V O L U M E 2 5 䡠 N U M B E R 6 䡠 F E B R U A R Y 2 0 2 0 0 7
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`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
`Tomasz M. Beer, Christopher W. Ryan, Peter M. Venner, Daniel P. Petrylak, Gurkamal S. Chatta,
`J. Dean Ruether, Charles H. Redfern, Louis Fehrenbacher, Mansoor N. Saleh, David M. Waterhouse,
`Michael A. Carducci, Daniel Vicario, Robert Dreicer, Celestia S. Higano, Frederick R. Ahmann, Kim N. Chi,
`W. David Henner, Alan Arroyo, and Fong W. Clow
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`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 ␮g 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.
`
`J Clin Oncol 25:669-674. © 2007 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Calcitriol (1,25-dihydroxycholecalciferol, 1,25(OH)2-
`D3) is the natural ligand for the vitamin D receptor
`(VDR). This compound, as well as synthetic VDR
`ligands, has been extensively examined using in vitro
`and in vivo models of adenocarcinoma of the
`prostate1-7 and many other neoplasms. These stud-
`ies have indicated significant antitumor activity
`through inhibition of proliferation, induction of ap-
`optosis, and reduction in tumor invasiveness and
`angiogenesis. The antineoplastic activity of VDR li-
`gands is synergistic or additive with the activity of
`
`several classes of agents including cytotoxic chem-
`otherapy drugs, such as paclitaxel,8 docetaxel,9
`platinum compounds,10 and mitoxantrone.11 The
`antineoplastic activity of calcitriol occurs at con-
`centrations of calcitriol that substantially exceed
`the physiologic range, and are achievable with
`intermittent, but not continuous dosing of calcit-
`riol in humans.12-18
`Docetaxel-containing chemotherapy was re-
`cently shown to prolong survival and has become
`the standard of care in metastatic androgen-
`independent prostate cancer (AIPC).19,20 Calcit-
`riol was first combined with docetaxel in a phase
`
`From the Division of Hematology and
`Medical Oncology, Oregon Health &
`Science University, Portland, OR; Columbia
`Presbyterian Medical Center, New York,
`NY; University of Pittsburgh, Pavillion Hell-
`man Cancer Center, Pittsburgh, PA; Sharp
`HealthCare; San Diego Cancer Center,
`Vista; Kaiser Permanente Medical Center,
`Vallejo; Novacea Inc, South San Francisco,
`CA; Georgia Cancer Specialists, Tucker,
`GA; Oncology Hematology Care, Cincinnati;
`The Cleveland Clinic Foundation, Cleveland,
`OH; The Sidney Kimmel Comprehensive
`Cancer Center, Johns Hopkins University,
`Baltimore, MD; Seattle Cancer Care Alli-
`ance, Seattle, WA; University of Arizona
`Cancer Center, Tucson, AZ; Cross Cancer
`Institute, Edmonton; Tom Baker Cancer
`Centre, Calgary, Alberta; and the University
`of British Columbia Cancer Agency,
`Vancouver Centre, Vancouver, British
`Columbia, Canada.
`
`Submitted April 3, 2006; accepted
`November 28, 2006.
`
`Supported by Novacea Inc and sanofi-
`aventis.
`
`Presented in part at the Annual Meet-
`ing of the American Society of Clinical
`Oncology, May 13-17, 2005, Orlando,
`FL; and at the European Cancer Confer-
`ence (ECCO 13), October 30-November
`3, 2005, Paris, France.
`
`Oregon Health & Science University
`(OHSU) and Tomasz M. Beer have a
`significant financial interest in Novacea
`Inc, a company that may have a
`commercial interest in the results of
`this research and technology. This
`potential conflict was reviewed and a
`management plan approved by the
`OHSU conflict of interest in research
`committee and the integrity program
`oversight council was implemented.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Address reprint requests to Tomasz M.
`Beer, MD, Department of Medicine,
`Oregon Health & Science University,
`Mail Code CR-145, 3181 SW Sam
`Jackson Park Rd, Portland, OR 97239;
`e-mail: beert@ohsu.edu.
