Daniel Hoth

Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework*

genome are dramatically reshaping the research and development pathways for drugs, vaccines, and diagnostics. The growth in the number of molecular entities entering the drug development pipeline has accelerated as a consequence of powerful discovery and screening technologies such as combinatorial chemistry, mass spectrometry, high throughput screening, celland tissue-based DNA microarrays, and proteomic approaches.1 As a consequence, there is an escalating number of therapeutic candidates, which has caused the need for new technologies and strategies to streamline the process to make safe and effective therapies available to patients. One approach to the achievement of more expeditious and informative therapeutic research is the use of precise clinical measurement tools to determine disease progression and the effects of interventions (drugs, surgery, and vaccines). For example, gene-based approaches such as single nucleotide polymorphism maps are now being developed to distinguish the molecular and cellular basis for variations in clinical response to therapy.2 Another approach is the use of a wide array of analytical tools to assess biological parameters, which are referred to as biomarkers. Biomarker measurements can help explain empirical results of clinical trials by relating the effects of interventions on molecular and cellular pathways to clinical responses. In doing so, biomarkers provide an avenue for researchers to gain a mechanistic understanding of the differences in clinical response that may be influenced by uncontrolled variables (for example, drug metabolism). There are a variety of ways that biomarker measurements can aid in the development and evaluation of COMMENTARY

Pharmacokinetics and protein binding of cis-dichlorodiammine platinum (II) administered as a one hour or as a twenty hour infusion

SummaryThe pharmacokinetics of cis-dichlorodiamminoplatinum (II) (cisplatin) have been studied in seven patients, of whom four received the drug as a one hour infusion and three received it as a 20 h infusion. The patients receiving the drug over one hour exhibited biphasic clearance of total platinum with a rapid initial phase (8.7–22.5 min) and a prolonged second phase (30.5–106 h). Free (ultrafilterable) cisplatin was readily detectable in this group and was rapidly cleared (half-life about 22 min). The volume of distribution of the drug was 50.3–65.6 liters and it was 26.6–50% excreted in the urine in 48h. In the patients receiving the 20 h infusion, a more complex plasma elimination curve was seen, with the appearance of a secondary peak. Free drug was not detectable in these patients and they showed less urinary excretion (21.4–25.9% at 48 h) than the one hour group. Cisplatin was bound to several plasma proteins, including albumin, transferrin, and γ-globulin. The data indicate that cisplatin is retained in the body more extensively after a 20 h infusion than after a one hour infusion.

5-fluorouracil, adriamycin, and mitomycin-c (fam) combination chemotherapy in the treatment of advanced gastric cancer

Thirty‐six patients with advanced measurable gastric cancer were treated with a new combination chemotherapy program consisting of 5‐fluorouracil, Adriamycin and mitomycin‐C (FAM). Fifty percent of patients achieved an objective partial response. The median duration of remission was 9.5 months and the median survival for responding patients was 13.5 months, with 2 remaining alive at 14 and 26 months. The median survival for nonresponding patients was 3.0 months and all were dead by 6 months after initiation of therapy. The median survival of all 36 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, and produced only moderate bone marrow suppression. These results demonstrate that some patients with advanced gastric cancer can be effectively palliated with FAM chemotherapy. Phase III trials are warranted to assess the effect of the FAM regimen on the survival of patients with advanced gastric cancer.

Phase I studies on chlorozotocin.

A phase I investigation of chlorozotocin, a new‐water soluble chloroethylnitrosourea, was undertaken to define its pharmacologic effects in man. Forty‐three patients received single intravenous doses ranging from 5 to 175 mg/m2 every 6 wk. No signs of toxicity were observed at doses of under 120 mg/m2, but thrombocytopenia occurred at higher doses. The thrombocytopenic nadir appeared to be dose‐dependent and occurred 4 wk after treatment. Platelet transfusions were required in 2 patients who had previously received intensive chemotherapy. No significant leukopenia occurred. A mild reversible and delayed elevation of hepatic transaminases was found in 25% of courses of 120 mg/m2 or more. No renal toxicity was observed and gastrointestinal toxicity was mild. Investigation of clinical pharmacology revealed a rapid triphasic plasma clearance with initial t½s of 3, 15, and 30 min. The concentration of N‐nitroso intact drug at 1 hr was 10% of the initial peak level. Renal excretion accounted for half of the dose. No significant concentration of N‐nitroso intact or radiolabeled drug was detected in the cerebrospinal fluid of 2 patients in whom it was examined. There were objective signs of therapeutic activity in 5 patients, 3 of whom had melanoma. Based on these studies, the recommended dose for phase II investigation of chlorozotocin is 120 mg/m2 every 6 wk.

