Bortezomib-Irinotecan

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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 activation by bortezomib may enhance Irinotecan mediated cytotoxicity.

The present study evaluated the safety and biologic effects of co-administration of bortezomib and irinotecan in patients with advanced solid tumors.

The rationale for combining bortezomib with irinotecan is based on observations of antitumor activity in a murine model of colon tumor xenografts. Growth was inhibited to a greater extent by bortezomib plus SN-38, the active metabolite of irinotecan, than the sum of the activities of either agent alone. This suggested, given the different mechanisms of action, that the two agents might be synergistic in a clinical setting.17 Moreover, bortezomib inhibited SN-38-induced activation of the transcription factor nuclear factor _B (NF_B).17 This activation has been shown to be associated with irinotecan resistance because it suppresses apoptosis.

Irinotecan-induced protection from apoptosis in CRC cell lines was reversed by inhibition of NF_B, enhancing the antitumor response, and further supporting the use of combination bortezomib plus irinotecan in clinical trials in patients with advanced CRC.18

A similarly impressive antitumor effect of the bortezomib
and irinotecan combination was observed in
mice bearing BXPC3 pancreatic tumor xenografts.18
Those findings suggested that bortezomib may
enhance irinotecan-mediated cytotoxicity by preventing
NF-kB activation.

In a phase I trial in patients with advanced solid tumors, including 23 patients with CRC, bortezomib plus irinotecan was welltolerated without additive toxicities.19 Nausea, vomiting, and diarrhea were the principle dose-limiting toxicities, leading to maximum tolerated doses (MTD) of 1.3 mg/m2 bortezomib and 125 mg/m2 irinotecan.

The results of a Phase I clinical trial to evaluate
the safety and biologic effects of bortezomib and irinotecan coadministered to patients with advanced
solid tumors are described in this report. This study
was designed to establish the maximum tolerated
dose (MTD) of bortezomib on Days 1, 4, 8, and 11
together with irinotecan on Days 1 and 8 of each 21-
day cycle. Pharmacodynamic studies also were undertaken
to evaluate the effect of concurrently administered
irinotecan on proteasome inhibition in peripheral blood
cells.

METHODS. Patients who had received _1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m2, 1.3 mg/m2, or 1.5 mg/m2) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m2 to 125 mg/m2) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. 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...
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