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Biomedical subjects

G F Fleming

Publications and source records attributed to G F Fleming.

At least 37 records · Page 2Linked to original sources
PubMed2000

A phase I study of liposomal doxorubicin (Doxil) with topotecan.

New therapies are needed for patients with advanced ovarian cancer who relapse after initial treatment with platinum and/or paclitaxel-based regimens. This study sought to determine the toxicities of combined liposomal doxorubicin (Doxil) and topotecan, and to determine a regimen for future phase II testing in ovarian cancer. Nine patients with advanced malignancies were treated with topotecan 1.0 mg/m2/day X 5 days followed by liposomal doxorubicin at a starting dose of 30 mg/m2 on day 5. Cycles were repeated every 28 days. A total of 13 cycles of therapy were administered. Grade IV neutropenia and grade IV thrombocytopenia developed in both of the two patients treated at the first dose level. Subsequent patients received only 20 mg/m2 liposomal doxorubicin. At that dose level, three patients experienced dose-limiting toxicity (one grade IV neutropenia, two grade IV neutropenia and thrombocytopenia). No responses were observed. These data indicate that the described regimen of liposomal doxorubicin and topotecan is not feasible because of excessive hematologic toxicity. Escalation to doses of liposomal doxorubicin or topotecan that have previously demonstrated antitumor activity was not possible. Future strategies to minimize such toxicity may include limiting eligibility to patients with minimal prior therapy, reducing the number of days of topotecan administration, or use of oral topotecan.

Adult↗
PubMed2000

Phase I trial of paclitaxel and etoposide for recurrent ovarian carcinoma: a Gynecologic Oncology Group Study.

A phase I study was performed to determine the maximum tolerated doses of intravenous etoposide and paclitaxel for women with previously treated persistent or recurrent ovarian cancer. Starting doses were paclitaxel 135 mg/m2 during 24 hours and etoposide 50 mg/m2/day for 3 consecutive days. The study was designed to escalate first the dose of etoposide, and then the dose of paclitaxel, in successive cohorts of patients. In an attempt to determine whether toxicity was affected by sequence of the drugs, the order of administration of the two drugs was reversed on alternate cycles. The starting doses of paclitaxel (135 mg/m2/24 hours) and etoposide (50 mg/m2/day x 3) caused severe neutropenia even with the addition of granulocyte colony-stimulating factor, and the trial was amended to administer the paclitaxel during 3 hours. However, this also proved too myelosuppressive without growth factor support. Twenty-one women were treated. A complete response was observed in one of nine patients with measurable disease, and a major decrease in CA-125 was noted in two patients who did not have measurable disease. Because of the severe myelosuppression observed in most patients, dose reduction was often required after the first cycle. The power to detect sequence-dependent variation in toxicity was minimal; however, no large differences were observed. A combination of the usual doses of these drugs will be difficult to administer in patients who have received previous chemotherapy for ovarian cancer.

Adult↗
PubMed2000

Phase II evaluation of thalidomide in patients with metastatic breast cancer.

PURPOSE: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. RESULTS: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. CONCLUSION: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.

Adult↗
PubMed2000

Human breast cancer susceptibility to paclitaxel therapy is independent of Bcl-2 expression.

In laboratory studies, ectopic overexpression of the antiapoptotic protein Bcl-2 has been shown to result in resistance to the cytotoxic effects of many chemotherapeutic drugs. Furthermore, posttranslational modification of moderately expressed endogenous Bcl-2 has been correlated with susceptibility to paclitaxel treatment in vitro. To determine whether tumor expression of Bcl-2 protein correlates with response and ultimate outcome in vivo, we quantified Bcl-2 expression by immunohistochemical analysis of archived biopsy specimens from metastatic breast cancer patients treated with single-agent paclitaxel. The statistical association between the degree of Bcl-2 expression, objective tumor response, and clinical outcome was then determined. In patients (n = 39) whose tumors had low (< or = 10% cells positive) Bcl-2 levels by immunohistochemical analysis, the overall response (complete response + partial response) rate was 21% versus an overall response rate of 22% in patients (n = 36) with high (>10% cells positive) Bcl-2 expression (P = 0.92). In patients with low Bcl-2 expression, the median time to progression was 126 days [95% confidence interval (CI), 63-160 days]. This was not significantly different than the 105 days for patients with high tumor Bcl-2 expression (95% CI, 84-214 days). The median survival time from initiation of paclitaxel therapy for patients with low Bcl-2 expression was 663 days (95% CI, 456-1119 days) and was not significantly different than the 450 days (95% CI, 239-1058 days) observed for patients with high Bcl-2 expression. In conclusion, we found that in metastatic breast cancer, there is no significant association between tumor Bcl-2 expression and response to paclitaxel, median time to progression, or survival, suggesting that the main mechanism of paclitaxelinduced cytotoxicity in breast tumors is independent of Bcl-2 expression.

