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PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points. RESULTS: In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment. CONCLUSION: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.

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This study was designed as a multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized by center to placebo (16 patients, 31%), oral bexarotene 300 mg/m2/day (21 patients, 40%), or oral bexarotene 600 mg/m2/day (15 patients, 29%) following demonstration of stable or responsive disease after first-line chemotherapy. The study was prematurely terminated because of slow accrual after 54 patients enrolled. Median time to progression (TTP) from the beginning of study drug treatment was 56 days for placebo, 82 days for moderate-dose bexarotene (300 mg/m2/day), and 128 days for high-dose bexarotene (600 mg/m2/day) (P = 0.56, log-rank test). For prior chemotherapy responders only, median TTP from the beginning of study drug treatment was 56 days for placebo, 146 days for moderate-dose bexarotene, and 177 days for high-dose bexarotene. Of note, there were more chemotherapy responders randomized to the placebo group (63%) than the bexarotene treatment arms (48% and 47%), further supporting a bexarotene-related improvement in TTP. Bexarotene-related toxicity was manageable and consisted primarily of elevated serum triglycerides and asthenia, skin toxicity (dryness, peeling, flaking), thyroid dysfunction, and headache. Because this study was closed prematurely, it does not have the statistical power to detect differences among the treatment groups. This study shows that patients can tolerate bexarotene at initial doses up to 600 mg/m2/day after platinum-based chemotherapy and that bexarotene may have the potential to delay disease progression in patients with advanced non-small-cell lung cancer with previously stable or responsive disease following platinum-based chemotherapy.

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Fourteen patients with relapsing ovarian cancer were treated with a regimen of intravenous interferon gamma (IFN gamma). During an initial induction phase, patients received 2 mg/m2 IFN gamma intravenously over 2 h daily for 5 days, repeated every 2 weeks for six courses. Patients who responded were continued on a maintenance phase, receiving 3 mg/m2 intravenously over 2 h, twice weekly every 2 weeks for 2 to 6 months. All patients had received prior cisplatin containing chemotherapy regimens. Of the 14 patients entered, 7 completed the six courses of the induction treatment. Four patients were clinical responders and continued on maintenance therapy. The most commonly reported toxicities included malaise, fever, and deteriorating performance status. There appears to be some clinically apparent antitumor activity demonstrated by this dosing schedule of interferon gamma in ovarian cancers.

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A phase I and II evaluation of 42 patients with advanced renal cell carcinoma treated with recombinant interferon gamma was done. Patients were treated with either a daily 2-hour infusion or 24-hour infusion for 7 days every 3 weeks for at least 2 cycles. Patients who demonstrated stable disease or improvement on therapy then were continued on a maintenance program of 5 days of recombinant interferon gamma administered every 3 to 4 weeks. The initial starting dose was 10 mcg. per m.2 per day with escalations to 30, 100, 300, 1,000 and 3,000 mcg. per m.2. Dose-limiting toxicity occurred at 1,000 to 3,000 mcg. per m.2, and included leukopenia, chills, fevers, rigors and hepatotoxicity as manifested by elevation in the transaminase and bilirubin levels. Tumor responses were seen initially at the 300 mcg. per m.2 dose level. Over-all, of 41 patients evaluable for therapeutic effectiveness 1 demonstrated a complete response 6 months in duration and 3 demonstrated partial responses 2, 9 and 13 months in duration. However, 6 patients demonstrated organ site responsiveness, including resolution of pulmonary lesions (2 complete and 1 partial responses), lymphadenopathy (1 complete and 1 partial responses), a pleural-based lesion in 1 patient with a partial response and complete resolution of hepatic metastases in 1 patient. We conclude that recombinant interferon gamma at a dose of 1,000 to 3,000 mcg. per m.2 for 7 days and repeated every 2 to 3 weeks had demonstrable anticancer activity in patients with metastatic renal carcinoma.

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Thirty patients with documented metastatic melanoma were randomly assigned to receive recombinant DNA-produced gamma-interferon (specific activity approximately, 20 MU/mg) intravenously (IV) over either two or 24 hours at dosages of 3, 30, 300, 1,000, or 3,000 micrograms/m2. Objective toxicity resembled that of alpha-interferon and included fever, chills, myalgias, headache, and fatigue. Neutropenia, elevations in liver enzymes, tachyarrhythmias, and CNS changes also were noted. Dose-limiting toxicity included neutropenia, liver enzyme abnormality, constitutional symptoms, and a change in mental status. The incidence of toxicity was qualitatively similar in both two- and 24-hour treatment arms, but was quantitatively more severe in the 24-hour continuous infusion arm. Maximum tolerated dose was 1,000 micrograms/m2 in both schedules. Pharmacokinetic studies showed a half-life of six to nine hours. One patient had a complete response after two cycles of therapy and an additional patient entered partial remission after three cycles. Recombinant gamma-interferon (rIRN-gamma) is tolerated at dosages of 1,000 micrograms/m2 administered daily either by two or 24 hour infusion for 14 days in patients with metastatic melanoma. The responses documented in this early trial warrant further evaluation for the treatment of metastatic melanoma.

