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W D Figg

Publications and source records attributed to W D Figg.

At least 91 records · Page 5Linked to original sources
PubMed1998

Elevated carcinoembryonic antigen in patients with androgen-independent prostate cancer.

BACKGROUND: Extraordinarily high serum carcinoembryonic antigen (CEA) values have been reported to be associated with many malignant disorders, including carcinoma with primary sites in the colon, pancreas, stomach, bile duct, lung, and breast. This study was undertaken to determine if a marked elevation of serum CEA levels in androgen-independent prostate cancer patients exists, and to evaluate the potential of using CEA monitoring as a marker for disease progression. METHODS: Records from 141 patients with progressive androgen-independent prostate cancer who were treated at the National Cancer Institute from 1990 to 1996 were analyzed. Serum CEA concentrations were measured using a micro-particle enzyme immunoassay. RESULTS: Among these cases of prostatic carcinoma, 69 (48.9%) had abnormally elevated plasma CEA values (greater than the normal upper limit of 2.5 ng/mL) at some time during their treatment on a clinical investigation protocol. No correlation was found between the elevated CEA concentrations and prostate specific antigen (PSA). In comparison, 32.5% of patients with elevated CEAs had disease that had metastasized to soft tissue (adenopathy, etc) versus 22.2% with normal CEA who had soft tissue involvement (p = 0.3 X2). We examined the CEA values with respect to survival time, defined as the interval from the date of the earliest CEA level to the date of death and found no association (p > 0.3). CONCLUSIONS: Based on these observations, it appears that in the context of androgen-independent prostate cancer, CEA can be elevated but is an inviable surrogate marker of disease progression with minimal prognostic value.

Androgens↗
PubMed1998

Augmented capillary leak during isolated hepatic perfusion (IHP) occurs via tumor necrosis factor-independent mechanisms.

Isolated organ perfusion of the liver or extremity with tumor necrosis factor (TNF) and melphalan results in regression of bulky tumors in the majority of patients. The efficacy of TNF in this setting is not known, although data suggest that it may exert antitumor effects primarily on tumor-associated neovasculature. We studied the effects of TNF on capillary leak in liver and tumor tissue during isolated hepatic perfusion (IHP) with melphalan. Twenty-seven patients with unresectable cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 7) or with 1.0 mg of TNF (n = 20). Complete vascular isolation was confirmed in all patients using an intraoperative leak monitoring I-131 radiolabeled albumin technique. Samples of tumor and liver were collected just prior to and immediately after IHP. There was no difference in I-131 radiolabeled cpm/g of tissue (cpm) in liver versus tumor at baseline (P2 = 0.44). After IHP, I-131 albumin cpm were higher in tumor versus liver (10,999 +/- 1,976 versus 3,821 +/- 780, respectively; P2 < 0.005). However, I-131 albumin cpm in tumor were not effected by TNF (11,636 +/- 2,518 with TNF versus 9,180 +/- 2,674 without TNF; P2 = 0.59). TNF did not affect melphalan concentrations in tumor (1,883 +/- 540 ng/g versus 1,854 +/- 861 ng/g without TNF; P2 = 0.9). Capillary leak, as reflected by diffusion of I-131 radiolabeled albumin into the interstitial space, is comparable in liver and tumor before IHP but is significantly higher in tumor after IHP. The increased diffusion in the capillary tumor bed must occur through TNF-independent mechanisms such as intrinsic features of tumor neovasculature, hyperthermia, or other unrecognized perfusion-related factors. These data indicate that TNF must continue to be critically evaluated in clinical trials before it is routinely used with melphalan in isolated organ perfusion.

Adult↗
PubMed1997

Flutamide withdrawal plus hydrocortisone resulted in clinical complete response in a patient with prostate carcinoma.