Adult↗
PubMed1999

A phase I study of oral uracil/ftorafur (UFT) plus leucovorin and bis-acetato-ammine-dichloro-cyclohexylamine-platinum IV (JM-216) each given over 14 days every 28 days.

PURPOSE: To determine the feasibility, maximal tolerated doses, and response rates for a combined regimen of the platinum and 5-fluorouracil oral analogues bis-acetato-ammine-dichloro-cyclohexyl-amine platinum(IV) (JM-216) and uracil/ftorafur (UFT) coadministered as a 14 consecutive-day every 28-day schedule. METHODS: Of 20 patients enrolled in this investigation, 17 on the following dose escalation scheme were evaluable for toxicity and/or response: I UFT 300 mg/day, JM-216 5 mg/day (three patients), II UFT 300 mg/day, JM-216 10 mg/day (four patients), III UFT 300 mg/day, JM-216 20 mg/day (ten patients). RESULTS: All 17 evaluable patients were evaluable for toxicity. At dose level III dose-limiting nausea and emesis were observed in one patient despite maximal antiemetic support. Importantly, neurotoxicity and nephrotoxicity were not observed at the JM-216 dose levels examined in this study. This observation is consistent with results seen with single agent JM-216. CONCLUSION: For JM-216 and UFT administered at 20 mg/day and 300 mg/day over 14 days, nausea and emesis were observed as the principal dose-limiting toxicities. These doses are considerably below the maximally tolerated doses of single agent JM-216 and UFT. Shorter administration schedules should be explored in an attempt to increase the dose intensity and minimize the toxicity of this combination oral regimen.

Administration, Oral↗
PubMed1999

Systemic therapy for advanced or recurrent endometrial carcinoma.

The prognosis for metastatic or recurrent endometrial cancer remains poor. Patients with local recurrences can sometimes be salvaged with radiation, and these salvage rates might improve with the addition of concomitant chemotherapy. Hormone therapy benefits a small group of patients, and routine immunohistochemical determination of tumor receptor status may help select patients most likely to benefit from such therapy. Anthracyclines, platinum compounds, and paclitaxel consistently produce response rates of over 20%. Combination chemotherapy produces higher response rates, but it is toxic and appears to have minimal effect on survival. New drugs and combinations continue to be tested. A subset of endometrial cancers overexpress the HER2/neu oncogene, and a trial of anti-HER2/neu monoclonal antibody for this group is planned through the Gynecologic Oncology Group.

Antineoplastic Agents↗
PubMed1998

Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071).

PURPOSE: 9-Aminocamptothecin (9-AC) is a topoisomerase I inhibitor with high antitumor activity but poor solubility in conventional vehicles. The purpose of this study was to evaluate the toxicities and pharmacokinetics of a colloidal dispersion (CD) formulation of 9-AC when administered orally on a 5 days per week every 2 weeks schedule. METHOD: This formulation, which was developed for intravenous administration, was orally administered in 20 ml orange juice. A group of 16 cancer patients were treated at doses of 0.2-0.68 mg/m2 daily. RESULTS: Grade 1-2 nausea (n = 9) was common, usually occurring during the last 2 days of dosing. No objective responses or cumulative toxicities were observed. Pharmacokinetic analysis of total 9-AC showed highly variable apparent oral 9-AC clearance and half-life. There was marked interpatient variability at each dose level in the 9-AC AUC and Cmax, and these parameters showed a poor correlation with dose (r2 = 0.07 and 0.38, respectively). CONCLUSIONS: We conclude that this formulation is not suitable for further clinical development because of poor bioavailability and highly variable and/or saturable absorption or elimination. Another formulation developed for oral administration is under study elsewhere.

Adult↗
PubMed1998

Phase II trial of paclitaxel and topotecan with granulocyte colony-stimulating factor support in stage IV breast cancer.

