Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors.

Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity-grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation-chemokine induction, T-cell stimulation, regulatory T cell depletion-was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.

Melanoma NOS1 expression promotes dysfunctional IFN signaling.

In multiple forms of cancer, constitutive activation of type I IFN signaling is a critical consequence of immune surveillance against cancer; however, PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Comparison of gene transcription and array comparative genomic hybridization (aCGH) between melanoma cells from different patients indicated that suppression of IFN-α signaling correlates with an amplification of the NOS1 locus within segment 12q22-24. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α. Furthermore, in an explorative study, NOS1 expression in melanoma metastases was negatively associated with patient response to adoptive T cell therapy. This study provides a link between cancer cell phenotype and IFN signal dysfunction in circulating immune cells.

Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: a phase II trial (CTEP 7190/Mel47).

PURPOSE: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. EXPERIMENTAL DESIGN: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood. RESULTS: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0-39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAF(WT) tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P < 0.001), and decreased mitotic rate (Ki67(+)) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4(+)FoxP3(+) cells. CONCLUSION: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAF(wt) melanoma. Mixed effects on immunologic function also support combination with immune therapies.

Surgical management of the patient with metastatic melanoma to the heart.

Melanoma has a high propensity for cardiac seeding, with heart involvement noted in a significant number of patients at autopsy. Therapeutic options are currently limited, and the prognosis of cardiac metastasis is poor. We report two cases of cardiac metastasis of melanoma and review the current literature. In addition, we propose an algorithm for dealing with this difficult problem.

Doege-Potter syndrome presenting with hypoinsulinemic hypoglycemia in a patient with a malignant extrapleural solitary fibrous tumor: a case report.

INTRODUCTION: Doege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. This tumor causes hypoglycemia by the secretion of a prohormone form of insulin-like growth factor II. We describe the diagnosis and management of Doege-Potter syndrome and the use of transarterial chemoembolization in a patient with a malignant extrapleural solitary fibrous tumor. CASE PRESENTATION: Our patient was a 64-year-old Caucasian woman who initially presented with urinary incontinence and was found to have a 14.5×9.0×9.0cm retroperitoneal solitary fibrous tumor compressing her bladder. Her tumor was surgically resected but recurred with multiple hepatic metastatic lesions. The hepatic metastases progressed despite systemic chemotherapy and treatment with doxorubicin transarterial chemoembolization. Her course was complicated by the development of recurrent fasting hypoglycemia, most likely secondary to Doege-Potter syndrome. Her hypoglycemia was managed with corticosteroid therapy and frequent scheduled nutrient intake overnight. CONCLUSIONS: The rarity of hepatic solitary fibrous tumors and consequent lack of controlled trials make this report significant in that it describes the diagnostic approach to Doege-Potter syndrome, describes our experience with the use of doxorubicin transarterial chemoembolization, and presents management options for tumor-associated hypoglycemia in the case of extensive disease not amenable to surgical resection.

A theory-based decision aid for patients with cancer: results of feasibility and acceptability testing of DecisionKEYS for cancer.

PURPOSE: Appropriate utilization of treatment is a goal for all patients undergoing cancer treatment. Proper treatment maximizes benefit and limits exposure to unnecessary measures. This report describes findings of the feasibility and acceptability of implementing a short, clinic-based decision aid and presents an in-depth clinical profile of the participants. METHODS: This descriptive study used a prospective, quantitative approach to obtain the feasibility and acceptability of a decision aid (DecisionKEYS for Balancing Choices) for use in clinical settings. It combined results of trials of patients with three different common malignancies. All groups used the same decision aid series. Participants included 80 patients with solid tumors (22 with newly diagnosed breast cancer, 19 with advanced prostate cancer, and 39 with advanced lung cancer) and their 80 supporters as well as their physicians and nurses, for a total of 160 participants and 10 health professionals. RESULTS: The decision aid was highly acceptable to patient and supporter participants in all diagnostic groups. It was feasible for use in clinic settings; the overall value was rated highly. Of six physicians, all found the interactive format with the help of the nurse as feasible and acceptable. Nurses also rated the decision aid favorably. CONCLUSIONS: This intervention provides the opportunity to enhance decision making about cancer treatment and warrants further study including larger and more diverse groups. Strengths of the study included a theoretical grounding, feasibility testing of a practical clinic-based intervention, and summative evaluation of acceptability of the intervention by patient and supporter pairs. Further research also is needed to test the effectiveness of the decision aid in diverse clinical settings and to determine if this intervention can decrease overall costs.