BACKGROUND: Combined androgen blockade (CAB) (medical or surgical castration plus antiandrogen therapy) is considered by many to be the optimal endocrine maneuver for patients with metastatic prostate carcinoma. When progression occurs after CAB, the discontinuation of the antiandrogen is recommended. The authors present a patient that had a clinical complete response to flutamide withdrawal plus hydrocortisone that, at last follow-up, had been maintained for more than 46 months. METHODS: A 71-year-old man with a positive family history of prostate carcinoma presented in 1989 with urinary frequency and a suspicious digital rectal examination. He was found to have a poorly differentiated adenocarcinoma (Gleason 4+4). He was started on CAB and his prostate specific antigen (PSA) concentration declined from 96 ng/mL to the normal range and was maintained for the next 24 months. In 1991 his PSA began to rise, and reached 64 ng/mL by 1993. The patient was enrolled on a clinical trial that discontinued the flutamide administration and hydrocortisone was initiated. RESULTS: Physical examination at the time of enrollment was unremarkable. His PSA declined to below the limits of detection after this maneuver and at last follow-up had been maintained there for more than 46 months. In 1995, the patient underwent a repeat biopsy of the prostate and all six tissue cores were negative for carcinoma. At last follow-up in December 1996, the patient had no evidence of disease and was being followed routinely; however, the authors were continuing treatment with testicular suppression (leuprolide) plus hydrocortisone. CONCLUSIONS: The authors believe the residual androgens and steroids produced by the adrenal cortex play a meaningful role in prostate carcinoma cell proliferation. Based on this case and data from trials supporting the activity of flutamide withdrawal plus adrenal suppression, it appears reasonable to evaluate prospectively the discontinuation of antiandrogen versus antiandrogen withdrawal plus adrenal suppression in individuals failing CAB.

Adenocarcinoma↗
PubMed1997

In vitro effect of gallium nitrate when combined with ketoconazole in the prostate cancer cell line PC-3.

Secondary hormonal manipulations are common following the failure of combined androgen blockade in patients with metastatic prostate cancer. Ketoconazole has been shown to have activity in this disease by inhibiting cytochrome P450 steroid hormone biosynthesis, thus inducing androgen deprivation. Gallium nitrate has been reported to target tumor tissue in vitro and some preliminary data suggests activity in patients with prostate cancer. Thus, we conducted a Phase II study of gallium nitrate in patients with androgen-independent prostate cancer. Two patients with progressive prostate cancer were removed from this study and subsequently placed on ketoconazole, as a palliative agent. Surprisingly, both of these patients had a greater than 50% decline in their prostate specific antigen (PSA) with this secondary endocrine maneuver. Based on this clinical observation, we conducted the following in vitro study to determine if there was a substantial additive effect of gallium nitrate followed by ketoconazole. Gallium nitrate or ketoconazole was added to the androgen-independent prostatic epithelial cell line, PC-3. One hundred and twenty hours (120 h) following the addition of one of the agents, the media was aspirated and the second agent was added to the wells. One plate was assayed every 24 h for cell viability using a non-isotopic cell proliferation assay kit. Cells treated with gallium nitrate followed by ketoconazole were 70-100% of control at the end of the gallium nitrate treatment; ketoconazole was then added and viability either remained constant or dropped steadily. Gallium nitrate by itself had a weak inhibitory effect on cell viability that only became apparent at the highest concentration evaluated. Ketoconazole, on the other hand, showed a substantial growth inhibition that was concentration-dependent. Cells treated with this agent alone showed a pronounced steady decrease in viability. Exposure to ketoconazole for 120 h followed by incubation in culture medium alone for 120 h caused a decrease in cell viability to 26.0% of control. Our in vitro results suggest that the combination of gallium nitrate and ketoconazole has no additive activity in the PC-3 cell line. Furthermore, this study confirms that ketoconazole added to prostate cancer cells has antiproliferative activity. The in vitro activity of ketoconazole has traditionally been thought to result from its inhibition of cytochrome P450-dependent enzymes responsible for steroidogenesis; however, an alternative hypothesis is necessary to explain the cytotoxic effect in the absence of adrenal and testicular androgen production as found in an in vitro system.

Antifungal Agents↗
PubMed1997

Pharmacokinetics of elemental platinum (ultrafiltrate and total) after a thirty minute intravenous infusion of ormaplatin.

