Bortezomib And Irinotecan
Background-done-I-10
Description-done-P-10
Proposed strategy-P/I-20 a Phase II study can be performed-Title
Rationale-P/I-20
Trial Outline-P/I-30
Background
Bortezomib, chemically a dipeptidyl boronic acid from the amino acids leucine and phenyl alanine, is a proteosome inhibitor.
It causes accumulation of the growth inhibitory molecules p21 and p27 subsequently leading to cell arrest and cell death.
• Irinotecan is a prodrug, whose active metabolite inhibits Topoisomerise 1 leading to generation and accumulation of irreversible double-strand breaks in DNA during synthesis and finally cell death.
Preclinical studies reported anti-tumour response of bortezomib and Irinotecan combination and suggested that prevention of NF-kB …show more content…
Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics.
RESULTS. Fifty-one enrolled patients with malignancies, including colorectal cancer
(n ¼ 23 patients), lung cancer (n ¼ 6 patients), gastroesophageal cancer (n ¼ 6 patients), and pancreatic cancer (n ¼ 3 patients), received _1 dose of study drug.
Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m2 bortezomib and 125 mg/m2 irinotecan.
The most common grade _3 bortezomib-related nonhematologic adverse events were fatigue (n ¼ 5 episodes), diarrhea (n ¼ 4 episodes), and nausea (n ¼ 4 episodes). grade _3 bortezomib-related hematologic adverse events included neutropenia
(n ¼ 6 episodes) and thrombocytopenia (n ¼ 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to …show more content…
It is the first therapeutic proteasome inhibitor to be tested in humans [9]. Initial laboratory findings showed that blocking the proteasome in vivo did not immediately alter the normal life cycle of the cell [10]. The ensuing studies revealed that the proteasome was important in the activation of NF-κB [11] implicated as one of the mechanisms of tumor cell resistance to apoptosis. Based on these observations, in August 1994, Julian Adams examined bortezomib as a possible anti-cancer molecular targeting agent. By 1997, it was also shown that bortezomib could have potential influence on inhibiting tumor growth and metastasis in a mouse model of lung cancer [12]. The phase I clinical trials at the University of North Carolina presented evidence that bortezomib was effective in treating multiple myeloma. It was an exciting observation that bortezomib erased all signs of cancer from a
47-year old woman, who was diagnosed with advanced stages of multiple myeloma.
Following phase II clinical trials, bortezomib was approved on May 13, 2003 by the US
FDA under a Fast-Track Application, as an injectable small molecule for the treatment of multiple myeloma. In December 2006, it was approved for the treatment of relapsed
Description-done-P-10
Proposed strategy-P/I-20 a Phase II study can be performed-Title
Rationale-P/I-20
Trial Outline-P/I-30
Background
Bortezomib, chemically a dipeptidyl boronic acid from the amino acids leucine and phenyl alanine, is a proteosome inhibitor.
It causes accumulation of the growth inhibitory molecules p21 and p27 subsequently leading to cell arrest and cell death.
• Irinotecan is a prodrug, whose active metabolite inhibits Topoisomerise 1 leading to generation and accumulation of irreversible double-strand breaks in DNA during synthesis and finally cell death.
Preclinical studies reported anti-tumour response of bortezomib and Irinotecan combination and suggested that prevention of NF-kB …show more content…
Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics.
RESULTS. Fifty-one enrolled patients with malignancies, including colorectal cancer
(n ¼ 23 patients), lung cancer (n ¼ 6 patients), gastroesophageal cancer (n ¼ 6 patients), and pancreatic cancer (n ¼ 3 patients), received _1 dose of study drug.
Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m2 bortezomib and 125 mg/m2 irinotecan.
The most common grade _3 bortezomib-related nonhematologic adverse events were fatigue (n ¼ 5 episodes), diarrhea (n ¼ 4 episodes), and nausea (n ¼ 4 episodes). grade _3 bortezomib-related hematologic adverse events included neutropenia
(n ¼ 6 episodes) and thrombocytopenia (n ¼ 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to …show more content…
It is the first therapeutic proteasome inhibitor to be tested in humans [9]. Initial laboratory findings showed that blocking the proteasome in vivo did not immediately alter the normal life cycle of the cell [10]. The ensuing studies revealed that the proteasome was important in the activation of NF-κB [11] implicated as one of the mechanisms of tumor cell resistance to apoptosis. Based on these observations, in August 1994, Julian Adams examined bortezomib as a possible anti-cancer molecular targeting agent. By 1997, it was also shown that bortezomib could have potential influence on inhibiting tumor growth and metastasis in a mouse model of lung cancer [12]. The phase I clinical trials at the University of North Carolina presented evidence that bortezomib was effective in treating multiple myeloma. It was an exciting observation that bortezomib erased all signs of cancer from a
47-year old woman, who was diagnosed with advanced stages of multiple myeloma.
Following phase II clinical trials, bortezomib was approved on May 13, 2003 by the US
FDA under a Fast-Track Application, as an injectable small molecule for the treatment of multiple myeloma. In December 2006, it was approved for the treatment of relapsed