- Email: [email protected]
II STUDY
0022-5347/05/1743-0888/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 174, 888 – 892, September 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000169261.42298.e6
HIGH DOSE PULSE CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR ANDROGEN INDEPENDENT PROSTATE CANCER: A PHASE I/II STUDY NATASHA M. TIFFANY, CHRISTOPHER W. RYAN,* MARK GARZOTTO,† EMILY M. WERSINGER , AND TOMASZ M. BEER‡ § From the Divisions of Hematology and Medical Oncology, and Urology, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, Oregon
ABSTRACT
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 g calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m2 docetaxel on day 2 (70 mg/m2 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 naı¨ve 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 naı¨ve 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. KEY WORDS: prostate, prostatic neoplasms, calcitriol, docetaxel, estramustine
The role of chemotherapy for prostate cancer has evolved from an established palliative intervention1 to a treatment that also prolongs survival. A survival advantage was recently identified for the combinations of docetaxel with prednisone2 and docetaxel with estramustine.3 After demonstrating high prostate specific antigen (PSA) response rates in early phase studies the combination of docetaxel and estramustine was recently shown to produce a 50% PSA response rate, a 17% response rate in measurable disease, a median time to progression of 6.3 months and a median survival of 17.5 months in Southwest Oncology Group (SWOG) 9916, a randomized, phase III study.3 We built on this regimen by testing it in combination with high dose calcitriol (1,25-dihydroxycholecalciferol). Calcitriol is the natural ligand for the vitamin D receptor and at supraphysiological levels it has demonstrated antiproliferative activity in prostate cancer cells in vitro4⫺9 and in
vivo.6, 10 The calcitriol antiproliferative activity mechanism includes pro-apoptotic and antiproliferative effects, and it remains incompletely characterized.11 Preclinical experiments suggest that calcitriol enhances the antineoplastic activity of taxanes.12, 13 Based on these data our group recently reported the results of a phase II study that combined high dose weekly calcitriol with weekly docetaxel.14 To develop a novel regimen that would build on the docetaxel plus estramustine combination we tested the safety of and gathered preliminary efficacy data on the 3 drug combination of high dose calcitriol, docetaxel and estramustine on a 21-day schedule. We selected the dose de-escalation approach first described by Blanke et al15 since we judged that the probability of unexpected toxicity would be low. PATIENTS AND METHODS
Submitted for publication November 29, 2004. Eligibility criteria. Men with histologically proven adenoStudy received approval from Institutional Review Boards, Oregon carcinoma of the prostate with measurable or evaluable metHealth and Science University, and Portland Veterans Affairs Medastatic disease progressing (new or increased measurable or ical Center. Supported by Grant IIT 16136 from Aventis Pharmaceuticals and evaluable disease, and/or progression by serum PSA16) deGrant 3M01RR00334 –33S2 from the National Institutes of Health. spite standard hormonal therapy, including antiandrogen * Financial interest and/or other relationship with Aventis. withdrawal (4 weeks for flutamide and 6 weeks for others) † Financial interest and/or other relationship with Aventiswere eligible. Additional requirements were Eastern CooperPasteur Pharmaceuticals. ‡ Correspondence: Department of Medicine, Oregon Health and ative Oncology Group (ECOG) performance status 2 or less, Science University, Mail Code CR145, 3181 Southwest Sam Jackson PSA greater than 5 ng/ml in patients without measurable Park Rd., Portland, Oregon 97239 (telephone: 503-494-3253; FAX: soft tissue disease, serum testosterone less than 50 ng/ml, life 503-494-6197; e-mail: [email protected]). § Financial interest and/or other relationship with Aventis and expectancy greater than 3 months and age 18 years or greater. Prior exposure to chemotherapy, including docetaxel Novacea. 888
CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR PROSTATE CANCER
and estramustine, was not restricted to allow exploration of the hypothesis that calcitriol may restore sensitivity to chemotherapy and because to our knowledge no standard therapy that produces a demonstrated clinical benefit is available for this patient population. Patients were excluded due to a second active malignancy, brain metastases, significant active medical illness, contraindications to aspirin, warfarin or heparin therapy, nephrolithiasis within 5 years, history of cancer related hypercalcemia, atrial fibrillation, myocardial infarction or uncontrolled heart failure, recent history of cerebrovascular accident, active thrombophlebitis, history of hypercoagulability or pulmonary embolus, hypersensitivity to drugs formulated with polysorbate-80, symptomatic third space fluid accumulation, grade 2 or greater peripheral neuropathy, investigational therapy within 28 days, prior radiation therapy to 20% or greater of bone marrow, radiation within the last month or any previous treatment with radiopharmaceuticals, major surgery within 21 days, white blood count less than 3,000/mm3, neutrophil count less than 1,500/mm3, platelet count less than 100,000/mm3, conjugated bilirubin greater than upper limit of normal (ULN), alanine transaminase (ALT) or aspartate transaminase (AST) greater than 2.0 ⫻ ULN when alkaline phosphatase was 2.5 or less ⫻ ULN, ALT or AST greater than 1.5 ⫻ ULN when alkaline phosphatase was greater than 2.5 ⫻ ULN, creatinine greater than 2 mg/dl, calcium greater than ULN and alkaline phosphatase 4.0 or greater ⫻ ULN, except in patients with bone metastases and normal conjugated bilirubin, AST and ALT. Signed, informed consent was obtained from all patients and the study was approved by the Institutional Review Boards of the Oregon Health and Science University, and Portland Veterans Affairs Medical Center. Evaluations. Pretreatment evaluation included medical history, physical examination, whole body bone scan, computerized tomography of the abdomen and