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Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8 + T cells. T-cell receptor (TCR)β screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8 + T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: To determine the overall and dose-limiting toxicities (DLTs) of alitretinoin (9-cis-retinoic acid) in combination with tamoxifen and the pharmacokinetics of alitretinoin alone and when combined with tamoxifen in patients with metastatic breast cancer. The effect of tamoxifen and alitretinoin on MIB-1, a marker of proliferation, in unaffected breast tissue was explored., Patients and Methods: Eligible patients had metastatic breast cancer. Previous tamoxifen therapy was allowed. Planned dose levels for alitretinoin ranged from 50 to 140 mg/m2/d with 20 mg/d tamoxifen in all patients after 4 weeks of alitretinoin as a single agent. Plasma concentrations of alitretinoin and retinol were measured at baseline and after 1, 2, and 3 months. Breast core biopsies were obtained at baseline and after 2 months of therapy., Results: Twelve patients with metastatic breast cancer received a total of 86 cycles of therapy. At 90 mg/m2/d, three of five patients experienced a DLT: grade 3 headache, grade 3 hypercalcemia, and grade 3 noncardiogenic pulmonary edema. At 70 mg/m2/d, one of six patients experienced a DLT (headache), and this level was considered the maximal tolerated dose in this study. Three toxicities occurred that had not been reported previously with alitretinoin: an asymptomatic delay in dark adaptation, a marked decrease in high-density lipoprotein cholesterol, and the occurrence of enthesopathy. Two of the nine assessable patients had a durable clinical response: one partial response and stable disease for 18 months and one complete response in continuous remission for 48+ months. Both responding patients were estrogen receptor-positive and had had previous tamoxifen therapy. There was a high degree of interpatient variability of plasma alitretinoin concentrations, although a significant decline in alitretinoin plasma levels over time was observed. MIB-1 scores declined in four of the eight paired breast specimens obtained., Conclusion: The combination of tamoxifen and alitretinoin is well tolerated and has antitumor activity in metastatic breast cancer. The recommended phase II dose is 70 mg/m2/d with 20 mg/d tamoxifen.

Suramin has been shown to have an effect on bone resorption in in vitro models. It is not clear if a similar effect is seen in patients treated with suramin. The clinical effect of suramin treatment on total serum calcium was examined in two groups of patients with hormone-refractory prostate cancer. In all, 28 patients in group 1 were examined within 2 weeks before and 2 weeks after suramin treatment and 72 patients in group 2 were examined within 2 weeks before, during, and after treatment with suramin. In addition, calcium controls spiked with suramin were run in three different commercially available assays for evaluation of the effect of suramin dose on calcium determination. Group 1 patients showed a decrease in serum calcium after treatment with suramin. The mean uncorrected serum calcium level was 2.29 +/- 0.025 mmol/l before treatment and 2.09 +/- 0.025 mmol/l after treatment (P < 0.0001, paired Wilcoxon test). The mean serum calcium value corrected for albumin was 2.33 +/- 0.02 mmol/l before treatment and 2.24 +/- 0.02 mmol/l after treatment (P = 0.0022, paired Wilcoxon test). Group 2 patients also displayed a decrease in serum calcium after treatment with suramin. The mean baseline value was 2.23 mmol/l (median 2.26 mmol/l, range 1.20-2.54 mmol/l). The mean level of serum calcium corrected for albumin as determined at the end of treatment was 2.14 mmol/l (median 2.16 mmol/l, range 0.98 2.46 mmol/l). In all, 48 patients for whom pre- and post-treatment values were available for analysis displayed a median calcium decrease of 0.09 mmol/l (P = 0.0005, Wilcoxon signed-rank test for the null hypothesis of no change). For 68 patients in group 2, data on serial serum calcium measurements during treatment were available for analysis. A projected median decrease in serum calcium of 0.06 mmol/l (range 0.43 to 0.72 mmol/l) over an 8-week interval of suramin therapy was found. Overall, 47 of the 68 slopes were negative (P = 0.0022, Wilcoxon signed-rank test). Nine patients were treated with suramin for less than 6 weeks. These patients' calcium levels were significantly higher than those of 50 patients treated for longer periods (median value 2.24 versus 2.16 mmol/l, P = 0.035, Wilcoxon rank-sum test). No correlation was found between suramin dose and calcium level using the Kodak Ektachem, Hitachi 914, or Synchron Clinical System CX3 method. In conclusion, suramin treatment was consistently associated with decreases in serum calcium in two groups of patients with hormone-refractory cancer. Suramin placed in calcium controls did not affect calcium determination using three commercially available methods.

The pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) was characterized in patients with peritoneal carcinomatosis. Cisplatin was added into the perfusate with escalating doses from 100 mg/m2 to 400 mg/m2. The hyperthermic perfusion was maintained for 90 minutes with a flow rate of 1.5 L/min and a target peritoneal temperature of 42.5 degrees C after a tumor debulking procedure. Samples of both the perfusate and blood were obtained during the perfusion and 30 minutes after the perfusion. Cisplatin plasma and perfusate concentrations were determined by flameless atomic absorption spectrometry with a lower limit of detection of 2 ng/ml and a coefficient of variation (CV) < 10%. Fifty-six patients were enrolled in the study. The mean (+/- SD) percentage of cisplatin present in the perfusate at the completion of perfusion was 27.8% +/- 20% of the total dose. The maximum cisplatin concentrations in the perfusate were 10 times higher than those in plasma. The area under the concentration-time curve (AUC) of the perfusate was 13 times higher than the AUC of plasma. A two-compartment model with an additional peritoneal cavity compartment fits to the data best based on the Akaike information criterion. However, the interpatient variability was considerably high (CV < 100%). In conclusion, cisplatin administered by hyperthermic peritoneal perfusion resulted in a pharmacological advantage by obtaining higher and direct drug exposure to the tumor in the peritoneal cavity while limiting systemic absorption and toxicity. Using a complex two-compartment model, the authors were able to characterize the pharmacokinetics of cisplatin given intraperitoneally via this technique.

Background: Tumor necrosis factor (TNF), hyperthermia, and cisplatin have synergistic cytotoxicity against cancer cells in vitro. This combination may be well suited to the regional treatment of peritoneal tumor spread in patients. Continuous hyperthermic peritoneal perfusion (CHPP) is a technique that allows uniform delivery of cytotoxic agents and heat to the peritoneal surface. A Phase I trial of CHPP with TNF and cisplatin was conducted to define the maximum tolerated dose (MTD) for TNF and cisplatin under moderate hyperthermia in the treatment of peritoneal carcinomatosis., Methods: Twenty-seven patients with peritoneal carcinomatosis underwent exploratory laparotomy and tumor debulking followed by a 90-minute CHPP with cisplatin (100-350 mg/m2) and TNF (0-0.3 mg/L). Perfusion parameters included a perfusate volume of 3-9 L, a peritoneal temperature of 42-43 degrees C, and a flow rate of 1.5 L/minute. Sodium thiosulfate was administered systemically during and after the perfusion as a cisplatin binding agent., Results: There was no operative or treatment-related mortality in this study. CHPP resulted in a 14-fold higher area under the concentration versus time curve (AUC) for cisplatin in the perfusate compared with plasma, and a 4854-fold higher AUC for TNF. The MTD was defined as 250 mg/m2 cisplatin plus 0.1 mg/L TNF. The dose-limiting toxicity was renal insufficiency. No other systemic toxicity was identified, and no significant regional toxicity was identified. The median time to toleration of a regular diet was 8 days (range, 5-20 days)., Conclusions: The favorable regional pharmacologic profile of the combination of cisplatin and TNF suggests that these agents administered via CHPP warrant further evaluation as prophylaxis against or treatment for peritoneal carcinomatosis.