A phase II study of chlorozotocin in metastatic malignant melanoma

Thirty‐five patients with metastatic malignant melanoma underwent treatment with chlorozotocin administered as a single dose of 120 mg/m2 by means of rapid intravenous infusion every six weeks. There were 1 complete and 4 partial remissions with an overall response rate of 14%. The median duration of response was 18 weeks; the patient in complete remission continues disease‐free in excess of 42 weeks. The sites of response included: lung, 2; subcutaneous, 2; and lymph node, 1. There was minimal myelotoxicity: for the first cycle, the median white blood cell count nadir was 5400/mm3, and the platelet nadir was 210,000/mm3. No evidence of cumulative platelet toxicity was observed. Chlorozotocin is active against metastatic melanoma to the same degree as other chloroethylnitrosoureas in clinical use, but without causing bone marrow toxicity. These data suggest that chlorozotocin should be evaluated in combination with other agents active against melanoma.

Mitomycin C: Experience in the United States, with emphasis on gastric cancer

Mitomycin C is an antibiotic alkylating agent isolated from the fermentation of Streptomyces caespitosus in 1958. Clinical trials were initiated in Japan soon after the demonstration of antitumor activity against a broad spectrum of transplanted animal tumors [2]. Mitomycin C was reported to have a high degree of efficacy for human cancer, which prompted a cooperative multiinstitution evaluation of this agent in the United States. A preliminary summary of the results of the initial experience was reported in 1959 by Jones [11]. Of 120 patients treated, objective responses were observed in 21 (18.5%) including breast cancer, Hodgkins disease, lymphocytic lymphoma, and chronic granulocytic leukemia. Treatment was discontinued in 87% of patients because of severe hematologic toxicity. It was concluded that mitomycin C had an extremely narrow therapeutic index, while demonstrating only limited efficacy. The result was a sharply reduced interest for mitomycin C as an anticancer agent in the United States. Because of the variance in results from Japanese and American investigators, Frank and Osterberg in 1960 undertook an analysis of 14 clinical trials conducted in Japan [7]. A total of 351 individual case records were reviewed using the following criteria as evidence of an objective response: reduction in tumor size, decreased pleural or ascitic fluid, marked reduction in jaundice, or a significant improvement in peripheral blood or bonemarrow findings in patients with leukemia. The overall tumor response was found to be 37%. Responses were recorded in gastric cancer (35%), breast cancer (42%), and lung cancer (37%). In addition, higher levels of activity were recorded in a smaller number of patients with chronic myelogenous leukemia, reticulum cell sarcoma, and seminoma. It was found that both toxicity and antitumor effect were a function of the total dose administered. Hematologic toxicity was an accompaniment of tumor response in 68% of cases and was severe in cases

The FAM Regimen for Gastric Cancer: A Progress Report

The FAM regimen for upper gastrointestinal cancer was developed during 1974. It incorporated three anticancer drugs which had demonstrated independent activity against gastric cancer: 5-fluorouracil, adriamycin [2], and mitomycin-C [3]. In an attempt to insure adequate patient tolerance and allow for chronic administration, an intermittent schedule was designed (Table 1). In particular, mitomycin-C was to be administered only once every 2 months because of its then appreciated delayed and cumulative bone marrow toxicity. We have recently reported the criteria for entry into this study, including the strict requirement for followable disease criteria for patient response, as well as the initial response rates and survival curves [1]. This progress report describes the updated results in the treatment of 62 patients with advanced and measurable gastric cancer.

Preclinical and clinical studies on chlorozotocin, a new nitrosourea with decreased bone marrow toxicity.

Chlorozotocin is a glucose-substituted chloroethyl nitrosourea with pharmacologic properties suggesting it is a relatively nonmyelosuppressive cancer chemotherapy drug. Preclinical studies have shown that this drug possesses approximately twice the in vitro alkylating activity of the chloroethyl nitrosoureas BCNU and CCNU. In the L1210 leukemia system, chlorozotocin has curative activity at doses that result in minimal bone marrow toxicity. In vitro studies of human bond marrow stem cells have shown that chlorozotocin is relatively sparing of these cells compared to BCNU. Phase I and phase II trials in man have been performed that show that chlorozotocins dose-limiting toxicity is thrombocytopenia at doses greater than 120 mg/m2. In the phase II trial, 16% of patients with colon cancer and 20% of patients with malignant melanoma evidenced objective regression of disease. Chlorozotocin is now undergoing phase II evaluation in combination chemotherapy trials in colon and stomach cancer.