Everolimus is a selective mammalian target of rapamycin (mTOR) inhibitor with promising anticancer activity. In order to identify a rationally based dose and schedule for cancer treatment, we have ...conducted a tumor pharmacodynamic phase I study in patients with advanced solid tumors.
Fifty-five patients were treated with everolimus in cohorts of 20, 50, and 70 mg weekly or 5 and 10 mg daily. Dose escalation depended on dose limiting toxicity (DLT) rate during the first 4-week period. Pre- and on-treatment steady-state tumor and skin biopsies were evaluated for total and phosphorylated (p) protein S6 kinase 1, eukaryotic initiation factor 4E (elF-4E) binding protein 1 (4E-BP1), eukaryotic initiation factor 4G (eIF-4G), AKT, and Ki-67 expression. Plasma trough levels of everolimus were determined on a weekly basis before dosing during the first 4 weeks.
We observed a dose- and schedule-dependent inhibition of the mTOR pathway with a near complete inhibition of pS6 and peIF-4G at 10 mg/d and >or= 50 mg/wk. In addition, pAKT was upregulated in 50% of the treated tumors. In the daily schedule, there was a correlation between everolimus plasma trough concentrations and inhibition of peIF4G and p4E-BP1. There was good concordance of mTOR pathway inhibition between skin and tumor. Clinical benefit was observed in four patients including one patient with advanced colorectal cancer achieving a partial response. DLTs occurred in five patients: one patient at 10 mg/d (grade 3 stomatitis) and four patients at 70 mg/wk (two with grade 3 stomatitis, one with grade 3 neutropenia, and one with grade 3 hyperglycemia).
Everolimus achieved mTOR signaling inhibition at doses below the DLT. A dosage of 10 mg/d or 50 mg/wk is recommended for further development.
Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic ...targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST.
GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome.
Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P =.0006) and 0.0% (P <.0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation.
Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.
The cutaneous malignant tumor dermatofibrosarcoma protuberans (DFSP) is typically associated with a translocation between chromosomes 17 and 22 that places the platelet-derived growth factor-B ...(PDGFB) under the control of the collagen 1A1 promoter. The purpose of this study was to evaluate molecular, cytogenetic, and kinase activation profiles in a series of DFSPs and to determine whether these biologic parameters are correlated with the clinical responses of DFSP to imatinib.
We analyzed the objective radiologic and clinical response to imatinib at 400 mg twice daily in eight patients with locally advanced DFSP and two patients with metastatic disease.
Each of eight patients with locally advanced DFSP had evidence of t(17;22) and showed a clinical response to imatinib. Four of these patients had complete clinical responses. The two patients with metastatic disease had fibrosarcomatous histology and karyotypes that were substantially more complex than those typically associated with localized DFSP. One patient with metastatic DFSP and an associated t(17;22) had a partial response to imatinib but experienced disease progression after 7 months of therapy. In contrast, the other patient with metastatic disease had a tumor lacking t(17;22), and there was no clinical response to imatinib. Unexpectedly, there was minimal platelet-derived growth factor receptor-beta phosphorylation in the untreated DFSP, despite the documented presence of a PDGFB autocrine mechanism.
Imatinib has clinical activity against both localized and metastatic DFSP with t(17;22). However, fibrosarcomatous variants of DFSP lacking t(17;22) may not respond to imatinib.
To determine the clinical efficacy of imatinib in patients with advanced aggressive fibromatosis (AF) and to identify the molecular basis of response/nonresponse to this agent.
Nineteen patients with ...AF were treated with imatinib (800 mg/d) as part of a phase II clinical study. Tumor specimens were analyzed for mutations of KIT, PDGFRA, PDGFRB, and CTNNB1 (beta-catenin). Tumor expression of total and activated KIT, PDGFRA, and PDGFRB were assessed using immunohistochemistry and immunoblotting techniques. We also measured plasma levels of PDGF-AA and PDGF-BB in patients and normal patient controls.
Three of 19 patients (15.7%) had a partial response to treatment, with four additional patients having stable disease that lasted more than 1 year (overall 1 year tumor control rate of 36.8%). No mutations of KIT, PDGFRA, or PDGFRB were found. Sixteen of 19 patients (84%) had mutations involving the WNT pathway (APC or CTNNB1). However, there was no correlation between WNT pathway mutations and clinical response to imatinib. AF tumors expressed minimal to null levels of KIT and PDGFRA but expressed levels of PDGFRB that are comparable with normal fibroblasts. However, PDGFRB phosphorylation was not detected, suggesting that PDGFRB is only weakly activated. AF patients had elevated levels of PDGF-AA and PDGF-BB compared with normal patient controls. Notably, the plasma level of PDGF-BB was inversely correlated with time to treatment failure.
Imatinib is an active agent in the treatment of advanced AF. Imatinib response in AF patients may be mediated by inhibition of PDGFRB kinase activity.
Prevalence of KIT expression in human tumors Went, Philip Th; Dirnhofer, Stephan; Bundi, Marcel ...
Journal of clinical oncology,
11/2004, Letnik:
22, Številka:
22
Journal Article
Recenzirano
KIT is a target for imatinib mesylate (Gleevec; Novartis Pharma, Basel, Switzerland). Gastrointestinal stromal tumors (GISTs) express KIT and respond favorably to imatinib therapy. To determine other ...tumors in which such a molecular targeted therapy might be indicated, we investigated KIT expression in different human tumor types. Because recent studies in GISTs suggest that KIT-activating mutations predict response to imatinib therapy, we also sequenced a subset of positive tumors.