Molecular insights on the peripheral and intratumoral effects of systemic high-dose rIL-2 (aldesleukin) administration for the treatment of metastatic melanoma.

PURPOSE: We have previously shown that within tumors, recombinant interleukin-2 (rIL-2, aldesleukin) consistently activates tumor-associated macrophages and upregulates IFN-stimulated genes while inducing minimal migration, activation, or proliferation of T cells. These effects are independent of tumor response to treatment. Here, we prospectively evaluated transcriptional alterations induced by rIL-2 in peripheral blood mononuclear cells (PBMC) and within melanoma metastases. EXPERIMENTAL DESIGN: We evaluated gene expression changes by serially comparing pre- to posttreatment samples in 13 patients and also compared transcriptional differences among lesions displaying different responsiveness to therapy, focusing on 2 lesions decreasing in size and 2 remaining stable (responding lesions) compared with nonresponding ones. RESULTS: As previously described, the effects of rIL-2 were dramatic within PBMCs, whereas effects within the tumor microenvironment were lesion specific and limited. However, distinct signatures specific to response could be observed in responding lesions pretreatment that were amplified following rIL-2 administration. These signatures match the functional profile observed in other human or experimental models in which immune-mediated tissue-specific destruction (TSD) occurs, underscoring common pathways leading to rejection. Moreover, the signatures observed in pretreatment lesions were qualitatively similar to those associated with TSD, underlining a determinism to immune responsiveness that depends upon the genetic background of the host or the intrinsic genetic makeup of individual tumors. CONCLUSIONS: This is the first prospectively collected insight on global transcriptional events occurring during high-dose rIL-2 therapy in melanoma metastases responding to treatment.

Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma (PDA) represent a high-risk group of patients due to tumor or patient-related characteristics. The optimal management of these patients has not been fully defined. MATERIALS AND METHODS: All patients undergoing evaluation for PDA between 2005 and 2008 were identified. Clinical, radiographic, and pathological data were retrospectively reviewed. Patients were staged as borderline resectable using the M.D. Anderson Cancer Center (MDACC) classification. RESULTS: A total of 170 patients with PDA were identified, 40 with borderline resectable disease. Of these, 34 borderline resectable patients (85%) completed neoadjuvant therapy and were restaged; pancreatic resection was completed in 16 patients (46%). Also, 8 patients completed 50 Gy of radiation in 28 fractions in 6 weeks, whereas 8 patients received 50 Gy in 20 fractions in 4 weeks plus chronomodulated capecitabine. An R0 resection was achieved in 12 of the 16 patients (75%). Also, 5 patients (63%) treated in 20 fractions had >90% pathologic response versus 1 (13%) treated in 28 fractions (P < .05). Borderline resectable patients completing surgery had similar survival to patients with resectable disease who underwent surgery. Patients receiving accelerated fractionation radiation had improved survival compared with patients treated with standard fractionation protocol. CONCLUSIONS: A neoadjuvant approach to borderline resectable PDA identifies patients who are most likely to benefit from pancreatic resection. Preoperative capecitabine-based chemoradiation is an effective, well-tolerated treatment for these patients. Neoadjuvant therapy for borderline resectable PDA warrants further investigation using treatment schedules that can safely intensify irradiation dose.

Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy.

BACKGROUND & AIMS: Photodynamic therapy (PDT) for unresectable cholangiocarcinoma is associated with improvement in cholestasis, quality of life, and potentially survival. We compared survival in patients with unresectable cholangiocarcinoma undergoing endoscopic retrograde cholangiopancreatography (ERCP) with PDT and stent placement with a group undergoing ERCP with stent placement alone. METHODS: Forty-eight patients were palliated for unresectable cholangiocarcinoma during a 5-year period. Nineteen were treated with PDT and stents; 29 patients treated with biliary stents alone served as a control group. Multivariate analysis was performed by using Model for End-Stage Liver Disease score, age, treatment by chemotherapy or radiation, and number of ERCP procedures and PDT sessions to detect predictors of survival. RESULTS: Kaplan-Meier analysis demonstrated improved survival in the PDT group compared with the stent only group (16.2 vs 7.4 months, P<.004). Mortality in the PDT group at 3, 6, and 12 months was 0%, 16%, and 56%, respectively. The corresponding mortality in the stent group was 28%, 52%, and 82%, respectively. The difference between the 2 groups was significant at 3 months and 6 months but not at 12 months. Only the number of ERCP procedures and number of PDT sessions were significant on multivariate analysis. Adverse events specific to PDT included 3 patients with skin phototoxicity requiring topical therapy only. CONCLUSIONS: ERCP with PDT seems to increase survival in patients with unresectable cholangiocarcinoma when compared with ERCP alone. It remains to be proved whether this effect is attributable to PDT or the number of ERCP sessions. A prospective randomized multicenter study is required to confirm these data.

