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R Mick

Publications and source records attributed to R Mick.

At least 73 records · Page 4Linked to original sources
PubMed1994

Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456).

Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent that appears to form DNA adducts via the reactive pyrazine diazonium ion and produces substantial antitumor activity in preclinical models. We conducted a phase I trial to determine the maximally tolerated dose of PZDH that could be administered as a 5-min i.v. bolus for 5 consecutive days repeated every 28 days. Thirty-one patients with advanced cancer refractory to standard therapy received a total of 65 cycles of therapy at 7 sequential PZDH dose levels: 18, 36, 45, 56, 75, 100, and 133 mg/m2/day. At the maximally tolerated dose (133 mg/m2/day x 5), all 4 patients experienced grade 3-4 thrombocytopenia, and 3 of 4 had grade 3-4 neutropenia. At the recommended phase II dose (100 mg/m2/day x 5), the median WBC nadir following the first cycle was 2.5 x 10(3)/microliters (range, 0.6-7.6) occurring on day 36, and the median platelet nadir was 87 x 10(3)/microliters (range, 9-155) occurring on day 26. Nausea and vomiting occurred at all dose levels, but were well controlled with ondansetron. No evidence of hepatic, renal, pulmonary, cardiac, venous, dermatological, or neurological toxicity was observed. Pharmacokinetic evaluations were performed on 28 of the 31 patients using an analytical method including derivatization of the parent drug to 2-chloropyrazine. We report the total 2-chloropyrazine, which represents PZDH converted per method plus PZDH converted in vivo. Although the assay quantitation limit is 10 ng/ml, PZDH could only be detected at the first dose level for 30-90 min after the i.v. bolus. Compartmental modeling of the first 4 dose levels was most consistent with a 2-compartment model. Subsequent dose levels revealed a third phase to the plasma decay curve. The area under the plasma drug concentration-time curve increased proportionally with dose; there was no evidence for dose-dependent pharmacokinetics. Pharmacokinetic parameters for 12 patients analyzed by the 3-compartment model revealed an alpha-half-life (t1/2 alpha) of 2.83 +/- 1.57 (mean +/- SD), a t1/2 beta of 11.9 +/- 4.42, and a t1/2 gamma of 161 +/- 47.1 min, with a mean clearance of 1.86 +/- 0.91 liters/min. At the 100- and 133-mg/m2 dose levels, the mean areas under the plasma drug concentration-time curve were 105 and 169 micrograms min/ml, respectively. There was a moderate correlation between body surface area and clearance (r = 0.45, P = 0.015) but a better correlation between weight and clearance (r = 0.53, P = 0.004).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Bootstrap validation of pharmacodynamic models defined via stepwise linear regression.

When a pharmacodynamic model is to be considered as the basis for individualized drug dosing, validation of the model is clearly warranted. Rigorous validation is problematic when the training data set to be modeled has too few data points and no independent test data set exists. A simulation method known as the bootstrap lends itself particularly well to this dilemma. Bootstrap sampling allows simulation of needed test data sets that mimic the initial data set. Model validation is then undertaken by repeating the model formulation procedure on the bootstrap samples. For illustration, a pharmacodynamic model for leukopenia was constructed by stepwise linear regression from data of 41 patients with cancer treated with the drug amonafide. Stepwise regression analyses were then repeated for 100 bootstrap samples, which verified the initial selection of covariates for the model. Next the regression parameters and residual error standard deviation of the model were repeatedly estimated for 200 additional bootstrap samples. The bootstrap results confirmed the initial formulation of the pharmacodynamic model from the training data set.

Acetylation↗
PubMed1994

Hematuria in sickle cell anemia--not always benign: evidence for excess frequency of sickle cell anemia in African Americans with renal cell carcinoma.