pelvis, electrocardiogram, serum testosterone measurement, chemistry panel, PSA and complete blood count with automated differential. Assessment of adverse events and physical examination, serum PSA, chemistry panel, international normalized ratio and complete blood count were repeated every 3 weeks. In patients with measurable disease measurements by the same imaging modality were repeated every 9 weeks. Bone scans were repeated as clinically indicated. Patients taken off study without evidence of progression were monitored until progression. All patients off study were followed until the stabilization or resolution of toxicity and for survival every 6 months. Treatment regimen. Patients entering the study on a gonadotropin-releasing hormone agonist continued gonadotropin-releasing hormone agonist therapy. Concomitant use of corticosteroids, antiandrogens, estrogens, thiazide diuretics, magnesium containing antacids or bile-resin binders was prohibited. Calcium supplements were prohibited during week 1 of each treatment cycle. Patients were encouraged to increase oral hydration for 3 days beginning 12 hours before each calcitriol dose. Calcitriol (60 g as 0.5 g tablets) was given orally in 4 divided doses for 4 hours on day 1. Dexamethasone (8 mg orally) was given twice daily for the first 3 days and 280 mg estramustine were given orally 3 times daily for days 1 through 5. Docetaxel (60 mg/m2) intravenously was given for 60 minutes on day 2 of treatment week 1 and then increased to 70 mg/m2 for subsequent cycles if there was no grade 3 or greater toxicity during cycle 1. Treatment was administered every 21 days for 12 cycles unless there was disease progression or unacceptable toxicity. Aspirin (325 mg) was given orally daily and patients received 2 mg warfarin orally daily, which was decreased to 1 mg if the international normalized ratio was greater than 1.5. Patients were routinely asked at followup visits whether they were able to ingest all calcitriol pills. Growth factors
889
were allowed after the first cycle of treatment at physician discretion as long as dose decrease guidelines in the protocol were followed. Bisphosphonate use was not restricted. Dose Modifications for Docetaxel: The dose of docetaxel was decreased by 25% if the start of a cycle was delayed by a persistently low platelet or neutrophil count, or there was grade 4 afebrile neutropenia 7 days or greater in duration, grade 4 febrile neutropenia, grade 4 thrombocytopenia, AST or ALT 2.5 to 5 ⫻ ULN with alkaline phosphatase 2.5 or less ⫻ ULN, or AST or ALT was 1.6 to 5 ⫻ ULN and alkaline phosphatase was 2.5 to 5 ⫻ ULN. Therapy with docetaxel was withheld for a platelet count of less than 100,000/mm3 or a neutrophil count of less than 1,500/mm3 until the 2 counts were above these parameters. Therapy was withheld for bilirubin greater than ULN, alkaline phosphatase greater than 5 ⫻ ULN, or AST or ALT greater than 5 ⫻ ULN. Therapy was resumed at a 25% dose decrease in patients in whom liver function tests recovered within 3 weeks. Docetaxel was discontinued for any grade 4 allergic reaction or for grades 3 or greater neuropathy. For other grades 3 or greater nonhematological toxicities docetaxel treatment was withheld until toxicity resolved to grade 1 or less and then reinstituted at a 25% dose decrease. Patients were removed from the study due to toxicity related treatment delays in excess of 3 weeks. Dose Modifications for Estramustine: Patients with a thromboembolic complication could continue estramustine only with therapeutic anticoagulation. Estramustine was stopped for uncontrolled, intolerable nausea. Patients who could not continue estramustine were allowed to stay on study with docetaxel and calcitriol. Dose Modifications for Calcitriol: Patients were allowed a maximum of 2 calcitriol dose decreases, that is the first to 45 g and the second to 30 g. Calcitriol was held for grade 2 or 3 hypercalcemia until the return of normocalcemia and then it was decreased by 1 dose level. Calcitriol was held for grade 2 creatinine increase or for other grade 3 calcitriol related toxicities until resolution to grade 1 or less. It was then decreased by 1 dose level. Development of a calcium containing kidney stone prompted a 1 dose level decrease. Calcitriol was discontinued for grade 4 hypercalcemia, a grade 3 or higher creatinine increase, the development of a second kidney stone and for any grade 4 toxicity or recurrent grade 3 toxicity attributable to calcitriol. Assessment of outcome. The primary objective was to assess the safety of the combination of calcitriol with docetaxel and estramustine. Toxicity was measured using National Cancer Institute common toxicity criteria, version 2.0. Dose limiting toxicity (DLT) was defined as grades 3 or greater nonhematological toxicity, neutropenic fever, prolonged neutropenia (absolute neutrophil count less than 500/mm3 more than 7 days in duration) or grade 4 thrombocytopenia. Prospectively planned efficacy analyses included the fraction of patients who had a 50% or greater and 75% or greater decrease in serum PSA, the fraction of patients with measurable disease who met Response Evaluation Criteria In Solid Tumors criteria for response,17 time to progression and time to death. Progression was defined by standard criteria for measurable and evaluable disease,17 and for PSA.16 Two or more new lesions were required to document progression on whole body bone scan. Statistical design. The primary end point was toxicity of the combination of calcitriol, docetaxel and estramustine. The trial design called for treatment of 6 patients at the planned doses and dose de-escalation of calcitriol if greater than 2 of the first 6 patients experienced DLT during chemotherapy cycle 1. After the first 12 patients were treated the protocol was amended to enroll 24 to collect more robust toxicity data and preliminary efficacy data. With 24 patients treated the 95% exact binomial CI of the rate of severe toxicities was no wider than 40%. The probability of observing at least 1 toxicity of grade 4 or higher was 71% and 92%
890
CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR PROSTATE CANCER
if the true rate of grade 4 or higher toxicities were 5% and 10%, respectively. RESULTS
