[Show abstract][Hide abstract] ABSTRACT: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.
Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained.
Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks).
UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.
Full-text · Article · Jun 2011 · Cancer Chemotherapy and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: This phase 1 study evaluated the pharmacokinetic and pharmacodynamic effects of cetuximab on patients with epithelial malignancies.
Following a skin and tumor biopsy, patients with advanced epithelial malignancies were randomized to receive a single dose of cetuximab at 50, 100, 250, 400, or 500 mg/m2 i.v. Repeat skin (days 2, 8, 15, and 22) and tumor (day 8) biopsies were obtained. Immunohistochemical expression of epidermal growth factor receptor (EGFR) and its pathway members was done on biopsies. Blood samples were obtained over 22 days for pharmacokinetic analyses. After day 22, all patients received weekly 250 mg/m2 cetuximab until disease progression or unacceptable toxicity.
Thirty-nine patients enrolled. Rash was noted in 26 (67%) patients. Three patients (two with colon cancer and one with laryngeal cancer) achieved a partial response and 13 patients had stable disease. Pharmacokinetic data revealed mean maximum observed cetuximab concentrations and mean area under the concentration-time curve from time zero to infinity increased in a dose-dependent manner up to 400 mg/m2 cetuximab. Mean clearance was similar at cetuximab doses>or=100 mg/m2, supporting saturation of EGFR binding at 250 mg/m2. Pharmacodynamic evaluation revealed that patients with partial response/stable disease had a higher-grade rash and higher cetuximab trough levels than those with progressive disease (P=0.032 and 0.002, respectively). Administration of single doses (250-500 mg/m2) of cetuximab resulted in a dose-dependent decrease in EGFR protein expression levels in skin over time, supporting a minimal dose of cetuximab at 250 mg/m2 for a pharmacodynamic effect.
This study provides a pharmacokinetic and pharmacodynamic rationale for the dosing of cetuximab.
Preview · Article · Mar 2007 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Advanced non-small cell lung cancer (NSCLC) remains a difficult cancer to treat, and evolution of platinum-free regimens in a first-line setting is ongoing. This was a dose-finding study on the docetaxel and vinorelbine combination. Docetaxel was given at 60 mg/m(2) on day 1 only, and vinorelbine was given on days 1 and 15 starting at 20 mg/m(2), then escalated to 30 and 40 mg/m(2) in two dose cohorts. Each cycle lasted 28 days. The maximum tolerated dose was 60 mg/m(2) docetaxel and 30 mg/m(2) vinorelbine. Twenty-one patients were enrolled and showed an overall response rate of 9.5%, with stable disease documented in 33% of patients. The dosage schedule of this combination resulted in acceptable toxicities. The median time to progression was 5.86 months (95% CI 2.50-9.22), and median survival was 10.96 months (95% CI 1.42-20.51) with a 1-year survival rate of 50%. This combination may be important for patients with NSCLC.
No preview · Article · Feb 2006 · Oncology Reports
[Show abstract][Hide abstract] ABSTRACT: Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20–25 mg m-2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m-2 and escalated in an accelerated titration design to 25 mg m-2. Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m-2. The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10–73) ml h-1 m-2 in cycle 1 to 18 (3–37) ml h-1 m-2 with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m-2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.Keywords: doxil, multidrug resistance, pegylated liposomal doxorubicin, PSC 833, valspodar
Full-text · Article · Jun 2005 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of docetaxel infused over 1 hour when given in combination with oral zosuquidar to patients with resistant solid tumors.
In cycle 1, patients received docetaxel alone. In subsequent cycles, zosuquidar was administered with docetaxel, which was escalated from 75 to 100 mg/m2. Zosuquidar was escalated from 100 to 300 mg/m2 every 8 hours on days 1 to 3 for a total of 7 doses, or from 400 to 500 mg every 12 hours for 2 doses administered 2 hours before docetaxel. The pharmacokinetics of docetaxel with and without zosuquidar administration were obtained.
Thirty-six of 41 patients completed at least one cycle of docetaxel and zosuquidar. The maximum tolerated dose was docetaxel 100 mg/m2 and zosuquidar 500 mg every 12 hours for 2 doses. The most common toxicity was neutropenia. In 35 patients, zosuquidar produced minimal increases in the docetaxel peak plasma concentrations and area under the curve. Dosing over 3 days with zosuquidar (7 doses) did not show benefit over the 1-day dosing. Of the 36 patients, one patient had a partial response, and 14 patients had disease stabilization.
Docetaxel at 75 or 100 mg/m2 and zosuquidar 500 mg 2 hours before docetaxel and 12 hours later is well tolerated. Zosuquidar minimally alters the pharmacokinetics of docetaxel, allowing full dose docetaxel to be given with this P-glycoprotein modulator. A Phase II study with this combination in advanced breast carcinoma is underway.
Preview · Article · Dec 2004 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Pegylated liposomal doxorubicin (PEG-LD) and docetaxel have single-agent activity in several malignancies. The authors conducted a Phase I trial to evaluate the maximum tolerated dose (MTD), toxicities, and effect of dose sequencing of this combination in patients with advanced malignancies.
Twenty-two patients were enrolled in this two-arm, accelerated, dose escalation trial. Both drugs were administered on Days 1 and 15 of a 28 day cycle. In Arm A, dose escalation proceeded from a sequence and starting dose of 15 mg/m(2) PEG-LD and 30 mg/m(2) docetaxel. In Arm B, dose escalation proceeded from a sequence and starting dose of 30 mg/m(2) docetaxel and 15 mg/m(2)PEG-LD. In both arms, the dose of each drug was increased alternately by 5 mg/m(2) at each dose level.