Between 1952 and 1992, we identified 117 African Americans with renal cell carcinoma (RCC) at the University of Chicago. Three of these had sickle cell disease (SS) and 11 had presumed sickle trait (AS). Based on genotype frequencies, these represented a 16.7-fold excess of SS patients (p < 0.0001), but the incidence of AS patients was as expected. In addition, the median age for the SS patients at presentation with RCC (36 years) was significantly less (p = 0.04) than for the AS patients (55 years). We have found no prior reports of SS in RCC patients and suggest that chronic renal injury from sickling and possible immunosuppressive effects of multiple red cell transfusions may be risk factors. We also suggest the need to be aware of the possibility of RCC in SS patients who may have hematuria solely related to sickling.

Adult↗
PubMed1994

Intensified concomitant chemoradiotherapy with and without filgrastim for poor-prognosis head and neck cancer.

PURPOSE: We previously demonstrated high locoregional control rates in patients with poor-prognosis head and neck cancer using fluorouracil (5-FU), hydroxyurea (HU), and concomitant radiotherapy (FHX). In two trials reported here, we added cisplatin with and without granulocyte colony-stimulating factor (G-CSF) to 5-FU, HU, and concomitant radiotherapy. PATIENTS AND METHODS: Eligible patients had failed to respond to prior local therapy (group 1); previously untreated patients with unresectable and/or metastatic disease and a projected 2-year survival rate less than 10% were also eligible (group 2). Chemoradiotherapy consisted of 1.8 to 2.0 Gy on days 1 to 5 with simultaneous infusional 5-FU at 800 mg/m2/d and HU administered every 12 hours for 11 doses at escalating doses. Cisplatin was administered at 100 mg/m2 during every other cycle. Cycles were repeated every 14 days until completion of radiotherapy. In study 2, G-CSF was added on days 6 to 13 at 5 micrograms/kg/d. RESULTS: Acute and cumulative myelosuppression limited the feasibility of adding cisplatin to FHX without G-CSF. G-CSF allowed for escalation of HU to 1 g orally every 12 hours without dose-limiting acute toxicity during cycles 1 and 2. Dose-limiting cumulative toxicity consisted of severe or life-threatening myelosuppression and mucositis. To decrease total treatment duration and, thus, cumulative toxicity, a hyperfractionated radiation therapy schedule was investigated using the established chemotherapy doses with 1.5 Gy twice daily on days 1 to 5 (75 Gy over five treatment cycles). No increase in acute toxicities was seen; cumulative toxicities remained frequently severe or life-threatening. Thirty-eight of 45 assessable patients responded. The median survival duration was 12 months for both groups. Median time to treatment failure was 8 months for group 1 and has not been reached for group 2. At 1 year, local control rates were 74% and 91% for groups 1 and 2, respectively. CONCLUSION: The addition of cisplatin to 5-FU, HU, and concomitant radiotherapy is feasible using G-CSF. The high locoregional control rate and failure-free interval justify further investigation of this regimen in previously untreated patients.

Adult↗
PubMed1994

Pentostatin treatment for hairy cell leukemia patients who failed initial therapy with recombinant alpha-interferon: a report of CALGB study 8515.

Eighty-five hairy cell leukemia (HCL) patients who had failed initial therapy with recombinant alpha interferon were enrolled for pentostatin therapy. All had HCL confirmed by central pathology review and were eligible for evaluation. The median age was 55 years (range 31-83 years). Fifteen patients were between 31- and 40-years-old. There were 72 males (85%) and 13 females (15%). Fifty-four patients (64%) had prior splenectomy. All had been previously treated with interferon; nine had achieved a complete response (CR), 36 had a partial response (PR), 35 had stable disease (SD), and five patients had progressive disease. Patients with a CALGB performance status (PS) of 0-2 (78 patients) received 4 mg/m2 i.v. on days 1 and 15, repeated every 4 weeks. Patients with a performance status of 3 or 4 (seven patients) were started at 2 mg/m2 i.v. in the absence of grade 3 toxicity, the dose was escalated. Complete responses were seen in 36 patients (42.4%) and 35 patients had partial responses (41.2%) for an overall response rate of 83.6%. Median time to best response was 6.5 months. Eight patients had stable disease, and one patient had progressive disease. Three patients died early during the treatment phase and two were not evaluable due to treatment violations. Of seven patients with a CALGB performance status of 3 or 4, there were no CRs and only two PRs. Of 31 evaluable PS 0-2 patients who had previously achieved only stable disease on interferon, 13 had a CR on pentostatin and 12 had a PR. Based on PS 0-2 patients, the median follow-up is 44 months and 36 month remission duration and survival rates and 95% confidence intervals are 84% (CI 68-93%) and 91% (CI 81-96%). The 36 month survival rate was 29% (CI 10-58%) for PS 3-4 patients. Drug dosage was modified in 39 (51%) of 76 evaluable patients. Leukopenia and/or infection were the most frequent toxicities leading to a dose modification. Pentostatin is an effective agent and induces an excellent response in relapsed HCL patients previously treated with alpha-interferon (alpha-IFN).

