Fractionated Docetaxel and Radium 223 in Metastatic Castration-Resistant Prostate Cancer
NCT ID: NCT03737370
Last Updated: 2025-10-07
Study Results
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Basic Information
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COMPLETED
PHASE1
43 participants
INTERVENTIONAL
2018-01-30
2025-09-30
Brief Summary
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Detailed Description
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Secondary Objectives include: assessment of progression-free survival, time to treatment failure, overall survival, ability of subjects to complete 6 cycles of the combination therapy, assessment of Prostate Specific Antigen (PSA) kinetics and objective responses (measurable disease), assessment of quality of life and assessment of bone bio-marker outcomes.
The study features a 4-week lead-in period with docetaxel monotherapy to assess for docetaxel intolerance. The lead-in period is then followed by combination therapy with Ra-223 every 4 weeks for 6 cycles in a traditional Phase I dose-escalation design.
A provision has been made to include prophylactic granulocyte colony stimulating factor (G-CSF) cohorts after the lead-in period if neutropenia is the dose limiting toxicity at either dose level.
The investigators hypothesize that the fractionated dosing of docetaxel will significantly mitigate the hematologic toxicity, preserve antineoplastic activity and allow for maintenance of the 4-weekly Ra-223 schedule.
Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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Dose escalation
There are four dose cohorts (1, 1a, 2, 2a) in this arm and two dose levels of docetaxel (40mg/m\^2 \[level 1\] and 50mg/m\^2 \[level 2\]). Dosing of Radium 223 remains the same in all cohorts (55 KBq/kg given every 28 days for 6 cycles).
Maximum tolerated dose (MTD) of docetaxel will be assessed. MTD is defined as the highest dose-level, among those tested, associated with a rate of less than a 33% dose limiting toxicity (DLT).
Docetaxel
Docetaxel will be administered every 2 weeks (on Day 1 and Day 15 of a 28 day cycle). Fractionated dosing dependent on cohort.
Radium 223
Radium 223 will be delivered every 28 days (on day 1) for 6 cycles.
Dose expansion
If the maximum tolerated dose (MTD) of docetaxel is found in arm 1, this dose level will be expanded to include an additional 25 subjects to confirm the safety and explore the preliminary anti-cancer effect. If the MTD is not identified, the study will be stopped and the expansion cohort will not be accrued.
Docetaxel
Docetaxel will be administered every 2 weeks (on Day 1 and Day 15 of a 28 day cycle). Fractionated dosing dependent on cohort.
Radium 223
Radium 223 will be delivered every 28 days (on day 1) for 6 cycles.
Interventions
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Docetaxel
Docetaxel will be administered every 2 weeks (on Day 1 and Day 15 of a 28 day cycle). Fractionated dosing dependent on cohort.
Radium 223
Radium 223 will be delivered every 28 days (on day 1) for 6 cycles.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Documented metastatic castration resistant disease with PSA progression, radiographic progression, or both, despite medical or surgical castration
3. Two or more bone metastases detected on skeletal scintigraphy
4. Eligible for docetaxel chemotherapy
5. ECOG Performance Status 0-2
6. Adequate organ function:
1. Hemoglobin \> 10 g/dL
2. Absolute Neutrophil Count ≥ 1,500 K/mL
3. Platelet count ≥ 150,000 x 10\^9/L
4. Total bilirubin ≤ 1.5x upper limit of normal range, excluding Gilbert syndrome
5. Serum AST ≤ 1.5 x upper limit of normal range
6. Serum ALT ≤ 1.5 x upper limit of normal range
7. Estimated glomerular filtration rate (GFR) \> 30mL/min
8. Ongoing castration (androgen deprivation therapy or prior orchiectomy)
9. Male subjects with female sexual partners of childbearing potential must agree to use at least one highly effective methods of birth control.
10. Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures.
