Mario Sznol

Phase I Study of the Intravenous Administration of Attenuated Salmonella typhimurium to Patients With Metastatic Melanoma

PURPOSEnA strain of Salmonella typhimurium (VNP20009), attenuated by chromosomal deletion of the purI and msbB genes, was found to target to tumor and inhibit tumor growth in mice. These findings led to the present phase I study of the intravenous infusion of VNP20009 to patients with metastatic cancer.nnnPATIENTS AND METHODSnIn cohorts consisting of three to six patients, 24 patients with metastatic melanoma and one patient with metastatic renal cell carcinoma received 30-minute intravenous bolus infusions containing 10(6) to 10(9) cfu/m(2) of VNP20009. Patients were evaluated for dose-related toxicities, selective replication within tumors, and antitumor effects.nnnRESULTSnThe maximum-tolerated dose was 3 x 10(8) cfu/m(2). Dose-limiting toxicity was observed in patients receiving 1 x 10(9) cfu/m(2), which included thrombocytopenia, anemia, persistent bacteremia, hyperbilirubinemia, diarrhea, vomiting, nausea, elevated alkaline phosphatase, and hypophosphatemia. VNP20009 induced a dose-related increase in the circulation of proinflammatory cytokines, such as interleukin (IL)-1beta, tumor necrosis factor alpha, IL-6, and IL-12. Focal tumor colonization was observed in two patients receiving 1 x 10(9) cfu/m(2) and in one patient receiving 3 x 10(8) cfu/m(2). None of the patients experienced objective tumor regression, including those patients with colonized tumors.nnnCONCLUSIONnThe VNP20009 strain of Salmonella typhimurium can be safely administered to patients, and at the highest tolerated dose, some tumor colonization was observed. No antitumor effects were seen, and additional studies are required to reduce dose-related toxicity and improve tumor localization.

Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study.

Forty-seven patients with metastatic malignant melanoma were treated with two 5-day cycles of 100,000 U/kg recombinant interleukin-2 (IL-2) intravenously (IV) every 4 hours separated by 1 week. This dose and schedule of IL-2 were identical to those used in a previous combined IL-2 and lymphokine-activated killer (LAK) cell phase II clinical trial of the IL-2/LAK Working Group. Patient eligibility criteria, and clinical management guidelines were similar to those used in the previous trial. Forty-six patients were assessable for response. Objective responses were observed in 10 of 46 patients (two complete responses [CRs], eight partial responses [PRs]) or 22% with responses occurring in lung and liver as well as lymph nodes and subcutaneous sites. The median response duration was 8 months. Toxicity was significant; three patients developed myocardial infarction, and one patient died during therapy. Overall the toxicity and response rate for single-agent IL-2 are similar to that observed with IL-2 administered in combination with LAK cells in the previous trial. These results suggest that single-agent therapy with IL-2 when administered in this schedule has significant antimelanoma activity in humans, and that LAK cells generated from peripheral blood add little to the antimelanoma activity of this dose and schedule of IL-2.

Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma.

PURPOSEnTo compare the response rate, survival, and toxicity of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus interferon alfa-2a (IFN-alpha) with high-dose IL-2 alone in patients with advanced melanoma in a randomized phase III trial design.nnnPATIENTS AND METHODSnEighty-five patients with advanced melanoma were randomly assigned to receive IL-2 6 X 10(6) U/m2 per dose every 8 hours as tolerated for a maximum of 14 doses on days 1 through 5 and 15 through 19, or IL-2 4.5 X 10(6) U/m2 per dose, plus IFN-alpha 3 X 10(6) U/m2 using an identical schedule. A planned interim analysis was performed after 85 patients were entered, which forms the basis for this report.nnnRESULTSnPartial response (PR) occurred in two of 44 patients (5%; 95% confidence interval, 1% to 15%) receiving IL-2 alone, compared with four of 41 patients (10%; 95% confidence interval, 3% to 23%) receiving IL-2/IFN-alpha (P = .30). There were no complete responses (CRs). The median duration of response was 11.5 months (range, 2.0 to 15.7+). There was no significant difference in the median survival duration for patients receiving IL-2 alone (10.2 months) compared with patients receiving IL-2/IFN-alpha (9.7 months). The median and mean number of doses of IL-2 were equivalent in both groups, as was toxicity. There were three treatment-related deaths, two in the IL-2-alone arm and one in the IL-2/IFN-alpha arm. The trial was terminated after the first interim analysis based on predefined early-stopping rules, which included termination if the response rate in the IL-2/IFN-alpha arm was less than 25%.nnnCONCLUSIONnUsing the preparation, dose, and schedule of IL-2 in our trial, IFN-alpha failed to enhance significantly the response rate to high-dose IL-2 in the treatment of patients with advanced melanoma.

