Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study.

Purpose: To determine if variability in toxicity of amonafide during phase II trials could be correlated with pharmacokinetic variability.

Patients And Methods: Seventy-three patients enrolled onto three Cancer and Leukemia Group B (CALGB) phase II trials of amonafide (300 mg/m2 daily for 5 days) were studied, using a limited sampling strategy (45 minutes and 24 hours) to estimate the amonafide area under the plasma concentration-time curve (AUC). Concentrations of N-acetyl-amonafide, an active metabolite, were also determined.

A population model for the leukopenic effect of etoposide.

We present a new model-dependent approach to quantify hematologic toxicity in a patient population after anticancer therapy. The population model consists of three submodels that are simultaneously fit to the data: (1) a cubic spline function describing the average response of the population versus time ("structural model"), (2) a covariate model, which relates parameters of the structural model to measured demographic or therapeutic variables that are found to be of predictive value (in this study: white blood cell (WBC) count baseline, drug concentration, serum albumin, and serum bilirubin concentration), and (3) a variance model, which estimates the contribution to the response from random variability between patients and from variability within patients, both between courses and within courses, between days. To demonstrate the approach, previously reported data from 118 courses of etoposide therapy in 71 patients with cancer were used to model the decrease in WBC count after 3-day continuous infusions of drug.

Encephalopathy is the dose-limiting toxicity of intravenous hepsulfam: results of a phase I trial in patients with advanced hematological malignancies.

Hepsulfam is a bisulfamic ester which is similar in structure to busulfan and is believed to act as a bifunctional alkylator inducing both DNA-DNA and DNA-protein crosslinks. Prior studies in patients with refractory solid tumors have identified the dose-limiting toxicity of hepsulfam to be cumulative myelosuppression resulting in prolonged leukopenia and thrombocytopenia. This phase I trial was designed to determine the maximally tolerated dose of hepsulfam administered intravenously in patients with refractory leukemias and other advanced hematologic malignancies.

Physician-determined patient risk of toxic effects: impact on enrollment and decision making in phase I cancer trials.

Background: The conventional phase I trial design yields an estimate of the maximum tolerated dose (MTD) of a new drug defined from treatment toxic effects observed in a small heterogeneous cohort of patients. The MTD is specific for those patients treated in the study and may not be reproducible in another patient series, a limitation known as cohort dependency.

Purpose: We conducted an opinion survey of phase I investigators in an attempt to characterize physician attitudes and clinical practices regarding assessment of risk of toxic effects in patients.

Prognostic factors for survival in patients treated in phase I clinical trials.

Background: Patients with advanced or metastatic cancer treated in Phase I clinical trials are considered to have a poor prognosis. Survival from first treatment in a Phase I trial was determined for 349 patients. Univariate and multivariate survival analyses were performed to determine whether potential prognostic factors and distinct risk groups could be identified.

Bootstrap validation of pharmacodynamic models defined via stepwise linear regression.

When a pharmacodynamic model is to be considered as the basis for individualized drug dosing, validation of the model is clearly warranted. Rigorous validation is problematic when the training data set to be modeled has too few data points and no independent test data set exists. A simulation method known as the bootstrap lends itself particularly well to this dilemma.

Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea.

Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptotheci n (CPT-11) is hydrolyzed by the enzyme carboxyl esterase to 7-ethyl-10-hydroxycamptothecin (SN-38), which further undergoes glucuronic acid conjugation to form the corresponding SN-38 glucuronide (SN-38G). SN-38 is believed to be the cause of treatment-related diarrhea, a dose-limiting toxicity of CPT-11 observed in phase I clinical trials. This study investigated the effect of glucuronidation on the concentrations of SN-38 following CPT-11 infusion in 21 patients undergoing a phase I trial.

Phase I trial of a genetically engineered interleukin-2 fusion toxin (DAB486IL-2) as a 6 hour intravenous infusion in patients with hematologic malignancies.

DAB486IL-2 is a recombinant fusion toxin, created by replacement of the receptor binding domain sequences of the diphtheria toxin gene with the sequences for human interleukin-2 (IL-2). It selectively binds to and intoxicates cells expressing the high-affinity IL-2 receptor. A total of 17 patients with refractory hematologic malignancies were entered in a phase I study of DAB486IL-2, administered as a 6 hour continuous intravenous infusion on days 1, 2, 8, 9, 15, and 16 of each 28 day cycle.

A phase I study of intermittent infusion cladribine in patients with solid tumors.

Background: Cladribine (2-CdA, 2-chlorodeoxyadenosine), a chlorinated adenosine analog, is active in the treatment of hairy cell leukemia and other hematologic malignancies, but its use in treating solid tumors is still under investigation, as is the optimal schedule for administering this drug. The authors conducted a dose-finding study to define the maximal tolerated dose and toxicities of this agent when given to patients with refractory solid tumors having normal renal, hepatic, and bone marrow function.

Methods: Cladribine was given as a 1-hour intermittent infusion, repeated daily for 5 days, with a cycle length of 28 days.

Phase I study of adozelesin administered by 24-hour continuous intravenous infusion.

Background: Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations.

Purpose: We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase II testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed.

Phase-I trial of Thiotepa, granulocyte-macrophage colony-stimulating factor and prednisone or pentoxifylline in patients with refractory solid tumors.

