S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma.

BACKGROUND: Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers. METHODS: Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively. RESULTS: Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1-20%), with a median progression-free survival of 2 months (95% CI: 2-3), and median overall survival of 6 months (95% CI: 3-8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash. CONCLUSIONS: Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.

Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma.

PURPOSE: To compare the response rate, survival, and toxicity of treatment with high-dose intravenous (IV) bolus interleukin-2 (IL-2) plus interferon alfa-2a (IFN-alpha) with high-dose IL-2 alone in patients with advanced melanoma in a randomized phase III trial design. PATIENTS AND METHODS: Eighty-five patients with advanced melanoma were randomly assigned to receive IL-2 6 X 10(6) U/m2 per dose every 8 hours as tolerated for a maximum of 14 doses on days 1 through 5 and 15 through 19, or IL-2 4.5 X 10(6) U/m2 per dose, plus IFN-alpha 3 X 10(6) U/m2 using an identical schedule. A planned interim analysis was performed after 85 patients were entered, which forms the basis for this report. RESULTS: Partial response (PR) occurred in two of 44 patients (5%; 95% confidence interval, 1% to 15%) receiving IL-2 alone, compared with four of 41 patients (10%; 95% confidence interval, 3% to 23%) receiving IL-2/IFN-alpha (P = .30). There were no complete responses (CRs). The median duration of response was 11.5 months (range, 2.0 to 15.7+). There was no significant difference in the median survival duration for patients receiving IL-2 alone (10.2 months) compared with patients receiving IL-2/IFN-alpha (9.7 months). The median and mean number of doses of IL-2 were equivalent in both groups, as was toxicity. There were three treatment-related deaths, two in the IL-2-alone arm and one in the IL-2/IFN-alpha arm. The trial was terminated after the first interim analysis based on predefined early-stopping rules, which included termination if the response rate in the IL-2/IFN-alpha arm was less than 25%. CONCLUSION: Using the preparation, dose, and schedule of IL-2 in our trial, IFN-alpha failed to enhance significantly the response rate to high-dose IL-2 in the treatment of patients with advanced melanoma.

Phase I study of streptozocin- and carmustine-sequenced administration in patients with advanced cancer.

BACKGROUND: Fewer than 20% of patients with nonhematologic malignancies treated with chloroethylnitrosoureas (CENUs) respond, but streptozocin (STZ), which depletes O6-methylguanine-DNA-methyltransferase (MGMT), has been shown to reverse resistance to CENUs in vitro. PURPOSE: The purpose of this phase I study was to determine (a) the maximum tolerated dose (MTD) of carmustine (BCNU), a CENU, plus a fixed dose of STZ; (b) the toxic effects of the drugs; and (c) the effects on peripheral blood mononuclear cells (PBMC). METHODS: A clinical phase I study of STZ followed by BCNU was designed to simulate conditions that produce maximal sensitization of CENU-resistant HT-29 cells in vitro. Patients received a 20-minute infusion of the MTD of STZ (2 g/m2) followed 1 hour later with a 60-minute infusion of BCNU (100, 125, 137.5, or 150 mg/m2). Treatment was repeated after 6 weeks. Twenty-four patients with advanced malignancies received 32 courses of therapy (range, 1-2 courses). RESULTS: The MTD of BCNU was 125 mg/m2. The dose-limiting toxic effect was thrombocytopenia occurring about 22 days after treatment, with recovery between days 28 and 35. Transient hypophosphatemia and proteinuria were common, and serum creatinine was elevated in 9% of the courses. Two patients who received therapy died--one due to pulmonary toxic effects and one due to hepatic toxic effects. Two patients with previously untreated carcinoid achieved partial response. In three patients, MGMT levels in PBMC were more than 85% depleted after STZ administration and more than 90% depleted after BCNU infusion. CONCLUSIONS: These results show that the magnitude of MGMT depletion by STZ in PBMC is in the range necessary to produce sensitivity to CENUs in resistant cell lines but also that, when BCNU is combined with STZ, the MTD of BCNU is about 50% that of BCNU as a single agent and that platelet count suppression occurs earlier. IMPLICATIONS: We plan to conduct phase II studies of STZ plus BCNU in tumor types with low response to CENUs. One of the major goals will be to demonstrate that depletion of MGMT is greater in tumor cells than in normal cells.

Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine-activated killer cells.

Fifty patients with advanced melanoma received high-dose bolus and continuous infusion interleukin-2 (IL-2) with lymphokine-activated killer (LAK) cells in an attempt to improve the therapeutic index of this active but toxic therapy. Treatment began with up to nine bolus doses of IL-2 administered over 3 days. After 1 day of rest, patients underwent daily leukapheresis for 4 days, and the leukocytes were cultured with IL-2 in vitro to prepare LAK cells. Continuous infusion IL-2 was begun 1 day after the last leukapheresis and continued for up to 148 hours; LAK cells were administered on days 1, 2, and 4 of the infusion. Responding patients were eligible to receive up to two additional cycles of therapy at 3-month intervals. Most patients completed each cycle without dose reduction. One patient had a complete response and six patients had partial responses (14% response rate). The complete responder and three of the partial responders (8%) remain free from disease progression with follow-up of 21 to 24 months. Of these four patients with durable remissions, one had extensive liver and lymph node metastases, one had lymph node, pleural, and parenchymal lung metastases, and two had disease limited to lymph nodes or subcutaneous tissues. Seventeen patients (34%) required pressors for hypotension, three patients (6%) developed hemodynamically significant arrhythmias, and six patients (12%) developed dyspnea at rest, but none required intubation and there were no treatment-related deaths. Unacceptable toxicity developed in two patients during bolus IL-2 administration and therapy was aborted; both returned to baseline status within 4 days of discontinuing IL-2. Fever, oliguria, and elevated creatinine or transaminase levels occurred frequently but were also transient. Despite less frequent severe toxicity with this modified regimen, these results confirm the ability of IL-2 and LAK cell therapy to induce durable remissions in some patients with advanced melanoma.

Inhibition of a specific DNA repair system and nitrosourea cytotoxicity in resistant human cancer cells.

In this report we present evidence which suggests that pretreatment of a highly nitrosourea-resistant human colon tumor cell line with non-cytotoxic doses of streptozotocin (STZ) prior to, or simultaneously with, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) exposure produces synergistic increases in cytotoxicity of several logs over the cytotoxicity produced by exposure to BCNU alone. STZ pretreatment or simultaneous treatment with BCNU allowed BCNU-induced DNA interstrand crosslinks to form in this cell line, in which BCNU alone did not induce DNA interstrand-crosslinks. Reversal of the schedule (i.e., STZ following BCNU) was less effective in producing synergistic cell kill or increased DNA interstrand crosslinking. Replacement of BCNU with fresh BCNU was not effective in producing increased cell kill and produced no observable interstrand crosslinking. Direct assays for guanine O6-DNA alkyltransferase activity confirmed that more than 75% inhibition of this important DNA repair system occurred following exposure to 2.5 mM STZ and that the inhibition was virtually complete when STZ pretreatment was combined with BCNU exposure.

A comparative study of the cytotoxicity and DNA-damaging effects of cis-(diammino)(1,1-cyclobutanedicarboxylato)-platinum(II) and cis-diamminedichloroplatinum(II) on L1210 cells.

Utilizing the DNA alkaline elution technique we have compared qualitatively and quantitatively the DNA lesions produced in L1210 cells after a 2 h exposure to the antitumor agents, cis-(diammino) (1,1-cyclobutanedicarboxylato)-platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (DDP). DNA-protein and DNA interstrand cross-links are formed in cells exposed to either CBDCA or DDP. However, in comparison to DDP peak levels of these lesions occur 6 to 12 h later in CBDCA treated cells. Cytotoxicity studies reveal that CBDCA is 45 times less potent than DDP to L1210 cells when compared on a molar basis. The decreased cytotoxicity of CBDCA and the 12 h delay in peak cross-linking when compared to DDP is interpreted as a decreased reactivity of the intact CBDCA towards the DNA. This decreased reactivity may be due in part to the presence of a stable bidentate dicarboxylate chelate ring structure of CBDCA resulting in a much slower rate of hydrolysis to the active form of the drug.