`
`© 2007 by American Society of Clinical
`Oncology
`
`0732-183X/07/2506-669/$20.00
`
`DOI: 10.1200/JCO.2006.06.8197
`
`Downloaded from jco.ascopubs.org on June 26, 2014. For personal use only. No other uses without permission.
`Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
`
`669
`
`002006
`
`AVENTIS EXHIBIT 2006
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Beer et al
`
`II trial reported by investigators at Oregon Health & Science Uni-
`versity (Portland, OR).21 Prostate-specific antigen (PSA) decline of
`50% or greater was seen in 81% of patients.
`In order to overcome the limitations of previous calcitriol formu-
`lations (nonlinear, variable pharmacokinetics and the very large num-
`ber of capsules required at one time), Novacea Inc (South San
`Francisco, CA) developed DN-101, a high concentration formulation
`of calcitriol specifically designed for use in cancer treatment.22
`AIPC Study of Calcitriol Enhancing Taxotere (ASCENT) is a
`double-blind randomized phase II study to further evaluate the effi-
`cacy and safety of DN-101 (high-dose calcitriol) plus weekly docetaxel
`compared with placebo plus weekly docetaxel in AIPC.
`
`PATIENTS AND METHODS
`
`Eligibility
`Men with histopathologically or cytologically proven metastatic adeno-
`carcinoma of the prostate with evidence of progression (the development of
`new metastatic lesions or rising PSA23) despite standard hormonal manage-
`ment (orchiectomy, gonadotropin-releasing hormone agonist or antagonist
`including withdrawal of antiandrogens, if applicable; 6 weeks for bicalutamide,
`4 weeks for flutamide or nilutamide) were eligible. Other eligibility criteria
`were: serum PSA ⱖ 5.0 ng/mL, serum testosterone level ⱕ 50 ng/dL, Eastern
`Cooperative Oncology Group performance status ⱕ 2, life expectancy ⱖ 3
`months, age ⱖ 18 years, patient agreement to use adequate contraception, and
`patient ability to give informed consent.
`Patients were excluded if they had an active malignancy within 5 years
`(except nonmelanoma skin cancer), significant active medical illness that
`would preclude protocol treatment, a history of hypercalcemia or vitamin D
`toxicity, or hospitalization for treatment of angina, myocardial infarction, or
`congestive heart failure in the previous 12 months. Patients were also excluded
`for kidney stones (calcium salt) within 5 years, hypersensitivity to calcitriol or
`drugs formulated with polysorbate-80, grade 2 or higher peripheral neuropa-
`thy, neutrophil count less than 1,500/mm3, platelet count lower than 100,000/
`mm3, serum creatinine more than upper limit of normal (ULN), serum
`calcium more than ULN (for patients with an albumin lower than 3.0, a
`corrected calcium ⫽ serum calcium ⫹ [0.8][3.5 ⫺ serum albumin] was used),
`conjugated bilirubin more than ULN, alkaline phosphatase more than 4 ⫻
`ULN (patients with known bone involvement and a normal conjugated bili-
`rubin, ALT, and AST were not excluded), ALT or AST more than 2.0 ⫻ ULN
`when alkaline phosphatase is less than 2.5 ⫻ ULN, ALT or AST more than
`1.5 ⫻ ULN when alkaline phosphatase is more than 2.5 ⫻ ULN.
`In addition, patients were excluded for prior investigational therapy or
`use of calcitriol within 30 days, prior chemotherapy for prostate cancer except
`for adjuvant therapy more than 12 months before enrollment, prior chem-
`otherapy with docetaxel, treatment with radiotherapy within 4 weeks or
`treatment with other radiopharmaceuticals within 8 weeks. The study was
`approved by institutional review boards at all participating institutions.
