Phase I study investigating the safety and feasibility of combining imatinib mesylate (Gleevec) with sorafenib in patients with refractory castration-resistant prostate cancer

Abstract

Background:Determining the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of sorafenib (S) plus imatinib (IM) in castration-resistant prostate cancer (CRPC) patients.Methods:Refractory CRPC patients were enrolled onto this 3+3 dose escalation designed study. Imatinib pharmacokinetics (PK) were determined on day 15, 4 h post dose with a validated LC–MS assay.Results:Seventeen patients were enrolled; 10 evaluable (6 at 400 mg S qd with 300 mg IM qd (DL0) and 4 at 400 mg S bid with 300 mg IM qd (DL1)); inevaluable patients received <1 cycle. The median age was 73 (57–89); median prostatic serum antigen was 284 ng ml−1 (11.7–9027). Median number of prior non-hormonal therapies was 3 (1–12). Dose-limiting toxicities were diarrhoea and hand-foot syndrome. Maximum tolerated dose was 400 mg S and 300 mg IM both daily. No biochemical responses were observed. Two patients had stable disease by RECIST. Median time to progression was 2 months (1–5). Median OS was 6 months (1–30+) with 3/17 patients (17%) alive at 21 months median follow-up. Ten patients had PK data suggesting that S reduced IM clearance by 55%, resulting in 77% increased exposure (P=0.005; compared with historical data).Conclusion:This is the first report showing that S+IM can be administered in CRPC at a dose of 400 mg S and 300 mg IM, daily.

Bone-induced c-kit expression in prostate cancer: A driver of intraosseous tumor growth

“…In this scenario, it has been of interest the use of different drugs targeting RTKs, which showed encouraging results in many preclinical models of bone metastasis . Clinical studies in CRPC patients with bone metastases with the groundbreaking RTK inhibitor imatinib mesylate have led to inconclusive results . However, recent studies with the small molecule inhibitor of multiple RTKs Cabozantinib (a.k.a.…”

“…[21][22][23][24] Clinical studies in CRPC patients with bone metastases with the groundbreaking RTK inhibitor imatinib mesylate have led to inconclusive results. 25,26 However, recent studies with the small molecule inhibitor of multiple RTKs Cabozantinib (a.k.a. XL184) have shown significantly prolonged progression free survival and improved bone scans in metastatic CRPC patients, bringing new excitement to the field.…”

Paradoxical and contradictory effects of imatinib in two cell line models of hormone-refractory prostate cancer

“…Imatinib mesylate (Gleevec 1 , Novartis Pharmaceuticals, East Hanover, NJ) is a potent and selective tyrosine kinase inhibitor [9] that has been clinically used to treat gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia [10,11]. Imatinib also has been tested for treatment of HRPC but with modest therapeutic effectiveness in the clinical setting [12][13][14][15][16]. These outcomes contrast with experimental findings in cultured cells and animal models, where imatinib, alone or in combination with other chemotherapeutic drugs, had cytotoxic effects [17][18][19][20] and improved chemo-and radiosensitivity of PCa cells [17,18,21].…”

Ageing is a risk factor in imatinib mesylate cardiotoxicity

“…The introduction of imatinib has revolutionized the treatment of CML patients, with an outstanding 70% cytogenic remission and initial minimal side effects, namely peripheral oedema and dyspnoea . Imatinib use is being extended to the treatment of other cancers, including gastrointestinal stromal tumours and prostate cancer …”