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F Muggia

Publications and source records attributed to F Muggia.

At least 19 recordsLinked to original sources
PubMed2006

A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody, in patients with platinum-resistant ovarian and primary peritoneal malignancies.

OBJECTIVE: The primary objective of this study was to determine the rate of response to matuzumab in patients with recurrent, EGFR-positive ovarian, or primary peritoneal cancer. Secondary end points included safety and tolerability, time to tumor progression, duration of response, and overall survival. METHODS: A multi-institutional single arm phase II trial. RESULTS: Of 75 women screened for the study, 37 were enrolled and treated. Median age of the treated patient population was 58 years, and most patients had more than four prior lines of chemotherapy. Therapy was well tolerated, the most common toxicities being a constellation of skin toxicities, including rash, acne, dry skin, and paronychia, as well as headache, fatigue, and diarrhea. Serious adverse events were very rare but included a single episode of pancreatitis that may have been drug related. All patients completed therapy, receiving 1 to 30 infusions of matuzumab. There were no formal responses (RR=0%, 95% CI: 0-9.5%), although 7 patients (21%) were on therapy for more than 3 months with stable disease. CONCLUSIONS: Matuzumab at the dose and schedule selected is well tolerated. In this population of very heavily pretreated patients with epithelial ovarian and primary peritoneal malignancies, there was no evidence of significant clinical activity when matuzumab was administered as monotherapy.

Adult↗
PubMed2006

Proceedings of a GOG workshop on intraperitoneal therapy for ovarian cancer.

Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on intraperitoneal therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone.

BACKGROUND: We previously demonstrated that peak microtubule bundle formation (MBF) in peripheral blood mononuclear cells (PBMCs) occurs at the end of drug infusion and correlates with drug pharmacokinetics (PK). In the current study, a new expanded evaluation of drug target effect was undertaken. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with ixabepilone 40 mg/m2 administered as a 1-h i.v. infusion every 3 weeks. Blood, plasma, and tumor tissue sampling was carried out to characterize pharmacodynamics and PK. RESULTS: Forty-seven patients were treated with 141 cycles of ixabepilone. In both PBMCs (n=27) and tumor cells (n=9), peak MBF occurred at the end of infusion; however, at 24-72 h after drug infusion, the number of cells with MBF was significantly greater in tumor cells, relative to PBMCs. A Hill model (EC50=109.65 ng/ml; r2=0.94) was fitted, which demonstrated a relationship between percentage of PBMCs with MBF and plasma ixabepilone concentration. The percentage of PBMCs with MBF at the end of infusion also correlated with severity of neutropenia (P=0.050). CONCLUSIONS: Plasma ixabepilone concentration and severity of neutropenia correlate with the level of MBF in PBMCs. Therefore, this technically straightforward assay should be considered as a complement to the clinical development of novel microtubule-binding agents.

Adult↗
PubMed2003

Phase I clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose, recommended phase II dose (RPTD) and toxicities of the FOG regimen (infusional 5-fluorouracil, oxaliplatin, gemcitabine). PATIENTS AND METHODS: Patients with advanced solid tumors were treated in an accelerated titration scheme. 5-Fluorouracil was administered intravenously at 200 mg/m(2)/day for 14 days and repeated every 21 days (one cycle). Gemcitabine was administered on days 1 and 8 over 30 min at 450-650 mg/m(2). Oxaliplatin was administered on day 1 over 2 h at 85-130 mg/m(2). For cycles 1, 3 and beyond, gemcitabine followed oxaliplatin; for cycle 2, gemcitabine preceded oxaliplatin. RESULTS: Forty-five and 39 patients were assessable for toxicity and response, respectively. Cycle 1 dose-limiting toxicities (DLT) included neutropenia, thrombocytopenia and diarrhea. No DLT was observed in cycle 1 at the first four dose levels (DL). At DL-5, two of four (50%) patients experienced DLT in cycle 1. Expanding DL-4, nine of 26 (35%) patients experienced DLT in cycle 1. Because recurrent grade 3 toxicities were observed in three of six (50%) patients at DL-3, DL-2 was considered the RPTD. At the RPTD, three patients had a partial response (response rate 23%). CONCLUSIONS: The RPTD for the 5-fluorouracil-oxaliplatin-gemcitabine combination is 200/100/450 mg/m(2). This novel regimen has demonstrated activity in advanced solid tumors and merits further investigation.