`
`Study End Points and Statistical Design
`The primary objective of this study was to evaluate the proportion of
`patients achieving PSA response (ⱖ 50% PSA reduction, confirmed at least 4
`weeks later) in the two treatment arms. Secondary objectives included overall
`survival, PSA,23 tumor, and clinical progression-free survival, tumor response
`rate in measurable disease, skeletal morbidity-free survival, as well as safety and
`tolerability of the study treatment. Progression by serum PSA was defined by
`consensus criteria.23 Tumor progression was defined by Response Evaluation
`Criteria in Solid Tumors (RECIST) criteria.24 Skeletal morbidity-free survival
`was defined as the time from random assignment to a skeletal-related event or
`death from any cause. Skeletal-related events were defined as pathologic bone
`fracture, spinal cord compression, surgery to the bone, or radiation to the
`bone. Clinical progression was defined as either tumor progression, occur-
`rence of a skeletal-related event, or death from any cause.
`
`The primary analysis for efficacy was on the intention to treat population
`and toxicity was evaluated in the as-treated population. These two populations
`were identical.
`A sample size of at least 116 patients per treatment group was ex-
`pected to provide 85% power to detect a 20% absolute increase in the PSA
`response rate (from 45% to 65%) with a two-sided significance level of .045
`based on a two-group comparison using an uncorrected ␹2 test. The
`significance level of .045 was selected to account for the alpha of .005
`allocated to a planned interim analysis of PSA response rate. The power for
`the secondary end points was lower than 80% and there was no plan for
`correction for multiple comparisons.
`The initial analysis plan underwent two modifications. The first modifi-
`cation was made before any analysis and called for a change in the primary end
`point from PSA response overall to PSA response achieved within 6 months of
`enrollment and for elimination of a planned interim analysis of the primary
`end point. The second modification to the analysis plan was made after the
`analysis of the primary end point and an interim analysis of secondary end
`points and prior to the prespecified final analysis of survival. This modification
`specified that the final analysis of survival was to be performed using multivar-
`iate Cox regression including the known prognostic factors of baseline hemo-
`globin and performance status as covariates. The modified analysis plan also
`included a sensitivity analysis of survival data with unadjusted log-rank test.
`
`Pretreatment Evaluation
`A complete physical examination, history of skeletal-related events, and
`concomitant medications were reviewed. A radionuclide bone scan, com-
`puted tomography scan of the abdomen and pelvis, and radiographs of the
`lateral, thoracic, and lumbar spine were obtained. Pretreatment laboratory
`evaluations included a hematology profile, serum chemistry profile, serum
`lactate dehydrogenase, serum PSA, and a urinalysis.
`
`Random Assignment
`An unstratified random assignment, blocked by center was used to assign
`patients to the DN-101 or placebo groups.
`DN-101 (45 ␮g) or placebo was administered orally on day 1 followed by
`docetaxel 36 mg/m2 intravenously on day 2 along with dexamethasone (4 mg
`orally 12 hours before, 1 hour before, and 12 hours after docetaxel adminis-
`tration). This regimen was administered weekly for 3 consecutive weeks of a
`4-week cycle. For each patient, the first dose of docetaxel (week 1, cycle 1 only)
`was attenuated (27 mg/m2) to collect additional safety data for the combina-
`tion of DN-101 with docetaxel.
`Treatment on ASCENT continued until disease progression (either
`by PSA measurements or tumor assessments by imaging), unacceptable
`toxicity, or patient request. Patients enrolled in ASCENT who reached a
`confirmed PSA ⱕ 4.0 ng/mL and met criteria for PSA response had the
`option to continue their treatment in the form of intermittent chemother-
`apy as previously described.25 Briefly, treatment was suspended until PSA
`rose by 50% and was at least 2 ng/mL or there was other evidence of
`progression, at which time study treatment was resumed. Patients contin-
`ued regular monitoring during this intermittent therapy phase. For pa-
`tients on intermittent treatment, progression during active treatment was
`required for withdrawal from study treatment.
`
`Concomitant Medications
`Primary hormonal therapy with gonadotropin-releasing hormone ago-
`nists or antagonists was maintained during the study. Magnesium-containing
`antacids, bile-resin binders, calcium supplements, ketoconazole and related
`compounds, estrogen-containing compounds and any other hormonal or
`chemotherapeutic agents, radiopharmaceutical or external-beam radiation
`for prostate cancer were not allowed during study treatment. The use of
`bisphosphonates was not restricted.
`
`On Study Evaluations
`Physical examination, assessment of adverse events including skeletal-
`related events, concomitant medications, urinalysis, and serum PSA were
`completed every 4 weeks. In addition, body weight, hematology profile, chem-
`istry profile, and urinalysis (cycles 1 and 2 only) were evaluated weekly on
`treatment visits. A radionuclide bone scan was obtained at the time of PSA
`
`670
`
`JOURNAL OF CLINICAL ONCOLOGY
`Downloaded from jco.ascopubs.org on June 26, 2014. For personal use only. No other uses without permission.
`Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
`
`

`
`High-Dose Calcitriol Plus Docetaxel in AIPC
`
`performance status, extent of disease, serum PSA, and serum lactate
`dehydrogenase. There were no statistically significant differences be-
`tween the two groups in any of these categories.
`Response to Therapy
`PSA decline (⬎ 50% confirmed 4 weeks later) within 6 months of
`enrollment, the primary end point, was reached in 49% of placebo-
`treated patients and 58% of DN-101-treated patients (P ⫽ .16). At any
`time while on study, this end point was achieved in 52% of placebo-
`treated patients and 63% of DN-101-treated patients (P ⫽ .07). Me-
`dian time to PSA response was 5.3 months in placebo-treated patients
`and 2.9 months in DN-101-treated patients (P ⫽ .06). Median dura-
`tion of PSA progression-free survival was 7.6 months for placebo-
`treated patients and 7.9 months for DN-101-treated patients (P ⫽ .7).
`Measurable disease meeting RECIST criteria was present in 59
`of placebo-treated patients (47%) and 48 of DN-101 treated pa-
`tients (38%). Tumor response in this group of patients was seen in
`14 (24%) and 14 (29%) of placebo and DN-101-treated patients,
`respectively (P ⫽ .51). Median duration of tumor progression-free
`survival and median duration of clinical progression-free survival
`could not be reliably assessed due to the lack of regularly scheduled
`tumor imaging for those patients (57%) who entered the study
`without measurable tumor lesions meeting RECIST criteria as
`target lesions and because many of the patients with measurable
`disease were removed from the study due to increases in PSA
`without evidence for objective disease progression.
`Skeletal Morbidity-Free Survival
`Duration of skeletal morbidity-free survival is shown in Figure 1.
`The median duration of skeletal morbidity-free survival trended in
`favor of DN-101 (13.4 months) over placebo (11.9 months; hazard
`ratio [HR], 0.78; 95% CI, 0.57 to 1.074; P ⫽ .13). Forty-five patients in
`the placebo group and 38 patients in the DN-101 group experienced a
`skeletal-related event. The types of skeletal-related events observed in
`the placebo and DN-101 groups were: bone fracture (11 and 14),
`spinal cord compression (6 and 6), surgery to the bone (0 and 1), and
`radiation to the bone (29 and 18). The use of zoledronic acid was
`
`DN-101
`
`Placebo
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`Probability
`
`progression and as clinically indicated. In patients with measurable disease at
`baseline, computed tomography (CT) scans of the abdomen and pelvis were
`obtained every 8 weeks and at the time of PSA progression. In patients with no
`measurable disease at baseline, CT scans of the abdomen and pelvis were
`obtained at the time of PSA progression and as clinically indicated. Radio-
`graphs of the lateral thoracic and lumbar spine were obtained at the time of
`PSA progression and as clinically indicated to assess for skeletal-related events.
`
`RESULTS
`
`Patients
`Two hundred fifty patients were randomly assigned at 48 sites
`between September 2002 and January 2004. At the time of this data
`analysis the median duration of follow-up was 18.3 months, 229
`patients (92%) have completed study treatment and 122 patients
`(49%) have died. All randomly assigned patients were treated and all
`patients are included in the analyses presented here.
`The baseline characteristics of patients are summarized in Table
`1. Briefly, the two groups were well matched with respect to age,
`
`Table 1. Patient Characteristics
`
`Characteristic
`
`Placebo ⫹ Docetaxel DN-101 ⫹ Docetaxel
`
`Randomly assigned, No.
`Age, years
`Median
`Range
`Race, %
`White
`African American
`Other
`ECOG performance status, %
`0
`1
`2
`Site of metastatic disease, %
`Bone
`Any measurable disease
`Lymph nodeⴱ
`Liverⴱ
`PSA, ng/mL
`Median
`Range
`Hemoglobin, g/dL
`Median
`Range
`LDH, U/L
`Median
`Range
`Alkaline phosphatase, U/L
`Median
`Range
`Participated in intermittent
`chemotherapy
`
`125
`
`70
`47-92
`
`84
`10
`6
`
`47
`47
`6
`
`85
`47
`44
`5
`
`91
`5-6,288
`
`12.5
`8.1-15.5
`
`231
`82-1,688†
`
`130
`34-2,025§
`20
`
`125
`
`68
`45-87
`
`80
`13
`7
`
`54
`43
`3
`
`90
`38
`35
`8
`
`123
`4-4,453
`
`12.5
`8.0-15.2
`
`211
`93-3,759‡
`
`211
`36-3,739¶
`25
`
`Abbreviations: DN-101, high-dose oral formulation of calcitriol; ECOG,
`Eastern Cooperative Oncology Group; PSA, prostate-specific antigen; LDH,
`lactate dehydrogenase.
`ⴱSeveral patients had measurable disease in more than one site.
`†n ⫽ 111.
`‡n ⫽ 115
`§n ⫽ 120.
`¶n ⫽ 124.
`
`0
`
`3
`
`6
`
`9
`12
`Months
`
`15
`
`18
`
`21
`
`No. of events/No. at risk
`DN-101
`9/125
`15/115
`Placebo 12/125
`19/111
`
`18/97
`23/92
`
`13/78
`8/67
`
`11/64
`10/59
`
`3/40
`10/44
`
`Fig 1. Kaplan-Meier curves of skeletal morbidity-free survival. DN-101, a new
`high-dose oral formulation of calcitriol.
`
`www.jco.org
`
`671
`
`Downloaded from jco.ascopubs.org on June 26, 2014. For personal use only. No other uses without permission.
`Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Beer et al
`
`DN-101
`
`Placebo
`
`1.00
`
`0.75
`
`0.50
`
`0.25
`
`Probability
`
`0
`
`3
`
`6
`
`9
`12
`Months
`
`15
`
`18
`
`21
`
`No. of events/No. at risk
`DN-101
`3/125
`6/121
`Placebo 4/125
`14/120
`
`14/115
`16/105
`
`12/101
`5/88
`
`7/88
`12/83
`
`6/73
`10/63
`
`Fig 2. Kaplan-Meier curve of overall survival. DN-101, a new high-dose oral
`formulation of calcitriol.
`
`(P ⫽ .065). Adverse effects leading to discontinuation of therapy were
`seen in 28% of placebo-treated patients and 22% of DN-101-treated
`patients. Serious adverse events, generally those requiring hospitaliza-
`tion, were observed in 41% of placebo-treated patients and 27% of
`DN-101-treated patients (P ⫽ .023).
`Grade 3 or 4 hematologic toxicity was uncommon and no pa-
`tients in either arm were diagnosed with neutropenic fever. Among
`the grade 3 or 4 nonhematologic toxicities, the most common were
`fatigue (16% placebo; 8% DN-101), infection (13% placebo; 8% DN-
`101), and hyperglycemia (12% placebo; 6% DN-101). Adverse event
`frequencies are summarized in Table 2.