PURPOSE: This multicenter phase II trial investigated the efficacy and safety of a combination of paclitaxel and topotecan in patients with pretreated metastatic breast cancer. Plasma levels of paclitaxel and topotecan were obtained during cycle 1 to correlate pharmacokinetic parameters with toxicity. PATIENTS AND METHODS: Paclitaxel was administered intravenously (i.v.) at 230 mg/m2 over 3 hours on day 1 followed by topotecan 1.0 mg/m2 i.v. over 30 minutes on days 1 to 5. Patients received an abbreviated premedication regimen that consisted of ranitidine 50 mg, diphenhydramine 50 mg, and a single 20-mg dose of dexamethasone, all administered i.v. 30 minutes before paclitaxel. Granulocyte colony-stimulating factor (GCSF) was administered at 5 micrograms/kg/d subcutaneously starting on day 6 and continuing until the absolute granulocyte count (AGC) was greater than 10,000/microL. Plasma paclitaxel and topotecan concentrations were assessed during the first cycle using limited-sampling strategies. RESULTS: Seventeen patients were treated. The majority had visceral metastases. Four patients experienced neutropenic fever and one had mild bronchospasm. Only one partial response (PR) was observed. Nadir AGC correlated strongly with both duration of paclitaxel levels greater than 0.05 mumol/L and maximum concentration (Cmax) of paclitaxel. CONCLUSION: This regimen does not produce a response rate superior to that expected with single-agent paclitaxel at doses that do not require growth factor support.

Adenocarcinoma↗
PubMed1997

Phase II study of 96-hr continuous-infusion etoposide and doxorubicin with bolus cyclophosphamide in refractory epithelial ovarian cancer.

Effective salvage chemotherapy for patients with ovarian cancer who have failed platinum- and taxane-based regimens has not been identified. It has been reported that prolonged infusions of chemotherapy may be active in some malignancies which have become refractory to bolus treatments. We evaluated a regimen of 96-hr continuous-infusion doxorubicin (10 mg/m2/24 hr), etoposide (50 mg/m2/24 hr), and bolus cyclophosphamide (750 mg/m2) administered every 21 days to patients with ovarian cancer who had previously been treated with paclitaxel and a platinum compound. Nineteen women were treated, 15 of whom had platinum-refractory cancer. Six of the first 9 experienced a neutropenic fever after the first treatment cycle, and therefore all subsequent patients received prophylactic granulocyte-colony-stimulating factor. Other significant toxicities included hand and foot syndrome (1 patient) and mucositis (4 patients). There was one partial response in a patient with platinum-sensitive disease. We conclude that this regimen causes significant myelosuppression and does not have major activity in heavily pretreated patients with ovarian cancer.

Adult↗
PubMed1997

Phase I study of treatment with oral 13-cis-retinoic acid, subcutaneous interferon alfa-2a, cisplatin, and 24-hour infusion 5-fluorouracil/leucovorin.

UNLABELLED: A combination of oral 13-cis-retinoic acid (cis-RA) and subcutaneous interferon alfa-2a (IFN) has been reported to yield high response rates in patients with squamous cell carcinomas (SCCAs) of the cervix and skin. Cisplatin and 5-fluorouracil with leucovorin (5-FU/LV) are chemotherapeutic agents commonly used for SCCAs. PURPOSE: To determine the maximum tolerated doses (MTDs) of cisplatin and 5-FU/LV when combined with IFN and cis-RA, and to define a recommended phase II regimen for testing in cervical cancer and other appropriate tumor types. METHODS: Phase I cohort design. Cisplatin was administered every 3 weeks. 5-FU and LV were administered together as a weekly 24-h infusion. Cis-RA was given orally twice daily. IFN was initially given subcutaneously at a dose of 3 million units (MU) daily. RESULTS: A total of 31 patients were treated. The IFN dose was reduced to 3 MU three times weekly because of patient intolerance. Cytopenias prevented the administration of weekly 5-FU/LV. Single-agent cisplatin with three times weekly IFN and twice daily cis-RA was tolerable. Four partial responses were observed, in patients with adrenal cancer, bladder cancer, gastric cancer, and adenocarcinoma of unknown primary. CONCLUSIONS: The recommended phase II regimen is cisplatin 100 mg/m2 every 3 weeks, IFN 3 MU three times weekly, and cis-RA 1 mg/kg daily. This appears to be more toxic than single-agent cisplatin, but the preliminary activity observed warrants further testing.

Administration, Oral↗
PubMed1997

Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: a Gynecologic Oncology Group study.