Patient characteristics. A total of 24 men were recruited between January 2003 and March 2004. Table 1 lists pretreatment characteristics. Median patient age was 67 years. Median ECOG performance status was 1. All patients had metastatic disease to bone. Of the patients 13 (54%) received prior chemotherapy, including at least 1 docetaxel containing regimen, of whom the majority received more than 1 prior chemotherapy regimen. Seven of the 13 patients who received prior docetaxel based chemotherapy had responded (confirmed 50% decrease in PSA) to prior docetaxel based treatment. Median time since previous chemotherapy was 10 weeks (range 2 to 77) (table 1). Treatment. The median duration of treatment was 5 cycles (range 1 to 12). Four patients (16.7%) completed all 12 planned treatments and 15 (62.5%) stopped treatment due to disease progression, 4 (16.7%) because of toxicity and 1 (4.2%) due to a new diagnosis of lung cancer. The docetaxel dose was not escalated to 70 mg/m2 in 2 patients due to liver function abnormalities (1) and neutropenic fever (1). The calcitriol was dose decreased in 1 patient after 1 cycle for grade 2 hypercalcemia. The estramustine dose was decreased in 2 patients. Toxicity. Overall the regimen was well tolerated. One of the first 6 patients (16.7%) experienced protocol defined DLT (grade 3 liver function test increase) during chemotherapy cycle 1, and so the calcitriol dose remained at 60 mcg for the remainder of the study. There were no treatment related deaths. Table 2 lists all grades 2 or greater treatment related toxicities. Grade 3 or 4 neutropenia was seen in 3 patients (12.5%) and it was associated with fever in 2. Additional
TABLE 1. Patient characteristics at study entry
grade 1 toxicities likely related to calcitriol were hypercalcemia in 12.5% of cases and increased creatinine in 42%. Hypophosphatemia was notably common. One patient had grade 2 disorientation and ataxia on days 3 to 5 of cycles 8 and 9. No neurological or metabolic pathology was identified. The syndrome resolved spontaneously and the patient was withdrawn from the study. Four patients experienced thomboembolic complications, including pulmonary emboli in 1 and deep venous thromboses in 3. In 2 of these patients thromboembolism developed while anticoagulation was temporarily withheld due to minor surgical procedures. Response to therapy. PSA Decrease: Two patients were not evaluable for a PSA decrease. One patient had an initial PSA of less than 5 ng/ml and the other was removed from the study after only 1 treatment due to a diagnosis of lung cancer. Seven of the 22 patients (32%, 95% CI 12 to 51) evaluable for a PSA decrease achieved a confirmed PSA decrease in excess of 50%, while 3 (14%, 95% CI 0 to 28) achieved a confirmed greater than 75% decrease in PSA. Five patients had stable PSA for at least 4 treatment cycles (12 weeks). Table 3 lists response data. PSA decreases in excess of the 50% rate were seen in 55% of chemotherapy naı¨ve patients (95% CI 24 to 85) and in only 9% (95% CI 0 to 27) of those previously exposed to docetaxel. Response in Measurable Disease: A total of 16 patients had measurable disease and 15 were evaluable. Two patients had a confirmed partial response (13%, 95% CI 4 to 31), while 3 (20%, 95% CI 1 to 57) had confirmed stable disease. The 2 responders were chemotherapy naı¨ve. Time to Progression (TTP) and Survival: Median TTP was 17 weeks (95% CI 12 to 22). Median overall survival was 54 weeks (95% CI 47 to 61). Chemotherapy naı¨ve patients trended toward a longer median TTP than those who received prior chemotherapy (24 weeks, 95% CI 6 to 42, vs 16, 95% CI 5 to 27, log rank p ⫽ 0.08). Median survival was longer in chemotherapy naı¨ve patients (not achieved) than in patients who received prior chemotherapy (41 weeks, 95% CI 32 to 51, log rank p ⫽ 0.05).
Characteristic No. pts Median age (range) No. ECOG performance status: 0 1 2 Median ng/ml PSA (range) Median gm/dl hemoglobin (range) Median /l alkaline phosphatase (range) No. metastasis site (%): Bone only Bone ⫹ lymph nodes Bone ⫹ visceral metastases Bone, lymph node ⫹ visceral metastases No. prior radiation (%): External beam radiation to primary tumor External beam and brachytherapy to primary tumor External beam radiation to metastases Radiopharmaceuticals No. prior hormonal therapies for prostate Ca (%): 1 2 3 4 No. prior chemotherapy regimens for prostate Ca (%): 0 1 2 3 No. prior docetaxel (%): Docetaxel alone Calcitriol ⫹ docetaxel Docetaxel ⫹ estramustine No. prior experimental therapies (%)
24 67
DISCUSSION
(48–79)
11 10 3 114.8 (0.8–1,050) 12.5 (8.4–15.2) 134 (33–538) 7 12 3 2
(29) (50) (13) (8)
7 1
(29) (4)
8 1
(33) (4)
3 11 4 6
(13) (45) (17) (25)
11 8 4 1 13 5 4 6 4
(45) (33) (17) (4) (54) (39) (31) (46) (17)
The addition of calcitriol to docetaxel plus estramustine is feasible and no appreciable increase in toxicity was observed in this pilot study. The regimen was well tolerated with adverse events similar to what has previously been reported with docetaxel plus estramustine. Thromboembolic complications were seen despite the prophylactic use of anticoagulation. Neutropenic fever was seen in 2 patients. The study was not designed to determine if the addition of calcitriol increased treatment efficacy. PSA and measurable disease response rates in chemotherapy naı¨ve patients were similar to those seen in studies of docetaxel plus estramustine but the small number of patients and lack of randomization prevent us from drawing definitive conclusions about the efficacy contribution of calcitriol. Outcomes in patients who received prior therapy with docetaxel were poor, highlighting a desperate need for novel approaches to treatment in these patients. The contribution of estramustine to the efficacy of docetaxel for androgen independent prostate cancer remains uncertain, given similar survival outcomes for experimental arms with and without this agent in SWOG 9916 and TAX 327.2, 3 The addition of estramustine or other potentially synergistic agents to docetaxel based therapy in patients who do not respond to or who progress on initial docetaxel treatment is a strategy that warrants further investigation. One patient on this study achieved potential benefit in the form of a decrease in PSA after previously progressing on docetaxel plus calcitriol.