Preclinical data suggest that ormaplatin (tetrachloro-(dl-trans)-1, 2-diamminocyclohexaneplatinum) has substantial activity in cisplatin-resistant tumor models and may be less nephrotoxic than cisplatin. Based on these data we initiated a phase I clinical trial in patients with refractory metastatic cancer. This report characterizes the pharmacokinetic profile of both the total plasma concentrations of elemental platinum and the unbound ultrafiltrate concentrations of elemental platinum, following a 30 min intravenous infusion of ormaplatin. Platinum concentrations were determined by AAS, and pharmacokinetic parameters for both the total plasma concentration and the ultrafiltrate concentration of elemental platinum were determined using both compartmental and noncompartmental methods. Twenty-eight patients (14 males and 14 females; median age, 58) received ormaplatin. There was a linear relationship between Cmax and dose (r2 = 0.945) and AUC and dose (r2 = 0.976). Ormaplatin is more accurately described by a two-compartment model than by a one-compartment model. The distribution half-life (t1/2 alpha) was 0.3 h and the terminal half-life (t1/2 beta) was 39.1 h. The volume of the central compartment (V) was 68.6 L and the volume of distribution at steady state (Vdss) was 183 L. Like total plasma platinum, unbound platinum is also best characterized by a two-compartment model. The elimination of free platinum is also biphasic with a distribution half-life (t1/2 alpha) of 0.3 h and a terminal half-life (t1/2 beta) of 19.3 h. The mean volume of the central compartment (V) was 200.5 L, and the mean volume of distribution at steady state (Vdss) was 560.5 L. Clinical development of ormaplatin has been terminated due to increased frequency of neurological complications noted over other platinum agents; however, the pharmacokinetics are, in general, similar to those of other clinically used platinum compounds.

Adult↗
PubMed1997

Initial pharmacokinetics and bioavailability of PSC 833, a P-glycoprotein antagonist.

Resistant cancer cells have been shown to overexpress a 170-kd membrane glycoprotein called P-glycoprotein. P-glycoprotein, a product of the multidrug resistance 1 gene, functions as an energy-dependent efflux pump that decreases intracellular drug concentrations. A variety of nonchemotherapeutic agents have been shown to inhibit P-glycoprotein-dependent drug efflux including cyclosporin. PSC 833 is a nonimmunosuppressive derivative of cyclosporin D with the ability to reverse multidrug resistance because of P-glycoprotein overexpression in vitro. As part of early clinical development of PSC 833, the authors investigated the bioavailability of an oral formulation of PSC 833. PSC 833 (3 mg/kg) was administered as a 2-hour intravenous infusion on day 1 of the treatment cycle. Serial blood samples for the determination of PSC 833 whole blood concentrations were obtained after both the intravenous and oral doses. On day 5 of the study, patients received a single oral dose (9 mg/kg) of PSC 833. A total of 14 patients were treated. The intravenous data were best described by a two-compartment open model. The oral data also were described using a two-compartment model, with oral absorption incorporating a lag time to account for possible delays in absorption. There was large intra- and interpatient variability in the pharmacokinetics of PSC 833 in these patients. The absolute bioavailability of PSC 833 was 34% but ranged from 3% to 58% of the administered dose. The clearance (CI) of PSC 833, in general, was consistent between the two dose forms administered. The pharmacokinetic behavior of PSC 833 appears to be similar to that of cyclosporine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

New anti-angiogenesis agents: review of the clinical experience with carboxyamido-triazole (CAI), thalidomide, TNP-470 and interleukin-12.

Angiogenesis was postulated to be a critical prognostic factor and therapeutic focus for malignancy more than two decades ago. Recent studies indicate quantitative assessments of microvessel count to be an independent prognostic variable for disease-free and overall survival in a wide variety of tumors, and that angiogenesis may be a feasible target against which to intervene pharmacologically. Several new and old agents have been found to have anti-angiogenic activity and have reached clinical trial. This review will focus on four agents under investigation in the US: carboxyamido-triazole (CAI), thalidomide, TNP-470 and interleukin (IL)-12. CAI, originally identified for its anti-invasive capacity, has been shown to inhibit tumor and endothelial cell proliferation by inhibition of calcium uptake. It is administered orally, is generally well tolerated, and has been shown to induce disease stabilization and occasional reductions in tumor mass. Thalidomide was shown to inhibit growth factor-induced neovessel formation, a process that can also explain its earlier devastating clinical toxicity. It is administered orally, and is currently in phase II clinical trials for prostate cancer, glioblastoma multiforme and breast cancer. TNP-470 is a fumagillin analog that has been shown in in vivo models to be a potent inhibitor of angiogenesis at concentrations that are cytostatic to endothelial cells and tumor cells. Lastly, IL-12 may exert its anti-angiogenic effects through activation of interferon-gamma to up-regulate interferon-inducible protein-10, an anti-angiogenic cytokine. Phase I clinical trials of IL-12 have shown disease stabilization in several tumor types in response to s.c. administration or using genetically engineered IL-12-expressing patient fibroblasts. These promising new agents join the matrix metalloproteinase inhibitors as important new drugs in the anti-cancer armamentarium.

