Lorelei J. Hanson

Phase I and Pharmacologic Study of Sequences of Gemcitabine and the Multitargeted Antifolate Agent in Patients With Advanced Solid Tumors

PURPOSE Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy. PATIENTS AND METHODS Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m(2) on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m(2), given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses). RESULTS The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m(2) for group I and 1,250/500 mg/m(2) for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA. CONCLUSION The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m(2).

Complementary and Alternative Medicine Use by Patients Enrolled Onto Phase I Clinical Trials

PURPOSE To describe the prevalence, clinical characteristics, and pattern of use of complementary and alternative medicine (CAM) in patients enrolled onto phase I trials. PATIENTS AND METHODS Questionnaires were administered to 108 patients with advanced malignancies enrolled onto phase I chemotherapy trials at the Mayo Clinic Comprehensive Cancer Center (Rochester, MN). CAM was classified into two modalities, pharmacologic and nonpharmacologic. Clinical and demographic data, including age, sex, and prior cancer treatment, were subsequently obtained from patient charts and examined for any correlation with CAM use, using chi2 analysis. RESULTS One hundred two survey forms were returned. Among respondents, 88.2% (90 of 102) had used at least one CAM modality; 93.3% (84 of 90) and 53.3% (48 of 90) had used pharmacologic and nonpharmacologic CAM, respectively; and 46.7% (42 of 90) used both modalities. Vitamin and mineral preparations constituted 89.3% (75 of 84) of all pharmacologic CAM used. Intake was highest for vitamins E (48.8% [41 of 84]) and C (38.1% [32 of 84]), and 71.4% (60 of 84) of respondents took nonvitamin/mineral agents. Green tea (29.8% [25 of 84]), echinacea (13.1% [11 of 84]), and essiac (9.5% [8 of 84]) were the most popular. Prayer and spiritual practices were the most commonly used nonpharmacologic CAM, accounting for 52.1% (25 of 48). Chiropractors, the most frequently visited nontraditional medicine practitioners, were consulted by only 10% (9 of 90) of those who practiced CAM. Both CAM modalities were used more frequently by women (53.5% [23 of 43]) than men (40.4% [19 of 47]). CONCLUSION CAM use is common among patients in phase I trials and should be ascertained by investigators, because some of the agents used may interact with investigational agents and affect adverse effects and/or efficacy.

Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

Purpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced non–small cell lung cancer. Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed. Results: Thirty-one patients were treated (n = 12, part A; n = 19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib Cmax (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n = 8, part A; n = 12, part B) had stable disease ≥4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily. Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non–small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.

A Phase I and Pharmacologic Trial of Two Schedules of the Proteasome Inhibitor, PS-341 (Bortezomib, Velcade), in Patients with Advanced Cancer

Purpose: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. Patients and Methods: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. Results: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade ≥3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade ≥3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. Conclusion: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.

A Phase I Trial of the Novel Farnesyl Protein Transferase Inhibitor, BMS-214662, in Combination with Paclitaxel and Carboplatin in Patients with Advanced Cancer

Purpose: This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors. Experimental Design: Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662. Results: Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m2), paclitaxel (225 mg/m2) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (> 4 cycles) occurred in eight other patients. Conclusions: The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.

History of the Development of Antiemetic Guidelines at Mayo Clinic Rochester

This article describes the historic experience of the development of antiemetic guidelines for patients taking chemotherapy drugs at Mayo Clinic Rochester. The initial guidelines for the use of serotonin (5-hydroxytryptamine3) receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting were developed in early 1995 and implemented in September 1995. In February 1997, the guidelines were reviewed and modified. In the spring of 1998, major changes were made based on new data from the literature and discussions with antiemetic authorities in the United States. These guidelines were implemented in July 1998. The guidelines were again reviewed and modified in December 1998. In addition, we compared costs associated with the 1997 guidelines and the December 1998 guidelines. The developed guidelines, utilizing clinically available agents, seem to provide high-quality patient care at a reasonable cost.

A Phase I and Pharmacologic Study of Pyrazoloacridine (NSC 366140) and Carboplatin in Patients with Advanced Cancer