891
CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR PROSTATE CANCER TABLE 2. Grades 2 or greater treatment related toxicity Toxicity % Grade 2
% Grade 3
% Grade 4
% Total Grades 2–4
25 4.2 0.0 54.2 29.2 4.2 0.0 0.0 0.0
4.2 0.0 0.0 0.0 16.7 0.0 4.2 4.2 4.2
0.0 12.5 8.3 0.0 0.0 0.0 0.0 0.0 0.0
29.2 16.7 8.3 54.2 45.8 4.2 4.2 4.2 4.2
50.0 16.7 16.7 0.0 12.5 8.3 8.3 8.3 4.2 8.3 0.0 4.2 4.2 0.0 4.2 0.0 4.2 4.2 0.0 0.0 0.0 4.2
0.0 4.2 0.0 12.5 0.0 4.2 4.2 4.2 4.2 0.0 8.3 0.0 0.0 4.2 0.0 4.2 0.0 0.0 0.0 4.2 4.2 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 4.2 0.0 0.0 0.0
50.0 20.8 16.7 12.5 12.5 12.5 12.5 12.5 8.3 8.3 8.3 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2
Laboratory: Anemia Neutropenia Neutropenic fever Hyperglycemia Hypophosphatemia Hypercalcemia Hypokalemia Increased ALT Prothrombin time Clinical: Fatigue Nausea Constipation Deep venous thrombosis Dyspnea Edema Infection Vomiting Dehydration Oncholysis Syncope Ataxia Confusion Chronic obstructive pulmonary disease exacerbation Dizziness Edema Fever Headache Perforated diverticulum Pleural effusions Pulmonary embolism Weakness
TABLE 3. Activity by prior therapy Prior Chemotherapy
No. Pts
No. PSA Evaluable
No. Confirmed PSA Decrease 50% or Greater
None Any docetaxel Greater than 1 prior chemotherapy Calcitriol ⫹ docetaxel Docetaxel ⫹ estramustine Docetaxel alone
11 13 5 4 6 5
11 11 3 3 5 4
6 (55) 1 (9) 0 1 (33) 0 0
4.
5.
6.
7.
Given the results of SWOG 9916 and TAX 327, and Food and Drug Administration approval of docetaxel and prednisone for androgen independent prostate cancer, further development of this estramustine containing regimen is not planned. Instead, the addition of a new, high dose formulation of calcitriol that avoids the need to swallow a large number of pills (DN-101, Novacea, South San Francisco, California) to docetaxel is being tested in an international, double-blind, placebo controlled trial. Recent reviews provide further discussion of calcitriol biology, current status and future directions for its development in prostate cancer.11, 18 REFERENCES
1. Tannock, I. F., Osoba, D., Stockler, M. R., Ernst, D. S., Neville, A. J., Moore, M. J. et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol, 14: 1756, 1996 2. Tannock, I. F., de Wit, R., Berry, W. R., Horti, J., Pluzanska, A., Chi, K. N. et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med, 351: 1502, 2004 3. Petrylak, D. P., Tangen, C. M., Hussain, M. H., Lara, P. N., Jr., Jones, J. A., Taplin, M. E. et al: Docetaxel and estramustine
8.
9.
10.
11. 12.
13.
compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med, 351: 1513, 2004 Skowronski, R. J., Peehl, D. M. and Feldman, D.: Vitamin D and prostate cancer: 1,25-dihydroxyvitamin D3 receptors and actions in human prostate cancer cell lines. Endocrinology, 132: 1952, 1993 Peehl, D. M., Skowronski, R. J., Leung, G. K., Wong, S. T., Stamey, T. A. and Feldman, D.: Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res, 54: 805, 1994 Schwartz, G. G., Oeler, T. A., Uskokovic, M. R. and Bahnson, R. R.: Human prostate cancer cells: inhibition of proliferation by vitamin D analogs. Anticancer Res, 14: 1077, 1994 Skowronski, J. S., Peehl, D. M. and Feldman, D.: Actions of vitamin D3 analogues on human prostate cancer cell lines: comparison with 1,25-dihydroxyvitamin D3. Endocrinology, 136: 20, 1995 Hedlund, T. E., Moffatt, K. A. and Miller, G. J.: Vitamin D receptor expression is required for growth modulation by 1 alpha,25-dihydroxyvitamin D3 in the human prostatic carcinoma cell line ALVA-31. J Steroid Biochem Mol Biol, 58: 277, 1996 Zhuang, S. H., Schwartz, G. G., Cameron, D. and Burnstein, K. L.: Vitamin D receptor content and transcriptional activity do not fully predict antiproliferative effects of vitamin D in human prostate cancer cell lines. Mol Cell Endocrinol, 126: 83, 1997 Getzenberg, R. H., Light, B. W., Lapco, P. E., Konety, B. R., Nangia, A. K., Acierno, J. S. et al: Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system. Urology, 50: 999, 1997 Beer, T. M. and Myrthue, A.: Calcitriol in cancer treatment: from the lab to the clinic. Mol Cancer Ther, 3: 373, 2004 Hershberger, P. A., Yu, W. D., Modzelewski, R. A., Rueger, R. M., Johnson, C. S. and Trump, D. L.: Calcitriol (1,25dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis. Clin Cancer Res, 7: 1043, 2001 Beer, T. M., Hough, K. M., Garzotto, M., Lowe, B. A. and Henner,
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CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR PROSTATE CANCER
W. D.: Weekly high-dose calcitriol and docetaxel in advanced prostate cancer. Semin Oncol, 28: 49, 2001 14. Beer, T. M., Eilers, K. M., Garzotto, M., Egorin, M. J., Lowe, B. A. and Henner, W. D.: Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol, 21: 123, 2003 15. Blanke, C. D., Stipanov, M., Morrow, J., Rothenberg, M., Chinery, R., Shyr, Y. et al: A phase I study of vitamin E, 5-fluorouracil and leucovorin for advanced malignancies. Invest New Drugs, 19: 21, 2001 16. Bubley, G. J., Carducci, M., Dahut, W., Dawson, N., Daliani, D., Eisenberger, M. et al: Eligibility and response guidelines for
phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol, 17: 3461, 1999 17. Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L. et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 92: 205, 2000 18. Beer, T. M., Myrthue, A. and Eilers, K. M.: Rationale for the development and current status of calcitriol in androgenindependent prostate cancer. World J Urol, 23: 28, 2005
Vol. 174, 888 – 892, September 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000169261.42298.e6
HIGH DOSE PULSE CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR ANDROGEN INDEPENDENT PROSTATE CANCER: A PHASE I/II STUDY NATASHA M. TIFFANY, CHRISTOPHER W. RYAN,* MARK GARZOTTO,† EMILY M. WERSINGER , AND TOMASZ M. BEER‡ § From the Divisions of Hematology and Medical Oncology, and Urology, Oregon Health Sciences University and Portland Veterans Affairs Medical Center, Portland, Oregon
ABSTRACT
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 g calcitriol orally on day 1, 280 mg estramustine orally 3 times daily on days 1 to 5 and 60 mg/m2 docetaxel on day 2 (70 mg/m2 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 naı¨ve 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 naı¨ve 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. KEY WORDS: prostate, prostatic neoplasms, calcitriol, docetaxel, estramustine
The role of chemotherapy for prostate cancer has evolved from an established palliative intervention1 to a treatment that also prolongs survival. A survival advantage was recently identified for the combinations of docetaxel with prednisone2 and docetaxel with estramustine.3 After demonstrating high prostate specific antigen (PSA) response rates in early phase studies the combination of docetaxel and estramustine was recently shown to produce a 50% PSA response rate, a 17% response rate in measurable disease, a median time to progression of 6.3 months and a median survival of 17.5 months in Southwest Oncology Group (SWOG) 9916, a randomized, phase III study.3 We built on this regimen by testing it in combination with high dose calcitriol (1,25-dihydroxycholecalciferol). Calcitriol is the natural ligand for the vitamin D receptor and at supraphysiological levels it has demonstrated antiproliferative activity in prostate cancer cells in vitro4⫺9 and in
vivo.6, 10 The calcitriol antiproliferative activity mechanism includes pro-apoptotic and antiproliferative effects, and it remains incompletely characterized.11 Preclinical experiments suggest that calcitriol enhances the antineoplastic activity of taxanes.12, 13 Based on these data our group recently reported the results of a phase II study that combined high dose weekly calcitriol with weekly docetaxel.14 To develop a novel regimen that would build on the docetaxel plus estramustine combination we tested the safety of and gathered preliminary efficacy data on the 3 drug combination of high dose calcitriol, docetaxel and estramustine on a 21-day schedule. We selected the dose de-escalation approach first described by Blanke et al15 since we judged that the probability of unexpected toxicity would be low. PATIENTS AND METHODS
Submitted for publication November 29, 2004. Eligibility criteria. Men with histologically proven adenoStudy received approval from Institutional Review Boards, Oregon carcinoma of the prostate with measurable or evaluable metHealth and Science University, and Portland Veterans Affairs Medastatic disease progressing (new or increased measurable or ical Center. Supported by Grant IIT 16136 from Aventis Pharmaceuticals and evaluable disease, and/or progression by serum PSA16) deGrant 3M01RR00334 –33S2 from the National Institutes of Health. spite standard hormonal therapy, including antiandrogen * Financial interest and/or other relationship with Aventis. withdrawal (4 weeks for flutamide and 6 weeks for others) † Financial interest and/or other relationship with Aventiswere eligible. Additional requirements were Eastern CooperPasteur Pharmaceuticals. ‡ Correspondence: Department of Medicine, Oregon Health and ative Oncology Group (ECOG) performance status 2 or less, Science University, Mail Code CR145, 3181 Southwest Sam Jackson PSA greater than 5 ng/ml in patients without measurable Park Rd., Portland, Oregon 97239 (telephone: 503-494-3253; FAX: soft tissue disease, serum testosterone less than 50 ng/ml, life 503-494-6197; e-mail: [email protected]). § Financial interest and/or other relationship with Aventis and expectancy greater than 3 months and age 18 years or greater. Prior exposure to chemotherapy, including docetaxel Novacea. 888
CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR PROSTATE CANCER
and estramustine, was not restricted to allow exploration of the hypothesis that calcitriol may restore sensitivity to chemotherapy and because to our knowledge no standard therapy that produces a demonstrated clinical benefit is available for this patient population. Patients were excluded due to a second active malignancy, brain metastases, significant active medical illness, contraindications to aspirin, warfarin or heparin therapy, nephrolithiasis within 5 years, history of cancer related hypercalcemia, atrial fibrillation, myocardial infarction or uncontrolled heart failure, recent history of cerebrovascular accident, active thrombophlebitis, history of hypercoagulability or pulmonary embolus, hypersensitivity to drugs formulated with polysorbate-80, symptomatic third space fluid accumulation, grade 2 or greater peripheral neuropathy, investigational therapy within 28 days, prior radiation therapy to 20% or greater of bone marrow, radiation within the last month or any previous treatment with radiopharmaceuticals, major surgery within 21 days, white blood count less than 3,000/mm3, neutrophil count less than 1,500/mm3, platelet count less than 100,000/mm3, conjugated bilirubin greater than upper limit of normal (ULN), alanine transaminase (ALT) or aspartate transaminase (AST) greater than 2.0 ⫻ ULN when alkaline phosphatase was 2.5 or less ⫻ ULN, ALT or AST greater than 1.5 ⫻ ULN when alkaline phosphatase was greater than 2.5 ⫻ ULN, creatinine greater than 2 mg/dl, calcium greater than ULN and alkaline phosphatase 4.0 or greater ⫻ ULN, except in patients with bone metastases and normal conjugated bilirubin, AST and ALT. Signed, informed consent was obtained from all patients and the study was approved by the Institutional Review Boards of the Oregon Health and Science University, and Portland Veterans Affairs Medical Center. Evaluations. Pretreatment evaluation included medical history, physical examination, whole body bone scan, computerized tomography of the abdomen and pelvis, electrocardiogram, serum testosterone measurement, chemistry panel, PSA and complete blood count with automated differential. Assessment of adverse events and physical examination, serum PSA, chemistry panel, international normalized ratio and complete blood count were repeated every 3 weeks. In patients with measurable disease measurements by the same imaging modality were repeated every 9 weeks. Bone scans were repeated as clinically indicated. Patients taken off study without evidence of progression were monitored until progression. All patients off study were followed until the stabilization or resolution of toxicity and for survival every 6 months. Treatment regimen. Patients entering the study on a gonadotropin-releasing hormone agonist continued gonadotropin-releasing hormone agonist therapy. Concomitant use of corticosteroids, antiandrogens, estrogens, thiazide diuretics, magnesium containing antacids or bile-resin binders was prohibited. Calcium supplements were prohibited during week 1 of each treatment cycle. Patients were encouraged to increase oral hydration for 3 days beginning 12 hours before each calcitriol dose. Calcitriol (60 g as 0.5 g tablets) was given orally in 4 divided doses for 4 hours on day 1. Dexamethasone (8 mg orally) was given twice daily for the first 3 days and 280 mg estramustine were given orally 3 times daily for days 1 through 5. Docetaxel (60 mg/m2) intravenously was given for 60 minutes on day 2 of treatment week 1 and then increased to 70 mg/m2 for subsequent cycles if there was no grade 3 or greater toxicity during cycle 1. Treatment was administered every 21 days for 12 cycles unless there was disease progression or unacceptable toxicity. Aspirin (325 mg) was given orally daily and patients received 2 mg warfarin orally daily, which was decreased to 1 mg if the international normalized ratio was greater than 1.5. Patients were routinely asked at followup visits whether they were able to ingest all calcitriol pills. Growth factors
889
were allowed after the first cycle of treatment at physician discretion as long as dose decrease guidelines in the protocol were followed. Bisphosphonate use was not restricted. Dose Modifications for Docetaxel: The dose of docetaxel was decreased by 25% if the start of a cycle was delayed by a persistently low platelet or neutrophil count, or there was grade 4 afebrile neutropenia 7 days or greater in duration, grade 4 febrile neutropenia, grade 4 thrombocytopenia, AST or ALT 2.5 to 5 ⫻ ULN with alkaline phosphatase 2.5 or less ⫻ ULN, or AST or ALT was 1.6 to 5 ⫻ ULN and alkaline phosphatase was 2.5 to 5 ⫻ ULN. Therapy with docetaxel was withheld for a platelet count of less than 100,000/mm3 or a neutrophil count of less than 1,500/mm3 until the 2 counts were above these parameters. Therapy was withheld for bilirubin greater than ULN, alkaline phosphatase greater than 5 ⫻ ULN, or AST or ALT greater than 5 ⫻ ULN. Therapy was resumed at a 25% dose decrease in patients in whom liver function tests recovered within 3 weeks. Docetaxel was discontinued for any grade 4 allergic reaction or for grades 3 or greater neuropathy. For other grades 3 or greater nonhematological toxicities docetaxel treatment was withheld until toxicity resolved to grade 1 or less and then reinstituted at a 25% dose decrease. Patients were removed from the study due to toxicity related treatment delays in excess of 3 weeks. Dose Modifications for Estramustine: Patients with a thromboembolic complication could continue estramustine only with therapeutic anticoagulation. Estramustine was stopped for uncontrolled, intolerable nausea. Patients who could not continue