`Toxicities that might be expected with administration of supra-
`physiologic doses of calcitriol were uncommon with weekly adminis-
`tration of DN-101 except for mild hypercalcemia. There were no grade
`3 or 4 creatinine elevations, hypercalcemia, or renal calculi. Six percent
`of placebo-treated patients and 7% of DN-101-treated patients had
`grade 1 to 2 creatinine elevation, 8% of placebo-treated patients and
`33% of DN-101-treated patients had transient hypercalcemia. All the
`hypercalcemia episodes observed in the DN-101 arm were grade 1 and
`required no intervention, and did not result in dose reduction or delay
`in therapy. In the placebo arm, there was one episode of grade 3
`hypercalcemia and all other episodes of hypercalcemia were grade 1
`and were self-limited. No patients on placebo and one patient on
`DN-101 experienced symptomatic renal calculi.
`Exploratory Analyses of Toxicity
`The observed reduction in serious adverse events in the DN-
`101-treated group prompted exploratory analyses of safety. The
`observed reduction in serious adverse events in the DN-101 treated
`group does not appear to be due to a difference in the docetaxel
`exposure. The DN-101-treated group received a median cumula-
`tive dose of 1,044 mg (range, 64 to 3,586 mg) while the placebo-
`treated group received a median cumulative dose of 1,062 mg
`(range, 43 to 3,686 mg). When expressed as dose of docetaxel per
`body-surface area, the cumulative dose of docetaxel for DN-101-
`treated patients was 524.8 mg/m2 and for placebo-treated patients
`was 506.7 mg/m2. Likewise, the median length of time on study
`
`neither required nor prohibited in ASCENT (Table 2). Eighty-five
`subjects (40 placebo treated; 45 DN-101 treated) received zoledronic
`acid while on study. Among patients who received zoledronic acid, the
`skeletal-related event incidence rate in the DN-101 and placebo group
`was 29% and 40%, respectively. For the 165 subjects who did not
`receive zoledronic acid, the skeletal-related event incidence rate in the
`DN-101 and placebo groups was 31% and 34%, respectively.
`Overall Survival
`The secondary end point of overall survival is shown in Figure 2.
`After adjustment for baseline characteristics of hemoglobin and East-
`ern Cooperative Oncology Group performance status, overall survival
`showed a promising improvement in the DN-101 group over the
`placebo group with a HR of 0.67 (95% CI, 0.45 to 0.97; P ⫽ .04). While
`the median survival in the placebo was 16.4 months, it has not been
`reached in the DN-101 group, but is estimated to be 24.5 months using
`the adjusted HR. Likewise, in a sensitivity analysis, the unadjusted HR
`similarly favored DN-101 (HR, 0.70; 95% CI 0.48 to 1.028; P ⫽ .07).
`Toxicity
`All adverse events are reported regardless of perceived relation-
`ship to treatment. Overall, no increase in toxicity was seen with the
`addition of DN-101 to docetaxel. There were reductions in the fre-
`quency of several classes of adverse events observed in the DN-101-
`treated group. The incidence of any grade 3 or 4 adverse events was
`70% in placebo treated patients and 58% in DN-101 treated patients
`
`Table 2. Toxicity
`
`%
`
`Placebo ⫹
`Docetaxel
`(n ⫽ 125)
`
`Toxicity
`
`Grade 3/4
`
`Hematologic
`Leukopenia
`Neutropenia
`Neutropenic fever
`Anemia
`Thrombocytopenia
`Nonhematologic
`Fatigue
`Infection
`Nausea
`Diarrhea
`Dysgeusia
`Alopecia
`Anorexia
`Peripheral edema
`Constipation
`Nail disorder
`Lacrimation
`Insomnia
`Hyperglycemia
`Dyspnea
`Back pain
`Vomiting
`Arthralgia
`Cough
`Epistaxis
`Asthenia
`
`4
`8
`0
`6
`0
`
`16
`13
`3
`5
`1
`0
`2
`2
`2
`1
`1
`0
`12
`6
`4
`5
`4
`0
`0
`2
`
`All
`
`7
`14
`0
`33
`3
`
`81
`55
`52
`50
`41
`41
`38
`37
`33
`32
`31
`30
`26
`25
`24
`23
`22
`22
`22
`18
`
`DN-101 ⫹
`Docetaxel
`(n ⫽ 125)
`
`Grade 3/4
`
`4
`10
`0
`4
`0
`
`8
`8
`4
`5
`0
`0
`2
`1
`2
`0
`1
`0
`6
`3
`4
`2
`3
`0
`1
`5
`
`All
`
`9
`14
`0
`30
`4
`
`71
`45
`46
`48
`40
`45
`30
`31
`34
`33
`33
`24
`20
`18
`22
`23
`17
`30
`26
`20
`
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`JOURNAL OF CLINICAL ONCOLOGY
`Downloaded from jco.ascopubs.org on June 26, 2014. For personal use only. No other uses without permission.
`Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
`
`

`
`High-Dose Calcitriol Plus Docetaxel in AIPC
`
`treatment was 154 days for the DN-101-treated patients and 155
`days for the placebo-treated patients. There were fewer gastroin-
`testinal (2.4% v 9.6%; P ⫽ .02) and thromboembolic (1.6% v 7.2%;
`P ⫽ .03) serious adverse events in the DN-101 arm as compared
`with the placebo arm. All other categories of serious adverse events
`were balanced between the two groups.
`
`DISCUSSION
`
`ASCENT is the first placebo-controlled randomized study to test
`targeting the VDR for prostate cancer treatment. The addition of
`DN-101 to weekly docetaxel did not produce a statistically significant
`improvement in the PSA response rate. Overall the response rate was
`63% in DN-101-treated patients and 52% for placebo-treated patients
`(P ⫽ .07). In contemplating the meaning of these PSA response data,
`it is worthwhile to consider the limitations of the PSA response as a
`predictor of a survival benefit that have come to light since ASCENT
`was designed. Southwest Oncology Group 9916 investigators showed
`that a 50% reduction in PSA did not satisfy the Prentice criteria for
`surrogacy.26 TAX327 investigators reported that the PSA response rate
`explained approximately half of the observed survival differences.19,27
`ASCENT results are consistent with these observations in so
`far as the apparent survival advantage seen with DN-101 is more
`impressive than the PSA response rates might lead one to expect.
`The addition of DN-101 to docetaxel was associated with a reduc-
`tion in the risk of death by approximately one third. If confirmed in
`a phase III trial, this represents a large difference in this disease
`where randomized studies of 3-weekly docetaxel-based chemother-
`apy, using mitoxantrone and prednisone as control therapy, re-
`ported HRs for death of 0.8 and 0.76.19,20
`The addition of weekly DN-101 to weekly docetaxel was not
`associated with any apparent increase in toxicity. This encouraging
`finding is consistent with the previously reported phase II results from
`Oregon Health & Science University.21 The lack of toxicity attribut-
`able to DN-101 means that treatment assignment was in fact blinded
`to patients and caregivers and therefore increases our confidence in
`the observations made within ASCENT.
`In an exploratory safety analysis, the number of serious gastroin-
`testinal events was reduced in the DN-101 arm (2.4%) as compared
`with the placebo arm (9.6%; P ⫽ .02). Previous epidemiologic inves-
`tigations have established that serum concentrations of vitamin D are
`inversely correlated with the proliferation of the colonic epithelium as
`determined by the crypt index in rectal biopsies of healthy human
`subjects.28 Similar studies in animal models showed that higher levels
`of vitamin D metabolites are associated with reduced proliferation of
`gastrointestinal epithelial cells.29 Therefore, one mechanism by which
`DN-101 might reduce the gastrointestinal toxicity of docetaxel would
`be to induce temporary cell cycle arrest in the rapidly proliferating cells
`of the gastrointestinal tract, rendering them less sensitive to the cyto-
`toxic effects of docetaxel chemotherapy. This hypothesis should be
`tested prospectively in future studies of DN-101.
`The trends favoring DN-101 over placebo with regard to skeletal
`morbidity-free survival are consistent with the hypothesis that more
`effective antineoplastic therapy may result in delay of skeletal-related
`
`events. It is also possible that the observed trends reflect direct effects
`of DN-101 on bone metastases. These hypotheses should also be tested
`prospectively in future studies.
