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Despite both the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development during the last 10 years, the number of new treatments that have been approved for patients has not increased as expected. We propose the multi-arm, multi-stage trial design as a way to evaluate treatments faster and more efficiently than current standard trial designs. By using intermediate outcomes and testing a number of new agents (and combinations) simultaneously, the new design requires fewer patients. Three trials using this methodology are presented. [ABSTRACT FROM AUTHOR]

Background: Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2′-methoxyethyl modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA and has been reported to inhibit clusterin expression and enhance drug efficacy in xenograft models. The primary objective of this clinical study was to determine a biologically effective dose of OGX-011 that would inhibit clusterin expression in human cancer. Methods: Subjects (n = 25) with localized prostate cancer with high-risk features who were candidates for prostatectomy were treated with OGX-011 by 2-hour intravenous infusion on days 1, 3, and 5 and then weekly from days 8–29 combined with androgen blockade starting on day 1; prostatectomy was performed on days 30–36. Six different doses were tested, from 40 to 640 mg. OGX-011 plasma and prostate tissue concentrations were measured by an enzyme-linked immunosorbent assay method, and the pharmacokinetics of OGX-011 were determined from these data. Prostate cancer tissue, lymph nodes, and serial samples of peripheral blood mononuclear cells were assessed for clusterin expression using quantitative real-time polymerase chain reaction and immunohistochemistry. All statistical tests were two-sided. Results: Only grade 1 and 2 toxicities were observed. The plasma half-life of OGX-011 was approximately 2–3 hours, and the area under the concentration versus time curve and CMAX (peak plasma concentration) increased proportionally with dose (Ptrend«.001). OGX-011 in prostate tissue increased with dose (Ptrend«.001). Dose-dependent decreases in prostate cancer and lymph node clusterin expression were observed by polymerase chain reaction of greater than 90% (Ptrend = .008 and Ptrend«.001, respectively) and by immunohistochemistry (Ptrend«.001 and Ptrend = .01, respectively). Conclusions: OGX-011 is well tolerated and reduces clusterin expression in primary prostate tumors. The optimal biologic dose for OGX-011 at the schedule used is 640 mg. [ABSTRACT FROM AUTHOR]

Background: New targeted, non-cytotoxic anticancer agents, such as small-molecule kinase inhibitors, pose challenges to the current phase I paradigm of dose selection based on toxicity. Moreover, increasing the drug dose to toxicity may be unnecessary for drug effect, making the use of maximum tolerated dose as a surrogate of effective dose inappropriate in the phase I setting. Because little is known about the optimal methods of recommended phase II dose selection of targeted, non-cytotoxic therapies, we reviewed the strategies that were used in completed phase I studies of these drugs. Methods: We retrieved 60 publications of phase I studies involving 31 single agents representative of the most common targets of interest in the oncology literature. For each publication, we abstracted data regarding patient population, starting dose, methods of dose escalation and determination of recommended phase II dose, and inclusion of correlative studies in study conduct. Results: Of the 60 completed phase I studies, 36 used toxicity and eight used pharmacokinetics data as endpoints for selection of the recommended phase II dose. Nontraditional endpoints, such as measures of molecular drug effects in tumor or surrogate tissue or functional imaging studies, were not routinely incorporated into the study design and rarely formed the primary basis for dose selection. Conclusions: To date, phase I studies of targeted anticancer agents have generally used traditional endpoints for selection of the recommended phase II dose. More research is needed to define suitable molecular measures of drug effect and the means to incorporate them in the early drug development process. [ABSTRACT FROM AUTHOR]

Summarizes the issues discussed at the workshop 10th National Cancer Institute-European Organization for Research and Treatment of Cancer Symposium on New Drugs in Cancer Therapy held in the United States. Preclinical assessment; Phase I trial design of an anticancer drug; Lessons from nononcology drugs.