Journal Article↗
PubMed1997

Single-dose pharmacokinetics of thalidomide in human immunodeficiency virus-infected patients.

The pharmacokinetics of thalidomide in nine human immunodeficiency virus-infected patients were studied. Single doses of thalidomide were well absorbed, with mean peak concentrations (+/- standard deviations) of 1.17 +/- 0.21 and 3.47 +/- 1.14 microg/ml in the 100- and 300-mg dosing groups, respectively, and the mean elimination half-life was approximately 6 h. Adverse effects were mild, with drowsiness being reported for seven of nine patients.

Adult↗
PubMed1997

Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis.

The safety, tolerance, and pharmacokinetics of amphotericin B lipid complex (ABLC) were studied in a cohort of pediatric cancer patients. Six children with hepatosplenic candidiasis (HSC) received 2.5 mg of ABLC/kg of body weight/day for 6 weeks for a total dosage of 105 mg/kg. Mean serum creatinine (0.85 +/- 0.12 mg/dl at baseline) was stable at the end of therapy at 0.85 +/- 0.18 mg/dl and at 1-month follow-up at 0.72 +/- 0.12 mg/dl. There was no increase in hepatic transaminases. Mean plasma concentrations over the dosing interval (C(ave)) and area under the curve from 0 to 24 h (AUC(0-24h)) increased between the first and seventh doses but were similar between doses 7 and 42, suggesting that steady state was achieved by day 7 of therapy. Following the final (42nd) dose of ABLC, mean AUC(0-24h) was 11.9 +/- 2.6 microg h/ml, C(ave) was 0.50 +/- 0.11 microg/ml, maximum concentration of the drug in whole blood was 1.69 +/- 0.75 microg/ml, and clearance was 3.64 +/- 0.78 ml/min/kg. Response of hepatic and splenic lesions was monitored by serial computerized tomographic and magnetic resonance imaging scans. The five evaluable patients responded to ABLC with complete or partial resolution of physical findings and of lesions of HSC. During the course of ABLC infusions and follow-up, there was no progression of HSC, breakthrough fungemia, or posttherapy recurrence. Hepatic lesions continued to resolve after the completion of administration of ABLC. Thus, ABLC administered in multiple doses to children was safe, was characterized by a steady state attainable within 1 week of therapy, and was effective in treatment of HSC.

Adolescent↗
PubMed1997

Apoptosis: its role in the development of malignancies and its potential as a novel therapeutic target.

OBJECTIVE: To review the current literature regarding the role of apoptosis in the development of malignant cells and how the induction of this pathway could be used in cancer therapy. DATA SOURCE: A MEDLINE search of basic science articles pertinent to the understanding of the normal physiologic process of apoptosis was conducted. STUDY SELECTION: Because of the rapidly growing literature regarding apoptosis, only articles describing key processes in the biology of the cell and the genetic control of apoptosis were included. DATA SYNTHESIS: Apoptosis is imperative for host survival since it discards unwanted, damaged, and atypical cells. The process is therefore implicated in the continuous regulation of development, differentiation, and homeostasis. Furthermore, apoptosis is a response to physiologic and pathologic stresses that disrupt the balanced rates of cell generation and elimination. In a disease such as cancer, there is a lack of equilibrium between the rates of cell division and cell death; agents that promote or suppress apoptosis can manipulate these rates, influencing the anomalous accumulation of neoplastic cells. Pharmacologic manipulation of apoptosis can manipulate these rates, influencing the anomalous accumulation represents a novel approach in targeting malignant cells and has far-reaching implications for new directions in cancer therapy. CONCLUSIONS: Apoptosis is a highly organized physiologic mechanism of destroying injured and abnormal cells as well as maintaining homeostasis in multicellular organisms. Both the activation and inhibition of apoptosis are tightly controlled. Pharmacologic manipulation of this pathway is a novel therapeutic target in cancer therapy.

