A phase II study of ZD6474 (Zactima™), a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma—NCIC CTG IND.145

Abstract

Multiple myeloma is a disease in which angiogenesis is postulated to be a target for therapy. Based on this hypothesis, we conducted a phase II trial of ZD6474 (Zactima; a VEGFR inhibitor) 100 mg p.o. daily in patients with relapsed multiple myeloma. The primary efficacy endpoint was objective response as assessed by reduction in M protein. There were 18 patients with a mean age of 64 years. One patient was ineligible and one was not evaluable. Overall, ZD6474 was well tolerated and pharmacokinetic testing demonstrated that adequate drug levels were achieved. The most common drug-related adverse events were nausea, vomiting, fatigue, rash, pruritus, headache, diarrhea, dizziness, and sensory neuropathy, all of which were Grade I-II in severity. There were no drug-related serious adverse events. Laboratory adverse events were infrequent: one patient had Grade III anemia, and there were no Grade III changes in biochemistry. No significant QTc interval changes were seen. There were no responses in M protein levels. In conclusion, ZD6474 was well tolerated at a dose of 100 mg per day and achieved plasma levels predicted to inhibit VEGF signaling. However, this was not reflected in clinical benefit since none of the patients had a reduction in M protein.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…In our review, the weighted incidence of any vandetanib‐related QTc prolongation was 8.6%, with QTc >500 ms in 2.6% 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70155, 156, 157 Because of its long half‐life (19 days), special care is needed when monitoring patients with QTc prolongation. Because of its clinical efficacy, vandetanib was approved by the Food and Drug Administration for human use in 2012, but with safe prescription strategies that include obtaining a baseline ECG and at 2 to 4 and 8 to 12 weeks after starting the treatment and every 3 months thereafter 158…”

Pixantrone: a novel anthracycline-like drug for the treatment of non-Hodgkin lymphoma

“…It has a moderate-tohigh total plasma clearance with a low renal excretion (10% within the first 24 h) and a half-life of 21 h. The plasma clearance is mainly non-renal with a major biliary excretion of unchanged Pixantrone explaining why it should not be administered in patients with severe liver impairment. Age did not affect pharmacokinetics; however, clearance appeared dependant on body size measures [27,28].…”

“…Sudden deaths of rodents during and immediately after I.V. bolus administration were primarily attributable to the injection rate and the dose volume suggesting Pixantrone should be infused slowly [27]. Metabolism did not appear to be an important elimination pathway for Pixantrone.…”

Pixantrone dimaleate for treating non-Hodgkin’s lymphoma

“…In vivo studies evaluating the cumulative cardiotoxic potential of pixantrone compared with equivalent doses of doxorubicin and mitoxantrone in both doxorubicin-pre-treated and doxorubicin-naïve mice showed reduced cardiotoxic potential of pixantrone compared with doxorubicin and mitoxantrone. Exposure to pixantrone did not worsen pre-existing cardiomyopathy in doxorubicin-pre-treated mice [24].…”