Faculty Bibliography

Interleukin 1 alpha (IL-1 alpha) is a cytokine with pleiotropic effects, including cytotoxic-cytostatic activity against some tumor cell lines. We have conducted a phase I study of recombinant human IL-1 alpha (rhIL-1 alpha) in 17 patients with refractory malignancies to examine its toxicity and biologic activity. rhIL-1 alpha was given as a 2-h IV infusion daily for 5 days at five dose levels (0.08, 0.2, 0.8, 2.0, and 5.0 micrograms/m2). Seventeen patients with malignancies were treated, with no objective tumor responses noted. Common toxicities included: fever (100%), rigors and/or chills (96%), myalgia (54%), and headache (48%). Three patients developed grade III hypotension. The maximum tolerated dose was 2.0 micrograms/m2. rhIL-1 alpha induced a significant increase in absolute neutrophil count over baseline (p < 0.05), a delayed but significant increase in platelet count over baseline (p < 0.05), and there was a marked increase in the number of progenitors [colony-forming units (CFU)-G, CFU-M, CFU-GM, CFU-GEMM and burst-forming units (BFU-E)] observed in the peripheral blood. Nine of 12 evaluable patients showed an increase in bone marrow cellularity or myeloid:erthyroid ratio. Immunophenotyping did not demonstrate an increase in peripheral blood or bone marrow CD34+ cells. Interferon-gamma-mediated monocyte cytotoxicity (MCCTX) was significantly enhanced from baseline (p < 0.001), although an increase in direct MCCTX did not reach statistical significance. In summary, rhIL-1 alpha administration is well tolerated at a dose of 2.0 micrograms/m2 with fever, rigors, myalgia, and headache being the most frequent toxicities. Although there were no objective tumor responses, we have demonstrated significant biologic activity with increased neutrophil and platelet counts, increased peripheral blood progenitor cells, and enhanced interferon-gamma-mediated MCCTX

Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by forming 'cleavable complex,' a high molecular weight DNA protein adduct. The formation of such cleavable complexes results in depletion of the Mr 100,000 'free' topo-1 band detectable by Western blot. The objectives of this study were to determine the maximally tolerated dose of prolonged topotecan infusion in previously untreated and minimally pretreated patients. A secondary objective was to measure the effect of prolonged topotecan infusion on topo-1 levels in peripheral blood mononuclear cells (PBMCs) as a pharmacodynamic end point. In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J. Clin. Oncol., 12: 553-559, 1994), the maximum tolerated dose for patients treated previously was 0.53 mg/m2/day for 21 days every 28 days. In this study, patients with no prior therapy were treated similarly at 0.7 mg/m2/day for 21 days, and doses were escalated in 0.1 mg/m2/day increments. Patients who had one prior chemotherapy regimen or radiation therapy to a portal of </=20 cm2 were entered at the 0.6 mg/m2/day level. Cohorts of four patients were entered until the maximum tolerated dose was determined. Peripheral blood was sampled weekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot. For previously untreated patients, the dose-limiting toxicity was myelosuppression at the dose of 0.8 mg/m2/day. Anemia was seen as a cumulative effect. Unexpected nonhematological toxicity was not observed. topo-1 level analysis by Western blot in 11 cycles with weekly measurements showed progressive decrement in the percentage of free topo-1 (compared to baseline value) during weeks 1, 2, and 3. The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at week 2, and 77% (P = 0.016) at week 3. At week 4, off drug treatment, the median percentage of decrease from baseline was only 14%. Additional analysis of free topo-1 level as a function of both area under the curve (P = 0.005) and day of infusion (P = 0.003) demonstrated a significant relationship by regression analysis using a linear mixed effects model. In this Phase I study of topotecan prolonged infusion, hematological toxicity remained dose limiting without evidence of previously described nonhematological toxicity. The recommended Phase II dose is 0.7 mg/m2/day for 21 days every 28 days for previously untreated patients and 0.6 mg/m2/day for those with limited prior therapy. Western blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, which reached statistical significance by week 3. Within 1 week of stopping infusion, topo-1 levels return to baseline. A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated. These data suggest that prolonged administration of topo-1 inhibitory drugs results in sustained depletion of free topo-1 enzyme as measured by Western Blot analysis, which may be an important consideration in the clinical use of these agents. Direct randomized, comparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy

Objective: To evaluate the the efficacy and safety of an intravenous human monoclonal antibody to cytomegalovirus (CMV), MSL-109, as adjuvant treatment for CMV retinitis. Methods: Two hundred nine patients with acquired immunodeficiency syndrome and active CMV retinitis were enrolled in a multicenter, phase 2/3, randomized, placebo-controlled clinical trial. Patients received adjuvant treatment with MSL-109, 60 mg intravenously every 2 weeks, or placebo. Randomization was stratified on the basis of whether patients had untreated or relapsed retinitis. Primary drug therapy for CMV retinitis was determined by the treating physician. Results: The rates of retinitis progression, as evaluated in a masked fashion, were 3.04/person-year in the MSL-109-treated group and 3.05/person-year in the placebo-treated group (P=.98; Wald test); the median times to progression were 67 days in the MSL-109-treated group and 65 days in the placebo-treated group. No differences between the 2 groups were noted in the rates of increase in retinal area involved by CMV, visual field loss, or visual acuity outcomes. The mortality rate in the MSL-109-treated group was 0.68/person-year, and in the placebo-treated group, 0.31/person-year (P=.01). The mortality difference was not explained by differences in baseline variables or in concurrent antiretroviral therapy. Among patients with newly diagnosed retinitis, mortality rates were similar (MSL-109, 0.41/person-year; placebo, 0.42/person-year; P=.95), whereas among patients with relapsed retinitis the MSL-109-treated group had a greater mortality rate (MSL-109, 0.83/person-year, placebo, 0.24/person-year; P=.003). However, the mortality rate in the placebo-treated patients with relapsed CMV retinitis was lower than that in the placebo-treated patients with newly diagnosed CMV retinitis and lower than that in other trials of patients with relapsed CMV retinitis. Conclusions: Intravenous MSL-109, 60 mg every 2 weeks, appeared to be ineffective adjuvant therapy for CMV retinitis. The mortality rate was higher in the MSL-109-treated group, but the reasons for this difference remain uncertain