Animals↗
PubMed1997

Phase II trial of suramin, leuprolide, and flutamide in previously untreated metastatic prostate cancer.

PURPOSE: To assess the efficacy and toxicity of suramin, hydrocortisone, leuprolide, and flutamide in previously untreated metastatic prostate cancer. PATIENTS AND METHODS: Patients with stage D2 and poor-prognosis stage D1 prostate cancer were given suramin on a pharmacokinetically derived dosing schedule to maintain suramin concentrations between 175 and 300 micrograms/mL. Additionally, all patients received flutamide 250 mg orally three times daily, initiated on day 1 and continued until disease progression; depot leuprolide 7.5 mg intramuscularly begun on day 5 and repeated every 4 weeks indefinitely; and replacement doses of hydrocortisone. RESULTS: Fifty patients were entered onto the study: 48 with stage D2 and two with stage D1 disease. The median age was 59 years (range, 42 to 79) and 31 patients had a Karnofsky performance status (KPS) of 100%. Forty-five patients had bone metastases and 25 had measurable soft tissue disease. Forty-one (82%) had severe disease. The overall response rate in 49 assessable patients was three complete responses (CRs) and 30 partial responses (PRs) for an overall response rate of 67%. Eighteen patients have died. The median survival time has not been reached, with a median potential follow-up duration of 44 months. Grade 3 to 4 toxicity was seen in 38% of patients and was predominantly hematologic and reversible. CONCLUSION: The high response rate and prolonged survival in a poor-prognosis group of patients with metastatic prostate cancer warrant a phase III randomized comparison of this regimen versus hormonal therapy alone. Toxicity was moderate and reversible.

Adult↗
PubMed1997

Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations.

PURPOSE: Cytostatic agents targeted against angiogenesis and tumor cell invasive potential form a new class of investigational drugs. Orally administered carboxyamidotriazole (CAI) (NSC609974) is both antiangiogenic and antimetastatic. An encapsulated micronized powder formulation has been developed to optimize CAI administration. A phase I dose escalation trial with pharmacokinetic analysis has been performed. PATIENTS AND METHODS: Twenty-one patients with refractory solid tumors and good end organ function and performance status were enrolled onto the study. Patients received a test dose followed 1 week later by daily administration of CAI in the encapsulated micronized formulation at doses of 100 to 350 mg/m2. Patients remained on CAI until disease progression or dose-limiting toxicity. Plasma samples were taken to characterize the pharmacokinetic parameters of this formulation of CAI. RESULTS: All patients were assessable for toxicity and 18 were assessable for pharmacokinetics and response analysis. Grade 1 and 2 gastrointestinal side effects were observed in up to 50% of patients. Dose-limiting toxicity was observed in both patients treated at 350 mg/m2/d, consisting of reversible grade 2 to 3 cerebellar ataxia (n = 1) and confusion (n = 1). One minor response (MR) was observed in a patient with renal cell carcinoma and another nine patients had disease stabilization (MR + SD = 47%). Pharmacokinetic analysis demonstrated reduced bioavailability (58% reduction) compared with the PEG-400 liquid formulation previously reported. CONCLUSION: The better toxicity profile of encapsulated micronized CAI with similar frequency of disease stabilization and ease of administration compared with the liquid or gelatin capsule, suggests that the micronized formulation is a preferable formulation for subsequent studies. A dose of 300 mg/m2/d is proposed for phase II investigations.

Adult↗
PubMed1997

Pharmacokinetic studies with recombinant cytokines. Scientific issues and practical considerations.

