D. D. Von Hoff

Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.

PURPOSE Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

Hypersensitivity reactions from taxol.

Taxol is an antitumor agent in clinical trial that has been shown to have activity against advanced ovarian carcinoma and melanoma. Hypersensitivity reactions (HSRs) have been one of the toxicities observed with administration of this drug. Of 301 patients treated, 32 patients have had definite (27 patients) or possible (five patients) hypersensitivity reactions to taxol. All but one patient had the reaction from the first or second exposure to this agent. Reactions occurred at a variety of doses and were characterized most frequently by dyspnea, hypotension, bronchospasm, urticaria, and erythematous rashes. Thirteen (41%) patients had received premedication designed to prevent such toxicity; nevertheless, they sustained HSRs. Prolonging the drug infusion appears to have somewhat reduced, but not obviated, the risk of HSRs. The cause (taxol itself or its excipient Cremophor EL; Badische Anilin und Soda-Fabrik AG [BASF], Ludwigshafen, Federal Republic of Germany) and the mechanism of these reactions to taxol are unknown. We provide guidelines to prevent or minimize such toxicity and treat reactions if they still occur.

Phase III Trial of Gemcitabine Plus Tipifarnib Compared With Gemcitabine Plus Placebo in Advanced Pancreatic Cancer

PURPOSE To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. PATIENTS AND METHODS This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. RESULTS Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. CONCLUSION The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.

Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer

PURPOSE To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

Phase I Evaluation of ISIS 3521, an Antisense Oligodeoxynucleotide to Protein Kinase C-Alpha, in Patients With Advanced Cancer

PURPOSE To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha. PATIENTS AND METHODS Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites. RESULTS Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkins lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life. CONCLUSION No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.

A phase I trial of taxol given by a 6-hour intravenous infusion.

Taxol is a unique mitotic inhibitor that has entered phase II investigation. Phase I studies demonstrated hypersensitivity reactions that were related to the cremophor vehicle and to the rate of drug infusion. As a result, the time span of intravenous (IV) infusion of taxol was routinely prolonged to 6 hours or beyond, and premedication with diphenhydramine, dexamethasone, and cimetidine was initiated. Early studies showed antitumor activity, especially against malignant melanoma and ovarian carcinoma. This phase I trial was performed giving taxol, as a 6-hour IV infusion every 21 days, without premedication. The purpose was to study the necessity of premedication and its impact on toxicity and pharmacokinetics. Thirty-one patients received 64 assessable courses of taxol. One patient had a hypersensitivity reaction, which was easily controlled using routine measures. Myelosuppression was dose-limiting, but sporadic, with two fatalities due to sepsis. Nonhematologic toxicity was of grade 1 and 2 except for one patient with grade 3 mucositis and two patients with grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias, requiring discontinuation of drug in two patients. Four partial responses were seen (three in patients with non-small-cell lung cancer, one in a patient with adenocarcinoma of unknown primary). Pharmacokinetic values were consistent with those previously reported. The occurrence of myelosuppression or neurotoxicity appeared to be associated with the area under the concentration x time curve (AUC) of taxol. The recommended phase II starting dose on this schedule is 225 mg/m2. Taxol merits broad investigation at the phase II level.

Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP.

PURPOSE To evaluate the feasibility of administering biricodar (VX-710; Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that modulates multidrug resistance (MDR) conferred by overexpression of both the multidrug resistance gene product (MDR1) P-glycoprotein and the MDR-associated protein (MRP) in vitro, in combination with paclitaxel. The study also sought to determine the maximum-tolerated dose (MTD) of paclitaxel that could be administered with biologically relevant concentrations of VX-710 and characterize the toxicologic and pharmacologic profiles of the VX-710/ paclitaxel regimen. PATIENTS AND METHODS Patients with solid malignancies were initially treated with VX-710 as a 24-hour infusion at doses that ranged from 10 to 120 mg/m2 per hour. After a 2-day washout period, patients were re-treated with VX-710 on an identical dose schedule followed 8 hours later by paclitaxel as a 3-hour infusion at doses that ranged from 20 to 80 mg/m2. The pharmacokinetics of both VX-710 and paclitaxel were studied during treatment with VX-710 alone and VX-710 and paclitaxel. Thereafter, patients received VX-710 and paclitaxel every 3 weeks. RESULTS VX-710 alone produced minimal toxicity. The toxicologic profile of the VX-710/paclitaxel regimen was similar to that reported with paclitaxel alone; neutropenia that was noncumulative was the principal dose-limiting toxicity (DLT). The MTD levels of VX-710/ paclitaxel were 120 mg/m2 per hour and 60 mg/m2, respectively, in heavily pretreated patients and 120/60 to 80 mg/m2 per hour in less heavily pretreated patients. At these dose levels, VX-710 steady-state plasma concentrations (Css) ranged from 2.68 to 4.89 microg/mL, which exceeded optimal VX-710 concentrations required for MDR reversal in vitro. The pharmacokinetics of VX-710 were dose independent and not influenced by paclitaxel. In contrast, VX-710 reduced paclitaxel clearance. At the two highest dose levels, which consisted of VX-710 120 mg/m2 per hour and paclitaxel 60 and 80 mg/m2, pertinent pharacokinetic determinants of paclitaxel effect were similar to those achieved with paclitaxel as a 3-hour infusion at doses of 135 and 175 mg/m2, respectively. CONCLUSION VX-710 alone is associated with minimal toxicity. In combination with paclitaxel, biologically relevant VX-710 plasma concentrations are achieved and sustained for 24 hours, which simulates optimal pharmacologic conditions required for MDR reversal in vitro. The acceptable toxicity profile of the VX-710/ paclitaxel combination and the demonstration that optimal pharmacologic conditions for MDR reversal are achievable support a rationale for further trials of VX710/paclitaxel in patients with malignancies that are associated with de novo or acquired resistance to paclitaxel caused by overexpression of MDR1 and/or MRP.

