Results from an in vitro and a clinical/pharmacological phase I study with the combination irinotecan and sorafenib.

PURPOSE: This single-centre, open-label, phase I dose-escalation study was performed to investigate the safety, pharmacokinetics (PK) and efficacy of sorafenib, a multi-kinase inhibitor, combined with irinotecan, a cytotoxic agent, in patients with advanced, refractory solid tumours. PATIENTS AND METHODS: In an initial dose-escalation phase, patients received irinotecan 125 mg/m(2) and sorafenib 100, 200 and 400 mg twice daily (bid) (cohorts 1-3). In an extended phase, colorectal cancer (CRC) patients received fixed-dose irinotecan 140 mg and sorafenib 400 mg bid (cohort 4). RESULTS: Thirty-four patients were treated: 20 in the dose-escalation phase (common tumour types: CRC [45%], ovarian [5%], pancreatic [5%]) and 14 patients in the CRC extension. Frequent drug-related adverse events were gastrointestinal symptoms, dermatological reactions and constitutional symptoms. The maximum tolerated dose was not reached. Generally, concomitant administration of irinotecan had no impact on the PK of sorafenib. Sorafenib 100 or 200 mg bid had no impact on the PK of irinotecan or its metabolite SN38. In contrast, sorafenib 400 mg bid significantly increased irinotecan and SN38 exposures; however, this was not associated with increased toxicities. Stable disease was achieved in 12/20 (60%) evaluable patients in cohorts 1-3, and 10/13 (77%) evaluable patients in cohort 4. A further patient from cohort 4 had a partial response of >200 days. The increase of SN38 exposure might be due to inhibition of formation of the SN38 glucuronide by sorafenib. In vitro, sorafenib strongly inhibited SN38 glucuronidation in human liver microsomes as indicated by a K(i) value of 2.7 micromol/l. CONCLUSION: Sorafenib 400 mg bid can be combined with irinotecan 125 mg/m(2) or 140 mg for the treatment of patients with advanced, refractory solid tumours, although monitoring for toxicity is recommended.

Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for 6 months in 12% of patients (6% stabilized for 1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.

Prognosis in adult AML is precisely predicted by the DISC-assay using the chemosensitivity-index Ci.

We prospectively investigated the correlation between DISC-assay results and clinical response and also survival in patients with AML using a new method of evaluation.

Continuous 5-fluorouracil and leucovorin as a second-line therapy for advanced gastric carcinoma.

Eleven patients with chemotherapeutically pretreated advanced gastric cancer were treated in a phase II study with a combination of 5-fluorouracil (5-FU) and Leucovorin (LV, folinic acid). 5-FU (1,200 mg/m2) and LV (100 mg/m2) were given as a parallel continuous intravenous infusion over 48 h every 2 weeks for at least 8 weeks. Toxicity and response rates were evaluated. Results show that this chemotherapeutic regimen is well tolerable, without any side effects exceeding WHO grade 1 toxicity, but that it has no considerable effects on tumor growth. None of the patients achieved disease remission. In 8 out of the 11 study patients therapy had to be discontinued prematurely because of disease progression. Therefore we conclude that the studied protocol of 5-FU/LV as second-line treatment of advanced gastric cancer although well tolerable is not effective.

Side effects of AZT prophylaxis after occupational exposure to HIV-infected blood.

UNLABELLED: It was the objective of this study to document and evaluate AZT-induced short-term toxicity in healthy individuals. The study was designed as a longitudinal monocentric side-effect monitoring study with prospective data collection. It was carried out at the Cologne University Hospital. The study population comprised health care workers who were taking AZT prophylaxis after accidental exposure to HIV-infected blood. Fourteen individuals were included into the study; seven of them discontinued treatment prematurely, five due to severe subjective symptoms. In case of one worker AZT had to be stopped due to severe neutropenia (800 cells/microliters) with signs of upper respiratory tract infection. Four of 11 individuals taking AZT for at least 4 weeks developed neutropenia (2 WHO I, 1 WHO II, 1 WHO III). All other laboratory parameters stayed within normal range. In particular, no anemia was observed. IN CONCLUSION: Compared with other studies more neutropenias are observed. Due to side effects 50% of the workers discontinued AZT administration prematurely. The data presented herein show that AZT causes considerable side effects which must be weighed against the potential protective antiviral effect.

Serum cytokine levels in cancer patients treated with different schedules of ultra-low-dose interleukin-2.