estramustine were allowed to stay on study with docetaxel and calcitriol. Dose Modifications for Calcitriol: Patients were allowed a maximum of 2 calcitriol dose decreases, that is the first to 45 g and the second to 30 g. Calcitriol was held for grade 2 or 3 hypercalcemia until the return of normocalcemia and then it was decreased by 1 dose level. Calcitriol was held for grade 2 creatinine increase or for other grade 3 calcitriol related toxicities until resolution to grade 1 or less. It was then decreased by 1 dose level. Development of a calcium containing kidney stone prompted a 1 dose level decrease. Calcitriol was discontinued for grade 4 hypercalcemia, a grade 3 or higher creatinine increase, the development of a second kidney stone and for any grade 4 toxicity or recurrent grade 3 toxicity attributable to calcitriol. Assessment of outcome. The primary objective was to assess the safety of the combination of calcitriol with docetaxel and estramustine. Toxicity was measured using National Cancer Institute common toxicity criteria, version 2.0. Dose limiting toxicity (DLT) was defined as grades 3 or greater nonhematological toxicity, neutropenic fever, prolonged neutropenia (absolute neutrophil count less than 500/mm3 more than 7 days in duration) or grade 4 thrombocytopenia. Prospectively planned efficacy analyses included the fraction of patients who had a 50% or greater and 75% or greater decrease in serum PSA, the fraction of patients with measurable disease who met Response Evaluation Criteria In Solid Tumors criteria for response,17 time to progression and time to death. Progression was defined by standard criteria for measurable and evaluable disease,17 and for PSA.16 Two or more new lesions were required to document progression on whole body bone scan. Statistical design. The primary end point was toxicity of the combination of calcitriol, docetaxel and estramustine. The trial design called for treatment of 6 patients at the planned doses and dose de-escalation of calcitriol if greater than 2 of the first 6 patients experienced DLT during chemotherapy cycle 1. After the first 12 patients were treated the protocol was amended to enroll 24 to collect more robust toxicity data and preliminary efficacy data. With 24 patients treated the 95% exact binomial CI of the rate of severe toxicities was no wider than 40%. The probability of observing at least 1 toxicity of grade 4 or higher was 71% and 92%
890
CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR PROSTATE CANCER
if the true rate of grade 4 or higher toxicities were 5% and 10%, respectively. RESULTS
Patient characteristics. A total of 24 men were recruited between January 2003 and March 2004. Table 1 lists pretreatment characteristics. Median patient age was 67 years. Median ECOG performance status was 1. All patients had metastatic disease to bone. Of the patients 13 (54%) received prior chemotherapy, including at least 1 docetaxel containing regimen, of whom the majority received more than 1 prior chemotherapy regimen. Seven of the 13 patients who received prior docetaxel based chemotherapy had responded (confirmed 50% decrease in PSA) to prior docetaxel based treatment. Median time since previous chemotherapy was 10 weeks (range 2 to 77) (table 1). Treatment. The median duration of treatment was 5 cycles (range 1 to 12). Four patients (16.7%) completed all 12 planned treatments and 15 (62.5%) stopped treatment due to disease progression, 4 (16.7%) because of toxicity and 1 (4.2%) due to a new diagnosis of lung cancer. The docetaxel dose was not escalated to 70 mg/m2 in 2 patients due to liver function abnormalities (1) and neutropenic fever (1). The calcitriol was dose decreased in 1 patient after 1 cycle for grade 2 hypercalcemia. The estramustine dose was decreased in 2 patients. Toxicity. Overall the regimen was well tolerated. One of the first 6 patients (16.7%) experienced protocol defined DLT (grade 3 liver function test increase) during chemotherapy cycle 1, and so the calcitriol dose remained at 60 mcg for the remainder of the study. There were no treatment related deaths. Table 2 lists all grades 2 or greater treatment related toxicities. Grade 3 or 4 neutropenia was seen in 3 patients (12.5%) and it was associated with fever in 2. Additional
TABLE 1. Patient characteristics at study entry
grade 1 toxicities likely related to calcitriol were hypercalcemia in 12.5% of cases and increased creatinine in 42%. Hypophosphatemia was notably common. One patient had grade 2 disorientation and ataxia on days 3 to 5 of cycles 8 and 9. No neurological or metabolic pathology was identified. The syndrome resolved spontaneously and the patient was withdrawn from the study. Four patients experienced thomboembolic complications, including pulmonary emboli in 1 and deep venous thromboses in 3. In 2 of these patients thromboembolism developed while anticoagulation was temporarily withheld due to minor surgical procedures. Response to therapy. PSA Decrease: Two patients were not evaluable for a PSA decrease. One patient had an initial PSA of less than 5 ng/ml and the other was removed from the study after only 1 treatment due to a diagnosis of lung cancer. Seven of the 22 patients (32%, 95% CI 12 to 51) evaluable for a PSA decrease achieved a confirmed PSA decrease in excess of 50%, while 3 (14%, 95% CI 0 to 28) achieved a confirmed greater than 75% decrease in PSA. Five patients had stable PSA for at least 4 treatment cycles (12 weeks). Table 3 lists response data. PSA decreases in excess of the 50% rate were seen in 55% of chemotherapy naı¨ve patients (95% CI 24 to 85) and in only 9% (95% CI 0 to 27) of those previously exposed to docetaxel. Response in Measurable Disease: A total of 16 patients had measurable disease and 15 were evaluable. Two patients had a confirmed partial response (13%, 95% CI 4 to 31), while 3 (20%, 95% CI 1 to 57) had confirmed stable disease. The 2 responders were chemotherapy naı¨ve. Time to Progression (TTP) and Survival: Median TTP was 17 weeks (95% CI 12 to 22). Median overall survival was 54 weeks (95% CI 47 to 61). Chemotherapy naı¨ve patients trended toward a longer median TTP than those who received prior chemotherapy (24 weeks, 95% CI 6 to 42, vs 16, 95% CI 5 to 27, log rank p ⫽ 0.08). Median survival was longer in chemotherapy naı¨ve patients (not achieved) than in patients who received prior chemotherapy (41 weeks, 95% CI 32 to 51, log rank p ⫽ 0.05).