A randomized phase II trial of continuous infusion interleukin-2 or bolus injection interleukin-2 plus lymphokine-activated killer cells for advanced renal cell carcinoma.

PURPOSEnSince 1985, multiple centers have demonstrated that interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells produce durable anticancer responses in patients with metastatic renal cell carcinoma. High-dose recombinant IL-2 (rIL-2) has been administered by intravenous bolus injection (Rosenberg SA, et al: N Engl J Med 313:1485-1492, 1985) and by continuous intravenous infusion (West WH, et al: N Engl J Med 316:898-905, 1987) combined with lymphokine-activated killer (LAK) cells, with both methods producing responses in patients with advanced renal cell carcinoma. The Extramural IL-2/LAK Working Group has conducted a randomized phase II trial of two intravenous high-dose rIL-2 regimens (bolus three times daily or 24-hour continuous infusion) to determine if either one manifests greater anticancer activity or a more acceptable toxicity profile.nnnPATIENTS AND METHODSnNinety-four patients with measurable advanced renal cell carcinoma were enrolled on this study: 46 to the bolus injection arm and 48 to the continuous infusion arm. On both arms, patients underwent a priming phase of rIL-2 administration, four daily lymphocytaphereses to harvest mononuclear cells that were placed in 3- to 4-day culture for generation of LAK cells, and an rIL-2/LAK coadministration phase. Patients were then observed monthly for evidence of response to this therapy and were offered up to two additional courses of treatment every 3 months if evidence of response was detected.nnnRESULTSnTwenty percent of patients on the bolus injection arm experienced objective responses (three complete responses and six partial responses); 15% of patients on the continuous infusion arm responded (two complete responses and five partial responses). Complete responses were durable, persisting for 310+ to 700+ days. The incidence of severe life-threatening toxicities typical of high-dose rIL-2 therapy was similar in both arms (eg, patients with hypotension requiring pressors: bolus 71%, continuous 63%; oliguria less than or equal to 200 mL/8 hours: bolus 65%, continuous 71%). More episodes of fever, infection, and serum alkaline phosphatase elevation were associated with the continuous infusion arm, while more thrombocytopenia occurred on the bolus injection arm. Four patients (three bolus injection, one continuous infusion) died of respiratory and circulatory failure while under treatment. No clinical or laboratory parameter accompanying treatment on either arm was, by univariate or multivariate analysis, associated with an increased likelihood of response.nnnCONCLUSIONSnBoth methods of high-dose rIL-2/LAK cell administration produce nearly equivalent anticancer activity and toxicity in the treatment of renal cell carcinoma. The ability to predict responding patients based on patient or treatment characteristics is not possible.

The effects of treatment with interleukin-1α on platelet recovery after high-dose carboplatin

Background Thrombocytopenia is a frequent side effect of cancer chemotherapy and commonly limits attempts to escalate drug doses. To determine whether interleukin-1α could ameliorate carboplatin-induced thrombocytopenia, we combined it with high-dose carboplatin in 43 patients with advanced neoplasms. Methods High-dose carboplatin (800 mg per square meter of body-surface area) was administered alone to a control group. Subsequent patients were randomly assigned to receive the same dose of carboplatin with interleukin-1α, administered either before or after carboplatin. Interleukin-1α was given intravenously at a dose of 0.03, 0.1, or 0.3 μg per kilogram of body weight per day for five days. Results Carboplatin alone consistently produced thrombocytopenia with a median nadir of 19,000 platelets per cubic millimeter and a median of 10 days with less than 100,000 platelets per cubic millimeter. All 15 patients receiving interleukin-1α before carboplatin had similar findings. In contrast, 5 of the 15 patients...

