Paula M. Fracasso

A Phase 1 Escalating Single-Dose and Weekly Fixed-Dose Study of Cetuximab: Pharmacokinetic and Pharmacodynamic Rationale for Dosing

Purpose: This phase 1 study evaluated the pharmacokinetic and pharmacodynamic effects of cetuximab on patients with epithelial malignancies. Experimental Design: 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. Results: 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 ≥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. Conclusion: This study provides a pharmacokinetic and pharmacodynamic rationale for the dosing of cetuximab.

Phase I and pharmacodynamic study of Triapine®, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia

In a phase I study, 24 patients with refractory leukemia received Triapine, a novel ribonucleotide reductase (RR) inhibitor, as a continuous intravenous infusion over 96 h beginning on days 1 and 15 or days 1 and 8. On the days 1 and 15 regimen, the starting dose was 120 mg/m(2) per day, and the maximum tolerated dose (MTD) was 160 mg/m(2) per day. Three of eight patients receiving 160 mg/m(2) per day in the first course, and one patient escalated to this dose in a second course, developed hepatic dose-limiting toxicity (DLT). For the days 1 and 8 regimen, the first 96 h infusion was administered at a fixed dose of 140 mg/m(2) per day. The dose of the second infusion beginning on day 8 was escalated from 120 to 160 mg/m(2) per day without observing DLT. No objective responses occurred. Over 70% of patients had a >50% reduction in white blood cell counts. The steady-state levels of Triapine were between 0.6 and 1 microM. As expected from the in vitro studies, at these plasma concentrations there was a decline in dATP and dGTP pools and a decrease in DNA synthetic capacity of the circulating leukemia cells. Based on these clinical, pharmacokinetic, and pharmacodynamic data, Triapine warrants further study in patients with hematologic malignancies.

Phase II study of daily oral perifosine in patients with advanced soft tissue sarcoma

A multicenter Phase II study was performed to evaluate the clinical activity of an initial loading (150 mg every 6 hours × 4 doses) dose followed by continuous daily oral dosing (100 mg/day) of perifosine in patients with advanced soft tissue sarcomas (STSs).

Phase II Study of Oxaliplatin in Platinum-Resistant and Refractory Ovarian Cancer: A Gynecologic Group Study

PURPOSEnA phase II study was conducted to determine the efficacy of oxaliplatin therapy in patients with platinum-resistant or refractory epithelial ovarian carcinoma.nnnMATERIALS AND METHODSnEligible patients were to receive oxaliplatin 130 mg/m2 intravenously over 2 hours, every 21 days, until progression of disease or adverse effects prohibited further therapy.nnnRESULTSnOf 25 patients entered onto the study, 23 were eligible and assessable. There were no patients with complete response. One patient (4.3%) achieved a partial response, with a response duration of 6.4 months. Nine patients (39.1%) experienced stable disease, with a median duration of 5.6+ months (range, 1.8 to 13.1 months). The most frequently reported drug-related toxicities were hematologic, gastrointestinal, and neurologic.nnnCONCLUSIONnOxaliplatin as a single agent has minimal activity in patients with platinum-resistant or refractory ovarian cancer at the dosage and schedule tested. However, future studies of oxaliplatin combined with other active agents in women with platinum-naïve or platinum-sensitive epithelial ovarian carcinoma may be indicated.

Outcomes of High-Dose Chemotherapy and Autologous Stem-Cell Transplantation in Stage IIIB Inflammatory Breast Cancer

