Phase I, dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours.

PURPOSE: AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gemcitabine in xenograft models. METHODS: This open-label, Phase I, dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours (NCT00937664). Patients received intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed by AZD7762 plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of 22-day cycles, in ascending AZD7762 dose cohorts. RESULTS: Twenty patients received AZD7762 at doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was therefore regarded as non-tolerable. The most common adverse events (AEs) in cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia (45 %) and hypertension, fatigue and rash (30 % each). Grade ≥3 AEs were reported in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to affect AZD7762 PK. There were no objective responses; five patients (all lung cancer) had stable disease. CONCLUSIONS: The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m(2) was determined as 21 mg in Japanese patients.

Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD4877 in Japanese Patients with Solid Tumors.

INTRODUCTION: AZD4877 is a potent Eg5 inhibitor that has been shown to have an acceptable tolerability profile in a Phase I study of Western patients with solid tumors. This study was conducted to evaluate the safety, pharmacokinetic (PK) profile, maximum tolerated dose (MTD) and efficacy of AZD4877 in a Japanese population with solid tumors. METHODS: In this Phase I, open-label, dose-escalation study, AZD4877 (10, 15, 20 or 25 mg) was administered as a 1-hour intravenous infusion on days 1, 8 and 15 of repeated 28-day cycles to Japanese patients with advanced solid tumors. Adverse events (AEs) were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PK variables were assessed pre- and post dosing. The MTD of AZD4877 was determined by evaluating dose-limiting toxicities (DLTs). Efficacy was evaluated by assessing best response according to Response Evaluation Criteria In Solid Tumors version 1.0. RESULTS: Of the 21 patients enrolled, 18 received at least one dose of AZD4877 (N = 3 in both the 10 and 15 mg cohorts, N = 6 in both the 20 and 25 mg cohorts). The most commonly reported AEs were fatigue and nausea (39% of patients each). One patient in each of the 20 and 25 mg cohorts experienced a DLT (neutropenia and febrile neutropenia). Dose escalation was halted at 25 mg and the MTD was not defined in this population. CTCAE grade ≥3 abnormal laboratory findings/vital signs were reported in 12 patients, with neutropenia (56%) and leukopenia (44%) being the most commonly reported. Exposure to AZD4877 was not fully dose proportional and AZD4877 clearance and elimination half-life appeared independent of dose. The best response to AZD4877 was stable disease in five of 16 evaluable patients. CONCLUSION: AZD4877 up to doses of 25 mg was well tolerated in Japanese patients. There was little evidence of clinical efficacy.

[A case of bone marrow carcinosis from gastric cancer that presented hypocalcemia caused by zoledronic acid during the treatment of methotrexate/5-fluorouracil sequential therapy].

The case was a 64-year-old man. He was diagnosed as gastric cancer, lymph node metastases, brain metastases, bone marrow carcinomas, and disseminated intravascular coagulation(DIC). He was started on methotrexate(MTX)/5- fluorouracil(5-FU)sequential therapy(weekly administration of MTX(100 mg/m(2), iv bolus)followed by 5-FU(600 mg/m(2), iv bolus)with a 3 h interval). DIC was resolved, and the tumor marker decreased remarkably. Four weeks later, he received zoledronic acid 4 mg to prevent skeletal complication. Next day, fatigue and anorexia onset. Six days later, laboratory data showed severe hypocalcemia. He was started on calcium gluconate 3.4 g/day. The calcium level was normalized in twelve days, and the symptoms were improved. MTX /5-FU therapy was resumed, and his condition remained stable. However, after the ninth dosage, he developed fatigue and low back pain, and the DIC relapsed. We started paclitaxel therapy. But it was not effective and he died ten days later. It was considered that careful attention to hypocalcemia is necessary when we use zoledronic acid for the bone marrow carcinomas treated with chemotherapy.

[A case of advanced pancreatic cancer responding to combination chemotherapy with the individual maximum repeatable dose of gemcitabine and oral S-1].

The patient was a 70-year-old man with metastatic pancreatic cancer. After he received combination chemotherapy with gemcitabine and oral S-1 on day 1, he experienced severe general fatigue, anorexia and nausea. Then we changed the dose of gemcitabine from 1,000 mg/m(2) 2 to 500 mg/m(2) according to the criteria for an individual maximum repeatable dose (iMRD) determination method on day 8. His general condition recovered, and treatment schedule of gemcitabine with S-1 was continued sequentially at an outpatient clinic. His tumor marker levels, and the sizes of primary pancreatic tumor and liver metastatic lesions remarkably decreased. Partial response has been obtained for 7 months.