2136
`
`Phase II Trial of High-Dose, Intermittent Calcitriol
`(1,25 Dihydroxyvitamin D3) and Dexamethasone in
`Androgen-Independent Prostate Cancer
`
`1
`
`2
`
`Donald L. Trump, M.D.
`Douglas M. Potter, Ph.D.
`Josephia Muindi, M.D., Ph.D.
`2
`Adam Brufsky, M.D., Ph.D.
`Candace S. Johnson, Ph.D.
`
`1
`
`3
`
`1 Department of Medicine, Roswell Park Cancer
`Institute, Buffalo, New York.
`
`2 University of Pittsburgh Cancer Institute, Univer-
`sity of Pittsburgh, Pittsburgh, Pennsylvania.
`
`3 Department of Pharmacology and Therapeutics,
`Roswell Park Cancer Institute, Buffalo, New York.
`
`Supported by grants CA85142, CA95045, and
`CA67267 from the National Cancer Institute, and
`CaPCURE.
`
`Dr. Trump has received research support from
`Novacea Pharmaceuticals, Abbott, Aventis, and
`AstraZeneca.
`
`Drs. Trump and Johnson are patent coholders in
`the use of high-dose intermittent
`therapy with
`calcitriol and chemotherapy. The patent is held by
`the University of Pittsburgh and licensed to Novo-
`cea.
`
`The authors thank Ms. Christine Wick for tireless
`and precise assistance with the preparation of the
`article.
`
`Address for reprints: Donald L. Trump, M.D.,
`Department of Medicine, Roswell Park Cancer
`Institute, Elm and Carlton Streets, Buffalo,
`NY 14263;
`Fax:
`(716) 845-3423; E-mail:
`donald.trump@roswellpark.org
`
`Received August 10 2005; revision received De-
`cember 14 2005; accepted January 6 2006.
`
`BACKGROUND. Data suggest that vitamin D plays a role in the treatment and
`prevention of prostate cancer. The combination of high-dose, intermittent calcit-
`
`riol (1,25 dihydroxyvitamin D3) plus dexamethasone was studied based on evi-
`
`dence that dexamethasone potentiates the antitumor effects of calcitriol and
`
`ameliorates hypercalcemia.
`METHODS. Oral calcitriol was administered weekly, Monday, Tuesday, and
`Wednesday (MTW), at a dose of 8 ␮g, for 1 month, at a dose of 10 ␮g every MTW
`
`for 1 month, and at a dose of 12 ␮g every MTW thereafter. Dexamethasone at a
`
`dose of 4 mg was administered each Sunday, and MTW weekly. Calcium and
`
`creatinine were determined weekly and radiographs of the urinary tract were
`
`performed every 3 months. All patients were considered evaluable for toxicity.
`RESULTS. Forty-three men with androgen-independent prostate cancer were en-
`tered; 37 received at least 1 month of calcitriol given at a dose of 12 ␮g every day
`
`⫻ 3 per week. The majority of patients had bone metastases and rising prostate-
`
`specific antigen (PSA) levels. All had an Eastern Cooperative Oncology Group
`
`performance status of 0 or 1. Eight patients (19%) experienced partial responses by
`
`PSA criterion (PSA decline of ⱖ50%, persisting for ⱖ28 days). Subjective clinical
`
`improvement occurred in some patients. Toxicity was minimal: urinary tract
`
`stones in 2 patients; and a readily reversible, CTC (v.3.0) Grade ⬍2 creatinine
`
`increase in 4 patients. Throughout the study only 4 patients ever had a serum
`
`calcium level ⬎11.0 mg/dL and no patient had a calcium level ⬎12.0 mg/dL.
`CONCLUSIONS. The response rate reported in the current study (19%) was not
`found to be clearly higher than expected with dexamethasone alone. High-dose
`
`intermittent calcitriol plus dexamethasone appears to be safe, feasible, and has
`
`antitumor activity. Cancer 2006;106:2136 – 42. © 2006 American Cancer Society.