Background: Peritoneal carcinomatosis is a difficult management problem, and intraperitoneal treatment approaches may provide an opportunity to intensify dose and minimize toxicity. The current experiments were conducted to characterize the cytotoxic effects of cisplatin (cDDP), tumor necrosis factor (TNF), and hyperthermia (HT) on a gastric cancer cell line in vitro under conditions achievable with intraperitoneal treatment., Methods: Seoul National University gastric cancer cell line (SNU-5), a poorly differentiated gastric cancer cell line, was tested for sensitivity to various doses of cDDP, TNF, or combinations of the two at normothermia (37 degrees C) or HT (42.5 degrees C). The effect of TNF on cellular rates of cDDP accumulation, efflux, and cDDP-DNA adduct formation were evaluated using atomic absorbance spectrometry with Zeemen background correction., Results: During a 2-h exposure to various doses of cDDP HT, we observed a supraadditive cytotoxicity of SNU-5 with 1 to 50 micrograms/ml of TNF (p2 = 0.0001). In the presence of the three-agent combination (HT, TNF, and cDDP) we observed statistically significant increases in total cellular accumulation of cisplatin (p2 = 0.016); a nonsignificant decrease in cellular efflux of drug (p2 = 0.098); and a 40% increase in persistent cisplatin DNA damage as measured by atomic absorption spectrophotometry (p2 = 0.06). These patterns were specifically not seen with the combinations of cDDP and HT, or cDDP and TNF., Conclusions: These data provide the experimental basis for the use of TNF and cDDP with HT in the treatment of gastric cancer and support the investigation of these agents in vivo in the regional treatment of peritoneal carcinomatosis.

Background: The anticancer role of tumor necrosis factor-alpha (TNF-alpha) has been limited by toxicity. These experiments evaluate blocking endogenous interferon-gamma (IFN-gamma) activity to abrogate TNF-alpha toxicity., Methods: C57B1/6 mice bearing MCA 105 tumor were treated with TNF-alpha and anti-IFN-gamma antibody (Ab) to evaluate the effect on the acute lethality of TNF-alpha and their efficacy as evaluated by tumor growth rate, tumor histology, and survival., Results: Anti-IFN-gamma Ab decreased TNF-alpha lethality. Anti-IFN-gamma Ab alone increased tumor growth significantly more than did nonimmune IgG (p2 < 0.0001). Tumor-bearing mice that received nonimmune IgG and TNF-alpha had slower tumor growth (p2 < 0.02) and a trend toward improved survival (p = 0.07) compared with saline-treated controls. Anti-IFN-gamma Ab abrogated the antitumor effect of TNF-alpha, prevented acute tumor necrosis histologically, and resulted in tumor growth rate and host survival similar to that of controls. The findings in mice that received anti-IFN-gamma Ab and high-dose TNF-alpha were comparable with those in mice that received a lower, equitoxic dose of TNF-alpha alone., Conclusions: Blocking endogenous IFN-gamma accelerates tumor growth in this model and partially abrogates the toxic and antitumor activity of exogenous TNF-alpha equally. This suggests that blocking endogenous IFN-gamma activity is not a useful strategy for limiting TNF-alpha treatment toxicity.

Lovastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (the major regulatory enzyme of the mevalonate pathway of cholesterol synthesis), displays antitumor activity in experimental models. We therefore conducted a Phase I trial to characterize the tolerability of lovastatin administered at progressively higher doses to cancer patients. From January 1992 to July 1994, 88 patients with solid tumors (median age, 57 +/- 14 years) were treated p.o. with 7-day courses of lovastatin given monthly at doses ranging from 2 to 45 mg/kg/day. The inhibitory effects of lovastatin were monitored through serum concentrations of cholesterol and ubiquinone, two end products of the mevalonate pathway. Concentrations of lovastatin and its active metabolites were also determined, by bioassay, in the serum of selected patients. Cyclical treatment with lovastatin markedly inhibited the mevalonate pathway, evidenced by reductions in both cholesterol and ubiquinone concentrations, by up to 43 and 49% of pretreatment values, respectively. The effect was transient, however, and its magnitude appeared to be dose independent. Drug concentrations reached up to 3.9 micrometer and were in the range associated with antiproliferative activity in vitro. Myopathy was the dose-limiting toxicity. Other toxicities included nausea, diarrhea, and fatigue. Treatment with ubiquinone was associated with reversal of lovastatin-induced myopathy, and its prophylactic administration prevented the development of this toxicity in a cohort of 56 patients. One minor response was documented in a patient with recurrent high-grade glioma. Lovastatin given p.o. at a dose of 25 mg/kg daily for 7 consecutive days is well tolerated. The occurrence of myopathy, the dose-limiting toxicity, can be prevented by ubiquinone supplementation. To improve on the transient inhibitory activity of this dosing regimen on the mevalonate pathway, alternative schedules based on uninterrupted administration of lovastatin should also be studied.

