Samira Syed

A Phase I and Pharmacokinetic Study of Col-3 (Metastat), an Oral Tetracycline Derivative with Potent Matrix Metalloproteinase and Antitumor Properties

Purpose: The purpose of this research was to assess the feasibility of administering Col-3, an oral chemically modified tetracycline derivative with potent inhibitory effects on matrix metalloproteinase activity and production, and recommend a dose on an uninterrupted once-daily schedule. The study also sought to characterize the pharmacokinetic behavior of Col-3 and seek evidence of anticancer activity. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of Col-3 with dose level assignment according to an accelerated titration scheme. Because photosensitivity skin reactions were being reported in concurrent trials of Col-3, patients were instructed to apply sunscreen rigorously throughout the trial. The maximum tolerated dose was defined as the highest dose at which <2 of the first 6 new patients experienced dose-limiting toxicity. The pharmacokinetic behavior of Col-3 was characterized, and pharmacodynamic relationships were sought. Results: Thirty-three patients were treated with 73 courses of Col-3 at four dose levels ranging from 36 to 98 mg/m2/day. Unacceptably high incidences of photosensitivity skin reactions and malaise were noted in the first 28-day courses of patients treated with Col-3 at doses exceeding 50 mg/m2/day. At 50 mg/m2/day, severe toxicity occurred in 2 of 12 new patients in first courses, and no additional dose-limiting toxicities were observed in subsequent courses. Other mild to modest adverse effects included nausea, vomiting, liver function tests abnormalities, diarrhea, mucositis, leukopenia, and thrombocytopenia. The pharmacokinetics of Col-3 were dose proportional, and mean trough concentrations at steady state were similar to biologically relevant concentrations in preclinical studies. Major responses did not occur, but durable disease stability was noted in 3 patients, one each with carcinosarcoma of the uterus, pancreas, and ovary, all of whom had experienced disease progression before Col-3 treatment. Conclusions: The recommended dose for Phase II studies of Col-3 administered once daily on an uninterrupted schedule is 50 mg/m2/day accompanied by efforts that promote adherence to the use of sunscreen and other photoprotective measures. Pharmacokinetic results indicate that plasma concentrations above biologically relevant concentrations are readily maintained at this dose, and additional disease-directed studies, particularly in patients with soft tissue sarcoma, should be considered.

Phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of AP23573, an mTOR Inhibitor, administered IV daily X 5 every other week in patients (pts) with refractory or advanced malignancies

3076 Background: AP23573, a non-prodrug rapamycin analog, potently inhibits mTOR, a downstream effector of the PI3K/Akt and nutrient signaling pathways. AP23573 demonstrated potent inhibition of proliferation in vitroin several human tumor cell lines and elicited antitumor activity in vivo in multiple xenograft animal models. METHODS This dose escalation trial utilizes an accelerated titration scheme to determine safety, tolerability and maximum tolerated dose of AP23573 administered without premedication as 30-minute IV infusion daily x 5 days every 2 weeks for 4-week cycles. It also is designed to characterize the PK profile, evaluate potential PD markers using western blot analysis of peripheral blood mononuclear cells (PBMCs) and immunohistochemical analysis of skin biopsies, and ascertain preliminary data on antitumor activity. RESULTS As of 01 Dec 03: 11 pts (6M/5F), median age 57 yrs (range 23-65 yrs), were treated with AP23573 doses ranging from 3 to 28 mg in 5 dose level cohorts (total cycles, 32; median cycles, 2/pt). No dose-limiting toxicity or AP23573-related serious adverse events have been observed. Side effects for first cycle included grade (gr) 2 anemia (2 pts); gr 3 transient transaminase elevation (1 pt with hepatocellular cancer); gr 2 mucositis (2 pts); gr 1 skin rash (2 pts). PK analyses (doses 3 to 12.5 mg) suggest a mean AP23573 half-life of 44-54 hours. PD analyses (doses 3 and 6.25 mg) indicate rapid (within 1 hr) and prolonged (up to 10 days between doses) inhibition of mTOR activity as demonstrated by >80% decrease in phosphorylated 4EBP1 levels in PBMCs. Of 8 evaluable pts, one partial response has been observed in a pt with metastatic renal cell cancer; (6.25 mg) and 1 pt with metastatic sarcoma (3 mg) has had stable disease > 6 months. CONCLUSIONS AP23573 can be administered safely using this schedule, and has exhibited antitumor activity as well as evidence of a substantial PD effect. Patient dosing and enrollment are ongoing. Further dose escalation as well as exploration of the relationship between PD (PBMC and skin) and PK are planned. [Table: see text].

Phase I and Pharmacokinetic Study of Tasidotin Hydrochloride (ILX651), a Third-Generation Dolastatin-15 Analogue, Administered Weekly for 3 Weeks Every 28 Days in Patients with Advanced Solid Tumors

Purpose: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. Experimental Design: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. Results: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non–small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months. Conclusions: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.

Current issues in the management of advanced squamous cell carcinoma of the penis.