A phase II study of high-dose continuous infusion interleukin-2 with lymphokine-activated killer cells in patients with metastatic melanoma.

Thirty-three patients with metastatic melanoma were treated in a phase II study with an intravenous continuous infusion (IVCI) of interleukin-2 (IL2) given with lymphokine-activated killer (LAK) cells. The dose of IL2 was the optimal priming dose for LAK-cell induction, followed by the maximally tolerated LAK-cell dose that could be given by an IVCI schedule as determined by a previous phase I trial. The CI schedule was chosen for evaluation because of a postulated reduction in toxicity with the possibility of administering a more prolonged IL2 infusion and because greater rebound lymphocytosis and LAK-cell generation had been reported using this dose and schedule. The 33 patients were similar in age, performance status, and sites of disease to those treated in previous IL2 trials. All patients were assessable for response and toxicity. One patient (3%) achieved a partial response of 10 months duration. There were no other clinically significant responses. Significant toxicity included hypotension requiring pressors (45%), dyspnea (36%), renal insufficiency (24%), hepatic dysfunction (66%), and cardiac arrhythmias (18%). These toxicities reversed with cessation of the infusion. There were four deaths during the first 30 days of treatment, three from infection (one related to central line, one related to LAK cells, one related to tumor), and one from tumor-related hemorrhage. Toxicity was unexpectedly high and at least comparable to that seen in previous studies using a high-dose IV bolus schedule of IL2. When comparing the IVCI schedule with high-dose bolus IL2 to LAK cells in nonrandomized but sequential studies in patients with advanced melanoma, it appears that CI IL2 is less efficacious.

Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen.

Forty-seven patients with metastatic or unresectable renal cell carcinoma were treated with interleukin-2 (IL-2) and lymphokine-activated killer (LAK)-cell therapy, using a hybrid IL-2 regimen. IL-2 was administered initially by intravenous bolus (10(5) U/kg [Cetus Corp, Emeryville, CA] every 8 hours for 3 days) during the priming phase, and subsequently by continuous infusion (3 x 10(6) U/m2 for 6 days); during this second treatment period, in vitro-generated LAK cells were administered. Despite selection of patients for good performance status (PS) (29, PS 0; 18, PS 1) prior nephrectomy (43 of the 47 patients), and low tumor burden, the response rate was low (two complete [CRs] and two partial responses [PRs], for an overall objective response rate of 9%). Toxicity was comparable to that experienced with the high-dose bolus regimen. These results suggest that the dose and schedule of IL-2 administration may influence the likelihood of response to IL-2 in renal cell carcinoma.

Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma

Interleukin (IL-4) is a pluripotent cytokine that stimulates proliferation of activated T-cells and has antineoplastic activity against human renal tumors in animal systems. In phase I trials, IL-4 could be tolerated at doses up to 20 micrograms/kg, with dose-limiting toxicities consisting of fever, fluid retention, nasal congestion, and mucositis. We report the results of two separate Phase II trials of IL-4 in 30 patients with metastatic malignant melanoma and 19 patients with advanced renal cancer. IL-4 was administered intravenously every 8 h for 14 doses in two 5-day courses separated by a 9-day interval. The first 27 patients were treated at a dose of 800 micrograms/m2, but after three of these patients developed cardiac toxicities, the dose was decreased to 600 micrograms/m2. One complete response occurred in a patient with metastatic melanoma (duration > or = 30 months). No responses were seen among the patients with renal cancer. The most frequent side effects were fever, nausea, malaise, nasal congestion, and diarrhea. Reversible hepatic and renal dysfunction were also common. Hypotension was infrequent, but transient weight gain due to fluid retention was common. The major life-threatening toxicities were cardiac and gastrointestinal. Suspected cardiac ischemia was observed in two patients, pericarditis in one, and arrhythmias in two. Three patients had major upper gastrointestinal bleeding without evidence of local tumor. We conclude that IL-4, when given as a single agent on this schedule at maximum tolerated dose, does not possess meaningful activity in renal cancer or melanoma.