PURPOSEnTo evaluate the disease-free survival (DFS) and overall survival (OS), prognostic factors, and treatment-related mortality of women with stage IIIB inflammatory breast cancer (IBC) treated with combined modality therapy (CMT) and high-dose chemotherapy (HDCT) with autologous stem-cell transplantation.nnnPATIENTS AND METHODSnBetween 1989 and 1997, 47 consecutive patients with stage IIIB IBC were treated with CMT and HDCT and were the subject of this retrospective analysis. Chemotherapy was administered to all patients before and/or after definitive surgery. Neoadjuvant and adjuvant chemotherapy was administered to 33 and 34 patients, respectively, and 20 patients received both. All patients received HDCT with autologous stem-cell transplantation, and 41 patients received locoregional radiation therapy. Tamoxifen was prescribed to patients with estrogen receptor (ER)-positive cancer.nnnRESULTSnThe mean duration of follow-up from diagnosis was 30 months (range, 6 to 91 months) and from HDCT was 22 months (range, 0.5 to 82 months). At 30 months, the Kaplan-Meier estimates of DFS and OS from diagnosis were 57.7% and 59.1%, respectively. At 4 years, the Kaplan-Meier estimates of DFS and OS from diagnosis were 51.3% and 51.7%, respectively. In a multivariate analysis, the only factors associated with better survival were favorable response to neoadjuvant chemotherapy (P =.04) and receipt of tamoxifen (P =.06); however, the benefit of tamoxifen was only demonstrated in patients with ER-positive breast cancer. At last follow-up, 28 patients (59. 6%) were alive and disease-free. Seventeen patients (36.2%) developed recurrent breast cancer. Seventeen patients died: 15 from disease recurrence and two (4.2%) from treatment-related mortality due to HDCT.nnnCONCLUSIONnIn this analysis, the early results of treatment with CMT and HDCT compare favorably with other series of patients with stage IIIB IBC treated with CMT alone. These outcomes must be confirmed with longer follow-up and controlled studies.

Phase 1 and pharmacokinetic study of weekly docosahexaenoic acid-paclitaxel, Taxoprexin ® , in resistant solid tumor malignancies

PurposeTo determine the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of weekly docosahexaenoic acid-paclitaxel (DHA-paclitaxel), a taxane fatty acid conjugate.Experimental designDocosahexaenoic acid-paclitaxel was administered by 2-hour i.v. infusion weekly for three out of four weeks. DHA-paclitaxel 200xa0mg/m2 was dose escalated by 100xa0mg/m2 per cohort to 600xa0mg/m2. Blood samples for pharmacokinetics of DHA-paclitaxel and paclitaxel derived from DHA-paclitaxel were collected.ResultsTwenty-one patients received 42 cycles of treatment over five dose levels. Grade 3/4 neutropenia occurred in five patients but was not dose limiting. Grade 3 hyperbilirubinemia, a DLT, and grade 1 sensory neuropathy occurred at the highest dose level. PK analyses demonstrated dose proportional Cmax and AUC0−24. Limited accumulation of DHA-paclitaxel or paclitaxel occurred with weekly treatment. Increased DHA-paclitaxel and paclitaxel AUC0−24 were associated with increased neutropenia. Of the 19 patients evaluable for response, three patients with esophageal, melanoma and colon carcinoma had stable disease for 11, 16, and 17xa0weeks, respectively.ConclusionDocosahexaenoic acid-paclitaxel administered weekly to a maximum dose of 600xa0mg/m2 was well-tolerated. The slow release of paclitaxel from DHA-paclitaxel and the weekly schedule approximates continuous infusion paclitaxel which may be more active than every 3xa0week or weekly taxanes.PURPOSEnTo determine the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of weekly docosahexaenoic acid-paclitaxel (DHA-paclitaxel), a taxane fatty acid conjugate.nnnEXPERIMENTAL DESIGNnDocosahexaenoic acid-paclitaxel was administered by 2-hour i.v. infusion weekly for three out of four weeks. DHA-paclitaxel 200 mg/m(2) was dose escalated by 100 mg/m(2) per cohort to 600 mg/m(2). Blood samples for pharmacokinetics of DHA-paclitaxel and paclitaxel derived from DHA-paclitaxel were collected.nnnRESULTSnTwenty-one patients received 42 cycles of treatment over five dose levels. Grade 3/4 neutropenia occurred in five patients but was not dose limiting. Grade 3 hyperbilirubinemia, a DLT, and grade 1 sensory neuropathy occurred at the highest dose level. PK analyses demonstrated dose proportional C (max) and AUC(0-24). Limited accumulation of DHA-paclitaxel or paclitaxel occurred with weekly treatment. Increased DHA-paclitaxel and paclitaxel AUC(0-24) were associated with increased neutropenia. Of the 19 patients evaluable for response, three patients with esophageal, melanoma and colon carcinoma had stable disease for 11, 16, and 17 weeks, respectively.nnnCONCLUSIONnDocosahexaenoic acid-paclitaxel administered weekly to a maximum dose of 600 mg/m(2) was well-tolerated. The slow release of paclitaxel from DHA-paclitaxel and the weekly schedule approximates continuous infusion paclitaxel which may be more active than every 3 week or weekly taxanes.