Background: Cytomegalovirus (CMV) retinitis is a common infection and a major cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). Objective: To evaluate intravenous cidofovir as a treatment for CMV retinitis. Design: Two-stage, multicenter, phase II/III, randomized, controlled clinical trial. Setting: Ophthalmology and AIDS services at tertiary care medical centers. Patients: 64 patients with AIDS and previously untreated, small, peripheral CMV retinitis lesions (that is, patients at low risk for loss of visual acuity). Intervention: Patients were randomly assigned to one of three groups: the deferral group, in which treatment was deferred until retinitis progressed; the low-dose cidofovir group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with hydration and probenecid. Measurements: Progression of retinitis, evaluated in a masked manner by a fundus photograph reading center; the amount of retinal area involved by CMV; the loss of visual acuity; and morbidity. Results: Median time to progression was 64 days in the low-dose cidofovir group and 21 days in the deferral group (P = 0.052, log-rank test). The median time to progression was not reached in the high-dose cidofovir group but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis of the rates of increase in the retinal area affected by CMV confirmed the data on time to progression. The three groups had similar rates of visual loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in the deferral group, 2.8 per person-year in the low-dose cidofovir group (P > 0.2), and 6.8 per person-year in the high-dose cidofovir group (P = 0.135). No patient developed 4+ proteinuria, but two cidofovir recipients developed persistent elevations of serum creatinine levels at more than 177 mu mol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per person-year. Conclusions: Intravenous cidofovir, high- or low-dose, effectively slowed the progression of CMV retinitis. Concomitant probenecid and hydration therapy, intermittent dosing, and monitoring for proteinuria seemed to minimize but not eliminate the risk for nephrotoxicity

Topotecan, a topoisomerase-1 inhibitor, may have greater therapeutic index when given by prolonged infusion. In an earlier phase I trial of escalating low-dose infusion (MTD = 0.53 mg/m2/d x 21d) for previously treated pts (JCO; 12:553 1994), 3/6 heavily treated ovarian cancer pts responded. We administered 60 cycles of TPT to 16 pts in a phase II study starting at 0.4 mg/m2/d x 21 days. All pts had one prior platinum-containing chemotherapy regimen with progression or recurrence (early less than 6 mo vs later). All pts had PS 0-1, normal heme parameters and Creat less than 1.6. Measurable disease (greater than 2 cm on CT scan) was required. Four pts were able to be escalated to 0.5 mg/m2/d for 11 cycles and 6 were reduced to 0.3 in 15 cycles. Responses are presented in a table. Four pts had stable disease (3 still on rx), and 6 PD. Overall response rate is at least 37% (95% CI =12-62%). Hematologic toxicity included leukopenia and neutropenia gr 3 = 4 pts (7%) and gr 4 = 1 pt (2%) but no grade 3 or 4 thrombopenia. Eight pts required blood transfusions. Non-heme toxicity included grade 1 nausea = 7 pts and gr 2 =3 pts; grade 1 fatigue =5 and gr 1 alopecia = 4 pts. Two catheter related thromboses occurred; 2 had sepsis. Weekly PBMC topo-1 levels were obtained for pharmacodynamic studies (abstract submitted). This response rate is among the highest reported for second-line therapy of ovarian cancer and is seen in both platinum resistant and refractory disease. Data on these and additional pts currently being accrued will be presented. (C) American Society of Clinical Oncology 1997

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients

EDA is an analog of methotrexate which has clinical activity in a variety of solid tumors. We are studying EDA in combination with DOX to assess the toxicities and the maximally tolerated dose (MTD). Without G-CSF, the MTD was EDA 40 mg/m2 iv q 2 wk and DOX 30 mg/m2 iv q 4 wk. A 25% dose-escalation of both drugs resulted in dose-limiting neutropenia in 3/6 evaluable patients. Subsequently, G-CSF was added to the regimen on days 3-13. In addition, all patients received ice chip cryotherapy with EDA infusion. After these modifications, 6 patients (M/F; 5/1) have entered the trial. Median age 53 (range 44-61); median PS of 1. All had prior chemotherapy (2 greater than or equal to 2 regimens); 3 prior radiation. A total of 19 cycles were given. There were no significant toxicities noted during cycle 1 of chemotherapy with EDA 50 mg/m2 and DOX 37 mg/m2 + G-CSF. One patient developed grade 1 mucositis after cycle 4 requiring dose reduction and subsequent elimination of day 15 EDA. Despite this, he developed grade 3 mucositis and grade 4 neutropenia after cycle 7 requiring day 1 dose reduction of both EDA and DOX. Three patients have received at least 1 cycle of chemotherapy with EDA 62 mg/m2 and DOX 47 mg/m2 + G-CSF. There were no significant toxicities identified. The doses of both EDA and DOX can be escalated by the addition of G-CSF. Ice chip cryotherapy appears to reduce the severity of mucositis with this regimen. Dose escalation is continuing. Phase II studies are planned in soft tissue sarcoma and colon cancer. (C) American Society of Clinical Oncology 1997