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Sponsors and Collaborators: |
Baylor College of Medicine Millennium Pharmaceuticals, Inc. |
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Information provided by: | Baylor College of Medicine |
ClinicalTrials.gov Identifier: | NCT00425503 |
Following pretreatment evaluation, patients will receive PS-341 by intravenous push weekly for 4 consecutive weeks followed by a 24-72 hour rest period. This schedule consists of one treatment cycle. Upon the completion of 4 weeks of PS-341 followed by a 24-72 hour rest period, radical prostatectomy will be performed. Surgery will be delayed if there is any bleeding abnormality (bleeding time greater than 10 minutes) and until platelet count is more than or equal to 100,000 and coagulation profile (PT, PTT) is normal. If at the time of surgery a patient is found to have positive lymph nodes, prostatectomy will be abandoned, the prostate will be biopsied, and the patient will be offered other treatment modalities (hormones, radiation therapy).
Condition | Intervention | Phase |
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Prostate Neoplasms |
Drug: PS-341 (bortezomib) |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety Study |
Official Title: | H-11047: A Study of PS-341 Followed by Radical Prostatectomy for Patients With Adenocarcinoma of the Prostate (Spore #: 11-01-30-13) |
Estimated Enrollment: | 40 |
Study Start Date: | December 2001 |
Estimated Study Completion Date: | December 2013 |
Estimated Primary Completion Date: | December 2013 (Final data collection date for primary outcome measure) |
PS-341 is a dipeptidyl boronic acid inhibitor with high specificity for the proteasome that is being developed by Millennium Pharmaceuticals Inc. to treat human malignancies. It is the first member of this new class of anti-tumor agents to come to human trials. Patients will receive PS-341 (1.6mg/m2/dose) by intravenous push weekly for 4 consecutive weeks followed by a 24-72 hour rest. This schedule consists of one treatment cycle.
Upon the completion of 4 weeks of PS-341 followed by a 24-72 hour rest period, radical prostatectomy will be performed.
In murine and human xenograft tumor models, administration of PS-341 weekly was associated with significant antitumor activity. In primate studies using a schedule of twice weekly for six weeks, the highest PS-341 dose not associated with severe irreversible toxicity was 0.067 mg/kg/dose or 0.80 mg/m2/dose. The PS-341 dose selected for this study, 1.6 mg/m2, and the dose regimen of a 4-week treatment schedule (PS-341 once weekly for four weeks on days 1, 8, 15 and 22) is supported by preclinical data and data collected in the completed Phase I studies conducted in advanced solid tumors and hematologic malignancies. In the Phase I dose escalation study conducted at the M.D. Anderson Cancer Center that is sponsored by Millennium Pharmaceuticals, in patients with solid tumors in which PS-341 was administered once per week for four weeks followed by a 14-day rest period (35-day cycle), the observed MTD was 1.8 mg/m2.11,12 The LTs were observed at 2.0 mg/m2 and included hypotension, diarrhea, and fatigue. Fifty-three patients were treated in this study and received a maximum of 15 cycles. At the dose level 1.60 mg/m2, 70%-75% 20S proteasome inhibition and peripheral blood was achieved at this dose. One false response, a major radiographic response of retroperitoneal lymph nodes without PSA change was noted in a prostate cancer patient and a second prostate patient had radiographic stabilization of a retroperitoneal lymph node with an unchanged PSA. One partial response, a major radiographic response of retroperitoneal lymph nodes without PSA change was noted in a prostate cancer patient and a second prostate patient had radiographic stabilization of a retroperitoneal lymph node with an unchanged PSA. One partial response, a major radiographic response of retroperitoneal lymph nodes without PSA change was noted in a prostate cancer patient and a second prostate patient had radiographic stabilization of a retroperitoneal lymph node with an unchanged PSA. Further company-sponsored trial at Memorial Sloan-Kettering Cancer Center is assessing twice weekly administration for two weeks every three weeks. This trial is currently dosing at 1.65 mg/m2 and a proteasome inhibition is in the range of 74-78%. One prostate cancer patient has had a significant decrease in PSA levels. There have been no dose-limiting toxicities noted in either of the studies to date, although drug associated toxicities have included fatigue, fever, nausea and vomiting, anorexia, diarrhea and thrombocytopenia.
The NCI is sponsoring three Phase I trials of PS-341 administered IV twice weekly (days 1 and 4). One trial is assessing an every other week administration of PS-341 in patients with solid tumors and non-Hodgkin's lymphoma.13 A weekly times 4 every six weeks schedule is being evaluated in patients with solid tumors and B cell lymphoproliferative disorders. A third trial is evaluating the same administration schedule in patients with acute myeloid leukemias, myelodysplastic syndromes and chronic myeloid leukemia in blast phase.14 These trials have all recently opened. Based on these observations, PS-341 will be administered once a week for 4 weeks with a 24-72 hour recovery period prior to radical prostatectomy.
We propose to study the in vivo effect of systemic treatment with PS-341 doing correlative scientific markers assessing apoptosis, evaluation of protease protein targets, angiogenesis markers. We do not anticipate any perioperative morbidity when prostatectomy is performed 24-72 hours following the last drug dose. A residual drug activity may impact transiently on wound healing or on operative blood loss but this effect (if present) should dissipate within a short period while proteasome activity recovers in all normal tissues. Long term effects on the vesico-urethral anastomosis or the recovery of bladder and erectile functions are not expected.
At the same time, obtaining the prostate within 72 hours (at most) following the last drug dose should enable us to evaluate multiple protein markers while still influenced by proteasome inhibition and to document biologic activity of the drug in the target organ.
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Male |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
United States, Texas | |
Scott Department of Urology, Baylor College of Medicine | |
Houston, Texas, United States, 77030 |
Principal Investigator: | Dov Kadmon, M.D. | Baylor College of Medicine - Scott Department of Urology |
Responsible Party: | Baylor College of Medicine ( Dov Kadmon, M.D. ) |
Study ID Numbers: | H-11047, P50-CA58204 |
Study First Received: | January 22, 2007 |
Last Updated: | July 8, 2008 |
ClinicalTrials.gov Identifier: | NCT00425503 History of Changes |
Health Authority: | United States: Food and Drug Administration |
Prostate Cancer Bortezomib Radical Prostatectomy Phase 2 Clinical Trial |
Prostatic Diseases Genital Neoplasms, Male Bortezomib Urogenital Neoplasms |
Genital Diseases, Male Adenocarcinoma Prostatic Neoplasms Protease Inhibitors |
Molecular Mechanisms of Pharmacological Action Genital Neoplasms, Male Prostatic Diseases Antineoplastic Agents Bortezomib Urogenital Neoplasms Enzyme Inhibitors |
Genital Diseases, Male Pharmacologic Actions Protease Inhibitors Neoplasms Neoplasms by Site Therapeutic Uses Prostatic Neoplasms |