Faculty Bibliography

Our goal was to test the hypothesis that M-CSF would induce objective responses in ASTS. M-CSF is a recombinant glycoprotein produced in Chinese hamster ovarian cells by Genetics Institute, Cambridge, MA. We performed a phase II study of M-CSF in adults with measurable metastatic soft-tissue sarcomas. 14 patients (pts) were entered in a 4-mo period. Pt characteristics were 8 females, 6 males, 10 leiomyo, 2 lipo, 1 each rhabdomyo and Schwannoma; 5 pts had primary tumor in the peritoneal cavity, 4 uterus, 3 stomach, and 1 extremity. Six pts had radiation, including 1 who had pelvic radiation. 11 pts had been previously treated with a doxorubicin-containing combination. Three pts had not had prior therapy. Ten pts had a ECOG performance status (PS) of 1 and 4 had a PS of 0. Sites of measurable disease were abdominal cavity 5, liver 3, lung and soft tissue 2 each. Pts were given a course of continuous infusion of M-CSF for 7 days, every 14 days, at a dose of 80 ug/kg/day. Six pts have gone off study after 4 courses, 2 pts after 2 courses, 2 pts after 1 course. Four pts remain on study with, to date, 2 pts at 3 courses, and 1 pt each at 4 courses and 6 courses. M-CSF at this dose and schedule was well tolerated. No pt went off study because of toxicity. No delays in treatment occurred. The most significant toxicity was thrombocytopenia: grade 3, 4 pts; grade 2, 7 pts; grade 0, 3 pts. The platelet counts recovered within days of stopping the M-CSF. The other toxicities were grade 1 flu-like symptoms in 11 pts, which was self-limited and resulted in no change in PS. Grade 1 nausea was seen in 6 pts. Grade 1 itching of the eyes occurred in 3 pts. So far, no objective responses have been observed in this population on this dose and schedule. Seven pts had progressive disease. (C) American Society of Clinical Oncology 1997

Topotecan (TPT), a semi-synthetic, water soluble analog of camptothecin (CPT), acts by topoisomerase-1 inhibition. Previous studies with CPT analogs in human xenograft-bearing mice show that prolonged depot administration at nontoxic doses were curative (Giovanella et al, Science, 246:1046, 1989). We treated 33 patients (pts) (16 F, 17 M) with prolonged continuous infusion using ambulatory CADD pumps delivering 7 cc/day (d) with cassette changes every 3 d. Cohorts of 4-6 pts began at a dose of 0.2 mg/m2/day x 7 days with escalation to 10, 14, 17, and 21 days q 28 d. Further escalations were 0.3, 0.4, and 0.53 mg/m2/d x 21 d q 28 d. Disease sites included colon ca (13), NSCLC (4), sarcoma (3), gastric (3), ovarian (3), pancreatic (2); H and N, breast, renal, melanoma, anal (each 1). Median age was 63 (range 29 -79) yr; PS 1 (0-2); prior chemo = 33 (med 2 regimens); prior RT=10. A total of 72 cycles (med 2, range 1-6) were given for a total of 1090 pt-days of infusion. One infectious complication was seen (Mediport-pocket), 4 pts required transfusion; one pt with 3 prior chemo regimens and pelvic RT developed gr 4 leukopenia and thrombocytopenia at the 0.4 mg/m2 x 21 d level. No other hematologic toxicity has been observed. Nonhematologic toxicity included fatigue only. Steady state plasma conc for the active lactone form of TPT at 0.4 mg/m2/d was 1.4 +/- 0.29 ng/ml (N=3) and 4.4 +/- 0.99 (N=3) at the 0.53 level. Best responses were 1 PR (NSCLC), 1 mixed response (breast), 11 stable, 15 progression and 5 too early. TPT administration by this schedule is feasible and safe; we continue to accrue. Dose-limiting heme toxicity has not yet been reached, yet dose intensity (2.8 mg/m2/wk) exceeds that achieved using the recommended Phase II 1.5 mg/m2/d x5 schedule (1.9 mg/m2/wk). Once an MTD is reached, Phase III trials comparing this schedule to the daily x5 bolus schedule will be warranted. (C) American Society of Clinical Oncology 1997

To investigate the clinical relevance of antimelanoma antibody responses induced by melanoma vaccine immunization, we studied prospectively 81 patients with resected AJCC stage III malignant melanoma who were immunized to a partially purified, polyvalent, melanoma antigen vaccine. Antibody responses to melanoma surface antigens were measured by immunoprecipitation SDS-PAGE analysis prior to treatment and one week after the 4th immunization. Vaccine treatment induced or augmented melanoma antibodies in 33 (41%) patients. The responses were directed to one or more antigens of approximately 210, 150, 110, 75, and/or 38-43 kD. The median disease-free survival of patients with any antibody response was 47 months vs 19 months for nonresponders and median overall survival was 62 months vs 46 months. The proportion of patients that was disease-free at 4 years increased by 57% (from 33% to 52%) and overall survival by 64% (from 50% to 80%) in responders vs nonresponders. These differences in outcome were unrelated to disease severity or overall immunological competence (evaluated by response to recall antigens and ability to be sensitized to DNCB), suggesting they resulted from vaccine treatment. Thus, the antibody response to vaccine treatment is an immune marker of vaccine activity that appears to be predictive of a later reduction in the recurrence of melanoma. This finding suggests that vaccine treatment effectively slows the progression of melanoma in some patients, and that the protective effect is mediated in part by vaccine induced antimelanoma antibodies

