Detection of a point mutation in NQO1 (DT-diaphorase) in a patient with colon cancer.
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Adult↗
Biomedical subjects
H A Burris
Publications and source records attributed to H A Burris.
A phase I and pharmacokinetics study of 2-chlorodeoxyadenosine in patients with solid tumors.
Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m2 per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m2 per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m2 per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (< 1,000/microliters) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Non-hematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37 degrees-40 degrees C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cpss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m2 per day. Both the Cpss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m2 per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m2 per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies.
Adult↗
Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.
PURPOSE: To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS: Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS: Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION: The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.
Adult↗
Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent.
BACKGROUND: Docetaxel (RP 56976) is a new chemotherapeutic agent that has shown promise in a number of animal studies and is currently undergoing phase I and phase II trials. Early in the phase I trials, it was noted that a significant number of patients were experiencing a variety of cutaneous complaints, so we elected to prospectively evaluate the cutaneous reactions occurring during the first three courses of therapy in the first 12 patients enrolled for phase I chemotherapy at our institutions. OBSERVATIONS: All but one patient had some type of cutaneous eruption over the three courses of therapy. Of the 27 evaluable courses of docetaxel given, 19 (70%) resulted in a cutaneous eruption with four (21%) being asymptomatic and 15 (79%) being at least mildly symptomatic. The most common reaction seen was characterized by discrete erythematous to violaceous patches or edematous plaques similar to acral erythema. CONCLUSION: Although a majority of patients receiving docetaxel experience some degree of cutaneous reaction, the eruptions are usually mildly symptomatic and almost always self-limiting.
Acute Disease↗
Activity of DMP 840, a new bis-naphthalimide, on primary human tumor colony-forming units.
BACKGROUND: DMP 840 ((R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]-iso[quinoline-1,3(2H)-dione]dimethane- sulfonate; NSC-D640430) is one in a series of bis-naphthalimides that binds DNA with high affinity and has sequence specificity to multiple G and C bases. It is also a potent inhibitor of RNA synthesis. DMP 840 has been selected for clinical evaluation on the basis of a broad spectrum of activity (including cures) in human tumors in murine models. PURPOSE: We evaluated DMP 840 in a human tumor clonogenic assay to estimate what plasma concentrations may be necessary for clinical cytotoxic activity and to determine what types of tumors potentially might be primary targets for initial phase II studies. METHODS: A soft-agar cloning system assay was used to determine the in vitro effects of DMP 840 against cells from biopsy specimens of colorectal, breast, lung ovarian, renal cell, stomach, and bladder cancers and from other tumor types. A total of 260 human tumor specimens were exposed continuously during the assay to DMP 840; 103 were assessable (20 colonies or more on control plates and 30% or less survival for the positive control). An in vitro response was defined as at least a 50% decrease in tumor colony formation resulting from drug exposure compared with controls. RESULTS: In vitro responses were seen in 10% (one of 10), 54% (55 of 101), 80% (82 of 103), and 89% (82 of 92) of specimens tested at 0.01, 0.1, 1.0, and 10.0 micrograms/mL of DMP 840, respectively. At a concentration of 0.1 microgram/mL, specific activity was seen against melanoma (80%) and against renal cell (80%), ovarian (63%), breast (54%), non-small-cell lung (42%), and colorectal cancers (33%). DMP 840 demonstrated activity in tumor specimens resistant in vitro to methotrexate (88%), doxorubicin (58%), platinum (57%), cyclophosphamide (53%), vinblastine (53%), etoposide (53%), fluorouracil (37%), and paclitaxel (36%). CONCLUSIONS: At in vitro concentrations of 0.1 microgram/mL as a continuous exposure, DMP 840 has activity against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. IMPLICATIONS: Further clinical development of DMP 840 is warranted.
Antineoplastic Agents↗
Prevention of docetaxel-induced erythrodysesthesia with local hypothermia.
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Aged↗
Activity of intoplicine (RP60475), a new DNA topoisomerase I and II inhibitor, against human tumor colony-forming units in vitro.