Adult↗
PubMed2001

A Phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma.

BACKGROUND: The maximum tolerated dose (MTD) and efficacy of weekly 1-hour paclitaxel with 3 days of high dose oral estramustine were evaluated in patients with hormone-refractory prostate carcinoma. METHODS: Patients enrolled in cohorts of three received two cycles of six weekly treatments with 1 week of rest: Cohort I received paclitaxel 40 mg/m2 and estramustine 600 mg/m2, and Cohorts II-IV received paclitaxel 60 mg/m2, 75 mg/m2, or 90 mg/m2, respectively, and estramustine 900 mg/m2. Toxicity was assessed weekly, and response was measured by serum prostate specific antigen (PSA), abdominal computed tomography scans, and bone scans at Week 13. RESULTS: Eighteen patients were enrolled, with 12 in Cohorts III and IV. Four patients did not complete treatment. Grade 3 toxicity included one patient with nausea and diarrhea in Cohort III and one patient each with neutropenia and edema followed by Grade 4 thromboembolism in Cohort IV. Grade 1-2 anemia or myelotoxicity were not observed; 3 patients had neuropathy, 5 patients had hair loss, and 8 patients had gastrointestinal symptoms. A decline in the serum PSA level > or = 50% occurred in none of three patients, one of three patients, four of six patients, and four of six patients in Cohorts I-IV, respectively. An intent-to-treat analysis showed responses in 9 of 18 patients (50%) in Cohorts I-IV, with 9 of 15 responders (60%) in Cohorts II-IV. Seven patients achieved declines in serum PSA levels > 75%. The median duration of PSA response was 16.7 weeks. Response was observed in one of three patients with measurable disease. CONCLUSIONS: The MTD for 1-hour weekly paclitaxel was 90 mg/m2 with 3 days of 900 mg/m2 estramustine. Hematologic and neurotoxicity were reduced markedly, and gastrointestinal symptoms were ameliorated, but thromboembolic events were unaffected. PSA response rates were within the expected 60% range for these agents.

Administration, Oral↗
PubMed2001

Phase III data on Caelyx in ovarian cancer.

Impressive responses to pegylated liposomal doxorubicin (Doxil/Caelyx) in pretreated ovarian cancer patients during phase I studies led to a phase II study in platinum and taxane failures. A 26% objective response rate was obtained in this trial and this was confirmed by further phase II studies. The stage was set for a phase III trial in comparison with topotecan, the drug that had become standard in the salvage treatment of patients who were platinum-refractory or -resistant. The completed trial indicates equivalence of results in terms of response rates, time to treatment failure and survival. Differences exist in the toxicity spectrum and in subset analysis according to platinum resistance. On this basis, Caelyx is being positioned as part of chemotherapeutic regimens in first-line phase III trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Estramustine potentiates taxane in prostate and refractory breast cancers.

Estramustine is nornitrogen mustard linked to estradiol. It binds to tubulin and to microtubule-associated proteins, depolymerizes cytoplasmic microtubules, and disrupts the nuclear matrix. It has limited clinical activity as a single agent, but preclinical studies suggest that it is an effective modulator of antitubulins. This paper reviews the rationale for the combination of estramustine with antitubulins and the clinical toxicity profile of estramustine. Also discussed are data from phase II studies in hormone-resistant prostate cancer and in taxane-resistant breast cancer that suggest that the modulation of antitubulins by estramustine that has been demonstrated in vitro is indeed clinically relevant. Finally, current approaches to improving the tolerability of estramustine are described.

Breast Neoplasms↗
PubMed2001

Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy.