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Recombinant human gamma interferon (Biogen) and vinblastine were administered in a phase I study. Side effects included fever and chills, nausea and vomiting, acute symptomatic hyponatremia, reversible myelosuppression, hepatitis, transient hypotension, congestive heart failure, renal insufficiency, and nonselective proteinuria. In most patients, additional host factors contributed to these toxic effects. Side effects occurred despite dose reduction; therefore, protocol accrual was prematurely closed. No correlation between serum concentrations and toxicity was noted. Median serum vinblastine concentration was 1.04 ng/ml; median serum interferon concentration was 17.3 IU/ml.

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Fifteen patients with advanced carcinoma of the breast who had failed prior chemotherapy, were treated with recombinant gamma interferon at a dose of 2mg/m2 (1mg = 2.4 X 10(7) international units) intravenously for five consecutive days every other week. The median patient age was 51 and all patients had a performance status of 0-2 (Karnofsky greater than or equal to 50). Thirteen patients had two or three sites of metastatic disease and seven were estrogen receptor positive. No complete or partial responses were noted. Although some patients had brief periods of stable disease, almost all patients progressed after one or two courses. Only one patient was able to receive six courses of induction therapy and a brief course of maintenance. Flu-like symptoms and nausea were seen in all patients; vomiting and anorexia were frequent. Hepatic toxicity manifested by enzyme elevation was common and was most severe in patients with liver metastases. In this study a highly purified biologically active gamma interferon was not associated with anti-tumor activity in previously treated women with metastatic breast cancer.

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The clinical pharmacology of cisplatin was determined in six patients with malignant ascites secondary to ovarian cancer, and in one patient with peritoneal mesothelioma, following intraperitoneal administration of cisplatin (25-60 mg/m2). The drug was administered in 1 liter of normal saline as a 15- to 30-min infusion. Total, and in some patients free (ultrafilterable), platinum concentrations were determined in plasma, urine, and ascitic fluid by flameless atomic absorption spectrometry. The peak total platinum concentrations in ascitic fluid at the end of infusion were related to dose, a 50 mg/m2 dose producing a 20 to 80 micrograms cisplatin/ml concentration. Filterable platinum represented between 3 and 59% of total platinum in the peritoneum at 4 to 6.5 hr following its administration. Plasma platinum concentrations ranged between 0.2 to 1.6 micrograms/ml 4 hr following administration, and reached a plateau for the next 24 to 48 hr largely in the form of protein-bound platinum. The urinary excretion of cisplatin was consistent with variation in absorption from the peritoneum. Minimal gastrointestinal, bone marrow, and renal toxicities during therapy suggest that sustained free platinum concentrations in ascites may be obtained without significant toxicity and support the intraperitoneal route of administration as an effective strategy for cisplatin therapy of intra-abdominal malignancies.

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Measurement of drug activity as an oncolytic effect, use of the control only to monitor the quality of tissue implanted, and the rapid clearance of necrotic tissue from the subcapsular site, as significant factors incorporated into the design of the assay, have permitted use of a simple tumor size parameter for evaluating drug activity. The simplicity and economy of such a parameter, the predictability and reproducibility of the 6-day assay observed thus far, and evidence that the assay does measure a biological property of the tumor apart from host response, have warranted the continued use of the 6-day time frame and the normal immunocompetent CDF1 mouse as xenograft host. These studies have demonstrated the feasibility of using human tumor explants obtained from a variety of solid human malignancies in a straightforward, short term, in vivo predictive assay system. Preliminary correlations between in vivo (assay) tumor sensitivity and clinical response have given reasonable concurrence. This crucial point will require further study, with larger numbers of patients, under more rigid conditions. Final validation of this, and other, predictive assays will require a prospective, randomized study in large numbers of patients. Our present prospective study is being continued, therefore, with expansion to a multi-institutional design over a broader geographic area.

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Retrospective and prospective clinical trials were performed to determine the usefulness of the 6-day subrenal capsule (SRC) assay for the prediction of response to chemotherapy. Evaluable assays were obtained in 86% of 1000 consecutive specimens obtained from a variety of solid malignancies. Analysis of chemotherapeutic sensitivity in this assay gave reproducible and consistent results. The overall predictive accuracy of the assay in 62 retrospective clinical trials in 55 patients was 85%. Of 37 evaluable patients with chemotherapy refractory cancers treated in a prospective trial with single agent chemotherapy as determined by the assay, 14 (38%) responded. Greater degrees of tumor regression in the assay were associated with a higher probability of clinical response. The SRC assay shows potential value as a rapid predictive test for chemotherapeutic selection on an individual patient basis. However, additional prospective clinical trials are necessary to document its ultimate utility.

