Topics:

Current Clinical Trials With STI571

Current Clinical Trials With STI571

STI571 (Gleevec) is a member of the 2-phenylaminopyrimidine family of adenosine triphosphate (ATP) binding site inhibitors of protein tyrosine kinase. It potently inhibits the tyrosine kinase activity of Abl and Bcr-Abl,[1-3] platelet-derived growth factor receptor (PDGF-R), and Kit (stem cell factor receptor).[4-6]

The molecular abnormality in chronic myelogenous leukemia (CML) is considered to be caused by Bcr-Abl. CML is characterized by the presence of the Philadelphia chromosome (Ph), which is formed by a translocation between a portion of chromosome 22 and chromosome 9. The fusion of the Abl gene from chromosome 9 with the Bcr gene from chromosome 22 creates the Bcr-Abl fusion gene on chromosome 9.[7] Because STI571 potently inhibits Bcr-Abl tyrosine kinase, and selectively kills Bcr-Abl-expressing tumor cells,[8,9] it was chosen as a lead compound for clinical development in CML. Its demonstrated efficacy in patients with Bcr-Abl-positive leukemia in the initial clinical trial was a successful culmination of rationally designed molecularly targeted therapy.[10,11] Because STI571 also potently inhibits PDGF-R and Kit tyrosine kinases [4-6,12], the agent is being evaluated in tumors that abnormally express these regulatory proteins.

When STI571 is combined with other antileukemia agents, including interferon, daunorubicin (Cerubidine), doxorubicin, etoposide, 4-hydroperoxycyclophosphamide, vincristine, and cytarabine, the combination produces synergistic cytotoxicity in Bcr-Abl-expressing cells in vitro.[13,14] In contrast, the combination of STI571 and methotrexate appears to be antagonistic.[14] Interaction with hydroxyurea is uncertain since both additive[14] and antagonistic cytotoxicity have been reported.[13] The safety and efficacy of STI571 administered in combination with other chemotherapy agents is unknown and requires evaluation in adequately designed clinical trials.

STI571 inhibits the growth of glioma cells in vitro and in vivo, probably by disrupting the PDGF-R/PDGF autocrine loop, but without inducing apoptosis.[6] Similarly, in vitro treatment with STI571 inhibits the proliferation of Kit-expressing small-cell lung cancer cells without inducing apoptosis.[12,15] Thus, in contrast to the apoptosis induced by STI1571 in Bcr-Abl leukemia cells, the in vitro activity of this agent in PDGF-R-expressing glioma cells and Kit-expressing small-cell lung cancer cells appears to be cytostatic in nature.

The first phase I clinical study of STI571 was initiated in 1998 in patients with chronic phase CML after interferon-alpha failure. Sequential cohorts of patients received oral daily doses ranging from 25 to 1,000 mg/d. Nearly all patients with chronic phase CML who received at least 300 mg daily achieved a complete hematologic response. [10] Major cytogenetic responses (0% to 35% Philadelphia chromosome [Ph]-positive metaphase) occurred in 31% of these patients; 13% were complete cytogenetic responses.

STI571 also has substantial single-agent activity in patients with blast crisis CML and Ph-positive acute lymphocytic leukemia (ALL).[11] In contrast to chronic phase CML, most of these responses are short lived.[11] Although the dose-limiting toxicity was not identified, 400 mg daily was recommended for patients with chronic CML, and 600 mg daily for CML blast crisis. Preliminary results of phase II trials confirmed the phase I experience.[16,17] On May 11, 2001, the Food and Drug Administration approved STI571 as an oral therapy for the treatment of patients with CML in blast crisis (accelerated phase) or chronic phase after failure of interferon-alpha therapy.

Treatment with STI571 is generally well tolerated. The most common toxicities include mild nausea, muscle cramps, arthralgia, rash and edema.[10, 11] Reversible hepatic transaminase elevations may also occur, particularly at higher dose levels.

Because of the very high rate of response in patients with interferon-alpha-refractory CML, the role of STI571 in the frontline treatment of this disease is being evaluated. A multicenter phase III trial of STI571 vs interferon-alpha plus low-dose cytarabine in patients with previously untreated CML has been initiated but results are not yet available. To improve on the results in patients with blast crises and Ph-positive ALL, studies are currently evaluating the combination of STI571 with other standard chemotherapy agents.

STI571 has recently been shown to be highly efficacious in patients with gastrointestinal stromal tumor (GIST)—a relatively rare gastrointestinal neoplasm derived from mesenchymal cells that express Kit (in most cases as a result of activating mutations of the c-kit oncogene).[18,19-21] In a randomized phase II trial of STI571 administered at 400 or 600 mg/d, objective responses were observed in 59% of patients with unresectable or metastatic GIST.[19] The activity of STI571 in GIST is exceptionally good, given that this tumor is generally unresponsive to standard chemotherapy (response rate < 5%). Based on these very promising results, National Cancer Institute’s Division of Cancer Treatment and Diagnosis (NCI-DCTD) is sponsoring a phase III intergroup trial of STI571 comparing the safety and efficacy of treatment with 400 vs 800 mg daily.

In summary, STI571 is a potent inhibitor of Bcr-Abl, PDGF-R, and Kit tyrosine. Treatment with this agent results in high response rates among patients with CML. STI571 also has demonstrated remarkable activity in GIST, a c-kit expressing tumor. In collaboration with Novartis Pharmaceuticals, NCI-DCTD is sponsoring the clinical development of STI571 in CML, GIST, and a variety of other selected tumor types.

Pages

 
Loading comments...

By clicking Accept, you agree to become a member of the UBM Medica Community.