Adult↗
PubMed1994

Interferon treatment for hairy cell leukemia. An update on a cohort of 69 patients treated from 1983 to 1986.

We report follow-up information on 69 hairy cell leukemia (HCL) patients treated with interferon alfa-2b (IFN) as primary treatment from 1983 to 1986. Follow-up through April, 1993 shows that only 14 patients have expired. Forty-seven of the 61 patients completing the intended 12 or more months of initial IFN treatment were eventually considered IFN failures. Forty-three required re-treatment (41 received a second course of IFN and 2 received pentostatin). Four patients died without further therapy for HCL. The median time to interferon failure was 31.3 months. Fourteen patients are alive and have not required further treatment after completing their initial 12 or more months of interferon. Fifteen patients underwent a third course of interferon therapy at a median time after completion of a second course of IFN of 1.0 year. Eighteen patients were eventually treated with pentostatin and ten with 2-chlorodeoxyadenosine (2-CdA). Thirteen patients developed a second malignancy; six of these patients developed a hematologic malignancy between 44.6 months and 99.1 months after initiation of interferon therapy. We conclude that although interferon provides excellent palliation, that most patients will eventually require further treatment with interferon or chemotherapy. Future trials in HCL must be aware of the risk of second malignancies.

Adult↗
PubMed1994

High-dose chemotherapy with autologous stem cell rescue in women with metastatic breast cancer with involved bone marrow: a role for peripheral blood progenitor transplant.

This retrospective analysis was done to determine the response rate and survival of women with metastatic breast cancer with bone marrow involvement treated with high-dose cyclophosphamide and thiotepa and peripheral progenitor cell rescue. Eligibility criteria included histologically-documented metastatic breast cancer and either stable disease, a partial response or a complete response to conventional dose chemotherapy. Due to bone marrow involvement, all patients received peripheral progenitor cell reinfusion. Purging of the stem cell product was not performed. Cyclophosphamide (CY) 7.5 gm/m2 total dose and thiotepa 675 mg/m2 total dose was used as the intensification regimen. Of 27 treated patients, 4 (14%) died of treatment-related toxicity. Three patients were in complete remission after induction chemotherapy and remained so after high-dose chemotherapy. Three patients converted from a partial response after induction to a complete response after transplant. This yielded a complete remission rate of 21%. Five of these six patients continue in CR at 5, 6, 11, 14, and 26 months post-transplant. Eight patients (29%) are alive with stable disease post transplant. Ten patients developed disease progression. Six patients died shortly after disease progression; however, four patients are alive with disease at 18, 26, 33, and 53 months post-transplant. The median time to treatment failure is 12 months. In women with metastatic breast cancer with bone marrow involvement, durable responses after high-dose chemotherapy are possible utilizing peripheral blood progenitor support rather than marrow purging.

Adult↗
PubMed1993

Combined plateletpheresis and cytotoxic chemotherapy for symptomatic thrombocytosis in myeloproliferative disorders.