`In summary, the survival difference between the two groups,
`the other efficacy results, and the safety profile of DN-101 seen in
`ASCENT are compelling for further evaluation of this combina-
`tion in AIPC. These results have led to the initiation of a phase III
`study (ASCENT-2) that compares the weekly DN-101 plus weekly
`docetaxel regimen described here to the standard 3-weekly regi-
`men of docetaxel therapy.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`authors or their immediate family members indicated a financial interest.
`No conflict exists for drugs or devices used in a study if they are not being
`evaluated as part of the investigation. For a detailed description of the
`disclosure categories, or for more information about ASCO’s conflict of
`interest policy, please refer to the Author Disclosure Declaration and the
`Disclosures of Potential Conflicts of Interest section in Information
`for Contributors.
`Employment: W. David Henner, Novacea Inc; Alan Arroyo, Novacea
`Inc; Fong W. Clow, Novacea Inc Leadership: N/A Consultant: Tomasz
`M. Beer, Novacea Inc; Daniel P. Petrylak, Novacea Inc, sanofi-aventis;
`Gurkamal S. Chatta, sanofi-aventis, Novacea Inc; Michael A. Carducci,
`Novacea Inc; Frederick R. Ahmann, sanofi-aventis; Kim N. Chi, Novacea
`Inc Stock: Tomasz M. Beer, Novacea Inc; W. David Henner, Novacea
`Inc; Alan Arroyo, Novacea Inc; Fong W. Clow, Novacea Inc Honoraria:
`Daniel P. Petrylak, Novacea, Inc, sanofi-aventis; Gurkamal S. Chatta,
`sanofi-aventis; Michael A. Carducci, sanofi-aventis; Robert Dreicer,
`sanofi-aventis; Frederick R. Ahmann, sanofi-aventis Research Funds:
`Peter M. Venner, Novacea Inc; Daniel P. Petrylak, Novacea Inc; Charles
`H. Redfern, Novacea Inc Testimony: N/A Other: N/A
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Tomasz M. Beer
`Administrative support: Alan Arroyo
`Provision of study materials or patients: Christopher W. Ryan, Peter M.
`Venner, Daniel P. Petrylak, Gurkamal S. Chatta, J. Dean Ruether,
`Charles H. Redfern, Louis Fehrenbacher, Mansoor N. Saleh, David M.
`Waterhouse, Michael A. Carducci, Daniel Vicario, Robert Dreicer,
`Celestia S. Higano, Frederick R. Ahmann, Kim N. Chi
`Collection and assembly of data: Christopher W. Ryan, Peter M.
`Venner, Daniel P. Petrylak, Gurkamal S. Chatta, J. Dean Ruether,
`Charles H. Redfern, Louis Fehrenbacher, Mansoor N. Saleh, David M.
`Waterhouse, Michael A. Carducci, Daniel Vicario, Robert Dreicer,
`Celestia S. Higano, Frederick R. Ahmann, Kim N. Chi, W. David
`Henner, Alan Arroyo
`Data analysis and interpretation: Tomasz M. Beer, W. David Henner,
`Fong W. Clow
`Manuscript writing: Tomasz M. Beer, Christopher W. Ryan, W. David
`Henner
`Final approval of manuscript: Tomasz M. Beer, Christopher W. Ryan,
`Peter M. Venner, Daniel P. Petrylak, Gurkamal S. Chatta, J. Dean
`Ruether, Charles H. Redfern, Louis Fehrenbacher, Mansoor N. Saleh,
`David M. Waterhouse, Michael A. Carducci, Daniel Vicario, Robert
`Dreicer, Celestia S. Higano, Frederick R. Ahmann, Kim N. Chi, W. David
`Henner, Alan Arroyo, Fong W. Clow
`
`www.jco.org
`
`673
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`Downloaded from jco.ascopubs.org on June 26, 2014. For personal use only. No other uses without permission.
`Copyright © 2007 American Society of Clinical Oncology. All rights reserved.
`
`

`
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