PURPOSE: Neoadjuvant chemotherapy for breast cancer creates new possibilities for the analysis of biological factors in the tumor and/or host, which may play a role in the response to treatment. In this study we analyzed whether changes in local antitumor immunity take place after neoadjuvant paclitaxel therapy and if they correlate with response to treatment. EXPERIMENTAL DESIGN: Neoadjuvant chemotherapy (paclitaxel, 200 mg/m2 q2w, 4 treatments) was followed by definitive surgical management. Histological sections from the pre- and post-treatment surgical specimens of 25 patients were analyzed for the extent of lymphocytic infiltration and presence of tumor infiltrating lymphocytes (TILs). The cumulative apoptotic response in the tumor after the first dose of paclitaxel was also studied in 10 of 25 patients. RESULTS: Pretreatment lymphocytic infiltrate in the tumor was minimal in the majority of patients and showed no relationship with clinical response. In the patients without TILs before treatment, development of TILs after treatment was noted in 0/3 (0%) patients with stable disease, 3/12 (25%) patients with clinical partial response, and 4/6 (67%) patients with clinical complete response and pathological residual disease. These correlated with the tumor cell apoptotic response to the first dose of paclitaxel. CONCLUSIONS: These results suggest that development of TILs after treatment correlates with clinical response to neoadjuvant paclitaxel therapy. The possible mechanism(s) whereby neoadjuvant chemotherapy may lead to induction of antitumor T cells is discussed. Immunological processes may influence the response of breast cancer patients to neoadjuvant treatment.

Adult↗
PubMed2000

Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2.

BACKGROUND: The indications for pegylated liposomal doxorubicin (doxil) are expanding. We, therefore, wished to assess the safety of delivering doses exceeding 500 mg/m2 of doxil to patients with solid tumors. PATIENTS AND METHODS: Subjects accrued to eight phase I and II protocol studies conducted at two institutions, were assessed for cardiac function at baseline and at specified intervals by MUGA scans. In this retrospective analysis, the findings of 42 patients, from the total of 237 entered, who had reached or exceeded cumulative doses of 500 mg/m2 (range 500-1500 mg/m2) were reviewed. Changes in left ventricular ejection fraction (LVEF), and in clinical cardiac status were analyzed. Six patients, three who had received prior doxorubicin, also underwent endomyocardial biopsies after cumulative doses of 490-1320 mg/m2. RESULTS: None of the 42 patients had clinical congestive heart failure (CHF) secondary to cardiomyopathy. Post doxil MUGA scans were available for 41 of the 42 patients. Five had a drop of 10% or more in LVEF; three of these had received prior doxorubicin. Billingham endomyocardial biopsy scores ranged from 0-1 in five patients, while the sixth had a score of 1.5 after both 900 mg/m2 and 1320 mg/m2 doxil. Of a remaining 195 patients, 1 episode of CHF was recorded in a patient who had received 312 mg/m2 doxil over 120 mg/m2 of mitoxantrone and chest radiation. CONCLUSIONS: Cumulative doses in excess of 500 mg/m2 of doxil appear to carry a considerably lesser risk of cardiomyopathy as judged by serial LVEF's and clinical follow-up, than is generally associated with free doxorubicin. Heart biopsies have provided reassuring data in a small number of patients, even if pretreated with doxorubicin. However, since three doxorubicin pretreated patients were among the five experiencing drops in LVEF, more data are warranted on such patients.

Adult↗
PubMed2000

Intraperitoneal topoisomerase-I inhibitors. Preliminary findings with 9-aminocamptothecin.

The i.p. administration of topoisomerase I (Topo I) inhibitors has a pharmacologic advantage over intravenous application, including preservation of the biologically active lactone form. In our ongoing study, patients have received 9-amino-20(S)-camptothecin (9-AC) i.p. on days 1, 3, 5, 8, 10, and 12, repeated every 4 weeks. The daily dose has been escalated to level IV of 1.5 mg/m2 (9.0 mg/m2 per course), median of 3 cycles, range 1-4, with a reversible Grade 3 neutropenia in one patient. Responses included one CR (resolution of a pleural effusion), two patients without progressive disease (PD), two not evaluable, and two patients too early for evaluation. The area under the curve (AUC)i.p./AUCpl ratio (pharmacologic advantage) ranged from 7.6 to 16.5 on average, and, using nonlinear modeling, the pharmacologic decay data were fit to one- or two-compartmental models. Overall, a 9-AC i.p. application is well tolerated and anticipated to be an active regimen against i.p. malignancies, particularly those known to be sensitive to systemic Topo-I inhibitors.

