN-101 formulation of calcitriol. S44 VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY