Quality of Life of Prostate Cancer Survivors Participating in a Remotely Delivered Web-Based Behavioral Intervention Pilot Randomized Trial.

BACKGROUND: Following a prostate cancer (PC) diagnosis, treatment-related symptoms may result in diminished quality of life (QoL). Improved diet and increased exercise may improve QoL in men with PC. METHODS: We conducted a 4-arm pilot randomized trial to assess feasibility and acceptability of a 3-month web-based diet and exercise intervention, among men (>18 years of age) with PC (reported elsewhere). The purpose of this study is to describe the change in QoL measured by surveys (eg, QLQ-C30, PROMIS Fatigue) at enrollment and following the intervention. Men were randomized 1:1:1:1 to increasing levels of web-based behavioral support: Level 1: website; Level 2: Level 1 plus personalized diet and exercise prescription; Level 3: Levels 1-2 plus Fitbit and text messages; Level 4: Levels 1-3 plus 2 30-minute coaching calls. T-tests were used to compare pre-post change in mean QoL scores between each Level and Level 1. RESULTS: Two hundred and two men consented and were randomized (n = 49, 51, 50, 52 for Levels 1-4, respectively). Men were predominantly white (93%), with a median age of 70 years (Intra-quartile Range [IQR]: 65,75) and 3 years (IQR: 1,9) post primary treatment for mostly localized disease (74% with T1-2). There were no meaningful changes in QoL, but there were notable trends. Level 3 participants had small improvements in QLQ-C30 Global Health (5.46; 95% CI: -0.02, 10.95) compared to Level 1. In contrast, Level 2 participants trended toward decreasing Global QoL (-2.31, 95% CI: -8.05, 3.42), which may reflect declines in function (eg, Cognitive: -6.94, 95% CI: -13.76, -0.13) and higher symptom burden (eg, Diarrhea: 4.63, 95% CI: -1.48, 10.74). CONCLUSIONS: This short, web-based intervention did not appear to have an impact on PC survivors' QoL. Most men were several years past treatment for localized disease; the potential for this approach to reduce symptoms and improve QoL in men who have worse health may still be warranted.

Protocol for GET FIT Prostate: a randomized, controlled trial of group exercise training for fall prevention and functional improvements during and after treatment for prostate cancer.

BACKGROUND: Many prostate cancer survivors are treated with androgen deprivation therapy (ADT), but these therapies may increase frailty, worsen physical functioning, and increase fall risk. While exercise may counter functional declines associated with ADT, no studies have tested whether and which type of exercise may reduce falls and frailty. The purpose of this trial is to compare the relative efficacy of strength training versus tai ji quan training against each other and to a stretching control group on falls, frailty, and physical functioning in men expose to ADT for prostate cancer. METHODS: Prostate cancer survivors treated with ADT (N = 360) who have fallen in the past year or are at risk of a fall based on validated risk factors will be recruited to participate in this single-blind, parallel group, randomized trial. Participants will be randomized to one of three supervised, group training programs: (i) strength training, (ii) tai ji quan training, or (iii) stretching (control), that train 3×/week for 6 months. Outcomes are assessed at baseline, 3 (mid-intervention), 6 (immediately post-intervention), and 12 (follow-up) months. The primary outcome is falls assessed by monthly self-report. Secondary outcomes include the following: frailty (low lean body mass (by bioelectrical impedance analysis), exhaustion (by SF-36 vitality scale), low activity (by CHAMPS physical activity survey), slowness (by 4 m usual walk speed), and weakness (by chair stand time)); objective and subjective measures of physical function will also be collected. Negative binomial regression models will be used to assess differences in falls between groups, while mixed effects modeling will be used to compare the relative efficacy of training group on secondary outcomes. DISCUSSION: Exercise represents a non-pharmacologic approach to mitigate the problem of falls experienced among men treated with ADT. By engaging in appropriate exercise, men may be able to avoid or delay falls, frailty, and disability associated with their cancer treatment. Findings of the trial are expected to inform clinical practice about how exercise could be prescribed as part of cancer care for prostate cancer survivors prescribed ADT. TRIAL REGISTRATION: ClinicalTrials.gov NCT03741335 . Registered on November 18, 2018.

Management of Anticoagulation in Patients With Prostate Cancer Receiving Enzalutamide.

Enzalutamide, a novel, oral androgen receptor antagonist used for the treatment of metastatic, castration-resistant prostate cancer, has been shown to improve overall and progression-free survival, prolong time to initiation of chemotherapy, reduce skeletal-related events, and carry a favorable adverse effect profile. Metastatic prostate cancer is a disease of older men, a population with an increased incidence of medical comorbidities warranting anticoagulation. Prostate cancer itself, along with some of its therapies, is also prothrombotic. Enzalutamide interacts with several anticoagulants through various mechanisms, making their concurrent use clinically challenging. As such, complex decisions about anticoagulation in these patients are frequently encountered by treating physicians. In this review, we describe the potential interactions between enzalutamide and various anticoagulants, and suggest management paradigms based on the current body of knowledge for patients with atrial fibrillation, venous thromboembolism, and mechanical heart valves.

Effects of ω-3 Fatty Acids and Catechins on Fatty Acid Synthase in the Prostate: A Randomized Controlled Trial.

Animal and human studies suggest fish oil and green tea may have protective effect on prostate cancer. Fatty acid synthase (FAS) has been hypothesized to be linked to chemoprotective effects of both compounds. This study evaluated the independent and joint effects of fish oil (FO) and green tea supplement (epigallocatechin-3-gallate, EGCG) on FAS and Ki-67 levels in prostate tissue. Through a double-blinded, randomized controlled trial with 2 × 2 factorial design, 89 men scheduled for repeat prostate biopsy following an initial negative prostate biopsy were randomized into either FO alone (1.9 g DHA + EPA/day), EGCG alone (600 mg/day), a combination of FO and EGCG, or placebo. We used linear mixed-effects models to test the differences of prostate tissue FAS and Ki-67 by immunohistochemistry between pre- and post-intervention within each group, as well as between treatment groups. Results did not show significant difference among treatment groups in pre-to-post-intervention changes of FAS (P = 0.69) or Ki-67 (P = 0.26). Comparing placebo group with any of the treatment groups, we did not find significant difference in FAS or Ki-67 changes (all P > 0.05). Results indicate FO or EGCG supplementation for a short duration may not be sufficient to produce biologically meaningful changes in FAS or Ki-67 levels in prostate tissue.

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer.

INTRODUCTION: Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. PURPOSE: Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. METHODS: We treated 20 patients who had recurrent prostate cancer with 200 µmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50% PSA declines, the primary endpoint. Only one subject experienced a ≥50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. CONCLUSIONS: Treatment with 200 µmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent.

Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure.

PURPOSE: Contemporary tumor-directed therapies for metastatic castration-resistant prostate cancer (mCRPC) are approved to prolong life, but their effects on symptoms such as pain are less well understood as a result of the lack of analytically valid assessments of pain prevalence and severity, clinically meaningful definitions of therapeutic benefit, and methodologic standards of trial conduct. This study establishes pain characteristics in the mCRPC population using a PRO measure. MATERIALS AND METHODS: Patients with prostate cancer participated in an anonymous survey at five US comprehensive cancer centers in the Prostate Cancer Clinical Trials Consortium that incorporated the Brief Pain Inventory (BPI), analgesic use, and interference with daily activities. Prevalence and severity of cancer-related pain and analgesic use were tabulated according to castration-resistant status and exposure to docetaxel chemotherapy. RESULTS: Four hundred sixty-one patients with prostate cancer participated, of whom 147 had mCRPC involving bone (61% [89 of 147] docetaxel exposed, 39% [58 of 147] docetaxel naive). Pain of any level was more common among docetaxel-exposed versus docetaxel-naive patients with mCRPC (70% [62 of 89] v 38% [22 of 58], respectively; P<.001). BPI score≥4 was reported by 38% (34 of 89) of docetaxel-pretreated and 24% (14 of 58) of docetaxel-naive patients with mCRPC; 40% of these patients with pain intensity≥4 reported no current narcotic analgesic. CONCLUSION: Pain prevalence and severity were higher in patients with prior docetaxel exposure. Analgesics were underutilized. These results provide a method for estimating accruals along the disease continuum, and for enabling design of trials appropriately powered to assess pain.

A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naïve prostate cancer.

OBJECTIVE: ATN-224 (choline tetrathiomolybdate) is an oral Cu(2+)/Zn(2+)-superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose-levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naïve prostate cancer. METHODS: Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) < 12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels > 150 ng/dl) were eligible. ATN-224 was administered at 2 dose-levels, 300 mg (n = 23) or 30 mg (n = 24) daily, by way of randomization. PSA progression was defined as a ≥ 50% increase (and >5 ng/ml) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the 2 treatment groups. RESULTS: At 24 weeks, 59% (95% CI 33%-82%) of men in the low-dose arm and 45% (95% CI 17%-77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21-40(+)) and 26 weeks (95% CI 24-39(+)) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (P = 0.006) and a significant mean PSADT increase (P = 0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes. CONCLUSIONS: Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient population remains uncertain. The absence of a dose-response effect also reduces enthusiasm, and there are currently no plans to further develop this agent in prostate cancer.

Prostate cancer and vitamin D: what does the evidence really suggest?

The optimal approach to vitamin D supplementation for the average healthy person is debatable. In patients with cancer, the role of vitamin D supplementation, possibly in treatment, is even less clear. Vitamin D is shown to play a role in prostate cancer biology; however, the clinical data have not consistently demonstrated a link. Additional studies are needed to determine if higher doses of vitamin D supplements could benefit selected populations (ie, the elderly or patients with cancer) even if they may not be beneficial for the general population.

Acupuncture for hot flashes in patients with prostate cancer.

OBJECTIVES: To determine the effect of acupuncture on hot flash frequency and intensity, quality of life, and sleep quality in patients undergoing hormonal therapy for prostate cancer. Hot flashes are a common adverse effect of hormonal therapy for prostate cancer. METHODS: Men who had a hot flash score > 4 who were receiving androgen deprivation therapy for prostate cancer underwent acupuncture with electrostimulation biweekly for 4 weeks, then weekly for 6 weeks, using a predefined treatment plan. The primary endpoint was a 50% reduction in the hot flash score after 4 weeks of therapy, calculated from the patients' daily hot flash diaries. The hot flash-related quality of life and sleep quality and biomarkers potentially related to hot flashes, including serotonin, calcitonin gene-related peptide, and urinary 5-hydroxyindoleacetic acid, were examined. RESULTS: A total of 25 men were enrolled from September 2003 to April 2007. Of these, 22 were eligible and evaluable. After 4 weeks, 9 (41%, 95% confidence interval 21%-64%) of 22 patients had had a > 50% reduction in the hot flash score. Of the 22 patients, 12 (55%, 95% confidence interval 32%-76%) met this response definition at any point during the therapy course. No patient had a significant increase in hot flash score during therapy. A reduced hot flash score was associated with improvement in the hot flash-related quality of life and sleep quality. CONCLUSIONS: Multiple placebo-controlled trials have demonstrated a 25% response rate to placebo treatment for hot flashes. Of the 22 patients, 41% had responded by week 4 and 55% overall in the present pilot study, providing evidence of a potentially meaningful benefit. Additional studies of acupuncture for hot flashes in this population are warranted.

A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer.

OBJECTIVE: To evaluate the preliminary efficacy, safety, and impact on quality of life (QoL) of high-dose calcitriol (DN-101) combined with mitoxantrone and glucocorticoids in androgen-independent prostate cancer (AIPC). PATIENTS AND METHODS: Nineteen patients with metastatic AIPC and no previous chemotherapy received DN-101 180 microg orally on day 1 and mitoxantrone 12 mg/m(2) intravenously on day 2 every 21 days with continuous daily prednisone 10 mg orally for a maximum of 12 cycles. A confirmed decline in prostate-specific antigen (PSA) levels by half was the primary endpoint. QoL was evaluated using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire, and pain and analgesic use were evaluated. RESULTS: Five of 19 patients (26%; 95% confidence interval, CI, 9-51) achieved a >/=50% decline in PSA level. The median (95% CI) time to PSA progression was 16 (6-26) weeks. The overall median (95% CI) survival was 16 (6-26) months; 47 (21-73)% of patients achieved an analgesic response. Toxicity was similar to that expected with mitoxantrone and prednisone alone. The QoL analysis suggested a decrease in physical functioning and increase in fatigue, insomnia, and diarrhoea. CONCLUSIONS: DN-101 given every 3 weeks does not add significant activity to mitoxantrone and prednisone in AIPC, as measured by the PSA decline. The high rate of analgesic response is encouraging. The addition of DN-101 does not appear to increase the toxicity of mitoxantrone.

The iroquois homeobox gene 5 is regulated by 1,25-dihydroxyvitamin D3 in human prostate cancer and regulates apoptosis and the cell cycle in LNCaP prostate cancer cells.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the most active metabolite of vitamin D3, has significant antitumor activity in a broad range of preclinical models of cancer. In this study, we show that the Iroquois homeobox gene 5 (Irx5) is down-regulated by 1,25(OH)2D3 in human prostate cancer samples from patients randomly assigned to receive weekly high-dose 1,25(OH)2D3 or placebo before radical prostatectomy. Down-regulation of Irx5 by 1,25(OH)2D3 was also shown in the human androgen-sensitive prostate cancer cell line LNCaP and in estrogen-sensitive MCF-7 breast cancer cells. Knockdown of Irx5 by RNA interference showed a significant reduction in LNCaP cell viability, which was accompanied by an increase in p21 protein expression, G2-M arrest, and an increase in apoptosis. The induced apoptosis was partially mediated by p53, and p53 protein expression was increased as a result of Irx5 knockdown. Cell survival was similarly reduced by Irx5 knockdown in the colon cancer cell line HCT 116 and in MCF-7 breast cancer cells, each being derived from clinical tumor types that seem to be inhibited by 1,25(OH)2D3. Overexpression of Irx5 led to a reduction of p21 and p53 expression. This is the first report that Irx5 is regulated by 1,25(OH)2D3 in humans and the first report to show that Irx5 is involved in the regulation of both the cell cycle and apoptosis in human prostate cancer cells. Irx5 may be a promising new therapeutic target in cancer treatment.

C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial.

BACKGROUND: Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen-independent prostate cancer (AIPC) who are initiating docetaxel-based chemotherapy. METHODS: Baseline plasma samples were stored (-80 degrees C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo-controlled trial comparing weekly docetaxel plus high-dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate-specific antigen (PSA) decline. RESULTS: C-reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20-1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52-5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60-0.92 [P = .007]). CONCLUSIONS.: Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel-based therapy.

Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel.

BACKGROUND: Survival in patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer (AIPC) is improved with 10 to 12 cycles of docetaxel-containing chemotherapy but further management is undefined. In the current study, the authors examined retreatment with the same regimen after a treatment holiday. METHODS: Patients treated with docetaxel at a dose of 36 mg/m(2) plus either high-dose calcitriol (DN-101; 45 mug) or placebo administered weekly for 3 of every 4 weeks could suspend treatment if their serum prostate-specific antigen (PSA) level was reduced >or=50% and reached a level or=50% and was >or=2 ng/mL or when there was other evidence of disease progression. The study was not powered to compare treatment holiday outcomes between the 2 arms. RESULTS: A total of 250 patients were randomized 1:1. Overall, 18% of patients (20% in the high-dose calcitriol group and 16% in the placebo group) entered the intermittent chemotherapy arm. The median duration of the first chemotherapy holiday was 18 weeks (range, 4%70 weeks). On resumption of treatment after the first holiday, 45.5% of evaluable patients responded with a >or=50% reduction in serum PSA from their postholiday baseline, 45.5% met the criteria for stable PSA for at least 12 weeks, and 9.1% of patients developed disease progression. CONCLUSIONS: To the authors' knowledge, the current study is the first report of intermittent chemotherapy in patients with AIPC who were prospectively tested in a large multi-institutional trial. This strategy results in a clinically significant duration of chemotherapy holidays and can be offered to a minority of patients. At the time of retreatment, the majority of patients again respond to treatment or their PSA levels stabilized. Additional studies of intermittent chemotherapy are needed to better characterize the optimal patient population and the optimal approach.

Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: a phase II study of the Southwest Oncology Group.

PURPOSE: This phase II study evaluated the activity of combined treatment with interferon alfa-2b and sorafenib, a Raf and multiple receptor tyrosine kinase inhibitor, in patients with advanced renal carcinoma. PATIENTS AND METHODS: Eligible patients had metastatic or unresectable renal carcinoma with a clear-cell component, no prior systemic therapy, performance status 0 to 1, and measurable disease. Treatment consisted of interferon alfa-2b 10 x 10(6) U subcutaneously three times weekly and sorafenib 400 mg orally bid. The primary end point was confirmed Response Evaluation Criteria in Solid Tumors response rate. RESULTS: Twelve (19%) of 62 assessable patients achieved an objective confirmed response. An additional 31 (50%) had an unconfirmed partial response or stable disease as best response. The median progression-free survival was 7 months (95% CI, 4 to 11 months). The most common adverse events were fatigue, anorexia, anemia, diarrhea, nausea, rigors/chills, leukopenia, fever, and transaminase elevation. Von Hippel-Lindau gene mutations were detected in four (22%) of 18 archival tumor specimens. CONCLUSION: The confirmed response rate for the combination of sorafenib and interferon in advanced renal carcinoma is greater than expected with either interferon or sorafenib alone. The toxicity of this combination is dominated by adverse events common to interferon that limit further development of this regimen.

Lifestyle factors and duration of androgen deprivation affect bone mineral density of patients with prostate cancer during first year of therapy.

OBJECTIVES: Androgen deprivation therapy (ADT) is associated with loss of bone mineral density (BMD) and increased fracture risk. We sought to examine the impact of ADT and lifestyle variables on BMD in 120 patients with prostate cancer without bone metastases entering a randomized clinical trial. METHODS: A total of 120 patients with prostate cancer and without bone metastases who had been treated with ADT for less than 12 months were enrolled in a clinical trial of zoledronic acid versus placebo. BMD measurements of the femoral neck, total hip, and lumbar spine were obtained before starting the study treatment by dual energy x-ray absorptiometry. The subjects answered a questionnaire regarding possible osteoporosis risk factors, including dairy product use, caffeinated beverage use, smoking history, alcohol intake, calcium/vitamin D supplementation, thyroid medication, and exercise. RESULTS: The median duration of ADT was 3 months (range 0 to 12). Osteopenia or osteoporosis (T score of less than -1) was detected in two thirds of the subjects at one or more measured sites. The mean baseline BMD Z scores were femoral neck -0.091 +/- 0.959, total hip 0.122 +/- 1.005, and lumbar spine 0.657 +/- 1.789. On multiple linear regression analysis, the duration of ADT was negatively associated with the Z score at all three sites and the body mass index, calcium/vitamin D supplementation, and alcohol use were positively associated with the Z score. CONCLUSIONS: BMD loss is a function of the duration of ADT during the first year of therapy. The body mass index, calcium/vitamin D supplementation, and alcohol use were associated with greater BMD, even after controlling for ADT exposure.

Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators.

PURPOSE: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel. PATIENTS AND METHODS: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. RESULTS: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%). CONCLUSION: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer.

BACKGROUND: DN-101 is a new, high-dose, oral formulation of calcitriol under investigation for the treatment of cancer. We sought to evaluate the tolerability and pharmacokinetics (PK) of weekly doses of DN-101 in patients with advanced cancer. METHODS: Patients who completed a previously reported single dose escalation study of DN-101 [Beer et al. (2005) Clin Cancer Res 11:7794-7799] were eligible for this continuation weekly dosing study. Cohorts of 3-10 patients were treated at doses of 15, 30, 45, 60, and 75 microg calcitriol. Once 45 microg was established as the maximum tolerated dose (MTD), this cohort was expanded to include 18 patients. Dose limiting toxicity (DLT) was defined as > or =grade 2 hypercalcemia or > or =grade 3 persistent treatment-related toxicities. RESULTS: Thirty-seven patients were recruited. DLT of transient reversible grade 2 hypercalcemia (serum calcium of 11.6-12.5 mg/dL) occurred in two of six patients treated with 60 microg of DN-101. No DLT was observed in the 18 patients who received DN-101 weekly at 45 microg. Overall, DN-101 was well tolerated. The most frequent adverse events were fatigue (27%), hypercalcemia (19%, including five grade 1, two grade 2, and no grade 3 or 4 events), and grade 1 nausea (16%). PK parameters following repeat dosing were comparable to those for the initial dose (n = 4). CONCLUSION: The MTD for weekly DN-101 was established as 45 mug. The DLTs observed were two episodes of rapidly reversible grade 2 hypercalcemia in two of the six patients treated at 60 microg weekly. Repeat doses of DN-101 at 45 microg weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients.

High dose calcitriol may reduce thrombosis in cancer patients.

The incidence of venous and arterial thrombosis in a placebo-controlled randomised trial of DN-101 (high dose calcitriol) with docetaxel versus docetaxel was compared. Of the 13 thrombotic events observed in the 250 patients enroled in this study, two occurred in DN-101 and 11 in placebo-treated patients (P = 0.01). This difference remained significant after adjustment for baseline history of thrombosis, atrial fibrillation and use of anti-thrombotic agents. In vitro and vitamin D receptor (VDR) knockout mouse studies predict that nanomolar concentrations of calcitriol may act as an antithrombotic agent. We report the first clinical observation that supports this hypothesis in humans.

Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of calcitriol, in patients with cancer.

BACKGROUND: Intermittent administration allows substantial dose escalation of calcitriol but limited bioavailability of the commercially available formulations at high doses is limiting. In this dose escalation study, we sought to evaluate the tolerability and pharmacokinetics of a single oral dose of DN-101, a high-dose calcitriol formulation. METHODS: DN-101 doses were escalated in sequential groups of three to six patients with advanced solid tumors. Dose-limiting toxicity was defined as grade > or =2 hypercalcemia or grade > or =3 persistent treatment-related toxicities. Single-dose administration of 15, 30, 60, 75, 90, 105, 135, and 165 mug was tested. RESULTS: Thirty-eight patients were enrolled in 2002 and 2003. The median age was 70 years (range, 44-91 years). Dose escalation was stopped at the 165 microg level when the number of capsules required at one time reached 11. No dose-limiting toxicities occurred. Transient and self-limited grade 3 toxicities were hyponatremia (2) and proteinuria (1). A dose-proportional increase in peak concentration (C(max)) and area under the concentration curve (AUC) was seen across the full range of DN-101 doses tested. At the 165 microg dose, C(max) was 6.21 +/- 1.99 ng/mL, AUC(0-24) was 41.3 +/- 9.77 ng h/mL, AUC(0-infinity) was 55.4 +/- 8.44, and half-life (T(1/2)) was 16.2 hours. CONCLUSIONS: At doses between 15 and 165 microg, DN-101 exhibits linear pharmacokinetics. At 165 microg, DN-101 achieves systemic exposure that is 5- to 8-fold higher than that achieved with commercial formulations of calcitriol, which makes DN-101 comparable to that required for antitumor activity in vivo in a murine squamous cell carcinoma model.

High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study.

PURPOSE: We determined the safety and preliminary efficacy of the combination of high dose pulse calcitriol (1,25-dihydroxycholecalciferol) with a standard regimen of docetaxel plus estramustine in patients with metastatic androgen independent prostate cancer. MATERIALS AND METHODS: Patients were treated with 60 microg calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m docetaxel on day 2 (70 mg/m after cycle 1) every 21 days for up to 12 cycles. Patients also received 325 mg aspirin and 1 or 2 mg warfarin orally daily. Regimen safety was assessed in the first 6 patients and a dose de-escalation scheme for calcitriol was planned if dose limiting toxicities were noted during treatment cycle 1 in greater than a third of patients. RESULTS: A total of 24 patients, including 11 who were chemotherapy naïve and 13 who had previously been treated with docetaxel, were evaluable for toxicity and 22 for prostate specific antigen decrease data. The regimen was generally well tolerated. Treatment related grades 3 or greater toxicity seen in more than 1 patient included hypophosphatemia in 16.7% and neutropenia in 12.5%. Four patients had thromboembolic complications. Asymptomatic hypercalcemia was seen in 4 patients, including grades 2 and 1 in 1 and 3, respectively. Six of 11 evaluable, chemotherapy naïve patients (55%) met prostate specific antigen response criteria. One of 11 patients (9%) treated with prior docetaxel met these criteria. CONCLUSIONS: High dose calcitriol may be safely added to docetaxel and estramustine administered on a 21-day schedule.