Animals↗
PubMed2000

Paclitaxel-induced apoptosis and mitotic arrest assessed by serial fine-needle aspiration: implications for early prediction of breast cancer response to neoadjuvant treatment.

The extent of tumor reduction from neoadjuvant chemotherapy for breast cancer correlates with outcome. We investigated whether the initial cellular responses to paclitaxel are related to the extent of tumor reduction. Eleven women with breast cancer received paclitaxel (every 2 weeks for 4 cycles) as neoadjuvant treatment. Serial fine-needle aspirations (FNA; 25-gauge, 1 pass) were obtained before treatment and at 24, 48, 72, and 96 h after the first paclitaxel dose. Microscopic counts of apoptotic and mitotic indices were performed. The change in cancer volume from treatment was determined using radiological measurements with allowance for change in the histopathological amount of cancer. Apoptotic and mitotic responses usually subsided within 4 days. The duration of the initial apoptotic response was different for women with different treatment results. Cumulative apoptotic response for the first 4 days inversely correlated with the proportion of residual cancer after neoadjuvant treatment. FNA is a versatile clinical method to obtain breast cancer cells for therapy response studies. Apoptotic response to the first dose of paclitaxel is almost complete within 4 days, implying that more frequent (weekly) paclitaxel dosing might be beneficial. The apoptotic response to the first dose of paclitaxel appeared to predict the amount of cancer reduction from this treatment. This is a promising start toward the development of an early chemopredictive assay for paclitaxel treatment of breast cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1999

MDR1 gene expression in primary and advanced breast cancer.

P-glycoprotein (Pgp)-associated multidrug resistance (MDR) is related to intrinsic and acquired cross resistance to anthracyclines, vinca alkaloids, and other antineoplastic antibiotics. Expression of MDR1 is widely considered to play an important role in conferring resistance to adjuvant chemotherapy in women with breast tumor cells in women with disseminated disease, although data supporting this view is, at best, conflicting. The expression of MDR1 gene and its gene product, P-glycoprotein, was investigated in primary and advanced breast cancers (both previously untreated and previously treated on specific treatment protocols) to assess the role of P-glycoprotein in determining responsiveness to adjuvant chemotherapy. Expression was assessed by immunohistochemistry, reverse transcription-PCR (RT-PCR), Northern Blot and Western Blot. MDR1 mRNA was detected in 40% of the breast cancers tested by RT-PCR with 40 cycles of PCR amplification. When reducing the PCR amplification cycles to 28, the MDR1 gene expression signal disappeared from breast cancers of the highest expressers; however, known MDR1 positive control normal tissues, such as adrenal, kidney, and liver continued to show an expression product. Western and Northern blots failed to demonstrate the MDR1 gene product, P-glycoprotein, in these breast cancers. In contrast, physiologic levels of P-glycoprotein was clearly detected in normal adrenal, kidney, and liver by these techniques. Immunohistochemistry confirmed that breast carcinoma cells lacked P-glycoprotein expression; however, interstitial mononuclear cells, morphologically consistent with lymphocytes or macrophages did show immunostaining in some of these breast tumors. MDR1 gene expression identified by RT-PCR was not correlated either with response to paclitaxel therapy (29 patients able to be evaluated, p = 0.34, Fisher Exact Test) or overall survival (32 breast cancer patients with clinical follow-up information, p = 0.336, log rank). In conclusion, P-glycoprotein was not expressed in breast carcinoma cells at significant levels, although it was expressed in stomal lymphocytes or macrophages. These results suggest that P-glycoprotein does not play a significant role in multidrug resistance of breast cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

High-dose toremifene as a cisplatin modulator in metastatic non-small cell lung cancer: targeted plasma levels are achievable clinically.