PURPOSE: A phase I and pharmacologic study to evaluate the feasibility of administering paclitaxel (PTX) in combination with topotecan (TPT) without and with granulocyte colony-stimulating factor (G-CSF) in women with recurrent or refractory ovarian cancer. PATIENTS AND METHODS: TPT was administered as a 30-minute infusion daily for 5 days and PTX was given as a 24-hour infusion (PTX-24) either before TPT on day 1 or after TPT on day 5. Each patient received both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or PTX-24 without and with G-CSF resulted in five dosage permutations of TPT/PTX (mg/ m2): 0.75/135 without G-CSF and 0.75/135, 1.25/135, 1.50/135, and 1.25/170 with G-CSF. RESULTS: Twenty-two patients received 109 courses of therapy. Dose-limiting myelosuppression consistently occurred at the first TPT/PTX-24 dose level (0.75/135 mg/m2) in the absence of G-CSF support. Although the addition of G-CSF resulted in reduced rates of complicated neutropenia, the incidences of dose-limiting neutropenia and thrombocytopenia were unacceptably high after the doses of either TPT or PTX-24 were increased. Paired analysis showed similar hematologic toxicities between the two sequences of drug administration. The pharmacologic behavior of both TPT and PTX-24 was not altered by drug sequencing. Major antitumor responses occurred in 40% of patients with measurable and assessable disease, including 45% and 9% of patients with potentially cisplatin-sensitive and -resistant tumors, respectively. CONCLUSION: The recommended doses of TPT on a daily times-five schedule combined with PTX-24 in these patients were 0.75 mg/m2/d and 135 mg/m2, respectively, with G-CSF support. Although this dose of PTX has significant single-agent activity in ovarian cancer, the dose of TPT is much lower than the TPT dose at which single-agent activity has been observed. Due to the inability to administer near relevant single-agent doses of both drugs in combination, as well as the requirement for G-CSF support, further evaluations of this regimen in women with refractory or recurrent ovarian cancer are necessary before it can be recommended for previously treated patients in this setting.

Adult↗
PubMed1996

Phase I study of escalating doses of mitoxantrone and paclitaxel with granulocyte-macrophage colony stimulating factor support.

BACKGROUND: Both paclitaxel and mitoxantrone demonstrate significant antineoplastic activity in breast cancer patients. Colony stimulating factor support allows significant dose escalation of each of these drugs when administered as a single agent. METHODS: We performed a Phase I study employing escalating doses of paclitaxel and mitoxantrone with granulocyte-macrophage colony stimulating factor (GM-CSF) support. Initially the paclitaxel dose was fixed at 175 mg/m2 and an attempt was made to escalate mitoxantrone from the starting dose of 14 mg/m2. Subsequently, the dose of mitoxantrone was fixed at 14 mg/m2 and the dose of paclitaxel was increased. Treatments were given every three weeks. RESULTS: In neither case could we safely escalate beyond a combination of paclitaxel 175 mg/m2 and mitoxantrone 14 mg/m2 which is, therefore, the recommended Phase II dose. The dose limiting toxicity was neutropenia. No unexpected toxicities were observed, although two patients were removed from the study because of chest pain possibly related to GM-CSF. There were no complete or partial remissions. CONCLUSIONS: We conclude that GM-CSF does not allow significant dose escalation of this combination of agents.

Adult↗
PubMed1996

Peripheral blood mononuclear cell dihydropyrimidine dehydrogenase activity in volunteers with and without diabetes mellitus.

It has been reported that cancer patients with diabetes mellitus receiving a continuous infusion of 5-fluorouracil (5-FU) have more toxicity and higher plasma 5-FU levels that patients without diabetes mellitus. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. DPD activity in peripheral blood mononuclear cells has been reported to correlate inversely with 5-FU plasma levels in patients. We therefore undertook a study to compare the activity of DPD in peripheral blood mononuclear cells of human subjects with and without diabetes mellitus. The study groups comprised 43 volunteers with and 39 without diabetes mellitus, and peripheral blood mononuclear cell DPD activity was assayed on samples obtained between 8 a.m. and 11 a.m. DPD activity was not decreased in diabetic subjects. There was no relationship between DPD activity and gender body mass index, or race. There was a modest correlation between DPD activity and age (r=0.19, P =0.08). We conclude that increases in 5-FU-related toxicities in diabetics must be related to factors other than peripheral blood mononuclear cell DPD activity.

Adult↗
PubMed1996

Etoposide combined with interferon alfa-2b: novel exploitation of established etoposide pharmacokinetics and pharmacodynamics.

