An innovative, multi-arm, complete phase 1b study of the novel anti-cancer agent tasisulam in patients with advanced solid tumors.

BACKGROUND: This phase Ib study used a parallel, multi-arm design to examine tasisulam-sodium (hereafter tasisulam), a drug with complex pharmacology, combined with standard chemotherapies in patients with advanced solid tumors, with the ultimate goal of accelerating drug development. METHODS: Patients received escalating doses of tasisulam (3 + 3 schema; target Cmax 300-400 µg/mL) every 28 days plus 1,000 mg/m(2) gemcitabine HCl (days 1 and 15), 60 mg/m(2) docetaxel, 200 mg/m(2)/day temozolomide, 75 mg/m(2) cisplatin, or 150 mg/day erlotinib. Following dose-escalation, patients were enrolled into specific tumor subtype arms, chosen based on the established activity of the standard agent. Because tasisulam is highly albumin-bound, patients in the tumor-specific confirmation arms were dosed targeting specific albumin-corrected exposure ranges (AUCalb) identified during dose-escalation (3,500 h*µg/mL [75th percentile] for docetaxel, temozolomide, and cisplatin; 4,000 h*µg/mL for gemcitabine and erlotinib). RESULTS: A total of 234 patients were enrolled. The safety profile of tasisulam with standard chemotherapies was sufficient to allow enrollment into the dose-confirmation phase in all arms. The primary dose-limiting toxicities were hematologic (thrombocytopenia and neutropenia). The most common grade ≥3 drug-related treatment-emergent adverse event was neutropenia, with the highest incidence in the docetaxel arm. CONCLUSIONS: The multi-arm design allowed the efficient determination of the maximum tolerated dose of tasisulam across multiple combinations, and a preliminary characterization of pharmacokinetics, safety, and potential efficacy. Although enrollment into all planned groups was not completed due to termination of compound development, these data support the feasibility of this approach for accelerated cancer drug development, even for drugs with complex pharmacology.

A phase I trial of pemetrexed plus gemcitabine given biweekly with B-vitamin support in solid tumor malignancies or advanced epithelial ovarian cancer.

PURPOSE: To determine the maximally tolerated dose (MTD) of biweekly pemetrexed with gemcitabine plus B(12) and folate supplementation in patients with advanced solid tumors and ovarian cancer. EXPERIMENTAL DESIGN: Patients with no prior pemetrexed or gemcitabine therapy enrolled in cohorts of three, expanding to six if dose-limiting toxicity (DLT) was observed. Pemetrexed, escalated from to 700 mg/m(2), was given before gemcitabine 1,500 mg/m(2) every 14 days. DLTs were grade 4 neutropenia lasting >7 days or febrile neutropenia, grade 4 or 3 thrombocytopenia (with bleeding), grade > or =3 nonhematologic toxicity, or treatment delay of > or =1 week due to unresolved toxicity. RESULTS: The ovarian cancer cohort enrolled 24 patients with unlimited prior cytotoxic chemotherapies. MTD was observed at pemetrexed 600 mg/m(2), with 2 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (83%), leukopenia (67%), lymphopenia (73%), and febrile neutropenia (12%). Median cycle per patient was 8 (range, 1-16). Six of 21 (28%) patients had confirmed partial responses. Study protocol was modified for the solid tumor cohort (n = 30) to enroll patients with two or more prior cytotoxic regimens. MTD was observed at pemetrexed 500 mg/m(2), with 1 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (63%), lymphopenia (43%), leukopenia (70%) and febrile neutropenia (6.6%). Median cycle per patient was 4 (range, 1-20). Three of 29 (10.3%) response-evaluable patients had confirmed partial responses: 2 squamous cell carcinomas of head and neck and 1 nasopharyngeal cancer. CONCLUSION: MTDs for the solid tumor and ovarian cancer cohorts were reached at pemetrexed 500 and 600 mg/m(2), respectively, given biweekly with gemcitabine 1,500 mg/m(2).

Phase II trial of subcutaneous interferon followed by intravenous hybrid bolus/continuous infusion interleukin-2 in the treatment of renal cell carcinoma: final results of Cancer Biotherapy Research Group 95-09.

OBJECTIVE: We conducted a phase II trial in metastatic renal cell cancer of outpatient subcutaneous (s.c.) interferon-alpha2b (IFN), followed by an inpatient hybrid schedule of bolus and continuous interleukin-2 (IL- 2). METHODS: Treatment consisted of monthly IFN 10 MU/m(2) s.c. for 4 consecutive days, followed by 36 MIU/m(2) bolus IL-2, then 72-hour continuous intravenous (i.v.) infusion of 18 MIU/m(2) IL-2 per day. Between May 1997 and June 2000, 25 men and 11 women enrolled, with a median age of 57 years (range, 42-77), including 9 patients over 65. Prior treatment included nephrectomy (31), radiation (8), biotherapy (7), and chemotherapy (4). Sites of disease included 26 lung, 13 lymph node, 9 bone, 8 liver, 4 kidney, and 4 adrenal locations. Patients received an average of 3.1 treatment cycles (range, 1-6). RESULTS: There was 1 complete and 3 partial responses, for a response rate of 11% (3% to 27%; 95% confidence interval [CI]); 40% had stable disease. Median failure-free survival was 2.5 months; median overall survival was 15.0 months. The 1-, 2-, and 5-year survival rates were 53%, 30%, and 12%, respectively. Only 8 patients required a reduction in IL-2 dose. The most frequent grade 3 or 4 toxicities were 11% fatigue, 9% renal insufficiency, and 7% hypotension. CONCLUSIONS: Response and survival rates were similar to those seen in other multicenter trials using inpatient high-dose IL-2.

A phase II study of gemcitabine in combination with radiation therapy in patients with localized, unresectable, pancreatic cancer: a Hoosier Oncology Group study.

OBJECTIVE: A Phase II study was conducted at Indiana University to evaluate the safety and efficacy of combined weekly Gemcitabine (GEM) with external beam radiotherapy (RT) in unresectable, locally advanced pancreatic cancer (LAPC). METHODS: Eligible patients had biopsy-proven LAPC without evidence of metastatic disease. In part A of the treatment plan, patients received GEM 600 mg/m(2) IV weekly, with concurrent RT (50.4 Gy in 28 fractions, 1.8 Gy/d, 5 days per week). Part B of the treatment plan began approximately 4 weeks after completing part A: patients without disease progression received weekly GEM 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle for 6 cycles or until disease progression. RESULTS: From April 2001 to June 2003, of 28 patients evaluated, 24 (86%) completed part A. About 22 patients had grade 3 toxicities, primarily hematologic (43%) and gastrointestinal (36%). Three patients (11%) had grade 4 toxicities (one each for hyperbilirubinemia, infection, and dyspnea). The median follow-up was 10 months (1-63 months) for all enrolled patients. Six patients (21%) had a radiologic partial response, 16 (57%) had stable disease, 5 (18%) had progressive disease, and 1 patient (4%) had an unevaluable response at last follow-up. Four patients (14%) underwent surgical resection (2 with R0 resection). Median time to progression was 6 months (0-36 months). Median survival time was 10.3 months (95% confidence interval, 7.9-14.6 months). The 1- and 2-year actuarial survival rates were 30% and 11%. At last analysis, all but 2 patients died. CONCLUSION: The activity and toxicity profile of combination GEM and RT indicates that this can be safely administered for patients with LAPC.