Barry R. Goldspiel

Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.

PURPOSE A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer. PATIENTS AND METHODS In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction. RESULTS Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied. CONCLUSION The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.

Clinical Overview of the Taxanes

Paclitaxel and docetaxel are taxane antineoplastic agents with broad antitumor activity. Since being introduced, they have become increasingly important in the treatment of a number of major solid tumors. Paclitaxel plus a platinum analog is now considered first‐line therapy for advanced ovarian cancer, and both paclitaxel and docetaxel have significant activity as single agents in recurrent ovarian cancer. Docetaxel may be useful in some of these women with ovarian cancer who fail or progress after paclitaxel‐containing treatments. Both drugs have significant response rates in the treatment of breast cancer and are options for patients with advanced disease, including anthracycline‐refractory disease. Administration of taxanes in new combination regimens and as adjuvant therapy for breast cancer is under investigation; for example, the combination of paclitaxel and doxorubicin is highly active, and comparative studies of taxanes and anthracyclines should help clarify optimal treatment regimens in breast cancer. Both drugs have significant activity alone in the treatment of advanced non‐small cell lung cancer (NSCLC) and head and neck cancers. For the former, paclitaxel‐cisplatin is now standard treatment in cooperative group combination therapy trials. As a result of its radiosensitizing properties, paclitaxel is undergoing extensive evaluation as combined modality treatment for advanced NSCLC and head and neck cancer. Both taxanes will probably be useful in combination regimens in head and neck cancer. Research is continuing to define further their roles and relative usefulness in other malignancies.

Sorafenib and sunitinib : Novel targeted therapies for renal cell cancer

Renal cell cancer (RCC) is a relatively uncommon malignancy with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High‐dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low‐dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia‐inducible factor and the Ras‐Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first‐ and second‐line therapy in patients with cytokine‐refractory metastatic RCC who have clear‐cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression‐free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first‐ and second‐line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand‐foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.

Phase I Study of Infusional Paclitaxel in Combination With the P-Glycoprotein Antagonist PSC 833

PURPOSE PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion. PATIENTS AND METHODS Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833. RESULTS In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma. CONCLUSION PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.

A Phase I Study of Infusional Vinblastine in Combination with the P-Glycoprotein Antagonist PSC 833 (Valspodar)

PSC 833 is a second‐generation P‐glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5‐day continuous infusion.

A Phase I Study of the P-Glycoprotein Antagonist Tariquidar in Combination with Vinorelbine

Purpose: P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. Experimental Design: Patients first received tariquidar alone to assess effects on the accumulation of 99mTc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. Results: Twenty-six patients were enrolled. Vinorelbine 20 mg/m2 on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver 99mTc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased 99mTc-sestamibi retention in a majority of tumor masses visible by 99mTc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. Conclusions: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastatic breast cancer.

PURPOSE We conducted a phase I/II trial of concurrently administered 72-hour infusional paclitaxel and doxorubicin in combination with granulocyte colony-stimulating factor (G-CSF) in patients with previously untreated metastatic breast cancer and bidimensionally measurable disease. PATIENTS AND METHODS We defined the maximum-tolerated dose (MTD) of concurrent paclitaxel and doxorubicin administration and then studied potential pharmacokinetic interactions between the two drugs. Forty-two patients who had not received prior chemotherapy for metastatic breast cancer received 296 total cycles of paclitaxel and doxorubicin with G-CSF. RESULTS The MTD was determined to be paclitaxel 180 mg/m2 and doxorubicin 60 mg/m2 each by 72-hour infusion with G-CSF. Diarrhea was the dose-limiting toxicity (DLT) of this combination, with three of three patients developing abdominal computed tomographic (CT) scan evidence of typhlitis (cecal thickening) at the dose level above the MTD. All patients developed grade 4 neutropenia (absolute neutrophil count [ANC] < 500 microL), generally less than 5 days in duration. This combination was generally safely administered at dose levels at or below the MTD. The overall response rate was 72% (28 of 39 patients; 95% confidence interval [CI], 55% to 85%), with 8% complete responses (CRs) (three of 39; 95% CI, 2% to 21%) and a median response duration of 9 months. The median overall survival time for all patients is 23 months, with a median follow-up duration of 28 months. Pharmacokinetic studies showed that administration of paclitaxel and doxorubicin together by 72-hour infusion did not affect the steady-state concentrations of either drug. CONCLUSION Concurrent 72-hour infusional paclitaxel and doxorubicin can be administered safely, but is associated with significant toxicity. The overall response rate of this combination in untreated metastatic breast cancer patients is similar to that achieved with other doxorubicin-based combination regimens. The modest complete response rate achieved suggests that this schedule of paclitaxel and doxorubicin administration does not produce significant additive or synergistic cytotoxicity against breast cancer.

Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer.

PURPOSE We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer. PATIENTS AND METHODS Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy. RESULTS The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations. CONCLUSION r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.

A Phase I/II Study of Infusional Vinblastine with the P-Glycoprotein Antagonist Valspodar (PSC 833) in Renal Cell Carcinoma

Purpose: P-glycoprotein (Pgp) inhibitors have been under clinical evaluation for drug resistance reversal for over a decade. Valspodar (PSC 833) inhibits Pgp-mediated efflux but delays drug clearance, requiring reduction of anticancer drug dosage. We designed an infusional schedule for valspodar and vinblastine to mimic infusional vinblastine alone. The study was designed to determine the maximally tolerated dose of vinblastine, while attempting to understand the pharmacokinetic interactions between vinblastine and valspodar and to determine the response rate in patients with metastatic renal cell cancer. Patients and Methods: Thirty-nine patients received continuous infusion valspodar and vinblastine. Vinblastine was administered for 3 days to compensate for the expected delay in clearance and the required dose reduction. Valspodar was administered initially at a dose of 10 mg/kg/d; the dose of vinblastine varied. Results: The maximum-tolerated dose of vinblastine was 1.3 mg/m2/d. As suggested previously, serum valspodar concentrations exceeded those needed for Pgp inhibition. Consequently, the dose of valspodar was reduced to 5 mg/kg, allowing a vinblastine dose of 2.1 mg/m2/d to be administered. Pharmacodynamic studies demonstrated continued inhibition of Pgp at lower valspodar doses by functional assay in Pgp-expressing CD56+ cells and by 99mTc-sestamibi imaging. A 15-fold range in cytochrome P450 activity was observed, as measured by midazolam clearance. No major responses were observed. Conclusions: These results suggest that the pharmacokinetic impact of cytochrome P450 inhibition by valspodar can be reduced although not eliminated, while preserving Pgp inhibition, thus separating the pharmacokinetic and pharmacodynamic activities of valspodar.

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

PURPOSE High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS Forty-one patients with drug-resistant Hodgkins and non-Hodgkins lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkins and non-Hodgkins lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.