Interleukin-2 (IL-2) induces secondary cytokines in vivo that may mediate antitumor effects as well as toxicity. The course and quantity of this in vivo reaction may depend on scheduling of IL-2 due to changes in responsiveness of the respective producer cells. This was evaluated in a phase-Ib study with ultra-low-dose IL-2 at 0.9 and 4.5 MIU/m2 administered once daily subcutaneously either once weekly (4 doses, stratum I), three times a week every other day (9 doses, stratum II), or five times a week every other week (10 doses, stratum III). Twenty-eight patients with advanced cancer were randomly assigned to the six treatment groups. Serum levels of IL-2, secondary cytokines, and soluble receptors were significantly increased after a single dose of 0.9 MIU/m2 s.c. demonstrating systemic efficacy. Baseline levels and native responsiveness were recovered after a 1-week treatment-free interval in stratum I patients with the exception of sCD8 that was still increased although readily inducible at that time. Stratum II patients exhibited a prolonged and possibly continuous elevation of all serum parameters studied. Values did not increase beyond the 2nd week of therapy and even decreased with respect to sCD8 and neopterin. A sequential mode of administration (stratum III) may obviate some of these adaptive mechanisms as evidenced from a progressive increase of neopterin and sCD8 levels after the second treatment cycle, although induction of sTNFRI was saturable under these conditions. Thus, scheduling of IL-2 profoundly affects in vivo responses as evidenced from cytokine and soluble receptor serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunomodulatory effects of ultra-low-dose interleukin-2 in cancer patients: a phase-IB study.

High-dose interleukin-(IL-2) has been broadly studied in tumor therapy, yet it may be inhibitory to T-cell-dependent immunity. Therefore immune and tumour responses mediated by low-dose IL-2 were studied systematically with respect to the feedback organisation of immune responses. IL-2 was administered once daily at three dose levels: 0.18, 0.9, 4.5 MIU/m2 according to three different schedules requiring subcutaneous (s.c.) injection once weekly (four doses, stratum I), thrice weekly every other day (nine doses, stratum II), or five times weekly every other week (ten doses, stratum III). A total of 46 patients with advanced cancer were randomly assigned to one of the nine treatment groups. Systemic effects were induced at doses as low as 0.18 MIU/m2 IL-2 s.c. as demonstrated from measurable IL-2 serum levels, induction of circulating IL-6, a transient lymphopenia, and stimulation of delayed-type hypersensitivity (DTH) responses of the skin. Analysis of the different IL-2 schedules demonstrated (a) prolonged effects of once-weekly injections on DTH responses, lymphocyte and eosinophil counts, and (b) maximum increase of eosinophil counts and preferential expansion of activated NK cells with repeated injections every 48 h or 72 h (stratum II), while sequential treatment according to stratum III was found to be more potent in increasing the number of activated T cells. A tumour response was observed in 1/15 patients with renal cell carcinoma who experienced more than 50% tumour regression for 8 months; 12 patients had stable disease for 4 months (median). These data demonstrate prolonged immunological effects of ultra-low doses of s.c. IL-2 despite its short half-life. Furthermore, scheduling of IL-2 was found to affect immune responsiveness specifically as demonstrated by the differential effects on natural killer and T cell populations.

Cytosine arabinoside, etoposide and aclarubicin (AVA) for the treatment of acute myeloid leukemia (AML) in elderly patients.

BACKGROUND: Elderly patients (age > or = 60 years) with acute myeloid leukemia (AML) have unfavourable prognoses when polychemotherapy regimens are used, because therapy response is characterized by low remission rates, short remission duration and high toxicity. PATIENTS AND METHODS: A phase II trial in elderly AML patients was conducted to determine the efficacy of two induction courses of a moderately-dosed combination of aclarubicin (25 mg/m2, 30 min i.v., days 1-4), etoposide (100 mg/m2, 30 min i.v., days 1-3) and conventional-dose cytosine arabinoside (ara-C, 100 mg/m2, c.i.v., days 1-3 and 30 min i.v., q 12 hours, days 4-7) (AVA-7), followed by one consolidation treatment using a reduced-dose schedule over five days (AVA-5) after three months in CR. RESULTS: Thirty-two AML patients with a median age of 66.2 years (range 60-76) were included in the study: three of them had histories of preexisting myelodysplasia and one of polycythemia vera. Following 1-2 courses of AVA-7 17 patients (53%) achieved CR, two PR (6%), and nine had resistant disease (28%); the overall response rate was thus 59%. Toxicity was significant but acceptable, with an overall treatment-related death rate of five of 32 patients (16%) after 63 courses of AVA. The median disease-free survival (DFS) was 12 months, and the median survival of all patients was 16.6 months. CONCLUSIONS: These results indicate that the combination of aclarubicin, etoposide and conventional-dose ara-C is effective in elderly AML patients. The relatively brief remission duration requires new consolidation and maintenance therapy approaches.

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.