PURPOSE: The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally > or =5 microM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically. METHODS: Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion. RESULTS: In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (+/- 8.6) microM and 9.8 (+/- 4.4) microM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations. CONCLUSIONS: We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

Aged↗
PubMed1998

Taxanes in adjuvant and neoadjuvant therapies for breast cancer.

Paclitaxel (Taxol) is a diterpene originally obtained from the bark of the Pacific Yew Tree, Taxus Brevifolia. Its mechanism of action is unique. It stabilizes microtubule polymerization, thus blocking cells in the G2/M phase of the cell cycle. In breast cancer, initial studies using paclitaxel demonstrated high activity. The first study was reported in 1991 by Holmes et al who gave paclitaxel as a 24-hour infusion at 250 mg/m2 to 25 patients with metastatic breast cancer following only one prior chemotherapy regimen--they achieved a 56% response rate. Since then, numerous studies have confirmed the effectiveness of paclitaxel in patients with metastatic disease. A second taxane, docetaxel (Taxotere), has also demonstrated excellent activity. Clinical research is now focused on integrating the taxanes into combination drug regimens and into neoadjuvant and adjuvant schedules for patients with early stage breast cancer, as well as looking at the biologic determinants of response and resistance to taxanes. This article will review developments in the use of taxanes in the adjuvant and neoadjuvant settings and it will review the information on possible molecular markers that may be useful in predicting tumor responsiveness to taxanes.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Original p53 status predicts for pathological response in locally advanced breast cancer patients treated preoperatively with continuous infusion 5-fluorouracil and radiation therapy.

PURPOSE/OBJECTIVE: 1) To test feasibility of preoperative continuous infusion (c.i.) 5-Fluorouracil (5-FU) and radiation (RT) in locally advanced breast cancer. 2) To study clinical and pathological response rates of 5-FU and radiation. 3) To attempt preliminary correlations between biological probes and pathological response. METHODS AND MATERIALS: Previously untreated, locally advanced breast cancer patients were eligible: only patients who presented with T3/T4 tumors that could not be resected with primary wound closure were eligible, while inflammatory breast cancer patients were excluded. The protocol consisted of preoperative c.i. infusion 5-FU, 200 mg/m2/day with radiotherapy, 50 Gy at 2 Gy fractions to the breast and regional nodes. At mastectomy, pathological findings were classified based on persistence of invasive cancer: pathological complete response (pCR) = no residual invasive cells in the breast and axillary contents; pathological partial response (pPR) = presence of microscopic foci of invasive cells in either the breast or nodal specimens; no pathological response (pNR) = pathological persistence of tumor. For each patient pretreatment breast cancer biopsies were analyzed by immunohistochemistry for nuclear grade, ER/PR hormonal receptors, her2/neu and p53 overexpression. RESULTS: Thirty-five women have completed the protocol and are available for analysis. 5-FU was interrupted during radiation in 10 of 35 patients because of oral mucositis in 8 patients, cellulitis in 1, and patient choice in another. Objective clinical response rate before mastectomy was 71% (25 of 35 patients): 4 CR, 21 PR. However, in all 35 patients tumor response was sufficient to make them resectable with primary wound closure. Accordingly, all patients underwent modified radical mastectomy: primary wound closure was achieved in all patients. At mastectomy there were 7 pCR (20%), 5 pPR (14%) and the remaining 23 patients (66%) had pathological persistence of cancer (pNR). Variables analyzed as potential predictors for pathological response (pPR and pCR) were: initial TNM clinical stage, clinical response, nuclear grade, hormonal receptor status, p53 overexpression, and Her2/neu overexpression in the pretreatment tumor biopsy. Only initial p53 status (lack of overexpression at immunohistochemistry) significantly correlated with achievement of a pathological response to this regimen (p = 0.010). CONCLUSION: The combination of c.i. 5-FU and radiation was well tolerated and generated objective clinical responses in 71% of the patients. With the limitation of the small sample size, the complete pathological response achieved (20%) compares favorably with that reported in other series of neoadjuvant therapy for similar stage breast cancer. These preliminary data suggest that initial p53 status predicts for pathological response (pPR and pCR) to the combination of c.i. 5-FU and radiotherapy in locally advanced breast cancer.

Adult↗