`
`KEYWORDS: calcitriol, prostate cancer, dexamethasone, Phase II trial.
`
`1,25 Dihydroxycholecalciferol (calcitriol), the most potent vitamin D
`compound, is a central factor in bone and mineral metabolism and is
`also antiproliferative in many malignant cell types.1–10 Calcitriol has
`significant antitumor activity in vitro and in vivo in murine squamous
`cell carcinoma (SCC); human xenograft prostatic adenocarcinoma
`(PC-3); rat metastatic prostatic adenocarcinoma Dunning (MLL)
`model systems; and human breast, colon, and pancreatic cancer, as
`well as leukemia, myeloma, and lymphoma lines.3–7,9,11 Calcitriol
`induces G0/G1 arrest and modulates p27Kipl and p21Waf1/Cipl.4,12–14
`Calcitriol also induces cleavage of caspase 3, polyadenyl ribose 6
`phosphate (PARP), and the growth-promoting/prosurvival signaling
`molecule mitogen-activated protein kinase (MEK) in a caspase-de-
`pendent manner.9,11 In association with these effects, full-length MEK
`
`© 2006 American Cancer Society
`DOI 10.1002/cncr.21890
`Published online 5 April 2006 in Wiley InterScience (www.interscience.wiley.com).
`
`Amerigen Exhibit 1124
`Amerigen v. Janssen IPR2016-00286
`
`

`
`and phospho-Erk (P-Erk) are lost. Calcitriol inhibits
`the phosphorylation and expression of Akt, a kinase
`regulating an important cell survival pathway. In
`contrast to changes that occur during cytotoxic drug-
`induced apoptosis, the proapoptotic signaling mole-
`cule MEKK-1 is significantly up-regulated by calcit-
`riol.9
`We have demonstrated that dexamethasone po-
`tentiates the antitumor effect of calcitriol and de-
`creases calcitriol-induced hypercalcemia.13,14 Both in
`vitro and in vivo, dexamethasone significantly in-
`creases vitamin D receptor (VDR) ligand binding in
`the tumor, while decreasing binding in intestinal mu-
`cosa, the site of calcium absorption.13–15 Phospho-Erk
`(P-Erk) and phospho-Akt (P-Akt) are also decreased
`more with the combination of calcitriol and dexa-
`methasone than with either agent alone.14
`These preclinical data in conjunction with the
`considerable need to develop new therapeutic ap-
`proaches for prostate cancer led us to evaluate a reg-
`imen of high-dose oral calcitriol and dexamethasone
`administered on an intermittent schedule. We had
`previously shown that subcutaneous calcitriol admin-
`istered at a dose of 8 ␮g every other day was safe and
`feasible (average weekly total dose of 28 ␮g).16 These
`data as well as preliminary pilot experience suggesting
`that high-dose calcitriol at a dose of 12 ␮g daily given
`⫻ 3 plus dexamethasone weekly would be well toler-
`ated led us to evaluate this regimen in men with
`androgen-independent prostate cancer (AIPC)
`for
`safety and activity.
`
`MATERIALS AND METHODS
`Patient Eligibility Criteria
`Patients eligible for this trial were those in whom
`prostate cancer was progressive despite androgen de-
`privation. Patients were required to have evidence of
`progressive disease as manifested by new radio-
`graphic lesions on bone scan or computed tomogra-
`phy (CT) scan and/or PSA increasing by ⬎50% com-
`pared with nadir achieved with androgen deprivation
`and clearly rising on 3 successive values each more
`than 2 weeks apart over 6-8 weeks before entry, de-
`spite gonadal suppression (surgical or medical castra-
`tion) and antiandrogen withdrawal, as appropriate (4
`weeks for flutamide, and 6 weeks for bicalutamide).