BACKGROUND: Intoplicine (RP60475) is the most active analogue evaluated in the 7H-benzo[e]-pyrido-[4,3-b]-indole series of antineoplastic compounds. It exerts its activity through inhibition of DNA topoisomerase I and II. PURPOSE: This study was planned to determine plasma concentrations of intoplicine necessary for optimal clinical antitumor activity, as well as to pinpoint possible responsive tumor types that can be included in phase II clinical studies. METHODS: Tumor specimens were collected from patients as part of routine clinical measures. Single-cell suspensions were prepared from freshly obtained solid tumor biopsy specimens and were exposed to intoplicine either for 1 hour or continuously. The sensitivity of these specimens to intoplicine was evaluated in a human tumor soft-agar cloning assay. Response was considered positive when the colony-forming unit count in drug-treated samples was 50% or less than the response of control tumor samples treated with saline. RESULTS: With 1-hour exposure to intoplicine at final concentrations of 2.5 micrograms/mL and 10.0 micrograms/mL, 26% and 54% of the assessable specimens showed positive in vitro responses, respectively. With continuous exposure to intoplicine at concentrations of 0.25 micrograms/mL and 2.5 micrograms/mL, 16% and 71% of the assessable specimens showed positive responses, respectively. Activity was seen against breast (71%), non-small-cell lung (69%), and ovarian (45%) cancer colony-forming units at a intoplicine concentration of 10.0 micrograms/mL after 1-hour exposure. Incomplete cross-resistance with doxorubicin, cisplatin, fluorouracil, 4-hydroperoxycyclophosphamide, vinblastine, and etoposide was also observed. CONCLUSIONS: Intoplicine appears to be active in vitro against a variety of human tumors, including a subgroup of tumors insensitive in vitro to standard antineoplastic compounds. If plasma levels of 10.0 micrograms/mL can be achieved in subjects in ongoing clinical trials, intoplicine could have significant clinical activity. IMPLICATIONS: These data indicate that further investigation of intoplicine is warranted.
Antineoplastic Agents↗
Preclinical and phase I trials of topoisomerase I inhibitors.
A total of three topoisomerase I inhibitors, including topotecan, CPT-11 (irinotecan), and intoplicine, have been studied in both preclinical and clinical/clinical pharmacology studies. In in vitro testing against human tumor colony-forming units, all three compounds were significantly more effective when tested as a continuous exposure as compared with a 1-h exposure. The dose-limiting toxicities were different for all three of the agents, with neutropenia and thrombocytopenia being dose-limiting for topotecan; diarrhea, for CPT-11; and hepatotoxicity, for intoplicine. In these phase I studies a number of marginal responses were noted with topotecan; partial and marginal responses, with CPT-11 (particularly in patients with colon cancer); and no response, with intoplicine. The detailed pharmacology of all three agents documented a very short half-life for topotecan, an intermediate half-life for CPT-11, and a prolonged half-life for intoplicine. Based on our experience to date, these compounds (particularly CPT-11) have promise as useful additions to our tremendous therapeutic armamentarium.
Antineoplastic Agents↗
Phase I clinical trial of gemcitabine given as an intravenous bolus on 5 consecutive days.
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Antimetabolites, Antineoplastic↗
A phase II trial of DaunoXome, liposome-encapsulated daunorubicin, in patients with metastatic adenocarcinoma of the colon.
CONTEXT: Liposomal encapsulation of drugs can potentially ameliorate toxicities and improve acute and chronic tolerance. The increased uptake of liposomes by colon adenocarcinoma cell lines may enable DaunoXome to circumvent the p-glycoprotein-mediated anthracycline resistance of colon cancer cells. PURPOSE: To determine if DaunoXome, liposome-encapsulated daunorubicin, has clinical activity in patients with adenocarcinoma of the colon who failed treatment with a 5-fluorouracil containing regimen. METHOD: In a Phase II trial, patients with metastatic adenocarcinoma of the colon, whose disease has progressed after receiving one 5-fluorouracil-containing regimen, were treated with DaunoXome 100 mg/m2 repeated every 3 weeks. RESULTS: In this trial 16 patients received 45 courses of therapy. No objective tumor responses were seen. Hematologic toxicities consisted of neutropenia (grade 3 and 4), grade 2 anemia, and grade 2 thrombocytopenia. Nonhematologic toxicities were mild and manageable. Of the 16 patients, 5 experienced flushing, shortness of breath, chest tightness, and back pain during DaunoXome infusion, which resolved with infusion interruption, diphenhydramine, and meperidine. CONCLUSIONS: DaunoXome is generally well tolerated at a dose of 100 mg/m2 every 3 weeks. Toxicities are mild and reversible. On this schedule DaunoXome does not have significant clinical activity in patients with metastatic adenocarcinoma of the colon who have progressed after one 5-fluorouracil-containing regimen.
Adenocarcinoma↗
Phase I trial of sulofenur (LY186641) given orally on a daily x 21 schedule.
Sulofenur (LY186641), a diarylsulfonylurea, was evaluated clinically utilizing either a daily x 21 schedule or a daily x 5 (with 2 days off) for 3 weeks schedule. Eighteen patients with refractory solid tumors received 47 evaluable courses of sulofenur given p.o. daily x 21 every 28 days at five dose levels while 14 received 29 courses of sulofenur given daily x 5 for 3 weeks every 28 days at three dose levels. Toxicities included anemia, methemoglobinemia and hemolysis. One patient experienced a fatal subendocardial infarction on the daily x 21 schedule. One partial response was observed in a patient with a sertoli cell tumor on the daily x 5 for 3 weeks schedule. Daily x 5 for 3 weeks is the schedule recommended for phase II trials.
Administration, Oral↗
Activity of CPT-11 (irinotecan hydrochloride), a topoisomerase I inhibitor, against human tumor colony-forming units.
