Influence of hepatic dysfunction on safety, tolerability, and pharmacokinetics (PK) of PTK787/ZK 222584 in patients (Pts) with unresectable hepatocellular carcinoma (HCC)

Koch, Inga; Baron, Aurore; Roberts, Stephen A.; Junker, Uwe; Palacay-Ramona, M.; Masson, Emmanuelle; Kay, Andrea; Wiedenmann, B.; Laurent, Dirk; Cebon, Jonathan

doi:10.1200/jco.2005.23.16_suppl.4134

Cited by 31 publications

(20 citation statements)

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“…Also, the relative contribution of either agent in the treatment of advanced HCC is still unknown, although in a phase 1 study conducted by Koch et al, a 750-mg daily dosage of PTK showed preliminary efficacy in advanced HCC patients. 32 Second, the study does not include any detailed pharmacokinetic or pharmacodynamic parameters for analysis. Third, disease assessment was only performed every 9 weeks instead of the current standard of 6 to 8 weeks in most systemic trials of advanced HCC patients.…”

Section: Discussionmentioning

confidence: 99%

Phase 1‐2 trial of PTK787/ZK222584 combined with intravenous doxorubicin for treatment of patients with advanced hepatocellular carcinoma

Yau

Chan

Pang

et al. 2010

Cancer

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BACKGROUND:This phase 1‐2 trial assessed the efficacy and tolerability of an oral angiogenesis inhibitor—PTK787/ZK222584 (PTK)—in combination with intravenous doxorubicin for the treatment of advanced hepatocellular carcinoma (HCC) patients.METHODS:In phase 1, advanced HCC patients received PTK at escalating doses together with doxorubicin 60 mg/m2 given as an intravenous bolus every 3 weeks to establish the maximum tolerated dose (MTD). Subsequently, in phase 2, all patients received the same regimen with oral PTK at the MTD dose every 3 weeks for a maximum of 6 cycles.RESULTS:Nine patients were recruited in phase 1, with the MTD established as 750 mg daily. Overall, 27 patients received the regimen with PTK at 750 mg daily. The median age was 52 years (range, 23‐73 years), and 63 percent of patients were chronic hepatitis B carriers. Notably, the majority of patients had Child‐Pugh B cirrhosis. The overall response rate was 26.0%, with all the responding patients having partial response. Another 20% of patients achieved stable disease for at least 12 weeks. The median progression‐free survival was 5.4 months (range, 0.27‐23.6 months), and overall survival was 7.3 months (range, 0.8‐23.6 months). The commonest grade 3 or 4 nonhematological toxicities were mucositis (11%) and alopecia (7%), respectively. Grade 3 or 4 neutropenia was observed in 7 (26%) patients; 2 had neutropenic sepsis.CONCLUSIONS:The combination of PTK with intravenous doxorubicin shows encouraging activity in treating advanced HCC patients. Cancer 2010. © 2010 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Phase 1‐2 trial of PTK787/ZK222584 combined with intravenous doxorubicin for treatment of patients with advanced hepatocellular carcinoma

Yau

Chan

Pang

et al. 2010

Cancer

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“…Preclinical studies suggested antiangiogenic and angiogenesisinde pendent effects on HCC growth arrest [40] . In a phase Ⅰ study of vatalanib in 18 patients with unresectable HCC, nine patients had a best response of stable disease (SD), and nine patients had progressive disease (PD) [41] .…”

Section: Vatalanibmentioning

confidence: 99%

Liver cancer: Targeted future options

Pircher

Medinger²,

Drevs³

2011

WJH

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Hepatocellular carcinoma (HCC) has a poor prognosis and systemic chemotherapies have disappointing resul ts. The increasing knowledge of the molecular biology of HCC has resulted in novel targets, with the vascular endothelial growth factor and epidermal growth fac tor receptor (EGFR)related pathways being of special interest. New blood vessel formation (angiogenesis) is essential for the growth of solid tumors. Antiangiogenic strategies have become an important therapeutic mo dality for solid tumors. Several agents targeting angio genesisrelated pathways have entered clinical trials or have been already approved for the treatment of solid tumors. These include monoclonal antibodies, receptor tyrosine kinase inhibitors and immunomodulatory drugs. HCC is a highly vascular tumor, and angiogenesis is be lieved to play an important role in its development and progression. This review summarizes recent advances in the basic understanding of the role of angiogenesis in HCC as well as clinical trials with novel therapeutic approaches targeting angiogenesis and EGFRrelated pathways.

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“…anorexia [29]. In a phase I trial with PTK787 which inhibits all known VEGFR, platelet-derived growth factor receptor (PDGFR), and c-KIT, no remissions of HCC were observed, but 9 of 18 (50%) evaluable patients had stable disease [30]. The predominant receptor tyrosine kinases that have been demonstrated to be targeted by sunitinib are VEGF-2, PDGFR-α, PDGFR-β, c-KIT, FLT3, CSF-1, and RET, while sorafenib strongly inhibits VEGF-2, VEGF-3, PDGFR-β, c-KIT, FLT3, and Raf-1.…”

Section: Clinical Studies With Multikinase Inhibitorsmentioning

confidence: 99%

Molecular Pathogenesis and Targeted Therapy of Hepatocellular Carcinoma

Zender

Kubicka²

2008

Onkologie

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Hepatocellular carcinoma (HCC) constitutes the 5th most frequent cancer worldwide, and due to a lack of treatment options, HCC represents the 3rd most lethal cancer worldwide. The incidence of HCC is continuously rising in Europe and Northern America, which can be explained by spreading of hepatitis C virus infections. Systemic chemotherapy is not an option for most patients with HCC. The most promising strategy for systemic treatment of HCC is targeted therapy. Successful targeted therapy has to inhibit pathways which are necessary for tumor growth, even in the late stages of carcinogenesis. The p16/Rb, p53, and IGF2R checkpoints as well as oncogenic alterations of telomerase, c-myc, Wnt/β-catenin, PI3K/Akt, hedgehog, and c-met/HGF are most frequently involved in human hepatocarinogenesis. However, currently, the most attractive target for molecular therapy of HCC appears to be the vascular endothelial growth factor (VEGF). Phase I/II studies showed high progression-free survival rates with antibodies or small molecules targeting the VEGF receptor pathway. Recently, a randomized placebo-controlled phase III study showed that the multikinase inhibitor sorafenib, which inhibits VEGF and Raf, significantly improves survival of patients with advanced HCC and Child A cirrhosis. As a consequence of this study, sorafenib is now the first available drug for effective systemic treatment of patients with advanced HCC.

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Influence of hepatic dysfunction on safety, tolerability, and pharmacokinetics (PK) of PTK787/ZK 222584 in patients (Pts) with unresectable hepatocellular carcinoma (HCC)

Cited by 31 publications

References 0 publications

Phase 1‐2 trial of PTK787/ZK222584 combined with intravenous doxorubicin for treatment of patients with advanced hepatocellular carcinoma

Phase 1‐2 trial of PTK787/ZK222584 combined with intravenous doxorubicin for treatment of patients with advanced hepatocellular carcinoma

Liver cancer: Targeted future options

Molecular Pathogenesis and Targeted Therapy of Hepatocellular Carcinoma

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