`Performance status was required to be 0, 1, or 2 ac-
`cording to the criteria of the Eastern Cooperative On-
`cology Group (ECOG). Patients were required to have
`normal hematologic and organ function parameters
`(white blood cell count ⬎4000/mm3, a platelet count
`⬎100,000/mm3, creatinine ⬍ 1.6/dL, bilirubin ⬍1.5
`mg/dL, and aspartate aminotransferase and alanine
`aminotransferase within normal limits). The corrected
`
`Calcitriol plus Dexamethasone in AIPC/Trump et al.
`
`2137
`
`serum calcium was required to be ⬍10.5 mg/dL. Pa-
`tients with any history of nephrolithiasis were ineligi-
`ble and all patients were required to have either a CT
`scan or ultrasound (US) examination of the kidneys
`and ureters that indicated no evidence of lithiasis
`within 30 days of study entry. There was no restriction
`on entry based on extent of prior therapy if other entry
`criteria were satisfied. Prior anticancer therapy with
`calcitriol or calcitriol analogs was not allowed. The
`maximum dose administered was 12 ␮g given every
`day ⫻ 3 because at the time the current study was
`conducted we believed this was the maximum safe
`dose. Informed written consent was required and this
`study was approved by the University of Pittsburgh
`Biomedical Institutional Review Board.
`
`Treatment Plan
`Calcitriol (Rocaltrol, Roche Pharmaceuticals, India-
`napolis, IN) was obtained from commercial sources as
`either 0.5-␮g or 0.25-␮g caplets and was administered
`according to the following schedule: 8 ␮g given on
`Monday, Tuesday, and Wednesday (MTW) ⫻ 4 weeks,
`10 ␮g given MTW ⫻ 4 weeks, and then 12 ␮g given
`MTW weekly thereafter. The calcitriol dose was esca-
`lated after 1 month if no dose-limiting therapy oc-
`curred. Dexamethasone was given at a dose of 4 mg
`orally on Sunday and MTW. Calcitriol was adminis-
`tered at bedtime and dexamethasone was adminis-
`tered at noon. Dietary calcium was not restricted dur-
`ing the study. The choice of this treatment plan was
`based on our prior studies of calcitriol that demon-
`strated that intermittent therapy was better tolerated
`than continuous therapy, that 28 ␮g/week was the
`maximum tolerated dose (MTD) on a every-other-day
`subcutaneous schedule, and a small pilot experience
`demonstrating that this dose and schedule appeared
`to be safe. This regimen was approached with caution,
`however, because at the time this was the highest dose
`of calcitriol ever given. Our prior work indicated that
`calcitriol toxicity was evident within 30 days of treat-
`ment initiation; therefore, the dose was escalated
`monthly to 12 ␮g given daily ⫻ 3 weekly. Dexameth-
`asone dose was chosen based on our prior experience
`with calcitriol plus dexamethasone16 and was roughly
`equivalent to the murine dose shown to potentiate
`calcitriol. The schedule for dexamethasone was cho-
`sen to provide potentially potentiating dexametha-
`sone with calcitriol rather than continuous dexameth-
`asone.
`
`Patient Monitoring and Dose Modification
`Serum calcium, phosphorus, creatinine, and electro-
`lytes were measured on the Thursday of each week;
`liver function tests and hematologic values were de-
`
`

`
`2138
`
`CANCER May 15, 2006 / Volume 106 / Number 10
`
`termined monthly, and US or CT evaluation for uri-
`nary tract stones was repeated every 3 months. When
`a symptomatic bladder stone was discovered in Pa-
`tient 18 after 411 days of therapy, it was realized that
`monitoring US examinations did not routinely include
`the bladder; subsequently, all patients underwent US
`of the kidney, ureter, and bladder. PSA was deter-
`mined monthly and radiographs to assess response
`were repeated every 3 months. In patients whose se-
`rum calcium was ⬎11.5 mg/dL on Thursday, the se-
`rum calcium measurement was repeated on Monday.