Phase I-II study of m-AMSA administered as a continuous infusion.

In vitro studies of 4'(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) with L1210 leukemia cells have demonstrated that a given level of DNA breakage and intraceLlular m-AMSA concentration depends upon the presence of a continuous concentration of extracellular drug and that cytotoxicity increases with an increasing duration of drug exposure. Since previous studies had shown that free m-AMSA has a half-life of 6-8 hours, a trial of m-AMSA given as a continuous infusion was undertaken in patients with solid tumors and lymphomas. Patients were treated with 30 mg/m2/day x 3, 30 mg/m2/day x 4, or 40 mg/m2/ day x 3. Myelosuppression was dose-limiting and occurred at about Day 13 after the start of the infusion. Recovery was noted by Day-21. There was no evidence of cumulative hematologic toxicity. The maximally tolerated dose was 30 mg/m2/day x 3 in our patient population. Mild phlebitis occurred in all patients. There were no instances of gastrointestinal, hepatic, renal, cardiac, or neurologic toxic reactions. Evidence of some antitumor effect was seen in three patients. We conclude that it is possible to given m-AMSA as a continuous infusion and that studies should be undertaken in patients with acute myelogenous leukemias to compare the efficacy of m-AMSA infusion with conventional bolus administration as a means to enhance the duration of response.

Reactivation of chronic hepatitis B virus infection by cancer chemotherapy.

Two patients referred for cancer chemotherapy were found to be chronic, asymptomatic hepatitis B surface antigen (HBsAg) carriers. They had normal serum aminotransferase levels, but their sera were positive for HGsAg and antibody to hepatitis B e antigen. Both patients developed acute, icteric hepatitis within 3 months of starting cycled chemotherapy. In both cases, the disease seemed to be caused by a recurrence of type B hepatitis; it was accompanied by a marked increase in HBsAg titer and the appearance of hepatitis B virus DNA and DNA polymerase in the serum. One patient had a second episode of acute hepatitis after a second course of chemotherapy, but both patients ultimately recovered and became seronegative for HBsAg. Thus, it seems that cancer chemotherapeutic agents can reactivate type B hepatitis in asymptomatic HBsAg carriers. This reactivation is most likely due to an increase in hepatitis B virus synthesis followed by a rebound in host immune responses to hepatitis B virus infection when therapy is stopped. Such a phenomenon could have important implications for the therapy of chronic hepatitis B virus infection.

Nephrotoxicity of semustine (methyl-CCNU) in patients with malignant melanoma receiving adjuvant chemotherapy.

The nephrotoxicity of semustine (methyl-CCNU) has been studied in 45 adult patients with surgically resected Stage I or II malignant melanoma who received this drug as adjuvant chemotherapy. Abnormalities of renal function (including three cases of renal failure) were noted in seven of 45 patients (16 percent); all these patients received more than 1,400 mg/m2. This represents an incidence of 26 percent in patients receiving more than 1,400 mg/m2 of semustine. Two distinct patterns emerged. Abnormal serum creatinine levels developed in two patients while receiving semustine and later progressed to renal failure. Five patients had normal serum creatinine levels throughout their treatment courses but had abnormal creatinine values one month to two years following the completion of drug therapy. Renal failure developed in one of these patients, but the remaining four have had stable renal function for one to two years of additional follow-up. No clinical signs of renal insufficiency were detected in any patients receiving less than 1,400 mg/m2 of semustine. No changes unequivocally attributable to semustine were seen in eight patients at autopsy despite the fact that three had received greater than 1,900 mg/m2 of nitrosourea. This incidence of nephrotoxicity appears to be significantly lower than that previously reported in children. Guidelines for future therapy with semustine are described.