Luke Dreisbach

Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia

Abstract Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3–4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.

A durable response to relapsing Clostridium difficile colitis may require combined therapy with high-dose oral vancomycin and intravenous immune globulin

Background: Recurrent Clostridium difficile antimicrobial-induced diarrhea follows initial successful therapy with metronidazole or oral vancomycin in 5% to 65% of patients. Specific antibody formation to Toxin A of C. difficile has been found in those patients who remain asymptomatic or experience a single episode of diarrhea after their initial infection. Because those individuals who often cannot produce specific antibody develop relapsing colitis, we administered intravenous immune globulin (IVIG) to 20 such hospitalized patients and evaluated their responses. Materials and Methods: C. difficile immunoglobulin G antibody was measured in 18 of 20 patients with recurrent colitis using an enzyme-linked immunosorbent assay. All patients were subsequently placed on oral vancomycin (dosage, 500 mg 3 times a day) and 2 doses of IVIG (dosage, 30 g within 24 to 96 hours after antibody levels were drawn). The time interval between both doses was about 24 hours. Results: Eighteen of 20 patients had a durable response to the previously mentioned therapy, of which 1 case recurred within a 3-month follow-up period. Two patients responded to therapy but died of underlying or associated disease (one of pneumonia and one of congestive heart failure). Ten patients also received oral Saccharomyces boulardii, a nonpathogenic yeast. One of these patients died of heart failure and another had a recurrent disease. Conclusions: IVIG and high-dose oral vancomycin may be an effective regimen in eradicating relapsing C. difficile colitis, probably confirming the suspicion that patients who develop the disease lack the ability to produce adequate quantities of neutralizing immunoglobulin G antibody against Toxin A. Oral S. boulardii may help maintain freedom from relapse, which, however, was not confirmed in this study, and its use could be complicated by fungemia.

Phase I study of fixed dose gemcitabine plus epirubicin in patients with advanced solid malignancies.

Objectives:A Phase I study was initiated to investigate fixed dose rate gemcitabine (GEM) combined with epirubicin (EPI) given weekly or every other week, since, GEM given as a standard 30 minute infusion has modest activity. The study was designed based on the hypothesis that prolonged exposure (over 90 minutes) may improve response rates and combination with epirubicin (EPI) is synergistic. Methods:Eligible patients had measurable refractory solid malignancies with adequate bone marrow, renal, and liver functions. Patients received GEM 800, 1000, 1250 mg/m2 over 90 minutes followed by EPI 10 or 15 mg/m2 as a 30 minutes infusion on days 1, 8, and 15 or days 1 and 15 of a 28 day cycle. Results:Twenty-eight patients were enrolled and 24 are evaluable for overall toxicities and response rate. Toxicities include neutropenia (Gr 3 of Gr 4, 9 pts), thrombocytopenia (Gr 3 of Gr 4, 3 pts), fatigue (Gr 3 of Gr 4, 4 pts), and myalgia (Gr 3 of Gr 4, 1 pt). Dose limiting toxicity was grade 4 neutropenia. Seven patients experienced stable disease for >16 weeks and 3 patients with pancreatic cancer had partial responses. Conclusions:The maximum tolerated dose is GEM 800 mg/m2/EPI 10 mg/m2 days 1, 8, 15 or GEM 1000 mg/m2/EPI 15 mg/m2 days 1, 15 given every 4 weeks. Further studies are warranted with targeted therapies to define the efficacy of this doublet.

Phase I trial of gemcitabine and epirubicin in patients with solid malignancies

4190 Background: Gemcitabine (G) given as a standard 30-minute infusion is well tolerated with modest clinical activity, but new data suggest prolonged exposure may improve response. In vitro studies of G combined with epirubicin (E), have demonstrated >50% growth inhibition in human pancreatic cancer cell lines, whereas the drugs were relatively ineffective as single agents in the same cell lines. A Phase I study was undertaken to investigate whether a fixed-dose-rate infusion of G combined with E can be given safely to patients on a weekly schedule. METHODS 6 patients with solid malignancies received G 800 mg/m2 IV with E 10 mg/m2 on a weekly schedule (days 1, 8, & 15 of a 28-day cycle). No dose-limiting toxicities were noted. 3 subsequent patients were treated with 1000 mg/m2 G and 10 mg/m2 E on the same weekly schedule; they all experienced grade 3/4 leukopenia, grade 3/4 thrombocytopenia, and/or inability to complete treatment. The protocol was amended, changing the dosing to biweekly (days 1 & 15 of a 28-day cycle). On this schedule, 3 patients were treated with G 800 mg/m2 plus E 10 mg/m2 and 3 with G 1000 mg/m2 plus E 10 mg/m2. RESULTS A total of 15 patients were enrolled and 12 were evaluable for toxicity. Grade 3/4 toxicities included neutropenia (n = 6), thrombocytopenia (n = 1), fatigue (n = 4), and myalgia (n = 1). All occurred in the 9 patients who received weekly dosing; no Grade 3/4 toxicities were seen in patients receiving biweekly dosing. There was 1 death, attributed to non-treatment-related acute cardiopulmonary failure. 7 patients experienced stable disease for >16 weeks, and 1 patient with pancreatic cancer had a partial response for 32 weeks (G 800 mg/m2 and E 10 mg/m2 on the weekly schedule). CONCLUSIONS The maximum tolerated dose of G (w/ 10 mg/m2 E) on day 1, 8 and 15 of a 28-day cycle is likely to be 800 mg/m2. When given on day 1 and 15 of a 28-day cycle, the combination is safe up to G 1000 mg/m2. Phase II studies are warranted to establish the efficacy of this combination. This clinical trial was supported by Pfizer Oncology. No significant financial relationships to disclose.