Background: Tumor shrinkage is a common end point used in screening new cytotoxic agents. The standard World Health Organization criterion for partial response is a 50% or more decrease in the sum of the products of two measurements (the maximum diameter of a tumor and the largest diameter perpendicular to this maximum diameter) of individual tumors. However, theoretically, the simple sum of the maximum diameters of individual tumors is more linearly related to cell kill than is the sum of the bidimensional products. It has been hypothesized that the calculation of bidimensional products is unnecessary, and a 30% decrease in the sum of maximum diameters of individual tumors (assuming spherical shape and equivalence to a 50% reduction in the sum of the bidimensional products) was proposed as a new criterion. We have applied the standard response and the new response criteria to the same data to determine whether the same number of responses in the same patients would result.Methods: Data from 569 patients included in eight studies of a variety of cancers were reanalyzed. The two response criteria were separately applied, and the results were compared using the kappa statistic. The importance of confirmatory measurements and the frequency of nonspherical tumors were also examined. In addition, for a subset of 128 patients, a unidimensional criterion for disease progression (30% increase in the sum of maximum diameters) was applied and compared with the standard definition of a 25% increase in the sum of the bidimensional products.Results: Agreement between the unidimensional and bidimensional criteria was generally found to be good. The kappa statistic for concordance for overall response was 0.95.Conclusion: We conclude that one dimensional measurement of tumor maximum diameter may be sufficient to assess change in solid tumors. [ABSTRACT FROM AUTHOR]

In four phase II trials of trimetrexate given iv daily for 5 days, we noted marked variability among patients in the development of severe or life-threatening toxic effects. In an effort to define which of 15 patients characteristics were associated with toxic effects of this degree, we have carried out single-factor and multifactor analyses on toxic effects during the first cycle of therapy in 68 patients. The final logistic regression model identified both low pretreatment serum protein levels and metastatic liver disease as significant correlates of severe toxic effects (P=.02 and P=.0005, respectively). While drug does was an important element of the best logistic model, its statistical significance was only borderline. Trimetrexate is extensively protein bound and is cleared primarily by hepatic metabolism, so it is not unreasonable to believe that alteration in protein binding of the drug or in metabolic capacity of the liver could produce enhanced toxic effects. Although the validity of these predictors should be confirmed, it seems prudent to recommend lower starting doses of trimetrexate for patients with metastatic liver disease and/or low protein levels and dose escalation if toxic effects allow it. [J Natl Cancer Inst 1988; 80: 1318–1322] [ABSTRACT FROM PUBLISHER]

Thirty-one patients with hairy-cell leukemia were treated with 2'-deoxycoformycin (DCF) in a National Cancer Institute of Canada multicenter trial. The DCF was administered in a cycle (4mg/miv weekly × 3), which was repeated every 8 weeks. Following a Complete remission, consolidation was done with two further cycles of DCF. Of 28 patients evaluable for response, 25 obtained a complete remission; 3 had a partial response. To date there has been only one relapse; the median time with no thereapy was 429.5 days (range 99–743days). Toxicity was moderate and included nausea and vomiting, lethargy, and skin rash; with the first cycle of treatment, neutropenia and an increased incidence of fever or infection were also observed. We conclude that low-dose DCF is highly effective in treating hairy-cell leukemia. [J Natl Cancer Inst 1988;80:765–769] [ABSTRACT FROM PUBLISHER]

Recombinant human granulocyte-mac-rophage colony-stimulating factor (rHuGM-CSF) may reduce myelosup-pression and, thus, allow dose escalation of certain chemotherapeutic agents. We conducted two sequential phase I trials of escalating doses of carboplatin and a Fixed dose and schedule of rHuGM-CSF in ovarian cancer patients who had not previously had chemotherapy, i.e., chemotherapy-naive patients. In the First trial, patients were assigned to regimens of increasing dose levels of carboplatin (starting at 400 mg/m) and fixed doses and schedules of cyclophosphamide (600 mg/m) and rHuGM-CSF (10 μg/kg given sub-cutaneously once daily on days 2–11). Chemotherapy was given every 3 weeks (regimen A). In the subsequent trial, the design was the same except that cyclophosphamide was omitted (regimen B). Fifteen patients received regimen A, and seven patients received regimen B. In regimen A, all three patients treated at the First dose level tolerated Five cycles at full doses. Hematologic toxicity was dose limiting at the 600-mg/m dose level. When 500 mg/m carboplatin was given, six of eight patients tolerated three or four cycles at full doses before requiring dose reductions or treatment delays. In regimen B, doses could not be escalated above the First dose level (600 mg/m) because of severe hematological toxicity. Nonhematological toxicity was tolerable and managed with acetaminophen, antihistamines, and/or non-steroidal, anti-inflammatory medication. Compliance was excellent. We conclude that (a) rHuGM-CSF can be given safely and reliably to chemotherapy-naive ovarian cancer patients receiving these treatment regimens, early and severe thrombocytopenia was a major problem with or without cyclophosphamide with doses of carboplatin at or above 600 mg/m, and (c) 500 mg/m carboplatin administered every 3 weeks is the highest dose in regimen A that can be given safely in the outpatient setting. [J Natl Cancer Inst 83:1748–1753,1991] [ABSTRACT FROM PUBLISHER]