PURPOSE: To construct an efficient pilot study design to determine whether interferon alfa-2b modifies the pharmacokinetics and pharmacodynamics of continuous-infusion etoposide. PATIENTS AND METHODS: A two-stage randomized 2 X 2 factorial design was used to evaluate interferon alfa-2b at two doses (2 or 10 MU/m2/day SQ for 3 days) and two schedules (interferon alfa-2b administered before or concurrent with 72-hour continuous-infusion etoposide). Etoposide was administered at 75, 100, or 125 mg/m2/day. In lieu of comparing the experimental arms to an etoposide-alone control arm to determine effect of interferon alfa-2b dose and schedule, a novel analytic approach was used. The effect of interferon alfa-2b on etoposide-induced leukopenia was assessed indirectly by comparison of the observed white blood cell (WBC) nadir to the nadir predicted from an established pharmacodynamic model for single agent etoposide. RESULTS: Based on 29 patients, dose-normalized 24-hour total and estimated free etoposide concentrations did not differ with interferon alfa-2b dose or schedule. Patients treated with interferon alfa-2b before etoposide had, on average a WBC nadir 545 +/- 225 cells microliter lower than that predicted by a pharmacodynamic model for etoposide alone. An optimal nonlinear model for leukopenia was defined by interferon alfa-2b schedule in addition to 24-hour etoposide concentration. CONCLUSION: A novel study design and statistical analysis provided an efficient preliminary evaluation of the combination of interferon alfa-2b with etoposide in a modest number of patients. Exploitation of a previously validated pharmacodynamic model allowed evaluation of interferon alfa-2b effect and eliminated the need for an etoposide-alone control arm. The pharmacokinetics of continuous-infusion etoposide at doses from 75 to 125 mg/m2/day appear to be unchanged by interferon alfa-2b at the doses and schedules tested and the combination appears to be feasible. We hypothesize that leukopenia may be enhanced when interferon alfa-2b is administered before etoposide, especially at a higher dose of interferon alfa-2b.

Adult↗
PubMed1994

Phase I study of adozelesin administered by 24-hour continuous intravenous infusion.

BACKGROUND: Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations. PURPOSE: We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase II testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed. METHODS: Adozelesin was given as a 24-hour continuous intravenous infusion. Treatments were initially scheduled every 3 weeks, but the prolonged myelosuppression observed necessitated a final dosing interval of every 6 weeks. The starting dose of 30 micrograms/m2 was escalated using a modified Fibonacci scheme until dose-limiting toxicity was encountered. RESULTS: Twenty-nine patients were entered in the study. Successive dose levels used were 30, 60, 100, 150, 120, and 100 micrograms/m2. Prolonged thrombocytopenia and granulocytopenia were dose limiting. No antitumor responses were observed. CONCLUSION: We recommend that the phase II dose of adozelesin given as a continuous 24-hour intravenous infusion be 100 micrograms/m2, repeated every 6 weeks. Other potentially less myelosuppressive schedules could be pursued.

Adult↗
PubMed1993

Dedifferentiated chordoma. Response to aggressive chemotherapy in two cases.

BACKGROUND: Dedifferentiated chordoma is an unusual and aggressive variant of chordoma which is likely to metastasize. Few reports exist of treatment of these tumors with chemotherapy. METHODS: In 1988, two patients with dedifferentiated sacral chordomas were seen at the University of Chicago Hospitals. Both developed metastatic disease less than a year after sacral resection and radiation therapy. These patients' diagnoses, courses, and treatments were reviewed along with the literature on chemotherapy in both conventional and dedifferentiated chordomas. RESULTS: Both patients obtained complete remissions, one to a six-drug regimen and the other to ifosfamide. CONCLUSIONS: A trial of reasonably aggressive chemotherapy is warranted in patients with metastatic dedifferentiated chordoma. The optimum regimen is unclear, but agents active in high-grade sarcomas are logical choices.

Adult↗
PubMed1992

Megestrol acetate reverses multidrug resistance and interacts with P-glycoprotein.

We evaluated the multidrug resistance (MDR)-modulating effects of progesterone (PRG) and an orally active, structurally related compound, megestrol acetate (MA), in several MDR human cell lines. At 100 microM, both steroids inhibited the binding of a Vinca alkaloid photoaffinity analog to P-glycoprotein (P-gp) in MDR human neuroblastic SH-SY5Y/VCR cells [which show greater than 1500-fold resistance to vincristine (VCR) in the tetrazolium dye (MTT) assay]. However, 100 microM MA markedly enhanced the binding of [3H]-azidopine to P-gp in both SH-SY5Y/VCR cells and the MDR human epidermoid KB-GSV2 cell line (which displays 250-fold resistance to VCR in the MTT assay). PRG had little effect on the binding of [3H]-azidopine to P-gp. MA at low doses was more effective than PRG in sensitizing cells to VCR and enhancing their accumulation of [3H]-VCR. The highly resistant SH-SY5Y/VCR subline exhibited significant collateral sensitivity to both steroids. These data suggest that MA may be a clinically useful modulator of MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