BACKGROUND: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. PURPOSE: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. METHODS: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). RESULTS: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10:1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 +/- 18.3 (mean +/- SD) hours; the area under the curve for plasma concentration of drug x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 +/- 0.30 hours and 4.16 +/- 2.94 hours, respectively. Total-body clearance was 111 +/- 87 microL/m2 per minute (N = 18); AUC was linear (r2 = .92), and the clearance rate was constant (r2 = .18) from 60 to 900 mg/m2. CONCLUSIONS: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10:1 to 12.5:1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. IMPLICATIONS: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies

BACKGROUND: Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthetic analogue of muramyl dipeptide (MDP), a component of bacterial cell walls that has potent in vitro monocyte-activating properties. We conducted a phase II clinical trial of MTP-PE in 30 patients with metastatic melanoma. PURPOSE: Our purpose was to define a clinical response rate for this agent in patients with advanced melanoma and to evaluate the agent's immunomodulatory properties. METHODS: Patients were randomly assigned to 1- or 4-mg dose levels of MTP-PE and received the drug intravenously once a week for 12-24 weeks. Immunological monitoring consisted of measurement of plasma tumor necrosis factor-alpha (TNF-alpha), neopterin, interleukin-1-beta, interleukin-6 (IL-6), and beta 2-microglobulin levels; phenotyping analysis of expression of human HLA-DR, CD-14 on mononuclear cells; and measurement of in vitro monocyte cytotoxicity against SKMel28 targets cells. RESULTS: MTP-PE was well tolerated; fever and chills were the major toxic effects. Plasma TNF-alpha levels increased 16-fold 2 hours after the first MTP-PE treatment. Increases in TNF-alpha levels after MTP-PE administration continued through week 12, but changes were of a lower magnitude after week 1. Plasma neopterin levels were significantly increased 24 hours after treatment at weeks 1, 6, and 12. A marked increase in IL-6 and a modest rise in beta 2-microglobulin levels were also seen at week 1. No significant changes from baseline IL-1 beta were observed. In the cytotoxicity assay, monocyte cytotoxic activity was significantly increased at weeks 4 and 6. Surface immuno-phenotyping revealed a consistent transient reduction in the number of circulating monocytes 2 hours after MTP-PE was administered. In addition, we observed a down-regulation (i.e., a decrease) in the expression of Leu M3 and HLA-DR on monocytes, 2 hours after MTP-PE treatment, followed by a recovery 24 hours after treatment. No objective clinical responses were seen in this advanced disease population. CONCLUSIONS: We conclude that MTP-PE has pleiotropic and potentially beneficial biologic effects and that further clinical investigations of MTP-PE are justified. IMPLICATIONS: In view of the clear immunomodulatory actions seen in our study and in earlier clinical trials, we believe that MTP-PE deserves further study in the adjuvant setting

The authors investigated whether there was a relationship between the induction of a delayed-type hypersensitivity (DTH) response to melanoma vaccine immunization and disease recurrence. They studied prospectively 94 evaluable patients with surgically resected Stage II malignant melanoma who were immunized to a partially purified, polyvalent, melanoma antigen vaccine. The DTH response to skin tests to the vaccine was measured before treatment and at the fourth vaccine immunization. Vaccine treatment induced a strong DTH response in 29 (31%) patients, an intermediate response in 24 (25%), and no response in 41 (44%). The median disease-free survival (DFS) of patients with a strong, intermediate, and no DTH response to vaccine immunization was more than 72 months, 24 months, and 15 months, respectively. The relationship between an increase in the DTH response and a prolonged DFS was statistically significant (P = 0.02); clinically meaningful (the median DFS of patients with a strong DTH response was 4.7 years longer than that of nonresponders); and, by multivariate analysis, independent of disease severity or overall immune competence. These findings suggest, but do not prove, that vaccine treatment can slow the progression of melanoma in some patients

A group of 16 patients with advanced malignancy were entered on a phase I trial of escalating doses of doxorubicin with ICRF-187 for cardioprotection and granulocyte/macrophage-colony-stimulating factor (GMCSF) for bone marrow protection. Patients received intravenous ICRF-187 (dose ratio 20:1 ICRF-187:doxorubicin) 30 min prior to doxorubicin. GMCSF at a dose of 15 micrograms kg-1 day-1 was self-administered subcutaneously on days 3-14 of the cycle. Doxorubicin was administered every 21 days. Substantial hematological and non-hematological toxicity was seen. Fever, malaise, and pulmonary symptoms, thought to be due to GMCSF, were not eliminated by reduction in the GMCSF dose to 10 or 5 micrograms kg-1 day-1. Severe hematological toxicity was seen despite GMCSF administration and it was not possible to escalate the doxorubicin dose above 72 mg/m2 with this combination. Dose escalation of doxorubicin may be more feasible with the use of other growth factors or growth factor combinations

The growth of melanoma in humans depends not only on the malignant potential of the tumor but also on the patient's immune response to the melanoma. As a result, a variety of strategies have evolved to treat melanoma by stimulating antitumor immune responses to melanoma. This article reviews the different approaches being taken and the results obtained to date