Faculty Bibliography

Twenty-four patients with solid malignancies were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) on a Phase 1b trial. The objective of the study was to evaluate the effects of GM-CSF on peripheral blood monocyte activation. GM-CSF was administered by subcutaneous injection daily for 14 days. Immune parameters measured were monocyte cytotoxicity against the human colon carcinoma (HT29) cell line, serum tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and in vitro TNF-alpha and IL-1 beta induction. All patients were evaluable for toxicity. Fifteen patients were evaluable for immunologic response. Treatment with GM-CSF led to a statistically significant enhancement in direct monocyte cytotoxicity against HT29 cells. There was no increase in serum TNF-alpha or IL-1 beta and no consistent in vitro induction of TNF-alpha or IL-1 beta from monocytes posttreatment. Treatment was well tolerated overall. We conclude that treatment with GM-CSF can lead to enhanced monocyte cytotoxicity. Further studies are in progress to evaluate the effect of GM-CSF on other parameters of monocyte functions

PURPOSE: The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer. PATIENTS AND METHODS: Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation. RESULTS: The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions). CONCLUSION: Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer

We report the results of an ongoing Phase II study of paclitaxel (Taxol) and DDP in women with metastatic breast cancer. Paclitaxel is administered at 200 mg/m2 iv 24 hr infusion on d1, bolus DDP at 75 mg/m2 d2; G-CSF 5 mcg/kg SQ qd d3 until WBC recovery, with premedications of dexamethasone, cimetidine, and diphenhydramine. Eligibility criteria are: age greater than 18, ECOG PS less than or equal to 2, measurable/evaluable disease, adequate BM, liver, and renal functions, no prior paclitaxel or DDP, and informed consent. Pts may have received adjuvant (adj) therapy (Rx) greater than 1 yr prior to enrollment and less than or equal to 1 prior chemotherapy (CT) regimen for metastatic disease. 27 pts are enrolled on study. Pt characteristics: median age 50 (range 25-69), stage IV 23, stage IIIB, prior adj CT 18, CT 2, hormone 9. Disease sites include lung 13, bone 11, soft tissue 12, lymph node 11, and liver 3 (19 pts have greater than or equal to 2 sites). 27 pts received 111 cycles, median of 5 cycles/pt. Of 21 evaluable pts, there were 2 CR, 9 PR, 9 SD, and 1 PD (overall response rate 52%) [1 pt was non-evaluable (toxic death in cycle 1); 5 pts are too early]. The median duration of response is 3+ months (range 1-12+ months). 16/27 pts (59%; (33/111 cycles)) had grade 4 neutropenia. 17 pts had grade greater than or equal to 2 fatigue (WHO). 9/27 (33%; 12 cycles) required RBC Tx. 8 pts went off study because of cumulative neuropathy. Other off study reasons: 5 PD, 1 toxic death (sepsis), anaphylaxis to DDP-1, and 2 pts went to surgery. Conclusion: Paclitaxel/DDP is an active regimen as first line therapy for metastatic breast cancer, but acute myelosuppression and cumulative neurotoxicity are limiting. (C) American Society of Clinical Oncology 1997

This study was conducted to examine whether immunization to a melanoma vaccine can induce antibodies that are functionally effective in killing melanoma cells. A group of 79 evaluable patients with surgically resected AJCC stage III melanoma were immunized every 3 weeks to a polyvalent melanoma antigen vaccine (40 mug/immunization). Cytolytic antibodies to melanoma cells, assayed by europium-based complement-dependent cytolysis before vaccine treatment and 1 week following the fourth immunization, were detected in 7 patients (9%) before vaccine treatment but in none of 17 control individuals. Vaccine treatment induced or increased the level of these antibodies in 37 patients (47%; p = 0.0001). Vaccine-induced cytolytic antibodies were predominantly directed to melanoma cells. There was no correlation between the induction of these antibodies and improved clinical outcome. These results indicate that melanoma vaccine treatment can induce antibodies that have the functional ability to kill melanoma cells in vitro but suggest that the induction of such cytolytic antibodies is not associated with a delay in the progression of melanoma

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