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B A Chabner

Publications and source records attributed to B A Chabner.

At least 37 records · Page 2Linked to original sources
PubMed1998

Translational research: walking the bridge between idea and cure--seventeenth Bruce F. Cain Memorial Award lecture.

Advances in the understanding of normal and malignant cell biology are allowing the development of biologically targeted drugs directed at specific differences between host and tumor. The array of potential new targets is vast, but drugs currently in development are targeted at cell-cycle regulators, growth factors and their receptors, signal transduction intermediates, angiogenesis, and the mechanisms that mediate apoptosis and DNA repair. Recent results raise the possibility that novel biologically targeted agents, perhaps in combination with traditional cytotoxic agents, may finally cure cancer. However, the development of a biologically targeted drug raises unique challenges in the design of clinical trials to demonstrate its efficacy, and despite the promising preclinical data that exist for most of the agents in development, the clinical trial remains the critical, final step across the bridge from basic research to clinical application. In this review, we discuss some of the challenges in the clinical development of biologically targeted agents and the implications for clinical trial design.

Antineoplastic Agents↗
PubMed1998

Clinical evaluation of biologically targeted drugs: obstacles and opportunities.

Recent insights into the molecular mechanisms of cancer have indicated that a variety of fundamental cellular processes are dysregulated in malignant cells. These processes include cell cycle control, signal transduction pathways, apoptosis, telomere stability, angiogenesis, and interactions with the extracellular matrix. Remarkable advances in molecular genetics, enzymology, and medicinal chemistry have permitted the design of compounds that modulate some of these processes with specificity that was unimaginable a decade ago. As these novel, biologically targeted compounds enter the clinic, they will require a strategy for clinical evaluation and development different from that used commonly for cytotoxic antineoplastic agents. This review examines the development of cancer drugs directed against angiogenesis, metastasis, signal transduction, telomerase, and molecular message (antisense), outlines strategies for the clinical testing of agents directed at these processes, and contrasts these efforts with traditional approaches to cancer drug testing.

Animals↗
PubMed1997

Antimetabolites.

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Animals↗
PubMed1996

Antimetabolites.

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Animals↗
PubMed1996

Concepts in use of high-dose methotrexate therapy.

In cancer chemotherapy, routine monitoring of drug concentrations has been practical only for methotrexate (MTX). The primary setting for pharmacokinetic monitoring of MTX is its use in high doses (HDMTX) for adjuvant therapy of osteosarcoma, for single-agent treatment of intracranial lymphomas, and in combination therapy of childhood leukemia as well as adult and pediatric non-Hodgkin lymphomas. Typically, HDMTX is infused in doses of 3-15 g/m2 over a period of 6-24 h. Precautions must be taken to ensure a high urine flow and an alkaline urine pH, so as to prevent precipitation of MTX in urine. Patients with decreased renal function, advanced in age, and taking nonsteroidal anti-inflammatory drugs or nephrotoxic agents are at increased risk of developing renal dysfunction during MTX infusion, thus being placed at high risk for toxicity. At the end of HDMTX infusion, and periodically thereafter for 24-48 h, drug concentrations are measured to assure that the disappearance rate of MTX from plasma is occurring at a normal rate. Also, at the end of HDMTX infusion, the patient is given leucovorin (5-formyl-tetrahydrofolic acid; LV), which replenishes intracellular stores of reduced folate and attenuates the toxicity secondary to HDMTX. In the presence of inappropriately high concentrations of MTX, routine doses of LV will be ineffective; the dose of LV required must be increased in proportion to the MTX concentration it faces in plasma. In practice, routine monitoring of plasma MTX concentrations allows early detection of abnormal clearance, as well as institution of early and effective countermeasures, including the use of increased and prolonged LV rescue.

Adult↗
PubMed1995

Modulation of multidrug resistance by dexverapamil in EPOCH-refractory lymphomas.

We conducted a controlled trial of dexverapamil, an inhibitor of Pgp, in 45 Hodgkin's (HD) and 154 Non-Hodgkin's (NHL) lymphomas refractory to EPOCH chemotherapy. A total of 154 patients initially received EPOCH alone and (4.2%) with stable disease over two cycles or progressive disease "crossed over" to receive dexverapamil with EPOCH. Dexverapamil was escalated 8 dose levels, from 240 to 1200 mg/m2 per day. When possible, serial biopsies were obtained to measure MDR-1 expression by quantitative polymerase chain reaction. Median age was 44 years, 67% had stage IV disease, and median (range) prior regimens were 2 (1-12) in NHL and 1 (1-4) in HD. The maximum tolerated dose of dexverapamil was 900 mg/m2/day, and median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 microM, respectively. There were 3 complete and 2 partial responses (12%) and 5 minor responses in NHL, and 2 of 10 HD patients achieved partial responses. MDR-1 was measured in 44 biopsies from 19 patients. Pre-therapy, MDR-1 was low (median 2.5 U) but increased (median 12.2 U) at cross-over. Among 6 patients with MDR-1 > 15, 3 responded to dexverapamil whereas only 1/8 patients with MDR-1 < 15 responded. EPOCH and dexverapamil were well tolerated. This study suggests that MDR-1 plays a role in clinical drug resistance of lymphomas, but also suggests that non-MDR-1 mechanisms are present in such patients. Earlier intervention with dexverapamil may be more effective and warrants further study.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Phase II study of paclitaxel in relapsed non-Hodgkin's lymphomas.