`If the serum calcium measurement on Monday was
`ⱕ11.5mg/dL, treatment was continued without dose
`or schedule modification. If the serum calcium re-
`mained ⬎11.5 mg/dL, calcitriol was held and calcium
`measurement was repeated on Thursday and Monday.
`Therapy was resumed at the same dose and schedule
`on the next Monday that the serum calcium was
`⬍11.5mg/dL. If a patient required 2 such dose inter-
`ruptions, the calcitriol dose was to be reduced by 50%
`when therapy was resumed. Because to our knowl-
`edge this was the highest dose of calcitriol ever given
`in prostate cancer patients at the time the current
`study began, toxicity was monitored very closely.
`
`Statistical Design
`This study was designed as a 2-stage Phase II trial, in
`which 19 patients were to be accrued in the first stage
`and 16 in the second. Good and poor response rates
`were established at 35% and 15%, respectively; the
`Types I and II errors were 15% and 5%, respectively.
`Responses were evaluated according to standard
`ECOG criteria for measurable disease response assess-
`ment (partial response [PR] was considered to be a
`ⱖ50% decrease in the sum of the products of bidimen-
`sional measurements of all measurable lesions; and
`complete response [CR] was considered to be the
`complete disappearance of all lesions) and PSA re-
`sponse was considered to have occurred if a PSA de-
`crease of 50% was sustained for ⱖ28 days. To deter-
`mine response after the highest dose of calcitriol
`administered, patients were considered evaluable for
`response assessment if they received at least 1 month
`of calcitriol at a dose of 12 ␮g given every day ⫻ 3
`weekly ⫻ 4; patients who did not satisfy this criterion
`were replaced. Progressive disease was not considered
`to have occurred during Months 1, 2, or 3 unless
`symptomatic and/or radiographic disease progression
`occurred. An increase in PSA during the first 3 months
`was not a criterion for progression. This approach was
`taken for 2 reasons: 1) there are in vitro data indicating
`that calcitriol causes the release of PSA from prostate
`cancer cells, suggesting that short-term changes in
`PSA may not reflect antitumor effects; and 2) we
`
`TABLE 1
`Patient Characteristics (n ⴝ 43)
`
`Prior therapy
`Medical castration plus antiandrogen
`Orchiectomy
`
`Secondary hormonal therapy
`Antiandrogen only
`ⱖ2 agents
`
`Prior cytotoxic therapy*
`1 regimen
`2 regimens
`
`Pain requiring narcotic analgesics
`
`Bone metastases
`
`Soft tissue metastases
`
`Median age, y (range)
`Median PSA (range)
`
`31
`15
`
`7
`15
`
`4
`1
`
`25
`
`38
`
`11
`
`69
`60.6 ␮g/mL
`
`Median alkaline phosphatase (range)
`
`1248 IU/mL
`
`44-82
`4-744.8
`
`8-2520
`
`Median hematocrit (range)
`
`39.3%
`
`30.3-48.4%
`
`PSA: prostate-specific antigen.
`* Mitoxantrone (2 patients), estramustine phosphate (1 patient), cyclophosphamide (1 patient), and
`mitoxantrone and docetaxel (1 patient).
`
`wished to evaluate PSA and clinical response at the
`highest dose of calcitriol possible. The duration of
`response was calculated as the interval between the
`date when a ⱖ50% decrease in PSA was observed and
`the date on which the PSA increased by ⱖ50% above
`the nadir PSA.
`
`RESULTS
`Patient Characteristics
`Patient characteristics are shown in Table 1. Forty-
`three patients were entered into study between Sep-
`tember 1998 and July 2000. All patients had an ECOG
`performance status of 0 (25 patients) or 1 (18 patients).
