Phase II trial of PS-341 in patients with renal cell cancer

A University of Chicago phase II consortium study

Nancy B. Davis, David A. Taber, Rafat H. Ansari, Christopher Ryan, Christopher George, Everett E. Vokes, Nicholas J. Vogelzang, Walter M. Stadler

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

Purpose: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. Patients and Methods: PS-341 1.5 mg/m2 was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m2 ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. Results: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P = .07 and .11, respectively). Conclusion: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.

Original languageEnglish (US)
Pages (from-to)115-119
Number of pages5
JournalJournal of Clinical Oncology
Volume22
Issue number1
DOIs
StatePublished - 2004
Externally publishedYes

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Renal Cell Carcinoma
Proteasome Endopeptidase Complex
Biopsy
Disease Progression
Bortezomib
Febrile Neutropenia
Neoplasms
Proteasome Inhibitors
Arthralgia
Pleural Effusion
Thrombocytopenia
Electrolytes
Vomiting
Fatigue
Anemia
Diarrhea
Thrombosis
Hemorrhage
Pain
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase II trial of PS-341 in patients with renal cell cancer : A University of Chicago phase II consortium study. / Davis, Nancy B.; Taber, David A.; Ansari, Rafat H.; Ryan, Christopher; George, Christopher; Vokes, Everett E.; Vogelzang, Nicholas J.; Stadler, Walter M.

In: Journal of Clinical Oncology, Vol. 22, No. 1, 2004, p. 115-119.

Research output: Contribution to journalArticle

Davis, NB, Taber, DA, Ansari, RH, Ryan, C, George, C, Vokes, EE, Vogelzang, NJ & Stadler, WM 2004, 'Phase II trial of PS-341 in patients with renal cell cancer: A University of Chicago phase II consortium study', Journal of Clinical Oncology, vol. 22, no. 1, pp. 115-119. https://doi.org/10.1200/JCO.2004.07.165
Davis, Nancy B. ; Taber, David A. ; Ansari, Rafat H. ; Ryan, Christopher ; George, Christopher ; Vokes, Everett E. ; Vogelzang, Nicholas J. ; Stadler, Walter M. / Phase II trial of PS-341 in patients with renal cell cancer : A University of Chicago phase II consortium study. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 1. pp. 115-119.
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abstract = "Purpose: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. Patients and Methods: PS-341 1.5 mg/m2 was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m2 ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. Results: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P = .07 and .11, respectively). Conclusion: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.",
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AU - Ryan, Christopher

AU - George, Christopher

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AU - Vogelzang, Nicholas J.

AU - Stadler, Walter M.

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N2 - Purpose: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. Patients and Methods: PS-341 1.5 mg/m2 was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m2 ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. Results: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P = .07 and .11, respectively). Conclusion: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.

AB - Purpose: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. Patients and Methods: PS-341 1.5 mg/m2 was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m2 ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. Results: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P = .07 and .11, respectively). Conclusion: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.

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