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New Drugs in Myeloproliferative Disorders
Published in Richard T. Silver, Ayalew Tefferi, Myeloproliferative Disorders, 2007
Srdan Verstovsek, Ruben A. Mesa
Vatalanib (PTK787/ZK 222584), an oral inhibitor of the VEGF receptor-1 (VEGFR-1) and VEGFR-2 tyrosine kinases has been used in clinical trials in patients with MPDs because of its antiangiogenic activity (45). PTK/ZK also inhibits a broad array of additional tyrosine kinases including PDGF receptor, c-KIT, and c-FMS (45). Although, in theory, PTK/ZK should have been quite active in the study patients, the responses observed were quite modest with mainly clinical improvement [CI by IWG-MRT criteria (46) seen (45)]. Twenty-nine patients with MF received a continuous dosing schedule of PTK/ZK of 500 or 750 mg twice-daily. One patient (3%) achieved complete remission and five patients (17%) achieved clinical improvement. Significant decrease in intramedullary angiogenesis was not observed, with only modest reductions in marrow hypercellularity described. Intriguingly, 1 patient did experience a complete remission [by IWG-MRT criteria (46)], suggesting a particularly sensitive target (not identified) in this individual.
Antiangiogenic Therapy for Lung Cancer: Small-Molecule Inhibitors
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Vatalanib: PTK787/ZK222584 is a synthetic, low-molecular-weight, orally bioavailable agent belonging to the chemical class of aminophthalazines. Vatalanib inhibits all three VEGFRs as well as PDGFR and c-Kit at submicromolar concentrations. At higher concentrations, this drug can inhibit epidermal growth factor receptor (EGFR) and fibroblast growth factor 1 or 2 (34). In a human lung adenocarcinoma model, PTK787 significantly reduced the formation of pleural effusion and suppressed vascular hyperpermeability (35). PK results for doses up to 1000 mg/day showed that vatalanib given QD is rapidly adsorbed, with a time to maximum concentration (Cmax) of 1.5 hours and a terminal half-life (t1/2) of about three to six hours (36). In a phase-I dose-escalation study, notable adverse events were grade 3 hypertension (4/26 patients), grade 3 transaminitis (6/26 patients) and lightheadedness (2/3 patients at the 1000 mg dose level), ataxia, and dyspnea (both in 3/22 patients) (37). Promising antitumor activity was observed in patients with metastatic colorectal cancer and led to further studies in colon cancer. An exploratory analysis in patients with pretreatment high serum levels of lactate dehydrogenase (LDH) showed a statistically significant longer progression-free survival (PFS) time in the group treated with vatalanib (38). High pretreatment serum levels of LDH may therefore predict for optimal benefit from vatalanib in inhibiting VEGF. The role of PTK787 in patients with NSCLC is being evaluated in a phase-II study [the growth arrest with oral anti-angiogenic agents in lung cancer (GOAL) Study] in France and Germany.
Lactate dehydrogenase: a marker of diminished antitumor immunity
Published in OncoImmunology, 2020
Sandra Van Wilpe, Rutger Koornstra, Martijn Den Brok, Jan Willem De Groot, Christian Blank, Jolanda De Vries, Winald Gerritsen, Niven Mehra
Patients with elevated LDH levels not only benefit less from immunotherapy, but also from many other anticancer therapies such as chemotherapy and targeted therapy.1,68 However, previous studies suggest that patients with high LDH levels benefit more from VEGF (receptor) inhibitors, such as vatalanib69 and bevacizumab,70,71 than patients with normal LDH levels. Two large, randomized controlled trials studied the efficacy of chemotherapy (FOLFOX) plus vatalanib versus FOLFOX alone in patients with colorectal carcinoma. Patients were randomized stratified according to baseline LDH levels (≤ or >1.5xULN). In the overall population, the addition of vatalanib exerted only moderate effects on PFS (HR 0.85, p = .005), whereas a major improvement was seen in patients with high LDH levels (HR 0.65, p < .001).69 It is not surprising that patients with elevated LDH levels benefit most from anti–VEGF therapy, since both glycolysis and hypoxia are associated with active angiogenesis.72,73 Moreover, previous studies found an association between high serum LDH levels and VEGF (receptor) overexpression in various tumors.74
An update on the conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting TKI-based therapy
Published in Expert Opinion on Drug Safety, 2019
Antonio Galvano, Aurelia Guarini, Federica Iacono, Marta Castiglia, Sergio Rizzo, Luigi Tarantini, Stefania Gori, Giuseppina Novo, Viviana Bazan, Antonio Russo
Vatalanib is an oral receptor tyrosine kinase inhibitor that targets VEGF, PDGF, and c-Kit receptors. Fen Wang et al., in a phase I study, evaluated the safety, tolerability, and biologic activity of the combination of vatalanib with pemetrexed in patients with advanced solid tumors. They found that this combination was feasible but not well tolerated. The most common side effects were fatigue 79%, nausea 60%, vomiting 48%, oral mucositis 31% and diarrhea 27.6% [48]. An open-label phase II multicenter therapeutic trial was aimed to investigate safety and efficacy of Vatalanib in patients with advanced and metastatic pancreatic cancer in patients that failed a first line gemcitabine-based. Dragovich et al. found that Vatalanib was well tolerated and the trial also resulted in favorable 6-month survival rate. Patients enrolled were 67 and the most common adverse events (all grades) were fatigue 40%, nausea 20%, hypertension 25%, abdominal pain 10%. They surprisingly found that hypertension and fatigue were the most common severe (grade 3 or higher) toxicities, and occurred in 20 patients [49]. A phase IB study led by Bitting et al., combined Everolimus and Vatalanib in order to evaluate safety and efficacy in patients with RCC. They found that many patients, in the treatment-naïve setting, achieved objective response with expected toxicities. Although this combination therapy has proven to prolong the survival rate in a specific setting of patients, further phase II/III studies need to be done [50].
Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges
Published in Expert Opinion on Pharmacotherapy, 2019
Maria Diab, Asfar Azmi, Ramzi Mohammad, Philip A. Philip
Vascular endothelial growth factor (VEGF) plays a key role in neoangiogenesis, a crucial mechanism for tumor growth and metastasis [169]. It is overexpressed in PDAC [170] which makes it an attractive target. Targeting VEGF was attempted through a number of small molecules. No survival benefit was observed from erlotinib/BV [171] and GEM/erlotinib/BV [172]. Axitinib, another potent, selective inhibitor of VEGF receptors 1, 2, and 3, was investigated in combination with for the treatment of LA/M PDAC [173]. Unfortunately, the combination did not improve survival [173]. Similarly, sorafenib, a multikinase inhibitor of B-raf, VEGF receptor 2, and platelet-derived growth factor (PDGF) receptor β, was not associated with a survival benefit when added to GEM in advanced PDAC [174]. Vatalanib, an oral poly-tyrosine kinase inhibitor with strong affinity for PDGF and VEGF receptors, was tested as single-agent therapy in GEM-refractory LA/M PDAC and was associated with a 6-month survival rate of 29% [175].