Benefit-Risk Assessment of Blinatumomab in the Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia.

Blinatumomab is the first-and-only Food and Drug Administration (FDA)-approved cluster of differentiation (CD) 19-directed CD3 bispecific T-cell engager (BiTE®) immunotherapy. It is currently FDA approved for the treatment of adults and children with Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-negative (Ph-) relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell precursor ALL with minimal residual disease. Similarly, initial marketing authorization for blinatumomab in the European Union was granted for the treatment of adults with Ph- R/R B-cell precursor ALL. The benefits of treating R/R B-cell precursor ALL patients with blinatumomab include increased overall survival, more favorable hematologic remission and molecular response rates, and a lower incidence rate of selected adverse events when compared with standard-of-care chemotherapy. The key risks associated with blinatumomab treatment include cytokine release syndrome, neurotoxicity, and medication errors. Here, we review the benefits and risks of blinatumomab treatment and describe how these risks can be mitigated.

Phase 1b study of motesanib, an oral angiogenesis inhibitor, in combination with carboplatin/paclitaxel and/or panitumumab for the treatment of advanced non-small cell lung cancer.

PURPOSE: Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti-epidermal growth factor receptor monoclonal antibody panitumumab in advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line). RESULTS: Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively. CONCLUSIONS: Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC.

Phase II trial of irinotecan in combination with amifostine in patients with advanced colorectal carcinoma.

BACKGROUND: Irinotecan is effective in patients with advanced colorectal carcinoma in both first-line and salvage settings but its use can be limited by serious side effects. Amifostine has been shown to reduce the incidence of cisplatin-induced cumulative renal toxicity in patients with advanced ovarian carcinoma and nonsmall cell lung carcinoma. In the current pilot Phase II trial, the authors examined the potential role of amifostine as a protective agent against irinotecan-induced diarrhea and myelosuppression and evaluated an every-2-weeks regimen as an alternative schedule for the administration of irinotecan in patients with previously treated metastatic colorectal carcinoma. METHODS: All patients received amifostine, 740 mg/m2, followed by irinotecan, 250 mg/m2, every 2 weeks. A 6-week cycle of chemotherapy (every 2 weeks for 3 treatments) was chosen to assess toxicity and response. The main objective of the current study was to evaluate the impact of amifostine on gastrointestinal and hematologic toxicity. RESULTS: A total of 22 patients entered the current study. Six of these 22 patients (27%) had WHO Common Toxicity Criteria Grade 3 or 4 diarrhea, including 2 patients (9%) with Grade 4 diarrhea. Eight of 22 patients (36.3%) developed Grade 3 or 4 neutropenia (Grade 4 in 4 of the 22 patients [18%]). Dose reduction was required in 25% of the treatment cycles. Five of the 22 patients (23%) withdrew from the trial due to amifostine toxicity. Of the 15 patients who were evaluable for response, 4 patients (26.6%) had achieved a partial response and 9 (60%) had stable disease as their best response. CONCLUSIONS: The combination of irinotecan with amifostine in patients with previously treated metastatic colorectal carcinoma did not appear to reduce irinotecan toxicity. Amifostine did not appear to interfere with the cytotoxic effect of irinotecan. The results of the current study did demonstrate efficacy and safety of the every-2-weeks irinotecan schedule that was comparable to other established regimens and these results support its feasibility as a reasonable alternative in this disease setting.

Dose-finding and pharmacokinetic study of cisplatin, gemcitabine, and SU5416 in patients with solid tumors.

PURPOSE: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416. PATIENTS AND METHODS: Patients received cisplatin 80 mg/m(2) on day 1, gemcitabine 1,250 mg/m(2) on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m(2)) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine. RESULTS: In the first cohort of three patients entered at the 85 mg/m(2) dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m(2)), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m(2) developed a thromboembolic event. The dose was then reduced to 85 mg/m(2) in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle-dependent manner. CONCLUSION: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.