AbstractBackground: Pyrazoloacridine (PZA) is thefirst of a new class of rationallysynthesized acridine derivatives to undergoclinical testing as an anticancer agent. We previously demonstrated cytotoxicsynergy between combinations of PZA andplatinum compounds. Subsequent studiesrevealed that PZA inhibits removal ofplatinum-DNA adducts in cultured A549cells. Based on these results, weundertook a phase I study of thecombination of PZA and carboplatin (CBDCA). Patients and methods: Twenty-eightpatients received 76 28-day courses (median2.5, range 1–6) of CBDCA (30-minuteinfusion) followed by PZA (3-hourinfusion), through six dose levels [PZA/CBDCA] (200/AUC 3,400/AUC 3, 400/AUC 4,400/AUC 5, 500/AUC 5, 600/AUC5 mg/m2/AUC). Pharmacokineticanalyses were performed to evaluate thedisposition of PZA. Retention ofplatinum-DNA adducts in peripheral bloodmononuclear cells of patients was alsoevaluated. Results: The most common anddose-limiting toxicity wasmyelosuppression, consisting of neutropeniaand leukopenia. Non-hematologic toxicitiesof anorexia, nausea and stomatitis weremild to moderate. In six patientsevaluated at the MTD, CBDCA did not appearto affect the pharmacokinetics of PZA. Onepatient with malignant melanoma had apartial response. Disease stabilizationfor greater than 4 courses of treatmentoccurred in 4 patients. Conclusion: The combination of PZAand CBDCA was well tolerated and may haveutility in some tumor types.

A phase I trial of the farnesyltransferase (FT) inhibitor, BMS-214662 (B) in combination with paclitaxel (P) and carboplatin (C) in patients with advanced cancer

3066 Background: FT, has emerged as an important target for cancer therapy. B, a parenterally-administered FT inhibitor, has enhanced potency against quiescent cells in vitro. The combination of P and C is broadly active and exhibited cytotoxic synergy with P in human tumor xenograft models. METHODS A phase I study was performed to define the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and clinical activity of the combination of escalating doses of P(IV d1) and C(IV d1) followed by B(IV d1), on a 21-day cycle in patients (pts) with advanced cancers. In vivo target inhibition was evaluated by FT enzyme assays and inhibition of HDJ2 farnesylation in peripheral blood mononuclear cells. RESULTS 32 pts received 141 cycles of treatment through 6 dose levels. Significant treatment-related toxicities in all cycles of treatment graded by NCI CTC (cumulative events in all cycles, CTC grade) were neutropenia (33 grade 3, 26 grade 4), thrombocytopenia ( 4 grade 3), leukopenia (34 grade 3, 12 grade 4), peripheral neuropathy ( 1 grade 3), nausea (3 grade 3), vomiting (1 grade 3) fatigue (4 grade 3) and diarrhea (1 grade 3). DLTs were neutropenia, severe nausea and vomiting. Two PRs were documented (relapsed ovarian cancer, taxane-resistant esophageal cancer). Regression of evaluable endometrial cancer was seen. Stable disease (> 4 cycles) occurred in 10 pts. MTD was defined at dose level 4. B Clp and t1/2 were not significantly altered by prior administration of P. Dose-dependent reversible FT inhibition occurred. CONCLUSIONS The combination of B with P and C is biologically effective and well-tolerated. [Figure: see text] No significant financial relationships to disclose.

Complementary and alternative medicine (CAM) use by patients enrolled in phase I clinical trials

8053 Background: CAM usage among cancer patients is common, but usage in patients enrolled in phase I trials is unknown. There are potential pharmacologic interactions between CAM agents and experimental cancer therapies. This study describes the prevalence, clinical characteristics, and patterns of CAM use among patients enrolled in phase I trials. METHODS Investigator-designed questionnaires were administered to 108 patients with advanced malignancies enrolled in phase I chemotherapy trials at Mayo Clinic. CAM was classified as pharmacologic and non-pharmacologic. RESULTS 88.2% of respondents (90/102) used at least one CAM modality of whom 93.3% (84/90) used pharmacologic and 53.3% (48/90) used non-pharmacologic form of CAM. 46.7% (42/90) combined both approaches. 91.1% of CAM users had received prior standard chemotherapy. Overall, CAM use was higher among females than males (53.5% vs. 40.4%). Vitamin and mineral supplements (vitamin E 48.8%; vitamin C 38.1%) constituted 89.3% of pharmacologic CAM use. 71.4% of patients took non-vitamin, non-mineral pharmacologic CAM preparations of which green tea (29.8%), echinacea (13.1%) and essiac (9.5%) were the most popular. Spirituality (prayer and faith) was the most commonly practiced non-pharmacologic form of CAM, accounting for 52.1%. Chiropractors, the most frequently visited non-traditional medical practitioners, were consulted by only 10% of CAM users. CONCLUSION CAM use is widespread among phase I patients. This increases the potential for anti-cancer drug interactions with such CAM agents as green tea and echinacea which are known to affect hepatic drug metabolism. Essiac contains cytotoxic anthraquinones and other substances that interact with hormone receptors ( e.g. estrogen). Investigators should ascertain the CAM therapies utilized by patients as interactions between CAM agents and experimental agents can potentially lead to increased toxicity or alter efficacy of experimental drug therapy. No significant financial relationships to disclose.