Advances in molecular biology and recombinant DNA technology have led to the development of cytokines as therapeutic agents for a variety of disease states. The pharmacokinetic analysis of cytokines involves the understanding of analytical methods capable of detecting these agents in biological fluids and recognition of several factors which may have an impact on the cytokine concentration-time curves. Enzyme-linked immunosorbent assays (ELISA) have become the most common method of detection and commercial kits are available for a wide variety of cytokines. Monoclonal antibody products are sensitive, have minimal cross-reactivity and are relatively inexpensive when compared with high performance liquid chromatography (HPLC). However, the primary limitation of these assays is their inability to measure biologically active protein. Conversely, bioassays do measure a biological event (i.e. proliferation or cytotoxicity) but are generally not used for cytokine analysis because of their high cost, long assay completion time, lack of specificity, poor sensitivity and influence of environmental conditions on the outcome. The pharmacokinetic profile of recombinant cytokines is influenced by a number of variables: endogenous production, circulating soluble receptors and cell-associated receptors, immunocompetence and antibody production against the cytokine all may influence the disposition of the agent. Thus, pharmacokinetic modelling of cytokines may involve complex models capable of characterising these nonlinear processes and resulting effects. The route of administration is an important variable since cytokines administered by subcutaneous injection may be partially metabolised by proteases present in the subcutaneous tissue. Other methods to simplify cytokine delivery are being actively investigated and include formulations for inhalation, topical and oral administration. A variety of cytokines (including interferon-alpha, interleukin-6 and tumour necrosis factor) are capable of inhibiting cytochrome P450 hepatic enzymes and, therefore, possess the potential to cause drug-cytokine interactions. Inhibition has been demonstrated in several in vitro systems and animal models, although clinical data are currently limited. An increased understanding of the many factors which can alter the analysis and pharmacokinetics of cytokines is essential to the design of optimal dosage regimens.

Animals↗
PubMed1997

Similar clinical outcomes in African-American and non-African-American males treated with suramin for metastatic prostate cancer.

African-American males have a higher incidence of prostate cancer than non-African-American males and an overall poorer prognosis. Environmental factors such as socioeconomic status and biological factors such as an increased frequency of androgen receptor mutation have been identified as causal. As androgen ablation therapy is ubiquitous in the treatment of metastatic prostate cancer, little information is available on clinical outcome independent of hormone therapy. Our experience at the Warren G. Magnusson Clinical Center, National Institutes of Health with the anticancer agent, suramin, offers the opportunity to study clinical outcome in patients treated with an agent whose tumoricidal activity is not dependent on androgen receptor function. Clinical outcome was examined retrospectively in 43 patients treated on a single suramin-based protocol and evaluated as a function of ethnic background. No significant difference in time to disease progression or survival was observed between African Americans (n = 4) and the other 39 patients. These findings are consistent with the hypothesis that therapies that work through mechanisms independent of the androgen receptor may result in similar outcomes across ethnic groups.

Aged↗
PubMed1996

A phase I study of bolus versus continuous infusion of the anti-CD19 immunotoxin, IgG-HD37-dgA, in patients with B-cell lymphoma.

IgG-HD37-SMPT-dgA is a deglycosylated ricin A chain (dgA)-containing immunotoxin (IT) prepared by conjugating the monoclonal murine (MoAb) anti-CD19 antibody, HD37, to dgA using the heterobifunctional hindered disulfide linker, N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio) toluene (SMPT). In this report, we have used two regimens for the administration of IgG-HD37-SMPT-dgA to patients with non-Hodgkin's lymphoma (NHL) in two concomitant phase I trials. One trial examined four intermittent bolus infusions administered at 48-hour intervals. The other studied a continuous infusion (CI) administered over the same 8-day period. In the intermittent bolus regimen, the maximum tolerated dose (MTD) was 16 mg/m2/8 d and the dose-limiting toxicity (DLT) consisted of vascular leak syndrome (VLS), aphasia, and evidence of rhabdomyolysis encountered at 24 mg/m2/8 d. Using the CI regimen, the MTD was defined by VLS at 19.2 mg/m2/8 d. At the MTD of both regimens, a novel toxicity, consisting of acrocyanosis with reversible superficial distal digital skin necrosis in the absence of overt evidence of systemic vasculitis, occurred in 3 patients. Of 23 evaluable patients on the bolus schedule, there was 1 persisting complete response (CR; > 40 months) and 1 partial response (PR). Of 9 evaluable patients on the continuous infusion regimen, there was 1 PR. Pharmacokinetic parameters for the bolus regimen at the MTD showed a mean maximum serum concentration (Cmax) of 1,209 +/- 430 ng/mL, with a median T1/2 beta for all courses of 18.2 hours (range, 10.0 to 80.0 hours), a volume of distribution (Vd) of 10.9 L (range, 3.1 to 34.5 L), and a clearance (CL) of 0.45 L/h (range, 0.13 to 2.3 L/h). For the CI regimen at MTD, the mean Cmax was 963 +/- 473 ng/mL, with a median T1/2 beta for all courses of 22.8 hours (range, 24.1 to 30.6 hours), a Vd of 9.4 L (range, 4.4 to 19.5 L), and a CL of 0.32 L/h (range, 0.12 to 0.55 L/h). Twenty-five percent of the patients on the bolus infusion regimen and 30% on the CI regimen made antibody against mouse Ig (HAMA) and/or ricin A chain antibody (HARA). We conclude that this IT can be administered safely and that both regimens achieve comparable peak serum concentrations at the MTD; these concentrations are similar to those achieved previously using other regimens with IgG-dgA ITs at their respective MTDs. Thus, toxicity is related to the serum level of the IT and does not differ with different targeting MoAbs.