BACKGROUND: Patients with myeloproliferative disorders (MPD) may have symptomatic thrombocytosis develop that requires prompt and sustained lowering of platelet counts to avert serious thrombotic or hemorrhagic sequelae. METHODS: The authors retrospectively studied the short- and long-term effects of plateletpheresis combined with three different chemotherapy regimens (busulfan, hydroxyurea, or busulfan/hydroxyurea) in 30 patients with MPD with symptomatic thrombocytosis. RESULTS: Twenty-nine patients entered first remission (FR) with initial treatment. The average number of plateletphereses to FR was three (standard deviation [SD], +/- 3). Average total dose of busulfan (216 mg) and time to FR (1.6 months) were less than for previously reported patients treated without plateletphereses. Addition of hydroxyurea to busulfan decreased the number of plateletpheresis needed (P = 0.02) but did not additionally reduce the amount of busulfan needed or the time to FR. The shortest time to FR was in the hydroxyurea group (mean, 0.6 +/- 0.3 months), but unmaintained remission could be achieved only in the busulfan-treated groups. With median follow-up of 68 months, median survival was 53 months for the busulfan group, 55 months for the hydroxyurea group, and was undefined with no deaths for the busulfan/hydroxyurea group. Neither fatal complications of recurrent symptomatic thrombocytosis nor development of acute leukemia has occurred, except for progression to blast crisis in two patients with chronic myelogenous leukemia. CONCLUSION: Combined plateletpheresis and chemotherapy is a rapidly effective initial treatment for patients with MPD with symptomatic thrombocytosis. With maintenance therapy or prompt treatment at relapse of disease, prolonged good quality survival can be expected.

Adult↗
PubMed1993

Phase I study of amonafide dosing based on acetylator phenotype.

Amonafide is extensively metabolized, including N-acetylation to an active metabolite. Prior studies have demonstrated that patients who are fast acetylators of amonafide (and other drugs) have increased toxicity at standard doses of amonafide. The primary objective of this study was to define the recommended phase II dose of amonafide separately for slow and fast acetylators. Twenty-six patients with advanced cancer underwent acetylator phenotyping with caffeine and were assigned to a dose level. Slow acetylators were treated at 375 mg/m2 (daily for 5 days) and had a median WBC nadir of 1600/microliters. Fast acetylators were treated at both 200 and 250 mg/m2, resulting in median WBC nadirs of 5300 and 2000/microliter, respectively. Two patients were not typeable, and two patients appear to have been misphenotyped, one in each phenotype category. Pharmacodynamic analysis yielded a model for nadir WBC including acetylator phenotype, 24-h N-acetyl-amonafide plasma concentration, gender, and pretreatment WBC. We recommend doses of 250 and 375 mg/m2 (for 5 days) for further phase II testing of amonafide in fast and slow acetylators, respectively.

Acetylation↗
PubMed1993

Phase I clinical and pharmacological study of iododeoxyuridine and bleomycin in patients with advanced cancer.

Studies previously performed in our laboratory demonstrated synergistic cytotoxicity and DNA strand break formation in human tumor cells following exposure to a combination of bromodeoxyuridine and bleomycin. Synergy was evident when bromodeoxyuridine was administered prior to or simultaneously with bleomycin and occurred over a wide range of concentration ratios. We therefore undertook a phase I clinical trial of the combination of iododeoxyuridine (IdUrd) and bleomycin to determine the maximally tolerated dose of IdUrd that could be administered with a standard dose of bleomycin and to determine the toxicities of the combination. Eligible patients were those with advanced cancer refractory to standard therapy who had a performance status of 0-2, measurable or evaluable disease, and adequate organ function. IdUrd was administered as a 5-day continuous i.v. infusion beginning at a dose of 250 mg/m2/day with escalation in cohorts of 3-6 patients according to a modified Fibonacci scheme. Bleomycin was administered at a dose of 15 mg/m2/day as a continuous i.v. infusion during the last 3 days of the IdUrd infusion. Cycles of therapy were repeated every 28 days. Plasma levels of IdUrd and iodouracil were determined by high performance liquid chromatography. Thirty patients received a total of 79 cycles of IdUrd/bleomycin. Dose-limiting toxicity was bone marrow suppression. At the maximally tolerated IdUrd dose of 2780 mg/m2/day, the median neutrophil nadir after the first cycle of therapy was 805/microliters and the median platelet nadir was 48,000/microliters. Other toxic effects included mucositis, fatigue, nausea, diarrhea, fever, and skin toxicity. Plasma steady-state concentrations of IdUrd increased proportionally to administered IdUrd dose. IdUrd clearance varied from 0.253 liters/min/m2 to 0.503 liters/min/m2 and did not correlate with IdUrd dose. IdUrd dose and concentration correlated significantly with granulocyte and platelet nadirs, and a pharmacodynamic model for white blood cell count nadir could be defined by pretreatment white blood cell count, IdUrd dose, and gender. The recommended IdUrd dose for phase II testing of this combination is 2140 mg/m2/day. Phase II studies will be of particular interest in those diseases, such as carcinomas of the head, neck, and esophagus, where bleomycin has documented activity as a single agent.