Phase I trial of anti-CD3-stimulated CD4+ T cells, infusional interleukin-2, and cyclophosphamide in patients with advanced cancer.

PURPOSEnWe performed a phase I trial to determine whether in vivo expansion of activated CD4+ T cells was possible in cancer patients. 111Indium labeling was used to observe trafficking patterns of the infused stimulated CD4+ T cells. The influence of cyclophosphamide (CTX) dosing on immunologic outcome was also examined.nnnPATIENTS AND METHODSnPatients with advanced solid tumors or non-Hodgkins lymphoma received CTX at 300 or 1,000 mg/m2 intravenously (i.v.). Leukapheresis was performed to harvest peripheral-blood mononuclear cells (PBMCs) either just before the CTX dose, or when the patient was either entering or recovering from the leukocyte nadir induced by CTX. An enriched population of CD4+ T cells was obtained by negative selection. The CD4+ T cells were activated ex vivo with anti-CD3, cultured with interleukin-2 (IL-2) for 4 days, and adoptively transferred. After adoptive transfer, patients received IL-2 (9.0 x 10(6) IU/m2/d) by continuous infusion for 7 days.nnnRESULTSnThe absolute number of CD4+, CD4+/DR+, and CD4+/CD45RO+ T cells increased in a statistically significant fashion in all cohorts after the first course of therapy. The degree of CD4 expansion was much greater than CD8 expansion, which resulted in a CD4:CD8 ratio that increased in 26 of 31 patients. The greatest in vivo CD4 expansion occurred when cells were harvested as patients entered the CTX-induced nadir. One complete response (CR), two partial responses (PRs), and eight minor responses were observed. Trafficking of 111Indium-labeled CD4 cells to subcutaneous melanoma deposits was also documented.nnnCONCLUSIONnCD4+ T cells can be expanded in vivo in cancer patients, which results in increased CD4:CD8 ratios. The timing of pheresis in relation to CTX administration influences the degree of CD4 expansion. Tumor responses with this regimen were observed in a variety of tumors, including melanoma and non-Hodgkins lymphoma; a high percentage of patients had at least some tumor regression from the regimen that produced the greatest CD4+ T-cell expansion.

Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer.

PURPOSEnAlthough high-dose interleukin-2 (IL-2) can produce durable remissions in a subset of responding patients with renal cell carcinoma (RCC), this occurs in the setting of significant toxicity. The purpose of this study is to define the maximum-tolerated dosage (MTD) of IL-2 and interferon alfa-2a (IFN alpha-2a) that can be administered chronically on an outpatient basis.nnnPATIENTS AND METHODSnFifty-three patients with advanced cancer of variable histology with good prognostic features were treated in six cohorts. Patients in cohorts one through five received IL-2 (1.5 or 3.0 x 10(6) million units (mU)/m2) Monday through Friday and IFN alpha-2a (1.5 or 3 x 10(6) mU/m2) daily for a 4-week cycle. In cohort six, IFN alpha-2a was given three times a week. Immunologic monitoring, including serum levels of soluble IL-2 receptor (sIL-2R) and neopterin, flow cytometry, and natural killer cell (NK) activity, were measured. Patients were evaluated for toxicity, response, and survival.nnnRESULTSnAlmost all patients developed grade I/II toxicities commonly associated with cytokine therapy. Symptoms were most severe with the first treatment of each week. Dose-limiting toxicities included grade III fatigue, hypotension, and creatinine elevations. The MTD was 1.5 mU/m2 daily x 5 given subcutaneously repeated weekly for IL-2 and 1.5 mU/m2 daily subcutaneously (dose level 3) for IFN. Six of 25 assessable patients with RCC (24%) achieved a partial response (PR), including four of eight patients who were previously untreated. There were no objective responses in patients with other tumors, including 12 melanoma patients.nnnCONCLUSIONnIL-2 and IFN alpha-2a can be given with tolerable toxicities on an outpatient basis and shows significant activity in patients with metastatic RCC.