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Keywords:

  • vitamin D;
  • calcitriol;
  • prostate cancer

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

ASCENT, the Androgen-Independent Prostate Cancer (AIPC) Study of Calcitriol Enhancing Taxotere, is a double-blind, placebo-controlled randomized clinical trial designed to determine if DN-101, a high-dose oral formulation of calcitriol designed for cancer therapy, significantly increases the proportion of patients who have > 50% reduction in serum prostate-specific antigen (PSA) levels in response to docetaxel. The secondary goals of ASCENT are to evaluate the effect of DN-101 combined with docetaxel on PSA progression-free survival, tumour response rate in measurable disease, tumour progression-free survival, skeletal morbidity-free survival, clinical progression-free survival, and overall survival, and to examine the safety and tolerability of DN-101 combined with docetaxel. ASCENT builds on phase I work showing that weekly dosing allows substantial dose-escalation of calcitriol, the natural ligand for the vitamin D receptor, and on phase II work that suggested that adding weekly high-dose ‘pulse’ calcitriol may enhance the activity of weekly docetaxel in patients with AIPC. The preclinical rationale for calcitriol and its combination with docetaxel for prostate cancer therapy is reviewed, as are the key clinical trials that led to the development of ASCENT. The ASCENT design and its strengths and limitations are presented.


Abbreviations
AIPC

androgen-independent prostate cancer

ASCENT

AIPC study of calcitriol-enhancing taxotere

AUC

area under the concentration curve

SWOG

South-west Oncology Group

OHSU

Oregon Health & Science University.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

Calcitriol, the most biologically active metabolite of vitamin D [1], is responsible for regulating calcium and phosphate homeostasis. When human skin is exposed to ultraviolet light, the steroid hormone vitamin D is synthesized from 7-dehydrocholesterol. The biologically active ligand for the vitamin D receptor, calcitriol, or 1,25-dihydroxyvitamin D, is formed when vitamin D is hydroxylated in the liver and then in the kidney.

PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

In preclinical studies, calcitriol and its analogues inhibit cell proliferation, induce apoptosis, and reduce tumour invasiveness and tumour-associated angiogenesis in a variety of models of cancer. These findings have motivated efforts to develop calcitriol as a cancer drug. Both in vitro and in vivo evidence of antineoplastic activity of calcitriol or its analogues against prostate cancer is extensive [2–8].

Several mechanisms explain calcitriol-mediated inhibition of cell proliferation. G1-phase cell-cycle arrest is extensively described [9–13] to be linked to transcriptional activation of cyclin-dependent kinase inhibitors p27Kip1 and p21Waf1[9,10] and to dephosphorylation of the retinoblastoma protein [14–17]. Calcitriol's antiproliferative activity may also be a consequence of alterations in growth factor signalling pathways. For example, calcitriol has been shown to alter components of the insulin-like growth factor system in prostate cancer cell lines [18] and recently a functional vitamin D response element was discovered in the promoter region of the insulin-like growth factor binding protein-3 [19].

Calcitriol inhibits the growth of tumour metastases [8], reduces invasiveness [20,21], inhibits angiogenesis [22,23], reduces activity of metalloproteinases [20,24], increases expression of E-cadherin [25], and reduces expression of α6 and β4 integrins [21]. Apoptosis has been induced in several prostate cancer tumour models exposed to calcitriol [26,27]. Calcitriol down-regulates the anti-apoptotic protein Bcl-2 [26]. Although conflicting information exists about the role of p53 in calcitriol-induced apoptosis, it has been suggested that a reduction in the expression of Akt may also contribute to the pro-apoptotic activity of calcitriol [28–33].

PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

There is synergistic or additive antineoplastic activity when calcitriol or its analogues are combined with several classes of agents. These observations may be explained by increases in signalling through the vitamin D receptor, simultaneous targeting of multiple components of the same pathway, or simultaneous targeting of redundant survival or death pathways.

The antineoplastic effects of calcitriol in vitro and in vivo are enhanced by the steroid dexamethasone [28,34]. Mechanisms that appear to play a role in this interaction include reduction of phospho-Erk1/2 and phospho-Akt levels, increased apoptosis [28,34,35], and increased inhibition of tumour-derived endothelial cell growth [29].

Antitumour activity of several cytotoxic agents is enhanced by adding calcitriol. Such interactions have been described for combinations with paclitaxel [36], docetaxel [37], platinum compounds [38], and mitoxantrone [39], and have been confirmed in animal models [36,39].

CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

Daily dosing

Motivated by strong preclinical data, several clinical investigators have pursued the testing of calcitriol for prostate cancer therapy. Initial efforts examined calcitriol administered daily in both patients who were hormone-naïve and those with AIPC. Hypercalcaemia and/or hypercalcuria developed at doses that were only modestly higher than standard replacement doses and substantial dose escalation proved impossible with this approach [40,41]. There were no confirmed responses in these studies, although the rate of rise of serum PSA levels appeared to slow after initiating calcitriol in the hormone-naïve study.

Intermittent dosing

In vitro, there is significant antineoplastic activity with calcitriol concentrations of ≥ 1 nmol/L, and it increases in a dose-dependent manner. Therefore, substantial increase in calcitriol appeared to be a prerequisite for developing this agent as a cancer drug. Intermittent dosing of oral or subcutaneous calcitriol has been tested in an effort to reach higher concentrations and avoid toxicities associated with daily administration. Subcutaneous administration of calcitriol every other day produced peak blood calcitriol concentrations of ≈ 0.7 nmol/L with dose escalation to 8 µg every other day [42].

The administration of calcitriol orally on a weekly schedule permitted further increases in dose. A phase I study evaluated dose levels of 0.06–2.8 µg/kg. With this approach, substantially higher peak calcitriol concentrations (Cmax) were reached [43]. However, at doses of calcitriol of > 0.48 µg/kg, Cmax and the area under the concentration curve (AUC) did not increase linearly, suggesting an absorption ‘ceiling’. At higher doses, the peak blood calcitriol concentrations were 3.7–6.0 nmol/L. The maximum tolerated dose was not determined, as no dose-limiting toxicities were encountered. Additional safety data were provided in a phase II trial testing this regimen (0.5 µg/kg of oral calcitriol weekly) for longer periods in hormone-naïve patients with prostate cancer and an increasing serum PSA level [44]. When peak calcitriol concentrations were measured in a subset of patients, the mean reached 2 nmol/L. There were no grade 3 or 4 toxicities in these patients and the median duration of treatment for all patients was 10 months.

When calcitriol (oral) capsules were administered at doses up to 38 µg for 3 consecutive days every 7 days in a phase I trial combined with paclitaxel, there were no dose-limiting toxicities [45]. Similar to previous studies, when the dose of calcitriol was increased, there was no linear increase in the AUC, and the Cmax was 1.4–3.5 nmol/L. Together, these studies established that peak calcitriol concentrations of > 1 nmol/L can be reached using this intermittent oral administration of calcitriol.

PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

Motivated by evidence of activity for single-agent docetaxel and preclinical evidence supporting combinations of calcitriol and taxanes, our group initiated a phase II clinical trial of weekly calcitriol (oral capsules) combined with docetaxel in patients with metastatic AIPC.

Thirty-seven chemotherapy-naïve patients received treatment with oral calcitriol (0.5 µg/kg) on day 1, followed by docetaxel (36 mg/m2) on day 2 delivered weekly on a 6- of 8-week schedule [46]; 81% (95% CI 68–94%) of patients had a confirmed reduction in serum PSA levels by more than half and there were measurable disease responses in eight of 15 patients (53%, 95% CI 27–79%) who had measurable disease. When compared with a single-agent docetaxel treatment regimen, there was no obvious increase in treatment-related toxicity. Furthermore, exploratory analyses found that neither agent affected the pharmacokinetics of its companion. These results encouraged the further development of this combination. As with all single-institution phase II results, these results must be viewed as useful only for generating hypotheses. Such small trials are particularly susceptible to patient selection that can bias the results. Available baseline patient characteristics from this phase II study are shown, for illustrative purposes, next to the baseline characteristics of patients enrolled in the two large randomized trials, the South-west Oncology Group (SWOG) 9916 and TAX327 in Table 1. The patients in the Oregon Health & Science University (OHSU) study appear to be similar to those enrolled in the two large randomized studies.

Table 1.  Baseline characteristics of patients enrolled in the OHSU Calcitriol + Docetaxel Phase II Study, SWOG 9916 and TAX 327
 OHSU StudySWOG 9916TAX 327
  1. NR, not reported.

No. of patients 377701006
Median (range) age, years 73 (46–83) 70 (43–88)  68–69 (36–92)
Eastern Cooperative Oncology
Group performance status, %
 0 or 1 76 89  87
 2 or 3 24 11  13
Median (range) PSA, ng/mL 99 (6–921) 84–90 (0.1–10 820) 108–123
Alkaline phosphatase, U/L127 (41–1304)NRNR
Site of metastases, %
 Bone 91 86  91
 Soft Tissue 40 44  40
N (%) of previous hormonal therapies for prostate cancer
 1  6 (16)NR   8
 2 23 (62)NR  70
 >2  8 (22)NR  23

HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

Commercially available formulations of calcitriol were not designed for cancer therapy, required patients to consume 70–100 capsules at a time, and were associated with considerable inter-patient variability in pharmacokinetics, as well as an apparent absorption ceiling that limited dose escalation. These limitations created the need to develop a high-concentration formulation of calcitriol (DN-101, Novacea, Inc., South San Francisco, CA) specifically for cancer therapy; DN-101 was used in the ASCENT trial.

ASCENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

The ASCENT trial was designed to confirm the phase II findings and provide clinical proof-of-principle for the further development of high-dose calcitriol combined with docetaxel. The ASCENT trial objectives are:

Primary: To evaluate the efficacy of high-dose pulse administration of DN-101 combined with docetaxel as measured by PSA response (>50% PSA reduction, confirmed ≥ 4 weeks later).

Secondary:

To evaluate the effect of DN-101 combined with docetaxel on:

  • • 
    PSA progression-free survival.
  • • 
    Tumour response rate in measurable disease.
  • • 
    Tumour progression-free survival.
  • • 
    Skeletal morbidity-free survival.
  • • 
    Clinical progression-free survival.
  • • 
    Overall survival.

To evaluate the safety and tolerability of DN-101 combined with docetaxel.

ASCENT randomly assigned chemotherapy-naïve patients with metastatic AIPC to treatment with DN-101 (45 µg) or placebo by mouth on day 1, followed by docetaxel 36 mg/m2 i.v. on day 2, with dexamethasone (4 mg oral 12 h before, again 1 h before, and 12 h after docetaxel administration) given weekly for 3 consecutive weeks of a 4-week cycle.

The first dose of docetaxel (week 1, cycle 1) was 27 mg/m2 in each patient. This attenuated dose was chosen to collect additional safety data for the combination of DN-101 with docetaxel. The dose of DN-101 was selected to approximate the actual doses administered in the phase II study that used oral calcitriol and on the basis of the results of a phase I study of weekly DN-101 as a single agent showing that doses of > 45 µg produce grade 2 hypercalcaemia, deemed a dose-limiting toxicity in that trial [47]. Weight-based dosing was not used, in the absence of evidence of a relationship between weight and calcitriol pharmacokinetics.

Treatment on ASCENT continues until disease progression (detected either by PSA level measurements or tumour assessments by imaging), unacceptable toxicity, or patient request. Progression by serum PSA level was defined as a > 25% increase from baseline in patients whose PSA level did not decrease, and of 50% from the nadir value in patients whose PSA level decreased. This increase in PSA level had to be ≥ 5.0 ng/mL, and confirmed by a second measurement, at least 1 week later. This definition was adapted from published consensus criteria [48]. Tumour progression was defined as a 20% increase in the sum of longest diameters of target measurable lesions over the smallest sum observed, or unequivocal progression of unmeasurable disease in the opinion of the treating physician, or appearance of any new lesion/site.

Following the design of the OHSU Phase II study, patients enrolled in ASCENT who reach a confirmed PSA level of ≤ 4.0 ng/mL and meet the criteria for PSA response have the option to continue their treatment in the form of intermittent chemotherapy as previously described [49]. Briefly, treatment is suspended until the PSA level rises by 50% and is ≥ 2 ng/mL, or there is any other evidence of progression, when treatment is resumed. Patients continue regular monitoring during this intermittent-therapy phase. In patients on intermittent treatment, progression during active treatment is required for withdrawal from the study. A schema of the ASCENT trial is shown in Fig. 1.

image

Figure 1. The ASCENT study design.

Download figure to PowerPoint

A sample size of at least 116 patients per treatment group (232 total) was expected to provide 85% power to detect a statistically significant difference between the group receiving the combined regimen of docetaxel plus DN-101 vs docetaxel plus placebo, for the primary efficacy endpoint. In all, 250 patients were accrued to this study. This estimate was based on the assumption that 65% of patients receiving the combined therapy will achieve a PSA response, vs 45% for the single-agent arm. The sample size and power were based on a two-group comparison using an uncorrected chi-square test at a two-sided significance level of α= 0.05. The power for the secondary endpoints is < 80%.

STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES

The strengths of ASCENT are: the trial is well controlled because of the placebo arm and double-blind design; it is robust in its statistical design for its primary endpoint; and it is accrued at many sites across two nations (USA and Canada). The data for ASCENT are collected centrally via an electronic data-collection system, and monitored. To properly interpret ASCENT results and use them to map the further development of calcitriol-based cancer therapy, it is important to also understand its limitations.

ASCENT was designed as a proof-of-concept trial that sought to confirm the findings of a single-institution phase II trial suggesting that adding calcitriol increases the frequency of the PSA response to docetaxel-based chemotherapy. A PSA-based endpoint (50% reduction confirmed by two measurements at least 4 weeks apart) was chosen because it is widely accepted as a tool to screen for activity in clinical trials of AIPC [48], it is easy to assess, and has relatively good reproducibility. This PSA endpoint is useful as a tool to screen for activity but does not directly measure the clinical benefit. At the time ASCENT was designed, no information was available about its utility as a surrogate for clinical benefit. Since then, analyses of SWOG 9916 [50] have shown that PSA level changes after therapy predict survival and satisfy Prentice's criteria for surrogacy [51]; however, change in PSA kinetics rather than a fixed 50% reduction may be a better assessment tool. Further, it is not known if the PSA endpoint is capable of fully capturing the contributions of calcitriol to the clinical activity of docetaxel in AIPC. ASCENT should provide much information about this question. To maximize the value of ASCENT, provisions were made to collect data on a range of clinical endpoints that measure clinical benefit (such as overall survival, or skeletal morbidity-free survival), but ASCENT was not adequately powered to provide definitive information about these endpoints, and it is expected that these results will provide information that will aid in the design of further trials.

The dose and schedule of calcitriol used in ASCENT was selected for several reasons including; (i) the encouraging phase II data seen with similar doses of calcitriol administered using the commercially available formulation (Rocaltrol, Roche Pharmaceuticals, USA) [46]; (ii) the finding in a phase I study of DN-101 as a single agent that doses of > 45 µg administered weekly produce grade 2 hypercalcaemia, deemed a dose-limiting toxicity in that trial [47]; and (iii) the expectation, commonly held at the time ASCENT was designed, that weekly administration is the preferred approach to docetaxel-based therapy for AIPC. Since ASCENT was conceived, Tannock et al.[52] showed that 3-weekly docetaxel plus prednisolone, but not weekly docetaxel plus prednisolone, improved overall survival in AIPC when compared to mitoxantrone plus prednisolone. The dose and schedule of weekly docetaxel used in ASCENT differed from that reported by Tannock et al. [52] and delivered a slightly higher dose intensity (27 vs 25 mg/m2 per week). Nevertheless, the results reported by Tannock et al. raise the question of whether DN-101 should be combined with docetaxel on a 3-weekly schedule. This in turn creates an opportunity for further increasing the dose of DN-101 when administered with docetaxel. As virtually all in vitro studies of calcitriol in prostate cancer show a steep dose-response relationship for both growth inhibition and induction of apoptosis, and significantly higher doses of DN-101 are probably feasible on the 3-weekly schedule, this approach will need to be considered as future studies are developed.

Accrual to ASCENT was completed in January 2004 and initial results are expected in 2005.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PRECLINICAL RATIONALE FOR CALCITRIOL AS A CANCER DRUG
  5. PRECLINICAL RATIONALE FOR COMBINATIONS OF CALCITRIOL WITH OTHER AGENTS
  6. CLINICAL STUDIES THAT LED TO THE DEVELOPMENT OF THE ANDROGEN-INDEPENDENT PROSTATE CANCER (AIPC) STUDY OF CALCITRIOL ENHANCING TAXOTERE (ASCENT) TRIAL
  7. PHASE II EVALUATION OF WEEKLY CALCITRIOL AND DOCETAXEL
  8. HIGHLY CONCENTRATED FORMULATION OF CALCITRIOL
  9. ASCENT
  10. STRENGTHS AND LIMITATIONS OF THE DESIGN OF THE ASCENT TRIAL
  11. CONFLICT OF INTEREST
  12. REFERENCES
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