Most cell culture and in vitro drug sensitivity assays utilize serum-supplemented media (SSM). However, fully defined serum-free media (SFM) offer several advantages and are being used increasingly for initiation and maintenance of cell cultures. Because serum inhibits the in vitro cytotoxicity of certain antineoplastic agents, we investigated the inter-relationships between medium type, cell proliferation and cytotoxic effect. Twenty-four human lung cancer cell lines were tested with nine anticancer agents in both media types. A semi-automated tetrazolium (MTT) colorimetric assay was used for assaying cell survival. Cell lines initiated and maintained in SFM preferentially proliferated in that medium type or proliferated equally well in both media types. In contrast, cell lines established in SSM varied considerably in their medium of preference. There appeared to be a direct correlation or trend between cell proliferative rate and cytotoxicity of all drugs with the possible exceptions of methotrexate and carmustine. In general, the cell lines were more sensitive to anticancer agents when they were exposed in the culture medium in which they preferentially proliferated. Therefore, to determine the influence of culture media on cytotoxicity, we analyzed the data only from lines that replicated equally efficiently in both media. After correction for cell proliferative rate, SSM had a negative effect on the cytotoxic action of some drugs (especially methotrexate, 5-fluorouracil and, to a lesser extent, mitomycin-C). Our results demonstrate that fully defined SFM may be suitable for initiating cell lines and for use in in vitro cytotoxicity assays for selection of individualized therapy or for screening of new anti-neoplastic agents, and thus may increase the number of antineoplastic agents that can be tested satisfactorily.

Background: The growth-inhibiting and differentiating effects of sodium phenylacetate against hematopoietic and solid tumor cell lines has aroused clinical interest in its use as an anticancer drug. In an earlier Phase I trial of phenylacetate aimed at maintaining serum drug concentrations in the range that proved active in vitro (> 250 micrograms/ml) for 2 consecutive weeks, infusion rates approached the maximum velocity of drug elimination and commonly resulted in drug accumulation and reversible dose-limiting neurologic toxicity. In this study, the authors described the nonlinear pharmacokinetics, metabolism, toxicity, and clinical activity of phenylacetate., Methods: The treatment regimen of this Phase I study was designed to expose patients intermittently to drug concentrations exceeding 250 micrograms/ml and to allow time for drug elimination to occur between doses to minimize accumulation. Sodium phenylacetate was administered as a 1-hour infusion twice daily (8 a.m., 5 p.m.) at two dose levels of 125 and 150 mg/kg for a 2-week period. Therapy was repeated at 4-week intervals for patients who did not experience dose-limiting toxicity or disease progression., Results: Eighteen patients (4 of whom previously were treated with phenylacetate by continuous intravenous infusion) received 27 cycles of therapy. Detailed pharmacokinetic studies for eight patients indicated that phenylacetate induced its own clearance by a factor of 27% in a 2-week period. Dose-limiting toxicity, consisting of reversible central nervous system depression, was observed for three patients at the second dose level. One patient with refractory malignant glioma had a partial response, and one with hormone-independent prostate cancer achieved a 50% decline in prostate specific antigen level, which was maintained for 1 month., Conclusions: Phenylacetate administered at a dose of 125 mg/kg twice daily for 2 consecutive weeks is well tolerated. High grade gliomas and advanced prostate cancer are reasonable targets for Phase II clinical trials.

Phenylacetate has recently been shown to suppress tumor growth and promote differentiation in experimental models. A phase I trial of phenylacetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continuous i.v. infusion of the drug. Twenty-one cycles of therapy were administered at four dose levels, achieved by increasing the rate of the continuous i.v. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 +/- 44.5 (SD) microgram/ml, Vmax = 24.1 +/- 5.2 mg/kg/h and Vd = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylacetylglutamine, which was excreted in the urine. Continuous i.v. infusion rates resulting in serum phenylacetate concentrations exceeding Km often resulted in rapid drug accumulation and dose-limiting toxicity, which consisted of reversible central nervous system depression, preceded by emesis. Three of nine patients with metastatic, hormone-refractory prostate cancer maintained stable prostatic specific antigen levels for more than 2 months; another had less bone pain. One of six patients with glioblastoma multiforme, whose steroid dosage has remained unchanged for the duration of therapy, has sustained functional improvement for more than 9 months. The use of adaptive control with feedback for the dosing of each patient enabled us to safely maintain stable phenylacetate concentrations up to the range of 200-300 micrograms/ml, which resulted in clinical improvement in some patients with advanced disease.