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Previous studies have reported antitumor activity and reduced cardiotoxicity for a putative 3:1 complex of iron:Adriamycin (ADR). We have studied the tissue distribution and metabolism of a wide variety of freshly prepared and lyophilized iron:ADR preparations after administration to BALB/c mice (ADR, 16 mg/kg i.v.). Tissue concentrations of ADR given without iron were initially highest in kidney and liver, and ADR fluorescence was lost from all tissues except the spleen with a t1/2 of 15 to 18 hr. ADR remained the major fluorescent species in liver and kidney from 0.5 to 72 hr after treatment. Freshly prepared iron:ADR (1:1) behaved similarly to ADR except for a slightly longer tissue t1/2 in heart, liver, and kidney. The tissue distribution of freshly prepared 2:1 and 3:1 iron:ADR was very different from that of ADR without iron; lung containing the highest concentrations of ADR fluorescence. Administration of freshly prepared 1:1, 2:1, and 3:1 iron:ADR resulted in some increase in adriamycinol in the liver, but ADR was always the major fluorescent species present. The tissue distribution of 1:1 iron:ADR that had been aged for 48 or 96 hr was similar to that of fresh 2:1 and 3:1 iron:ADR rather than ADR or fresh 1:1 iron:ADR. When lyophilized iron:ADR preparations were reconstituted and administered, the 0.5-hr tissue distribution of 0.1:1, 0.2:1, 0.25:1, and 0.33:1 iron:ADR was the same as ADR alone, but 0.5:1, 1:1, 2:1, and 3:1 iron:ADR were all accumulated primarily in the lung. Physicochemical studies confirm the production of microaggregated iron:ADR complexes and light microscopy allows visualization and sizing of these aggregates. We feel that trapping of these iron:ADR aggregates in the pulmonary vascular bed accounts for the observed dramatic alteration in tissue distribution. Light and electron microscopic studies confirm the intravascular sequestration of iron in pulmonary capillaries.

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Feasibility of utilizing the 6-day subrenal capsule (SRC) assay to screen drugs against fresh surgical explants of human tumors was confirmed by testing six clinically active chemotherapeutic agents against 141 human breast cancers. Response rates of the six drugs obtained in the assay compared favorably with clinical response rates for the same drugs as reported by Carter (5). The evaluable assay rate for breast tumors was 92% as compared to 89% for gynecologic tumors. Innate drug resistance was indicated with 16 of 57 tumors (28%) which did not respond to any of the six agents tested. Differences in responsiveness of tumors to each agent in a potential three-drug combination of either CMF or CAF suggest that the effectiveness of multiagent therapy might be enhanced if the individual agents of a potential drug combination were selected on the basis of tumor sensitivity to each of the agents in a predictive assay. Although cross-resistance between L-PAM and cytoxan was demonstrated and was statistically significant, 31% of these tumors responded individually to either one or the other agent, suggesting caution in extrapolating concomitance in activity between these two alkylators.

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The potential clinical activity of the new phase I drugs N-methylformamide (N-MF) and Echinomycin (ECH) was examined while still undergoing clinical toxicology trials by testing against fresh surgical explants of human tumors in the 6-day in vivo SRC Assay. Sixty-nine tumors representing different histologic types including breast, lung, colon, ovarian, and cervical, as well as neoplasms of undiagnosed origin, were screened against N-MF (NSC-3051) and ECH (NSC-526417) simultaneously with five standard chemotherapeutic agents used clinically for treatment of the specific type of cancer. Thus, activity of N-MF and ECH could be compared directly with that of standard agents tested in the same assay. Treatment schedule was QD1-5, and the criterion for drug activity was tumor graft regression greater than 20%. N-MF was active against 15/69 tumors with a response rate of 22%. ECH was also active against 15/69 tumors, yielding the same response rate. Although the response rates for N-MF and ECH were the same, indicating a similar degree of general anti-tumor activity as evaluated by the assay, N-MF showed greatest activity against lung tumors whereas ECH was more active against ovarian tumors. Twenty-six of 69 tumors (38%) were unresponsive to all drugs tested, only one tumor was responsive to both N-MF and ECH and no tumors were responsive to either N-MF or ECH alone. Cytoxan, one of the standard agents tested concurrently with both phase I drugs yielded a response rate of 35%, one and one-half times greater. Cervical and renal cancers and lymphomas were relatively unresponsive to both drugs.

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