Phase I trial of combined recombinant interleukin-2 with levamisole in patients with advanced malignant disease.

A Phase I study of rIL-2 and levamisole was performed to evaluate the activity, toxicity, and effect on immune parameters of this combination of agents in patients with advanced malignancy. Twelve patients with advanced cancer were included and begun on therapy with rIL-2, 1 x 10(6) U/m2 subcutaneously (SQ) daily for 5 days and levamisole beginning at 25 mg/m2 orally three times daily for 5 days. The dose of levamisole was increased to 50 mg/m2 thrice daily during this study. Immune parameter analysis included the percentages of lymphocyte subsets in peripheral blood, cellular cytotoxicity assays versus K562 and Daudi cells, and lymphocyte blastogenesis to the recall antigens tetanus toxoid and Candida albicans. The dose-limiting toxicities were pruritus, nausea, and facial edema. There were no indications of significant hematologic or hepatorenal toxicities. No patient fulfilled the traditional criteria for an objective response. In 8 of 9 patients with immune parameter data available there was an increase in cellular cytotoxicity and in the percentage of lymphocytes with the natural killer phenotype (CD3-, CD16/56+). This regimen can be given as an outpatient with acceptable toxicity. For Phase II investigations the doses of rIL-2, 1 x 10(6) U/m2 SQ daily x 5 days and levamisole, 50 mg/m2 three times daily x 5 days is recommended.

A phase II study of recombinant human alpha-interferon in advanced hormone-refractory prostate cancer.

To determine the efficacy of recombinant human leukocyte alpha-interferon (IFL-RA) in advanced hormone-refractory prostate cancer, the authors treated 40 patients with IFL-RA administered intramuscularly at a dose of 10 x 10(6) U/m2 three times weekly. Toxicity was substantial and necessitated at least a 50% dose reduction in all but five patients during the first 1-2 months of therapy. No responses were observed in patients with bone metastases, but complete and partial regression of nodal disease were observed in two patients with extraosseous disease (overall response rate, 5%; 95% confidence interval, 0.64-17.75%). The authors conclude that IFL-RA cannot be recommended at this dose and schedule in patients with advanced prostate cancer, but additional study of its use in patients with nodal disease may be warranted.

Does histologic grade in soft tissue sarcoma influence response rate to systemic chemotherapy?

To assess whether chemosensitivity in metastatic soft tissue sarcoma (STS) is influenced by the histologic grade of the tumor, the authors retrospectively analyzed tumor responses to doxorubicin-based chemotherapy in four prospective studies conducted at the Mayo Clinic, Rochester, Minnesota, between 1976 and 1984. A total of 131 patients with metastatic STS were included in these trials. All pathologic material was reviewed by one pathologist (H.M.R.) and graded according to the four-tier grading system of Broders. One hundred and sixteen patients were accepted for analysis. Objective regression rates according to grade were as follows: Grade 4, 55% (22 of 40 patients); Grade 3, 23% (7 of 31 patients); Grade 2, 19% (5 of 27 patients); and Grade 1, 0% (0 of 3 patients). Fifteen nongradable sarcomas were analyzed separately (27% [4 of 15]). In contrast to several reports suggesting that grade does not effect response, the authors found differences in response rates to be statistically significant for Grade 2 versus Grade 4 (P = 0.003) and Grade 3 versus Grade 4 (P = 0.006), but not for Grade 2 versus Grade 3 (P = 0.7). Additional comparisons adjusted for the histologic type of STS, chemotherapeutic regimen, performance status, age, and prior treatment confirmed these results. These results suggested that, in addition to being an important prognostic factor for survival in newly diagnosed STS, histologic grade may correlate with the probability of response and should be considered a stratification factor in future studies.

Administration of interleukin-2 (IL-2) results in increased plasma concentrations of IL-5 and eosinophilia in patients with cancer.