Characteristic No. pts Median age (range) No. ECOG performance status: 0 1 2 Median ng/ml PSA (range) Median gm/dl hemoglobin (range) Median /l alkaline phosphatase (range) No. metastasis site (%): Bone only Bone ⫹ lymph nodes Bone ⫹ visceral metastases Bone, lymph node ⫹ visceral metastases No. prior radiation (%): External beam radiation to primary tumor External beam and brachytherapy to primary tumor External beam radiation to metastases Radiopharmaceuticals No. prior hormonal therapies for prostate Ca (%): 1 2 3 4 No. prior chemotherapy regimens for prostate Ca (%): 0 1 2 3 No. prior docetaxel (%): Docetaxel alone Calcitriol ⫹ docetaxel Docetaxel ⫹ estramustine No. prior experimental therapies (%)
24 67
DISCUSSION
(48–79)
11 10 3 114.8 (0.8–1,050) 12.5 (8.4–15.2) 134 (33–538) 7 12 3 2
(29) (50) (13) (8)
7 1
(29) (4)
8 1
(33) (4)
3 11 4 6
(13) (45) (17) (25)
11 8 4 1 13 5 4 6 4
(45) (33) (17) (4) (54) (39) (31) (46) (17)
The addition of calcitriol to docetaxel plus estramustine is feasible and no appreciable increase in toxicity was observed in this pilot study. The regimen was well tolerated with adverse events similar to what has previously been reported with docetaxel plus estramustine. Thromboembolic complications were seen despite the prophylactic use of anticoagulation. Neutropenic fever was seen in 2 patients. The study was not designed to determine if the addition of calcitriol increased treatment efficacy. PSA and measurable disease response rates in chemotherapy naı¨ve patients were similar to those seen in studies of docetaxel plus estramustine but the small number of patients and lack of randomization prevent us from drawing definitive conclusions about the efficacy contribution of calcitriol. Outcomes in patients who received prior therapy with docetaxel were poor, highlighting a desperate need for novel approaches to treatment in these patients. The contribution of estramustine to the efficacy of docetaxel for androgen independent prostate cancer remains uncertain, given similar survival outcomes for experimental arms with and without this agent in SWOG 9916 and TAX 327.2, 3 The addition of estramustine or other potentially synergistic agents to docetaxel based therapy in patients who do not respond to or who progress on initial docetaxel treatment is a strategy that warrants further investigation. One patient on this study achieved potential benefit in the form of a decrease in PSA after previously progressing on docetaxel plus calcitriol.
891
CALCITRIOL, DOCETAXEL AND ESTRAMUSTINE FOR PROSTATE CANCER TABLE 2. Grades 2 or greater treatment related toxicity Toxicity % Grade 2
% Grade 3
% Grade 4
% Total Grades 2–4
25 4.2 0.0 54.2 29.2 4.2 0.0 0.0 0.0
4.2 0.0 0.0 0.0 16.7 0.0 4.2 4.2 4.2
0.0 12.5 8.3 0.0 0.0 0.0 0.0 0.0 0.0
29.2 16.7 8.3 54.2 45.8 4.2 4.2 4.2 4.2
50.0 16.7 16.7 0.0 12.5 8.3 8.3 8.3 4.2 8.3 0.0 4.2 4.2 0.0 4.2 0.0 4.2 4.2 0.0 0.0 0.0 4.2
0.0 4.2 0.0 12.5 0.0 4.2 4.2 4.2 4.2 0.0 8.3 0.0 0.0 4.2 0.0 4.2 0.0 0.0 0.0 4.2 4.2 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 4.2 0.0 0.0 0.0
50.0 20.8 16.7 12.5 12.5 12.5 12.5 12.5 8.3 8.3 8.3 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2 4.2
Laboratory: Anemia Neutropenia Neutropenic fever Hyperglycemia Hypophosphatemia Hypercalcemia Hypokalemia Increased ALT Prothrombin time Clinical: Fatigue Nausea Constipation Deep venous thrombosis Dyspnea Edema Infection Vomiting Dehydration Oncholysis Syncope Ataxia Confusion Chronic obstructive pulmonary disease exacerbation Dizziness Edema Fever Headache Perforated diverticulum Pleural effusions Pulmonary embolism Weakness
TABLE 3. Activity by prior therapy Prior Chemotherapy
No. Pts
No. PSA Evaluable
No. Confirmed PSA Decrease 50% or Greater
None Any docetaxel Greater than 1 prior chemotherapy Calcitriol ⫹ docetaxel Docetaxel ⫹ estramustine Docetaxel alone
11 13 5 4 6 5
11 11 3 3 5 4
6 (55) 1 (9) 0 1 (33) 0 0
4.
5.
6.
7.
Given the results of SWOG 9916 and TAX 327, and Food and Drug Administration approval of docetaxel and prednisone for androgen independent prostate cancer, further development of this estramustine containing regimen is not planned. Instead, the addition of a new, high dose formulation of calcitriol that avoids the need to swallow a large number of pills (DN-101, Novacea, South San Francisco, California) to docetaxel is being tested in an international, double-blind, placebo controlled trial. Recent reviews provide further discussion of calcitriol biology, current status and future directions for its development in prostate cancer.11, 18 REFERENCES
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phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol, 17: 3461, 1999 17. Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L. et al: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 92: 205, 2000 18. Beer, T. M., Myrthue, A. and Eilers, K. M.: Rationale for the development and current status of calcitriol in androgenindependent prostate cancer. World J Urol, 23: 28, 2005