More than 3,000 tumors from more than 120 different tumor categories were analyzed by immunohistochemistry in a tissue microarray format. Seven commercially available anti-KIT antibodies were initially evaluated. The antibody A4502 (DAKO) was selected for analysis because of a high frequency of positivity in GIST and low staining background in other tissues. To determine the frequency of KIT mutations in various tumor types, the exons 2, 8, 9, 11, 13, and 17 (where mutations previously were reported) were sequenced in 36 tumors with strong KIT expression.
KIT positivity was detected in 28 of 28 GISTs (100%), 42 of 50 seminomas (84%), 34 of 52 adenoid-cystic carcinomas (65%), 14 of 39 malignant melanomas (35%), and eight of 47 large-cell carcinomas of the lung (17%), as well as in 47 additional tumor types. KIT mutations were found in six of 12 analyzed GISTs, but only in one of 24 other tumors.
The results suggest that KIT expression occurs infrequently in most tumor types and that, with the exception of GISTs, KIT gene mutations are rare in immunohistochemically KIT-positive tumors.
The purpose of our study was to assess the objective response to imatinib administered to patients with small cell lung cancer (SCLC).
Eligible patients were those with SCLC who either had ...chemotherapy-naive extensive-stage or had SCLC in a sensitive relapse. Patients enrolled on the trial were treated with 600 mg of imatinib daily. The response was assessed using Southwest Oncology Group (SWOG) criteria after 3 and 6 weeks. Tumor specimens were examined by immunohistochemistry for the KIT receptor.
Nineteen patients with SCLC entered on the study, including 16 men and 3 women. Nine patients had previously untreated extensive-stage disease and 10 patients had sensitive relapse. A central pathology review confirmed SCLC in only 14 of the 19 patients. There were no objective responses; however, one patient with sensitive-relapse disease had prolonged stabilization of disease (>3 months) while on imatinib therapy. The median time to progression was 0.8 months (range, 0.6-1.3 months) and 1.2 months (range, 0.2-4.1 months) in the previously untreated and sensitive-relapse groups, respectively. Tumor tissue samples from 4 (21%) of the 19 patients had the KIT receptor (CD117).
There was no observed antitumor activity in this limited Phase II trial of patients with SCLC, of which only a few tumors showed expression of the imatinib target. The results of this trial are, thus, inconclusive about the antitumor activity of imatinib against SCLC with the targeted KIT receptor (CD117). Further testing of imatinib in patients with SCLC will focus on demonstration of KIT expression in the setting of confirmed SCLC histology.
In a phase I study conducted by the EORTC Soft Tissue and Bone Sarcoma Group, 40 patients with advanced soft tissue sarcomas, most of whom had gastrointestinal stromal tumors (GISTs), received ...imatinib at doses of 400 mg q.d., 300 mg b.i.d., 400 mg b.i.d., or 500 mg b.i.d. Dose-limiting toxicities, including severe nausea, vomiting, edema and rash, were seen at the highest dose level; the maximum tolerated dose was therefore 400 mg b.i.d. Imatinib was active in the group of 35 patients with GISTs, producing partial responses in 19 (54%) patients and stable disease in 13 patients (37%). Responding patients have now been followed for a minimum of 10 months. The most common side effects seen in patients continuing on therapy have been periorbital edema (40%), peripheral edema (37.5%), fatigue (30%), skin rash (30%) and nausea/vomiting (25%). Severe late myelosuppression has also been seen occasionally. Eighteen (51%) GIST patients continue to have partial responses and 11 (31%) continue with stable disease. Thus, 82% of patients with GISTs are still obtaining clinically important benefits with continued imatinib therapy. Some patients showed accelerated progressive disease shortly after starting imatinib. On the other hand, following drug withdrawal, 2 patients had reductions in tumor burden and remain alive without drug therapy. In summary, imatinib is generally well tolerated and has significant activity during long-term treatment of patients with advanced GISTs
Management of malignant gastrointestinal stromal tumours Joensuu, Heikki; Fletcher, Christopher; Dimitrijevic, Sasa ...
The lancet oncology,
November 2002, 2002-Nov, 2002-11-00, 20021101, Letnik:
3, Številka:
11
Journal Article
Recenzirano
Gastrointestinal stromal tumours (GISTs) are the most common form of mesenchymal tumour of the gastrointestinal tract. Clinically, they range from small indolent tumours curable with surgery alone to ...aggressive cancers. Making a distinction between an indolent and a malignant GIST is unreliable with conventional histopathological techniques. The presence of metastases at the time of diagnosis confirms malignancy, but all GISTs should be regarded as having malignant potential. GISTs characteristically express the KIT protein, a transmembrane tyrosine kinase receptor for stem-cell factor. Most GISTs have a mutation in the KIT proto-oncogene that translates into a gain-of-function constitutive activation of the KIT kinase. KIT activation seems to be an early tumour-promoting event in pathogenesis. Commonly, malignant GISTs show high-level primary resistance to conventional chemotherapy. Imatinib mesylate is an orally administered selective inhibitor of certain tyrosine kinases including KIT. Most patients with advanced malignant GISTs achieve clinical benefit and significant antitumour responses with imatinib mesylate. Responses have been durable, and most patients tolerate the drug well at clinically effective doses. Imatinib mesylate is the first effective systemic therapy for advanced GIST.