In a phase I trial, 13 patients with refractory solid tumors received thiotepa, granulocyte-macrophage colony-stimulating factor (GM-CSF), and either prednisone or pentoxifylline (PTX) on alternate cycles. The prednisone and PTX were administered in an attempt to ameliorate toxicity related to GM-CSF. Of the first six patients treated at a thiotepa dose of 60 mg/m(2), five experienced grade 3 or 4 thrombocytopenia and four grade 2 or greater leukopenia.

Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456).

Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent that appears to form DNA adducts via the reactive pyrazine diazonium ion and produces substantial antitumor activity in preclinical models. We conducted a phase I trial to determine the maximally tolerated dose of PZDH that could be administered as a 5-min i.v.

Pharmacodynamics and long-term toxicity of etoposide.

Etoposide has been used in the treatment of a wide variety of neoplasms, including small-cell lung cancer, Kaposi's sarcoma, testicular cancer, acute leukemia, and lymphoma. Its current therapeutic use is limited by myelosuppression, particularly neutropenia. Pharmacodynamic studies of etoposide show that this toxicity can be modeled using a modified Hill equation and that the dose intensity of etoposide can be successfully increased by adaptive control using this model.

Sequential therapy with dacarbazine and carmustine: a phase I study.

Depletion of the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (AGT) increases the sensitivity of cells in culture and of human tumor xenografts to chloroethylnitrosoureas such as carmustine (BCNU). We have previously demonstrated that dacarbazine (DTIC) can deplete AGT activity in cells in culture and in human tumor xenografts. A phase I trial of DTIC followed immediately by BCNU was conducted to determine the DTIC dose resulting in maximal depletion of AGT in the peripheral blood mononuclear cells (PBMC) of cancer patients and to determine the maximally tolerated dose of DTIC given as a 4-h infusion immediately prior to a fixed dose of BCNU.

Interferon treatment for hairy cell leukemia. An update on a cohort of 69 patients treated from 1983 to 1986.

We report follow-up information on 69 hairy cell leukemia (HCL) patients treated with interferon alfa-2b (IFN) as primary treatment from 1983 to 1986. Follow-up through April, 1993 shows that only 14 patients have expired. Forty-seven of the 61 patients completing the intended 12 or more months of initial IFN treatment were eventually considered IFN failures.

Modulation of vinblastine resistance with cyclosporine: a phase I study.

Objective: Tumor cell resistance is a major cause of failure to cure advanced malignancies. Multidrug resistance is thought to be an important mechanism of such resistance. Our aims were to identify doses of cyclosporine that would achieve blood levels effective in modulating multidrug resistance to vinblastine and to evaluate the toxicities and maximum tolerated dose of cyclosporine when administered in conjunction with vinblastine.

Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.

Background: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression.

5-Fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: a clinical and pharmacologic analysis.

Background: Iododeoxyuridine (IUdR) is a known radiation enhancer, and interacts biochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU).

Patients And Methods: IUdR was added to the previously studied regimen of continuous infusion 5-FU at 300 mg/m2/day for 5 days, HU 500 mg every 12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days, all administered for 7 consecutive weeks to patients with malignant glioma. IUdR was administered as 5-day continuous intravenous infusion during weeks 1 and 4.

Phase I study of amonafide dosing based on acetylator phenotype.

Amonafide is extensively metabolized, including N-acetylation to an active metabolite. Prior studies have demonstrated that patients who are fast acetylators of amonafide (and other drugs) have increased toxicity at standard doses of amonafide. The primary objective of this study was to define the recommended phase II dose of amonafide separately for slow and fast acetylators.

A phase I study of subcutaneous recombinant interleukin-2 and interferon alfa-2a.

Background: Both recombinant interferon alfa and interleukin-2 (IL-2) have been shown to have some activity as single agents in metastatic renal cell cancer (RCC), although their activity is minimal in more common solid tumors. Recent preclinical studies have suggested that the combination of these two agents is especially promising.

Methods: Subcutaneous recombinant interferon alfa-2a and IL-2 were administered at one of five dose levels to 33 patients with refractory solid tumors, including 21 patients with RCC.

Phase I clinical and pharmacological study of iododeoxyuridine and bleomycin in patients with advanced cancer.

Studies previously performed in our laboratory demonstrated synergistic cytotoxicity and DNA strand break formation in human tumor cells following exposure to a combination of bromodeoxyuridine and bleomycin. Synergy was evident when bromodeoxyuridine was administered prior to or simultaneously with bleomycin and occurred over a wide range of concentration ratios. We therefore undertook a phase I clinical trial of the combination of iododeoxyuridine (IdUrd) and bleomycin to determine the maximally tolerated dose of IdUrd that could be administered with a standard dose of bleomycin and to determine the toxicities of the combination.

Model-guided determination of maximum tolerated dose in phase I clinical trials: evidence for increased precision.

Background: A widely used phase I design in clinical trials of chemotherapy for cancer and for AIDS (acquired immunodeficiency syndrome) allows for dose escalation in cohorts of three to six patients. Escalation continues until a predefined percentage of patients experience unacceptable toxic effects at a given dose level. A safe and maximum tolerated dose (MTD) for phase II study is then determined.