`The median age was 69 years (range, 44-82 years), and
`all patients had evidence of progressive disease de-
`spite androgen deprivation and antiandrogen with-
`drawal of appropriate duration. A total of 31 patients
`had received medical castration plus an antiandrogen,
`15 had undergone orchiectomy (3 patients were sur-
`gically castrated after having undergone medical cas-
`tration), 7 had received a subsequent single-agent an-
`tiandrogen, 15 received ⱖ2 hormonal manipulations,
`4 had received 1 cytotoxic regimen, and 1 patient had
`received 2 cytotoxic regimens. One patient was receiv-
`ing a bisphosphonate. The median PSA was 60.6
`␮g/mL (range, 4-744.8 ␮g/mL). Twenty-five patients
`
`

`
`TABLE 2
`Toxicity Associated with Calcitriol/Dexamethasone Therapy (n ⴝ 43)
`
`Grade >2
`
`Grade 3
`
`Grade 4
`
`Hematopoietic
`Renal
`Hepatic
`Musculoskeletal
`Neurologic
`Gastrointestinal
`Cardiopulmonary
`Hyperglycemia
`
`None
`4.6%
`None
`None
`None
`None
`None
`2.3%
`
`None
`None
`None
`None
`None
`None
`None
`2.3%
`
`None
`None
`None
`None
`None
`None
`None
`None
`
`were receiving analgesics for pain at the time of study
`entry. Thirty-eight patients had bone metastases at the
`time of study entry and 11 had soft tissue metastases
`detected by CT. Thirty-five patients were eligible for
`response evaluation, having completed 3 months of
`calcitriol/dexamethasone therapy (1 month at a dose
`of 12 ␮g every day ⫻ 3 weekly ⫻ 4). Eight patients did
`not complete 3 months of therapy for the following
`reasons: consent withdrawn in 3 patients; symptom-
`atic, disease progression in 4 patients; and glucocor-
`ticoid toxicity in 1 patient. Disease progression in
`these 4 patients consisted of symptomatic progression
`in bone metastases requiring irradiation.
`
`Response Assessment
`No patient met the criteria for soft tissue disease re-
`sponse (11 patients were evaluable for soft tissue re-
`sponse). Eight of 43 patients (18.6%) experienced and
`maintained for ⱖ28 days a decrease in PSA of ⬎50%
`(median decrease, 64%; range, 55-92%). All 8 patients
`received at least 1 month of 12 ␮g of calcitriol given
`MTW. Time from PSA nadir to a 50% increase (dura-
`tion of PSA response) was generally short, with a me-
`dian of 28 days (range, 22-143 days). In 1 additional
`patient whose PSA fell by ⬎73%, confirmation of per-
`sistent decline for ⬎1 month was not achieved be-
`cause the patient died 6 weeks after the initiation of
`therapy due to a pulmonary embolism believed to be
`unrelated to therapy.
`
`Toxicity
`Toxicity was assessed using the National Cancer Insti-
`tute’s Common Toxicity Criteria (version 3.0). Aside
`from a single patient who developed Grade 3 hyper-
`glycemia within 1 month of beginning therapy, there
`were no toxicities ⬎Grade 2 associated with protocol
`treatment (Table 2). All Grade 1 and Grade 2 toxicities
`were readily and rapidly reversible without treatment
`interruption.
`
`Calcitriol plus Dexamethasone in AIPC/Trump et al.
`
`2139
`
`Serum Calcium
`Forty-three patients were on study for a total of 5451
`days and 806 weekly serum calcium values were as-
`sessed. Fifty-three serum calcium values were ⬎11
`mg/dL (6.6%) and 6 serum calcium values were ⬎12
`mg/dL (0.7%). In 8 patients (18.7%), serum calcium
`levels between 11 mg/dL and 12 mg/dL were detected
`on ⱖ1 occasions, and in 3 patients (6.9%) calcium
`levels ⬎12 mg/dL were detected. The study design
`mandated interruption of every day ⫻ 3 weekly calcit-
`riol dosing for a persistent serum calcium increase
`(⬎11.5 mg/dL for ⱖ5 days) unless symptoms or com-
`plications associated with hypercalcemia were noted.
