Background: This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours. Patients and methods: Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The starting dose (60 mg/m 2 ) was derived from an adult physiology-based PK model and scaled to children; dose escalation was followed by safety expansion of the MTD cohort. Treatment-emergent adverse events (TEAEs) were evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Regorafenib PK was evaluated using a population PK model. Results: Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60 e93 mg/m 2 ). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n Z 1]). The MTD was defined as 82 mg/m 2 . The most common Grade !3 drugrelated TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and handefoot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks. Conclusions: The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m 2 . Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients. Clinical trial number: NCT02085148.

Antimony-trioxide-and arsenic-trioxide-induced apoptosis in myelogenic and lymphatic cell lines, recruitment of caspases, and loss of mitochondrial membrane potential are enhanced by modulators of the cellular glutathione redox system. Annals of Hematology, Springer Verlag, 2009, 88 (11) (BSO). Other modulators of the cellular redox system showed this effect to a lower extent and enhancement was not consistent for the different cell lines tested. Caspase inhibitors protected cell lines from Sb 2 O 3 -and As 2 O 3 -induced apoptosis. When BSO was added, the inhibitors lost their protective ability. The ability of modulators of the cellular redox system in clinically applicable concentrations to enhance the apoptotic effects of the two oxides in a synergistic way may be helpful to reduce their toxicity by optimizing their dose.

No abstract

No abstract

Background: Dasatinib is a potent orally active, multi-targeted tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of tumor cells. A European compassionate use trial was conducted to provide dasatinib to patients (pts) who were ineligible to be enrolled into the START-trials. Methods: From April 2006 to February 2007, 26 pts were included in Germany. Diagnosis at inclusion: 9 Ph+ALL, 6 CML in accelerated phase, 5 CML in myeloid blast crisis, 2 biphenotypic Ph+ALL and 1 chronic phase CML. Additionally, 3 pts with systemic mastocytosis (SM), refractory to imatinib due to D816V mutation were also included. Pts had previously failed several chemotherapy regimens, including imatinib and/or nilotinib. Sixty-one percent were resistant, 35% were refractory and 4% intolerant to imatinib/nilotinib. Results: Of 26 patients, there were 17 male and 9 female pts. The median age was 56 years (range, 22–80 years). The average daily dose of dasatinib was 137 mg with a median duration of therapy of 69.5d (range 3–252d). Six (23%) pts required transient treatment interruption, 2 (8%) due to non-haematological toxicity (dyspnea and increased hepatic values), 4 (15%) due to haematological toxicities. Twenty-one pts discontinued therapy for the following reasons: study related toxicity (23%), SCT (15%), death (8%), lost to follow-up (11%) and patient’s wish (4%). Two patients still remain on therapy. The response rate was CHR in 42%, complete (CCyR) cytogenetic response in 19%, and PCyR in 4% of the pts. For patients with diagnosed SM one partial HR, one stable disease and one progression have been recorded. Disease progression occurred in 19% of cases. Adverse events were transient and generally mild to moderate in severity. Generally, the observed AE profile was similar to that seen in previous research trials. For all pts, the most common hematological side-effects Grade 3/4 AEs reported were thrombocytopenia (23%), neutropenia (4%), and anemia (4%). Most frequent non-hematological side-effects included dyspnea in 23% of pts (no grade 3–4), edema in 23% (grade 3, 8%), diarrhea in 15% (grade 3, 4%), headache in 15% (no grade 3–4), bone and neck pain in 11% (grade 3, 8%) and pleural effusion in 8% (grade 3, 4%). Conclusions: Dasatinib therapy appeared to be effective and was well tolerated in this difficult to treat patient population.