PURPOSE: To assess the efficacy and toxicity of paclitaxel administered as a 96-hour infusion to patients with relapsed non-Hodgkin's lymphomas (NHLs). PATIENTS AND METHODS: Eligible patients had relapsed NHL and measurable disease and were considered incurable. Paclitaxel was infused at a dose of 140 mg/m2 every 3 weeks. Premedications to prevent paclitaxel hypersensitivity reactions were not administered and no patients received corticosteroids. Expression of the multidrug resistance (mdr-1) gene was determined in tumor from 17 patients by mRNA quantitative polymerase chain reaction (PCR). RESULTS: Thirty-one patients received a total of 99 cycles of paclitaxel. Two patients were not assessable for response. The median age was 50 years, 71% had stage IV disease, and intermediate/high-grade histology was present in 65% of patients. Patients had received a median of three prior chemotherapy regimens, and 68% of patients had responded to the previous chemotherapy (chemotherapy-sensitive). Of 29 assessable patients, five (17%) achieved a partial response (PR). With a median potential follow-up time of 17 months, the median event-free and overall survival durations were 1.6 and 7.5 months, respectively. No correlation was found between response to paclitaxel and extent of prior treatment or response. The mdr-1 gene was easily detectable in 14 of 17 tumor biopsies, but was low in all but one sample. The most serious toxicity was grade 4 neutropenia, which occurred during 14% of cycles. CONCLUSION: Paclitaxel was well tolerated, but had a low response rate in patients with relapsed NHLs. There was no clear association between response to paclitaxel and extent of our response to prior treatment. Most patients had chemotherapy-sensitive disease, which suggests that the low response rate to paclitaxel was probably not due to general chemotherapy resistance. Paclitaxel provided good palliation in a minority of patients and is a reasonable agent to consider for use in patients who have failed to respond to standard chemotherapy.

Adult↗
PubMed1995

Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy.

PURPOSE: Dexverapamil is a competitive inhibitor of the P-glycoprotein (Pgp) efflux pump, a potent mechanism of multidrug resistance (mdr-1) in vitro. We performed a phase I study to determine the maximum-tolerated dose (MTD) and pharmacokinetics of dexverapamil with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory lymphoma or sarcoma. Patients initially received EPOCH alone, and those with stable or progressive disease were crossed-over to received dexverapamil on subsequent cycles of EPOCH. Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients. In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil. RESULTS: Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy. The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity. The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred. At the MTD, the median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 mumol/L, respectively. Dexverapamil did not affect the steady-state concentration (Css) of etoposide, but increased the Css of doxorubicin and doxorubicinol nearly twofold. The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change. CONCLUSION: The phase II recommended dose of dexverapamil with EPOCH is 150 mg/m2 every 4 hours. This dose was well tolerated on an outpatient basis and achieved plasma concentrations of dexverapamil and nor-dexverapamil within the effective range for Pgp inhibition in vitro. Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions. Dexverapamil should be considered for further study.

Adult↗
PubMed1994

The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer.

PURPOSE: We assessed the prognostic importance of the level of thymidylate synthase (TS) expression in patients with primary rectal cancer and whether, for Dukes' B and C cancer patients, the benefit of chemotherapy was associated with TS expression. PATIENTS AND METHODS: The level of TS expression in the primary rectal cancers of 294 of 801 patients enrolled on protocol R-01 of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was immunohistochemically assessed with the monoclonal antibody TS 106. RESULTS: Forty-nine percent of patients whose tumors had low TS levels (n = 91) were disease free at 5 years compared with 27% of patients with high levels of TS (n = 203; P < .01). Moreover, 60% of patients with low TS levels were alive after 5 years compared with 40% of patients with high TS levels (P < .01). The level of TS protein was significantly associated with Dukes' stage (P < .01); patients with a more advanced Dukes' stage had a significantly higher level of TS. The level of TS expression remained prognostic for both disease-free survival (P < .01) and survival (P < .05) independent of Dukes' stage and other pathologic characteristics evaluated. Thirty-eight percent and 54% of patients with high TS levels (n = 71) were disease free and alive, respectively, after 5 years when treated with chemotherapy, compared with 17% and 31%, respectively, of similar patients when treated with surgery alone (n = 64) (P < .01). No difference was noted in disease-free survival (P = .46) or survival (P = .43) in patients with low TS levels. CONCLUSION: The expression of TS is an important independent prognosticator of disease-free survival and survival in patients with rectal cancer. Adjuvant fluorouracil (5-FU)-based chemotherapy demonstrated significant improvement in disease-free and overall survival for patients with high TS levels. Prospective studies measuring TS levels will be needed to understand further the role of TS as a prognosticator of survival and chemotherapeutic benefit.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Antimetabolites.

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Animals↗