`Patients with symptomatic hypercalcemia were to
`cease therapy and resume treatment at a lower dose.
`The criteria for dose reduction/interruption based on
`hypercalcemia were not met in any patient.
`
`Urinary Tract Stones
`In 2 patients, urinary tract stones were diagnosed after
`179 days (Patient 4) and 411 days (Patient 18) of ther-
`apy. In Patient 4, a stone was diagnosed by US of the
`upper tract. This patient was totally asymptomatic. In
`Patient 18, the occurrence of hematuria and dysuria
`were followed by cystoscopic examination, which con-
`firmed a bladder stone. Both patients were removed
`from the current study because of the development of
`urinary tract stones. In Patient 37, a bladder stone was
`suspected because of new irritative voiding symptoms
`and hematuria. Although these symptoms resolved
`spontaneously, this patient had evidence of progres-
`sive disease; therapy was discontinued and the suspi-
`cion of a bladder stone was never confirmed.
`
`Renal Function
`Based on prior studies, hypercalcuria was expected to
`be universal with this regimen.16,17 Patients were care-
`fully monitored for renal dysfunction. Among 43 pa-
`tients with advanced prostate cancer, Grade 2 renal
`toxicity (serum creatinine 1.5-3.0 times the upper limit
`of normal) occurred in only 2 patients (4.6%). These
`patients were among the 35 patients who received ⬎3
`months of high-dose calcitriol therapy and represent
`5.7% of that population. Single serum creatinine val-
`ues of 2.4 mg/dL (Patient 6 at Day 289) and 2.3 mg/dL
`(Patient 27 at Day 112) were noted. In Patient 6, the
`serum creatinine was 1.9 mg/dL 1 week later and did
`not increase to ⬎2.1 mg/dL for the remaining 45 days
`the patient remained on study. In Patient 27, calcitriol
`was withdrawn when a creatinine level of 2.3 mg/dL
`was noted; 1 week later the creatinine level was 1.9
`mg/dL and calcitriol administration was resumed; the
`creatinine did not reach Grade 2 toxicity criteria dur-
`
`

`
`2140
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`CANCER May 15, 2006 / Volume 106 / Number 10
`
`ing the remaining 40 days the patient was on study.
`Therefore, renal toxicity was uncommon, transient,
`and nonrecurring in each patient. No renal dysfunc-
`tion ⬎Grade 2 was observed.
`
`DISCUSSION
`Considerable preclinical data suggest that vitamin D
`may be useful as an antiproliferative agent in clinical
`cancer management.1– 4 Our preclinical studies clearly
`indicate a steep dose-response relation for vitamin D
`antitumor effects.3,11–13 Initial clinical studies of vita-
`min D focused on hematologic malignancies and uti-
`lized daily oral dosing regimens. Limited indications
`of efficacy and worrisome increases in serum calcium
`were noted.18,19 Osborn et al.20 reported a trial of
`calcitriol in AIPC patients administered on a every-day
`schedule (1.0-1.5 ␮g every day). No responses were
`noted and a 30% frequency of hypercalcemia was en-
`countered. Since these initial studies were performed,
`we and others have shown that intermittent, high-
`dose calcitriol regimens are safe and feasible.16,21,22
`Beer et al.21 reported that high-dose weekly oral cal-
`citriol is well tolerated at doses up to 2.6 ␮g/kg/wk and
`Morris et al.22 noted that calcitriol up to 30 ␮g given
`every day ⫻ 3, weekly plus zoledronic acid was safe.