CPT-11 (irinotecan hydrochloride, 7-ethyl-10-[4-(piperidino)-1-piperidino] carbonyloxy-camptothecin) is a semisynthetic camptothecin derivative developed in Japan. The inhibitory activity of CPT-11 against human tumor colony-forming units from freshly explanted human tumors was explored using a soft agar cloning system. Final CPT-11 concentrations of 0.3-3.0 micrograms/ml were used for a 1 h exposure. At a concentration of 3.0 micrograms/ml antitumor activity was seen against colorectal, ovarian, nonsmall-cell lung, breast cancer and mesothelioma colony-forming units. CPT-11 should have activity against a broad spectrum of tumors in patients.
Antineoplastic Agents↗
Phase I and pharmacokinetic studies of topotecan administered as a 72 or 120 h continuous infusion.
Topotecan (SK&F 104864-A, NSC 609699) is a water-soluble, semi-synthetic analog of camptothecin which is an inhibitor of topoisomerase I. Since topoisomerase I is cell specific for S phase, we undertook a phase I study to determine the maximum tolerated dose and toxicities of continuous infusion (CI) topotecan. This phase I trial first explored a 5 day CI every 21 day schedule. Doses of topotecan included 0.17, 0.34 and 0.68 mg/m2/day. Fourteen patients [median age 60; median performance status (PS) of 1] with refractory malignancies received 59 courses of drug. Hematologic toxicities occurred only at the highest dose level; NCI grade 3-4 granulocytopenia and thrombocytopenia occurred in 4/8 and 3/8 patients, respectively. The protocol was amended to a 3 day infusion in an effort to ameliorate toxicity and obtain greater dose intensity (DI). Doses of 0.68, 0.85, 1.05, 1.3 and 1.6 mg/m2/day were evaluated. Thirty-two patients (median age 60; median PS of 1) received a total of 115 courses. The major toxicity seen was hematologic with 9/32 and 5/32 patients demonstrating grade 3-4 granulocytopenia and thrombocytopenia, respectively. Non-hematologic toxicities were mild (grade 1-2) in the two schedules and included nausea, vomiting, fatigue and alopecia. At the maximum tolerated dose (MTD) on the 5 day schedule, patients received 0.87 mg/m2/week, whereas they received 1.08 mg/m2/week at the MTD on the 3 day schedule (24% increase in relative dose intensity). A steady-state plasma lactone concentration of 5.5 mg/ml of topotecan was achieved at the phase II recommended dose of 1.6 ng/m2/day as a 3 day continuous infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Phase I clinical trial of ormaplatin (tetraplatin, NSC 363812).
Ormaplatin is a platinum analog that was developed because of an altered toxicity profile and non-cross resistance to cisplatin in both in vitro and in vivo models. To determine the toxicities and maximum tolerated dose of ormaplatin on a daily times five schedule, patients with refractory solid tumors received ormaplatin on five consecutive days at nine dose levels ranging from 1.0 to 15.0 mg/m2/day. A total of 35 patients received 70 cycles of therapy. Nausea and vomiting and myelosuppression were moderate and not dose-limiting. Dose-limiting neurotoxicity, consisting of a sensory peripheral neuropathy, was seen in all five patients who received cumulative doses greater than or equal to 165 mg/m2. This neurotoxicity was symptomatic in all patients and caused significant functional impairment in four patients with inability to walk in two patients. A sensitive atomic absorption spectroscopy analysis performed for one patient at the 13.0 mg/m2/day dose level showed a Cpmax of 163 ng/ml and a t1/2 of 10.9 min for free platinum. A phase II dose could not be determined due to the onset of peripheral neuropathy at low cumulative doses and not at absolute dose levels.
Adult↗
Pharmaceutical issues of paclitaxel. Preclinical pharmacology and phase I clinical trials.
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Animals↗
Summary of data from in vitro and phase I vinorelbine (Navelbine) studies.
The semisynthetic vinca alkaloid vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) is unique in its chemical structure, microtubule selectivity, and neurotoxicity profile. In preclinical studies, vinorelbine showed encouraging activity against a variety of cell lines and human xenografts. In phase I studies, partial responses were noted in a variety of tumor types, including lung, breast, and head and neck cancers; melanoma; and lymphoma. Toxicity has centered around neutropenia, with minimal nonhematologic toxicity observed. Neurotoxicity has been primarily limited to reversible paresthesias. Because of its broad spectrum of antitumor activity and mild toxicity profile, vinorelbine is a promising anticancer agent.
Animals↗
Topoisomerase I inhibitors. An overview of the camptothecin analogs.
The topoisomerase I inhibitors are an exciting new class of antineoplastic agents currently under clinical development. Analogues of camptothecin with improved toxicity profiles and antitumor activity included CPT-11 and topotecan. CPT-11 has demonstrated activity against a variety of tumor types, particularly colon and lung cancer. Early results with topotecan against ovarian and lung cancer are also encouraging. Combination trials with other antineoplastic agents including cisplatin and etoposide, and early clinical trials with new topoisomerase I inhibitors, such as 9-aminocamptothecin, are underway.
Antineoplastic Agents↗