Adult↗
PubMed1993

Model-guided determination of maximum tolerated dose in phase I clinical trials: evidence for increased precision.

BACKGROUND: A widely used phase I design in clinical trials of chemotherapy for cancer and for AIDS (acquired immunodeficiency syndrome) allows for dose escalation in cohorts of three to six patients. Escalation continues until a predefined percentage of patients experience unacceptable toxic effects at a given dose level. A safe and maximum tolerated dose (MTD) for phase II study is then determined. This standard phase I study design has serious inadequacies. MTD is not a model-based estimate of the true dose that would yield the targeted dose-limiting toxicity rate. Moreover, this simplistic study design allows some patients in the phase I study to be treated at doses unlikely to have therapeutic efficacy. PURPOSE: We constructed a novel quantitative assessment design that repetitively evaluates accumulating dose-toxicity data by repeatedly fitting and updating a pharmacodynamic model after small cohorts of patients are treated. The goal was to more accurately estimate the MTD. METHODS: One hundred phase I studies were simulated by both the standard and quantitative assessment phase I designs. We compared determination of MTD, frequency of grade 0 leukopenia (no toxicity), and study size in the studies simulated using the standard design with those in the studies simulated using the quantitative assessment design. RESULTS: The median MTD determined from the 100 studies was nearly identical for the two designs: 100 and 95 mg/m2 per day for standard and quantitative assessment designs, respectively. However, the interstudy variation in the MTD was decreased in the quantitative assessment design. Moreover, the study size was significantly reduced (P < .0001), and the median percentage of patients treated at subtoxic doses (no leukopenia) was significantly lower for the quantitative assessment design (44% versus 48%; P < .0001). CONCLUSION: Our results show clear evidence that a phase I study design using dose and toxicity data in a repetitive and quantitative manner can identify the MTD with more accuracy than the standard design. IMPLICATIONS: New approaches must be explored to improve our ability to identify the optimal dose for phase II studies of chemotherapy for cancer and for AIDS. There is evidence that the quantitative assessment design will identify the MTD with fewer patients, more precision, and fewer patients exposed to suboptimal doses.

Clinical Trials, Phase I as Topic↗
PubMed1993

Mitoxantrone, vincristine, and 5-fluorouracil with leucovorin modulation as induction chemotherapy prior to high-dose intensification in metastatic breast cancer.

We treated 39 women with newly diagnosed stage IV breast cancer with a new regimen of mitoxantrone 18 mg/m2 on days 1, 29, 57, vincristine 1.4 mg/m2 (maximum 2.0 mg) on days 1, 8, 15, 22, 29, 36, 43, 50, and 5-fluorouracil 375 mg/m2 on days 15-20, 43-47, 71-75 with leucovorin modulation 500 mg/m2 before each 5FU infusion (MVF). This regimen was utilized as an initial cytoreductive or induction program for these patients prior to high-dose intensification with autologous stem cell rescue. Ten patients (25%) obtained a clinical complete response and six patients (15%) obtained a partial response for an overall response rate of 40%. In addition, 10 patients had evaluable disease that was improved or stable (primarily bone and/or bone marrow metastases) after MVF induction. Thus, 26 patients (65%) were eligible for high-dose intensification with autologous stem cell rescue after MVF induction. Toxicity was primarily a mild mucositis and more commonly peripheral neuropathy. MVF therapy is an active treatment program for metastatic breast cancer but the neurotoxicity makes it difficult to recommend for widespread use.