11. Age ≥ 18 years
Exclusion Criteria
2. Prior docetaxel for CRPC. (Permitted if given for castration sensitive disease \> 6 months prior).
3. Antiandrogen therapy within 4 weeks of enrollment. However, patients with primary failure of secondary anti-androgen therapy OR symptomatic progression, objective progression and/or biochemical evidence of rising PSA less than 4 weeks after discontinuation of anti-androgen therapy will not have anti-androgen withdrawal responses and will not be excluded.
4. Preexisting peripheral neuropathy grade 2 or higher.
5. Other serious medical condition as judged by the investigator.
6. Active second malignancy that requires therapy.
7. Known brain or leptomeningeal metastases
8. Concurrent enrollment in any other investigational anticancer therapy
9. Treatment with any myelosuppressive agent within 30 days of enrollment
10. Presence of bulky visceral metastases, defined as any of the following:
1. ≥ 4 lung lesions (at least 1cm each in size in the longest diameter) or pulmonary lymphangitic metastasis
2. Liver metastases with sum of lesion diameters totaling ≥ 5cm
11. Evidence of neuroendocrine or small cell differentiation on prior biopsy
12. History of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80
18 Years
ALL
No
Sponsors
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Bayer
INDUSTRY
Lahey Clinic
OTHER
Henry Ford Hospital
OTHER
Ohio State University Comprehensive Cancer Center
OTHER
Tufts Medical Center
OTHER
Responsible Party
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Principal Investigators
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Paul Mathew, MD
Role: PRINCIPAL_INVESTIGATOR
Tufts Medical Center
Locations
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Lahey Hospital & Medical Center
Boston, Massachusetts, United States
Tufts Medical Center
Boston, Massachusetts, United States
Henry Ford Health System
Detroit, Michigan, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
Countries
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References
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Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzen L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland OS, Sartor O; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. doi: 10.1056/NEJMoa1213755.
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014 Sep 11;371(11):1028-38. doi: 10.1056/NEJMoa1315815. Epub 2014 Sep 3.
Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Nakazawa M, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer. JAMA Oncol. 2015 Aug;1(5):582-91. doi: 10.1001/jamaoncol.2015.1341.
Oudard S, Banu E, Beuzeboc P, Voog E, Dourthe LM, Hardy-Bessard AC, Linassier C, Scotte F, Banu A, Coscas Y, Guinet F, Poupon MF, Andrieu JM. Multicenter randomized phase II study of two schedules of docetaxel, estramustine, and prednisone versus mitoxantrone plus prednisone in patients with metastatic hormone-refractory prostate cancer. J Clin Oncol. 2005 May 20;23(15):3343-51. doi: 10.1200/JCO.2005.12.187. Epub 2005 Feb 28.
Kellokumpu-Lehtinen PL, Harmenberg U, Joensuu T, McDermott R, Hervonen P, Ginman C, Luukkaa M, Nyandoto P, Hemminki A, Nilsson S, McCaffrey J, Asola R, Turpeenniemi-Hujanen T, Laestadius F, Tasmuth T, Sandberg K, Keane M, Lehtinen I, Luukkaala T, Joensuu H; PROSTY study group. 2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 2013 Feb;14(2):117-24. doi: 10.1016/S1470-2045(12)70537-5. Epub 2013 Jan 4.
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-22. doi: 10.1056/NEJMoa1001294.
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 10;368(2):138-48. doi: 10.1056/NEJMoa1209096. Epub 2012 Dec 10.
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. doi: 10.1056/NEJMoa1405095. Epub 2014 Jun 1.
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26(7):1148-59. doi: 10.1200/JCO.2007.12.4487.
Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. doi: 10.1056/NEJMoa041318.
Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation counting. Appl Radiat Isot. 2010 Jul-Aug;68(7-8):1523-8. doi: 10.1016/j.apradiso.2009.11.068. Epub 2009 Dec 2.
Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R, Pibida L. Revision of the NIST Standard for (223)Ra: New Measurements and Review of 2008 Data. J Res Natl Inst Stand Technol. 2015 Mar 11;120:37-57. doi: 10.6028/jres.120.004. eCollection 2015.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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Other Identifiers
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IIR-US-2016-3279
Identifier Type: -
Identifier Source: org_study_id
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