Phase II evaluation of oxaliplatin in previously treated squamous cell carcinoma of the cervix: a gynecologic oncology group study

OBJECTIVEnA phase II study was conducted to determine the efficacy of oxaliplatin therapy in patients with previously treated squamous cell carcinoma of the cervix.nnnMETHODSnEligible patients were to have measurable disease and not more than one prior chemotherapy regimen that could include carboplatin or cisplatin but not oxaliplatin. Oxaliplatin 130 mg/m(2) was administered intravenously over 2 h. This treatment was repeated every 21 days until progression of disease or adverse effects prohibited further therapy.nnnRESULTSnTwenty-eight patients were entered onto this study, of whom 24 were evaluable for toxicity and 22 were evaluable for response; 23/24 evaluable patients had had prior platinum. There were two (8.3%) responses. One patient achieved a complete response which lasted 2.2 months, and a second patient attained a partial response which lasted 3.2 months. Nine (37.5%) patients had stable disease with a median duration of 7.6+ (3.1-21.2) months. The most frequently reported drug-related toxicities consisted of anemia, nausea and vomiting, and neurotoxicity. Three (12.5%) patients had a grade 3 allergic response that was infusion-related and was largely resolved by increasing infusion time.nnnCONCLUSIONSnOxaliplatin has limited activity in patients with persistent or recurrent squamous cell carcinoma of the cervix at the dose and schedule tested.

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

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 20–25u2009mgu2009m−2 intravenously over 1u2009h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72u2009h continuous intravenous infusion with PEG-LD beginning at 8u2009mgu2009m−2 and escalated in an accelerated titration design to 25u2009mgu2009m−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 25u2009mgu2009m−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) mlu2009h−1u2009m−2 in cycle 1 to 18 (3–37) mlu2009h−1u2009m−2 with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25u2009mgu2009m−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.

A phase 1, multicenter, open-label study of the safety of two dose levels of a human monoclonal antibody to human αv integrins, intetumumab, in combination with docetaxel and prednisone in patients with castrate-resistant metastatic prostate cancer

SummaryPurpose We evaluated the safety and efficacy of intetumumab in combination with docetaxel in patients with castrate-resistant metastatic prostate cancer. Patients and methods In this phase 1, open-label, multicenter, nonrandomized study, 75xa0mg/m2 docetaxel was administered on Day 1 of each of nine 21-day treatment cycles and intetumumab 5 or 10xa0mg/kg was administered on Days 1, 8, and 15 of Cycles 2 and 3 and on Day 1 of all subsequent cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during Cycles 2 and 3. Secondary endpoints included serum prostate-specific antigen (PSA) response and objective response based on Response Evaluation Criteria in Solid Tumors (RECIST). Results Ten patients were treated (5xa0mg/kg nu2009=u20093, 10xa0mg/kg nu2009=u20097). No DLTs occurred. Most treatment-emergent adverse events (TEAEs) occurred in the 10-mg/kg intetumumab group. Common TEAEs were neutropenia (10xa0mg/kg nu2009=u20096) and nausea (5xa0mg/kg nu2009=u20091, 10xa0mg/kg nu2009=u20095). Four 10-mg/kg-treated patients reported serious TEAEs; of these, only febrile neutropenia was considered probably intetumumab-related. In the 10-mg/kg group, four patients had a serum PSA response (two of whom responded within 3xa0months of treatment), one patient demonstrated partial tumor response for 11xa0weeks, and none had progressive disease at Cycle 9. No PSA or tumor response was observed in the 5-mg/kg group. Conclusions Intetumumab was generally safe and well tolerated in combination with docetaxel, with a higher incidence of TEAEs in the 10xa0mg/kg dose cohort. The efficacy of 10xa0mg/kg intetumumab in combination with docetaxel appears to warrant further study.

Phase I study of pegylated liposomal doxorubicin and gemcitabine in patients with advanced malignancies

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.