Peripheral eosinophilia is almost invariably observed during the course of interleukin-2 (IL-2) therapy and is frequently accompanied by the development of a capillary leak syndrome characterized by edema, weight gain, and oliguria. We studied five patients with advanced malignancy treated with IL-2. Eosinophilia was not present initially but developed in all patients late in the course of therapy, with counts ranging from 2,328/mm3 to 15,958/mm3. In all patients, there was a temporal relationship between the infusion of IL-2 and the appearance of elevated plasma concentrations of IL-5, a growth factor for eosinophils. Granulocyte-macrophage colony-stimulating factor was not detectable in plasma. IL-4 and gamma-interferon plasma levels were variably elevated. Plasma concentrations of major basic protein, a toxic eosinophil granule protein, began increasing before eosinophil counts increased. By the time of the third IL-2 infusion, high concentrations of major basic protein were present in all five patients (up to 5,600 ng/mL) and skin biopsies showed major basic protein deposition in the dermis. Four patients developed significant capillary leak syndrome and all of these patients showed markedly elevated major basic protein levels. The lowest peak plasma concentration of major basic protein (1,751 ng/mL) was observed in the one patient who did not develop edema and weight gain. These results suggest that IL-2 induces IL-5 leading to marked peripheral eosinophilia and extravascular eosinophil degranulation. The release of toxic eosinophil products at extravascular sites and in the circulation may contribute to the pathogenesis of the capillary leak syndrome complicating IL-2 therapy.

Phase I and clinical pharmacological evaluation of pirozantrone hydrochloride (oxantrazole).

Pirozantrone hydrochloride, an anthrapyrazole analogue, was selected for clinical evaluation based on broad antitumor activity against murine tumor systems and on potentially less cardiotoxicity when compared to anthracyclines. This anthrapyrazole analogue is currently under clinical evaluation, and we now report results on a Phase I clinical trial incorporating a pharmacologically guided dose-escalation scheme. Dose escalation was designed to proceed by factors of 2 until the patient drug exposure (concentration x time) was 40% of the murine exposure at the LD10 dose (90 mg/m2). Thereafter, more moderate dose escalations were employed. The target concentration x time value (59 micrograms-min/ml) derived from preclinical pharmacology data was exceeded in all three patients at a dose of 90 mg/m2. A dose of 160 mg/m2 was found to reproducibly result in appropriate myelosuppression. This dose is recommended for further testing in Phase II studies. Nonhematological toxicities encountered in this trial were mild, the most notable being phlebitis at the infusion site. Objective responses were observed in two patients, one with metastatic breast cancer and another with metastatic melanoma. Following a 60-min infusion, pirozantrone hydrochloride plasma elimination was monoexponential, with a half-life of approximately 30 min, mean total body clearance of 1.29 liters/min/m2, and mean steady state volume of distribution of 29 liters/m2.

Cytoplasmic alkalinization produced by the combination of anti-immunoglobulin antibody plus cytochalasin D in murine B lymphocytes.

The intracellular pH of murine splenic B lymphocytes was measured using the pH-sensitive fluorescent dye, bis(carboxyethyl)carboxyfluorescein (BCECF). After stimulation of B lymphocytes with anti-immunoglobulin antibody plus cytochalasin D, two agents that act in synergy to promote S-phase entry, a late increase in pH was detected that occurred prior to the onset of DNA synthesis. The degree of alkalinization observed was comparable to that produced by two additional mitogenic regimens. Cytoplasmic alkalinization was not blocked by dimethylamiloride. Cytoplasmic alkalinization represents a sign of, and may play a role in, stimulation of B lymphocytes to enter S phase.

Cancer immunotherapy: current status of treatment with interleukin 2 and lymphokine-activated killer cells.

In recent years, the medical community has witnessed a growing interest in the use of adoptive immunotherapy in patients with malignant lesions refractory to standard treatments. Systemic administration of interleukin 2, in combination with the adoptive transfer of a patient's own activated immune cells, has resulted in objective regression of several types of advanced cancers. Pronounced regression of tumor has also been observed with use of systemic interleukin 2 alone. This ability to augment the immune defense system of the host against cancer has stimulated intense clinical and laboratory investigations.