The MTD for Arm A was 20 mg/m(2) PEG-LD and 40 mg/m(2) docetaxel, both of which were administered on Days 1 and 15 of a 28-day cycle. The MTD for Arm B was 35 mg/m(2) docetaxel and 20 mg/m(2) PEG-LD, both of which were administered on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicities were Grade 3 (according to the National Cancer Institute Common Toxicity Criteria) skin toxicity and thrombocytopenia. One partial response was observed and stable disease was documented for three patients.
The recommended sequence and dose is 20 mg/m(2) PEG-LD followed by 40 mg/m(2) docetaxel on Days 1 and 15 of a 28-day cycle in Phase II trials for patients with breast and ovarian carcinoma to establish the efficacy of this well tolerated regimen.
[Show abstract][Hide abstract] ABSTRACT: To determine whether fluoxetine improves overall quality of life (QOL) in advanced cancer patients with symptoms of depression revealed by a simple survey.
One hundred sixty-three patients with an advanced solid tumor and expected survival between 3 and 24 months were randomly assigned in a double-blinded fashion to receive either fluoxetine (20 mg daily) or placebo for 12 weeks. Patients were screened for at least minimal depressive symptoms and assessed every 3 to 6 weeks for QOL and depression. Patients with recent exposure to antidepressants were excluded.
The groups were comparable at baseline in terms of age, sex, disease distribution, performance status, and level of depressive symptoms. One hundred twenty-nine patients (79%) completed at least one follow-up assessment. Analysis using generalized estimating equation modeling revealed that patients treated with fluoxetine exhibited a significant improvement in QOL as shown by the Functional Assessment of Cancer Therapy-General, compared with patients given placebo (P =.01). Specifically, the level of depressive symptoms expressed was lower in patients treated with fluoxetine (P =.0005), and the subgroup of patients showing higher levels of depressive symptoms on the two-question screening survey were the most likely to benefit from treatment.
In this mix of patients with advanced cancer who had symptoms of depression as determined by a two-question bedside survey, use of fluoxetine was well tolerated, overall QOL was improved, and depressive symptoms were reduced.
No preview · Article · Jun 2003 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies.
Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle.
The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients.
The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.
Full-text · Article · Dec 2002 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: Pegylated liposomal doxorubicin (PEG-LD) and gemcitabine have single-agent activity in breast and ovarian carcinoma patients. We conducted a Phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in patients with advanced malignancies.
Twenty-six patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of PEG-LD 20 mg/m(2) and gemcitabine 1000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle.
The MTD was PEG-LD 20 mg/m(2) and gemcitabine 2000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicity, a Grade 3 rash, was observed in one patient during Cycle 1 and Grade 3 stomatitis and a rash were observed in a second patient during Cycle 2 after administration of PEG-LD 25 mg/m(2) and gemcitabine 2000 mg/m(2). Other side effects included palmar-plantar erythrodysesthesia, nausea, and fatigue. One complete and two partial responses were observed.
The recommended Phase II dose is PEG-LD 20 mg/m(2) with gemcitabine 2000 mg/m(2) on Days 1 and 15 of a 28-day cycle. A trial with this combination is currently ongoing at this institution comprising patients with refractory ovarian carcinoma.
[Show abstract][Hide abstract] ABSTRACT: For limited-stage small cell lung cancer, twice-daily radiation with concurrent chemotherapy improves survival rate, but has dose-limiting esophageal toxicity. The authors studied 34 patients treated with amifostine in an attempt to decrease the incidence and grade of esophagitis. The results indicate that there was no reduction in toxicity, but the authors were able to maintain the high complete response rate that had been reported previously. These results differ from the use of amifostine in non-small cell lung cancer in which there is the observation of esophageal protection.
No preview · Article · Feb 2002 · Seminars in Radiation Onchology
[Show abstract][Hide abstract] ABSTRACT: We evaluated the impact of treatment modality on esthesioneuroblastoma.
Between 1976 and 1996, 25 patients with esthesioneuroblastoma were treated at Mallinckrodt Institute of Radiology. There were 11 male and 14 female patients; their ages ranged from 16 to 73 years (median, 57 years). The tumors were Kadish stage A in 3, Stage B in 13, C in 8, and modified D in 1 (cervical nodal metastasis). Seventeen patients were treated with surgery and radiation therapy, six were treated with irradiation alone, and two were treated with surgery only. Eight patients received neoadjuvant chemotherapy. Median follow-up was 8 years (range, 2-24 years).
The 5-year actuarial overall survival, disease-free survival, and local tumor control rates were 66.3%, 56.3%, and 73.0%, respectively. Kadish stage was not a significant prognosticator for local control or disease-free survival. Five-year local control rates were 87.4% for the combination of surgery and radiation therapy and 51.2% for irradiation alone. Two patients with Kadish stage A and B disease underwent surgical resection alone; both failed locally. In contrast, 33.3% of patients (three of nine) with Kadish stage A or B disease who received adjuvant radiation therapy had a local recurrence develop. With adjuvant radiation therapy, the surgical margin status did not influence local tumor control. Among the eight patients who received neoadjuvant chemotherapy, six patients showed no response, one had partial response, and one showed a complete response.
Surgical resection plus adjuvant radiation therapy yielded the best treatment outcome. More effective chemotherapy agents with a reproducible effectiveness are needed for patients with locally advanced esthesioneuroblastoma.