Effective treatment of penile carcinoma incorporates three modalities: surgery, radiation and chemotherapy. Surgery alone may offer a high cure rate in early stages of the disease. In certain patients radiation therapy may be utilized to eradicate the tumor and allow organ preservation. For patients with locally advanced disease, multi-modality approaches incorporating adjuvant or neoadjuvant chemotherapy and radiation therapy need to be studied. This approach may confer a survival benefit to a group that would otherwise have a poor prognosis. Finally, in the setting of metastatic disease, less toxic and more effective combination chemotherapy are sought. Novel targeted therapies that have been successful in squamous cell carcinoma at other sites must also be studied in this disease. We believe that multi-institutional trials should be designed in order to obtain prospective benchmark data from which to make valid comparisons of outcome.

Delayed hemolytic transfusion reaction in sickle cell disease

ABSTRACT: This article reports the details of delayed hemolytic transfusion reactions in four patients with sickle cell disease. These cases demonstrate the characteristics of the reactions, the significant risks involved, and the principles useful in diagnosis and treatment. Patients with sickle cell disease are at particular risk for delayed hemolytic transfusion reactions because they may be transfused at intervals over many years; they frequently form alloantibodies because of antigenic differences from the donor population; and they may receive emergency care in different hospitals where transfusion records are not available. In addition, exchange transfusions, which are often used for patients with sickle cell disease and which were given in three of these cases, raise the risks through increased exposure to foreign erythrocyte antigens and through an increased volume of erythrocytes susceptible to hemolysis. It was concluded that the hazards of these transfusion reactions justify preventive measures, such as extended erythrocyte phenotyping of patients with sickle cell disease and extended phenotypic matching of transfused cells.

Phase I, Pharmacokinetic and Biological Correlative Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor, and Cisplatin in Patients with Solid Tumors

Purpose: To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors. Experimental Design: CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored: 60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated. Results: Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity. Conclusions: The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.

Management of high-risk localized prostate cancer: the integration of local and systemic therapy approaches

Using a combination of PSA, Gleason score, and clinical stage, it is possible to identify a group of patients with prostate cancer who have a high risk of relapse following initial treatment (e.g., radiotherapy or radical prostatectomy). For these patients, multi-modal therapy may result in improved outcomes. We reviewed published literature to identify methods to identify high-risk patients as well as options for adjuvant or neoadjuvant therapy to reduce risk of disease recurrence. At the present time, the most promising adjuvant therapy is hormonal therapy following radiotherapy for locally advanced disease (T3-T4, or N1). In phase III trials in these patients, survival is improved. For all other applications, including adjuvant and neoadjuvant hormonal therapy, chemotherapy, or radiotherapy, the benefits are unclear. Perhaps most promising at this time, and the subject of a current phase III trial, is the utility of adjuvant chemotherapy in high-risk patients. It will be through the conduct of phase III trials that the benefits of multi-modal therapy will be evaluated. Patients with high-risk prostate cancer undergoing radiotherapy or surgery should be offered participation in these clinical trials.

Management of locally advanced bladder cancer: early vs deferred chemotherapy

Abstract. Locally advanced bladder cancer is associated with a high risk of local recurrence and distant metastases. Clinical and pathologic variables have been useful in predicting outcome in patients with muscle-invasive bladder cancer. Recently, a number of molecular prognostic markers have been identified that help predict tumor aggressiveness, response to chemotherapy, and survival. Transitional cell carcinoma is a chemosensitive tumor. The early use of chemotherapy to reduce the risk of recurrence and improve survival has been the focus of many randomized clinical trials. Unfortunately, the majority of studies have failed to show a survival advantage for chemotherapy-treated patients. Well-designed prospective trials that target high-risk patients, defined by clinical, pathological, and molecular features, and incorporate new more tolerable chemotherapeutic agents are needed to clarify the benefit of early chemotherapy.

Novel Therapies for Renal Cell Carcinoma

The treatment of advanced renal cell carcinoma presents a daunting challenge to medical, surgical and radiation oncologists. Although patients with localized renal cell carcinoma can be effectively treated by surgery with a 5 year survival of up to 88%, the treatment options are limited for patients with advanced disease with the 5 year survival rate under 10%.1’2Furthermore, systemic chemotherapeutic agents have had little impact on the natural history of this disease. A comprehensive review by Yagodaet at 3 encompassed 4542 patients enrolled in 83 clinical trials published from 1983 through 1993. Among the 4093 evaluable patients, a 6% overall response rate was determined which was comprised of 53 (1.3%) complete responses and 192 (4.7%) partial responses. This dismal level of antitumor activity is comparable to the reported rate of spontaneous objective responses observed for placebo treated patients entered in a randomized study.4

Adjuvant Therapy in Prostate Cancer: Patient Identification and Treatment Options

The recent downward shift in disease stage and patient age at diagnosis has led to an emphasis on definitive local therapy in patients with prostate cancer. However, patients with adverse prognostic factors (non-organ-confined disease, high prostate-specific antigen level, high Gleason score) have a significant risk of treatment failure. With our increasing ability to predict patients at high risk of failure, more patients are likely to receive adjuvant therapy. Adjuvant hormonal therapy extends overall survival after radiotherapy for locally advanced disease, while after surgery improved survival has been demonstrated in patients with node-positive disease. More recently, adjuvant chemotherapy has been investigated.