`Because the antitumor effects noted in in vivo models
`are observed with intermittent schedules and the
`safety of these regimens is now clear, recent clinical
`trials have evaluated intermittent, high-dose vitamin
`D analogs in cancer therapy.16,21–24
`To our knowledge, the MTD of calcitriol in ad-
`vanced cancer patients is unknown. Definition of the
`MTD would allow evaluation of the clinical activity of
`the maximal safe dose and would also determine
`whether the systemic exposure that results in antitu-
`mor activity in preclinical models can be achieved in
`patients.25 At the time the current trial was initiated,
`there were no data regarding the safety of high-dose,
`oral, intermittent calcitriol. The dose and schedule
`employed were chosen based on our prior work with
`subcutaneous calcitriol and limited pilot data indicat-
`ing that this regimen, which was believed to be an
`aggressive dosing schedule, appeared to be safe. Be-
`cause there is still considerable concern regarding the
`safety of high-dose calcitriol and many argue there is
`the need to develop analogs that are less inclined to
`cause hypercalcemia, we believe that an in-depth dis-
`cussion of these issues is warranted. To our knowl-
`edge, there are no other published data regarding this
`dose and schedule of calcitriol. Data from the current
`study and those of Beer et al.21 and Muindi et al.23
`indicate that doses higher than those used here are
`inconsistently and erratically absorbed. There are sev-
`eral challenges to determining the calcitriol MTD. The
`
`absorption of the currently available formulations ap-
`pears to be limited at high oral doses. In addition, it is
`not clear what is an acceptable or tolerable degree of
`modification of calcium metabolism among patients,
`especially patients with advanced cancer. Some stud-
`ies of calcitriol administration have limited calcitriol
`dosing based on the occurrence of hypercalcuria.17 An
`increase in urine calcium is universal in patients re-
`ceiving intermittent high-dose calcitriol. Based on the
`current study, as well as previously reported trials,
`there is little evidence that intermittent hypercalcuria,
`unaccompanied by any other biochemical change, has
`unacceptable consequences in patients with advanced
`cancer studied over a relatively short period of time
`(3-12 months).16,21–24 The current study and others
`suggests that a 6-month to 12-month treatment with
`intermittent high doses of calcitriol
`infrequently
`causes urinary tract stones. Hypercalcemia can cause
`clinical symptoms; however, the health consequences
`of intermittent, mild hypercalcemia are uncertain.
`In the current study, as well as those of other au-
`thors,21–28 it is unusual for serum calcium levels ⬎11.0
`mg/dL to occur; furthermore, such increases are tran-
`sient and often do not recur despite continued calcit-
`riol administration.
`The current study was initiated before it was clear
`that substantial dose escalation of oral calcitriol was
`possible and before the problem of incomplete ab-
`sorption of oral calcitriol was evident. Our initial stud-
`ies had shown that daily calcitriol administration re-
`sulted in symptomatic or
`clinically
`significant
`hypercalcemia in 30% of patients (dose intensity [DI]
`of 22 ␮g/14 days). A subsequent study of subcutane-
`ous calcitriol demonstrated that a dose of 10 ␮g given
`every other day resulted in hypercalcemia in all pa-
`tients (DI of 70 ␮g/14 days). The regimen in the cur-
`rent study (DI of 72 ␮g/14 days) achieved the admin-
`istration of high doses of calcitriol without limiting
`toxicity.