Adult↗
PubMed1996

Clinical investigation of a cytostatic calcium influx inhibitor in patients with refractory cancers.

Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-excitable calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. Inhibition of calcium influx and calcium-dependent events is a potential common mechanism underlying these effects of CAI. The cytostatic and antiangiogenic properties of CAI led to its development for clinical investigation. In a Phase I clinical trial open to patients with refractory solid tumors, 49 patients received p.o. administered CAI daily or every other day. Two oral formulations, PEG-400 CAI solution and a gelatin capsule containing CAI in PEG-400, were tested. All administered dosages of CAI yielded plasma concentration at or above the range demonstrated to be effective in inhibiting signaling and cancer progression in vitro and in preclinical models (1 microgram/ml, 2.3 microM). Toxicity of p.o. administered CAI most commonly consisted of dose-related grade 1-2 nausea, vomiting, and occasional anorexia. CAI administration at bedtime ameliorated gastrointestinal complaints in many patients; others required addition of simple antiemetic regimens, usually consisting of metoclopropamide or prochlorperazine. Gastrointestinal complaints were the cause for compliance-limiting toxicity at 175 mg/m2/day of the liquid formulation and 125 mg/m2/day of the gelatin capsule formation. Reversible and rare sensory axonal neuropathy (grade 3, 1 patient) and neutropenia (grade 4, 1 patient) were dose-limiting toxicities observed at the 330 mg/m2 every-other-day liquid CAI dose level. No evidence of cumulative end organ damage or central nervous system injury was observed. Disease stabilization and improvement in performance status was observed. Disease stabilization and improvement in performance status was observed in 49% of evaluable patients who had disease progression before CAI. Disease stabilization and associated improvement in performance status was seen in patients with renal cell carcinoma (7 months), pancreaticobiliary carcinomas (3, 5, and 5 months), melanoma (7 months), ovarian cancer (7 months), and non-small cell lung cancer (3 months). The recommended Phase II doses from this trial are 150 mg/m2/day in the liquid formation and 100 mg/m2/day in the gelatin capsule formation.

Administration, Oral↗
PubMed1996

Severe thrombocytopenia in patients treated with suramin: evidence for an immune mechanism in one.

Although suramin has long been used to treat human trypanosomiasis, recent clinical trials have tested its efficacy against the acquired immunodeficiency syndrome (AIDS) and various malignancies. Thromobocytopenia was observed in early trials with suramin in AIDS, but has been uncommon in patients treated for solid tumors. Here we describe 5 patients out of a total of 67 (7%) who developed severe thrombocytopenia while receiving suramin as part of a phase II clinical trial for metastatic prostate carcinoma refractory to hormonal therapy. IgG purified from one patient's plasma caused suramin-dependent platelet aggregation. There was also evidence of crossreactivity between suramin and heparin in this system. An immune mechanism, however, could not be documented in the other cases, suggesting that multiple mechanisms may be responsible for severe thrombocytopenia in this patient population.

Antineoplastic Agents↗