Adult↗
PubMed1993

Statistical approaches to pharmacodynamic modeling: motivations, methods, and misperceptions.

We have attempted to outline the fundamental statistical aspects of pharmacodynamic modeling. Unexpected yet substantial variability in effect in a group of similarly treated patients is the key motivation for pharmacodynamic investigations. Pharmacokinetic and/or pharmacodynamic factors may influence this variability. Residual variability in effect that persists after accounting for drug exposure indicates that further statistical modeling with pharmacodynamic factors is warranted. Factors that significantly predict interpatient variability in effect may then be employed to individualize the drug dose. In this paper we have emphasized the need to understand the properties of the effect measure and explanatory variables in terms of scale, distribution, and statistical relationship. The assumptions that underlie many types of statistical models have been discussed. The role of residual analysis has been stressed as a useful method to verify assumptions. We have described transformations and alternative regression methods that are employed when these assumptions are found to be in violation. Sequential selection procedures for the construction of multivariate models have been presented. The importance of assessing model performance has been underscored, most notably in terms of bias and precision. In summary, pharmacodynamic analyses are now commonly performed and reported in the oncologic literature. The content and format of these analyses has been variable. The goals of such analyses are to identify and describe pharmacodynamic relationships and, in many cases, to propose a statistical model. However, the appropriateness and performance of the proposed model are often difficult to judge. Table 1 displays suggestions (in a checklist format) for structuring the presentation of pharmacodynamic analyses, which reflect the topics reviewed in this paper.

Data Interpretation, Statistical↗
PubMed1993

Modulation of vinblastine resistance with cyclosporine: a phase I study.

OBJECTIVE: Tumor cell resistance is a major cause of failure to cure advanced malignancies. Multidrug resistance is thought to be an important mechanism of such resistance. Our aims were to identify doses of cyclosporine that would achieve blood levels effective in modulating multidrug resistance to vinblastine and to evaluate the toxicities and maximum tolerated dose of cyclosporine when administered in conjunction with vinblastine. METHODS: We conducted a phase I trial of vinblastine and escalating doses of cyclosporine. Cyclosporine was given by continuous intravenous infusion over 120 hours and vinblastine was administered by continuous infusion from hour 12 to hour 108. Sixty-two patients entered the trial, of whom 60 were evaluable. RESULTS: Cyclosporine was escalated from 1 to 15.6 mg/kg/day. Vinblastine doses were reduced to 1.6 and then 1.2 mg/m2/day because of increasing vinblastine toxicity at higher cyclosporine doses. The maximum tolerated dose of cyclosporine at 1.2 mg/m2/day vinblastine was 12.5 mg/kg/day; at this dose level, mean blood cyclosporine level was 1.25 +/- 0.41 mumol/L. Significant nephrotoxicity was observed at higher cyclosporine doses in two of four patients. Nephrotoxicity was not significant at doses at or lower than this maximum tolerated dose and was not cyclosporine dose dependent. Myelosuppression, neurotoxicity, and transient hyperbilirubinemia were observed and were cyclosporine dose dependent. CONCLUSIONS. Cyclosporine by continuous infusion may be safely given in high doses concurrently with continuous-infusion vinblastine. Plasma levels of cyclosporine > or = 1 mumol/L can be sustained during vinblastine administration. No sustained effect on T-cell subsets was observed. Vinblastine toxicity is enhanced by cyclosporine in a dose-dependent fashion and correlates with cyclosporine-induced hyperbilirubinemia.

Adult↗