`This regimen was very well tolerated. Our studies
`have shown that calcitriol at a dose of 38 ␮g every day
`⫻ 3 weekly plus paclitaxel (80 mg/m2) causes no hy-
`percalcemia. Our studies and those of Muindi et
`al.23,26 also clearly demonstrated that, at doses ⬎14 ␮g
`to 18 ␮g, the correlation between the administered
`dose and the concentration in blood is no longer lin-
`ear, suggesting a dose-related limitation of bioavail-
`ability at higher doses. We have observed this loss of
`dose-proportional increase in blood level with both
`commercially available caplet and liquid palm oil for-
`mulations. The regimen described in the current study
`was extremely well tolerated and permitted the ad-
`ministration of higher doses of calcitriol than we had
`previously achieved. Based on our preclinical studies,
`
`

`
`we believe that further dose escalation will be neces-
`sary and safe. Dose escalation using the currently
`available oral formulation is not justified because of
`concerns regarding bioavailability; furthermore, the
`small dosing sizes available (0.5 ␮g and 0.25 ␮g
`caplets) required the inconvenient administration of
`24 caplets every day ⫻ 3 in the current study. The
`development of a potentially improved, higher con-
`tent capsule currently is underway. Phase I studies of
`larger size formulation are complete and this agent
`has completed a phase III evaluation with docetaxel in
`patients with prostate cancer that clearly demon-
`strates that weekly calcitriol (at a dose of 0.5 ␮g/kg
`⫻ 1) plus docetaxel is safe.27,28
`The PSA response rate (19%) for this well-toler-
`ated regimen is interesting, but it is not possible to
`determine the extent to which this response rate was
`related to calcitriol, dexamethasone, or their combi-
`nation. To our knowledge, there are no data with
`respect to the PSA response rate after the use of dexa-
`methasone on this schedule (4 mg every day ⫻ 4,
`weekly). Glucocorticoids have been extensively stud-
`ied in AIPC as single agents in relatively small Phase II
`trials,29 –31 as important (and often overlooked) agents,
`in combination with other agents, including those that
`inhibit adrenal steroidogenesis (ketoconazole)32–34
`and as
`the control arm in trials of cytotoxic
`agents.36 –38 There are few, if any, data that have es-
`tablished the PSA response rate of various glucocorti-
`coids preparations and schedules. The largest studies
`of glucocorticoids published to date are the 3 random-
`ized trials of glucocorticoids ⫾ the cytotoxic agents
`mitoxantrone or suramin.36 –38 In these trials, the PSA
`response rates (⬎50%) of glucocorticoids alone were
`12%, 22%, and 16%, respectively. Some Phase II stud-
`ies suggest a much higher PSA response rate with the
`use of dexamethasone (62% and 61%, respective-
`ly).29 –31 These studies used different doses of dexa-
`methasone, and 1 study was a retrospective review of
`a clinical experience rather than a prospective clinical
`trial.39 Weitzman et al.35 studied high-dose, “pulse”
`dexamethasone in patients with AIPC to evaluate the
`role it might play in the PSA response noted after the
`administration of taxanes and attendant glucocorti-
`coids used as hypersensitivity prophylaxis. In this trial
`of only 12 patients, dexamethasone resulted in no PSA
`responses. Although the current regimen was very well
`tolerated, its role in the management of AIPC is diffi-
`cult to determine. Based on prior work of Beer et al.
`and Muindi et al.21,23,26 and our own studies, the
`plasma levels of calcitriol achieved with this regimen
`were likely quite high (0.5-1.0 ␮M). However, after the
`initiation of this trial, we determined that plasma con-
`centrations are substantially lower than the plasma
`
`Calcitriol plus Dexamethasone in AIPC/Trump et al.
`
`2141
`
`concentrations associated with calcitriol antitumor
`activity in animal models (PC3, LNCaP, and SCC).23,25
`Although the pharmacokinetic parameters for calcit-
`riol, which are associated with antitumor response,
`are not clear and there is risk in extrapolating murine
`response data and serum levels to human studies, we
`now believe that the calcitriol exposure achieved in
`the current study was not optimal to explore antitu-
`mor responses. Such data were not available when the
`current study was performed. Escalation of oral dosing
`with currently available preparations is unlikely to
`allow these higher plasma concentrations to be
`achieved due to issues of bioavailability as well as the
`extremely cumbersome requirement to administer
`dozens of calcitriol caplets. Our current approach is to
`continue to develop vitamin D analogs for the treat-
`ment of prostate cancer through the use of parenteral
`preparations, alternate formulations for oral use, and
`the exploration of other strategies to enhance delivery
`of high concentrations of vitamin D analog to tumor
`cells.
`
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