In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients.

BACKGROUND Ecteinascidin-743 (ET-743), a member of the ecteinascidin family selected for clinical development, is a tetrahydroisoquinolone alkaloid isolated from the marine ascidian, Ecteinascidia turbinata. This novel compound is a minor groove binding, guanine-specific alkylating agent which also interacts with the microtubule network and blocks cell cycle progression at late S/G2. MATERIALS AND METHODS A soft agar cloning assay was used to determine the in vitro effects of ET-743 against primary human tumor specimens taken directly from patients. A total of 93 evaluable specimens were exposed to ET-743 for one-hour (n = 25) and/or 14-day continuous exposure (n = 92) at concentrations ranging from 0.1 nM to 1 microM. In vitro responses were defined as an inhibition > or = 50% of human tumor colony forming units at a given concentration. RESULTS One-hour exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM induced in vitro responses in 0% (0/17), 6% (1/17), 16% (4/25), 13% (1/8), and 25% (2/8) of specimens, respectively. Continuous exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM, inhibited 0% (0/16), 13% (2/16), 49% (44/90), 62% (47/76), and 77% (58/75) of tumor specimens, respectively. Tumor-specific responses and concentration-dependent relationships were observed with a continuous exposure to ET-743. At 100 nM, the compound inhibited 79% (11/14) breast, 69% (9/13) non-small-cell lung, 58% (7/12) ovary, and 88% (7/8) melanoma specimens. At 1 microM, ET-743 inhibited 100% (14/14) breast specimens, 85% (11/13) non-small-cell lung, 67% (8/12) ovary and 86% (6/7) melanoma specimens. Activity of ET-743 at and above 10 nM was also observed against sarcoma and kidney tumors. At 10 nM concentration and continuous exposure ET-743 demonstrated incomplete cross-resistance with paclitaxel, alkylating agents, doxorubicin and cisplatin. CONCLUSIONS Our data from the cloning assay indicate that the duration of exposure to ET-743 is an important factor in human tumors. Therefore, long-term exposure to ET-743 may be preferred in future clinical trials. The activity of ET-743 in breast, non-small-cell lung, and ovarian cancers as well as in melanoma may deserve further clinical evaluations. The potential of ET-743 in sarcoma and renal tumors might also be considered. In addition, our data indicate that a plasma concentration of 100 nM of ET-743 must be considered as a target during the clinical development of the compound; also the concept of continuous/protracted exposure in clinical trials with ET-743 has to be taken into account.

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

PURPOSE To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

Phase II trial of docetaxel in patients with advanced cutaneous malignant melanoma previously untreated with chemotherapy.

PURPOSE A phase II study was undertaken to determine the efficacy of docetaxel in patients with metastatic malignant melanoma. PATIENTS AND METHODS Between June 1992 and March 1994, 40 patients with metastatic malignant melanoma and no prior chemotherapy were treated with docetaxel 100 mg/m2 administered intravenously over 1 hour every 21 days. None of the patients had brain metastasis. Toxicity and follow-up data are provided. RESULTS One patient had a histologically confirmed complete response that lasted for 14+ months. Four patients had partial responses, bringing the overall response rate to 12.5% (95% confidence interval [CI], 6% to 30%). A patient with a partial response had a single chest-wall metastasis and was rendered free of disease surgically after a maximal response to docetaxel and remained free of tumor recurrence after 18+ months. Tumor was stabilized in 22 patients. The overall median survival time was 13 months. The main hematologic toxicity was neutropenia, which was severe but transient. Peripheral neuropathy was the limiting nonhematologic toxicity in three patients. Other important toxicities included cutaneous toxicity, fluid retention, oral mucositis, and hypersensitivity reactions. Preadministration of dexamethasone and diphenhydramine reduced the incidence of hypersensitivity reactions, cutaneous toxicities, and fluid retention. CONCLUSION Docetaxel has definite but low-level activity against malignant melanoma. Further investigation of this drug should be conducted in multidrug combination programs.