Multimodality Treatment With Helical Tomotherapy Intensity Modulated Radiotherapy, Capecitabine, and Photodynamic Therapy is Feasible and Well Tolerated in Patients With Hilar Cholangiocarcinoma.

BACKGROUND AND PURPOSE: Unresectable cholangiocarcinoma is an intractable disease marked by recurrent bouts of biliary obstruction and infection. Traditional treatment methods provide only symptomatic relief and no proven survival advantage. We assessed the tolerability of helical tomotherapy intensity modulated radiotherapy (IMRT) with concurrent capecitabine and photodynamic therapy (PDT) in patients with unresectable hilar cholangiocarcinoma. METHODS: Ten patients with unresectable hilar cholangiocarcinoma were treated with helical tomotherapy IMRT. An accelerated dose of 50 Gy in 20 fractions (2.5 Gy/fraction) was used. Planning target volume (PTV) consisted of a 1.5 cm radial expansion and a 2 cm craniocaudal expansion of the magnetic resonance imaging and/or contrast enhanced computed tomography-defined gross target volume. PTV ranged from 123 cc to 693 cc (mean 349 cc). Concurrent chronomodulated capecitabine was administered on days of irradiation. Six patients received PDT. RESULTS: All patients developed side effects, including grade 2 nausea, and 9 of 10 experienced mild fatigue. Patients lost 3% of their body weight on average. Three patients required brief hospital admission and stent revision for cholangitis during chemoradiotherapy. Capecitabine was discontinued in one patient and decreased in dose for another due to increasing liver enzymes. Median overall survival was 13 months, and median disease-free survival was 10 to 11 months. One patient underwent successful cadaveric liver transplant after chemoradiotherapy and remains disease free 2 years later. CONCLUSIONS: Concurrent chemoradiotherapy with helical tomotherapy IMRT and capecitabine in conjunction with PDT is well tolerated in patients with hilar cholangiocarcinoma.

A phase II, pharmacokinetic, and biologic study of semaxanib and thalidomide in patients with metastatic melanoma.

PURPOSE: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination. PATIENTS AND METHODS: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib. RESULTS: Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months. CONCLUSION: The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.

Phase II study of consolidation paclitaxel after concurrent chemoradiation in poor-risk stage III non-small-cell lung cancer: SWOG S9712.

PURPOSE: A previous Southwest Oncology Group (SWOG) study (S9429) demonstrated efficacy and tolerability of concurrent chemoradiotherapy in poor-risk stage III non-small-cell lung cancer (NSCLC). This study evaluated adding consolidation paclitaxel after chemoradiotherapy for a similar patient cohort. PATIENTS AND METHODS: Patients with histologically/cytologically determined stage III NSCLC were eligible based on performance status (PS) 2 and either low albumin or weight loss more than 10%, poor pulmonary function, or comorbidities precluding cisplatin use. Treatment was carboplatin 200 mg/m2 days 1, 3, 29, and 31, and etoposide 50 mg/m2 days 1 through 4, and 29 to 32. Beginning day 1, thoracic radiation was delivered at 1.8 Gy in 25 fractions plus 16-Gy boost (total dose, 61 Gy). Patients without disease progression received paclitaxel 175 mg/m2 every 21 days for three cycles. RESULTS: Characteristics of 87 eligible patients were age 51 to 82 years; 57% PS 0 to 1, 43% PS 2; and 51% stage IIIA, 49% stage IIIB. Toxicities of concurrent chemoradiotherapy included grade 3 esophagitis (7%) and grade 3/4 neutropenia (43%). Fifty-four assessable patients received paclitaxel consolidation. Four treatment-related deaths occurred during chemoradiotherapy and four occurred during consolidation. Overall response rate was 53%. Median progression free- and overall survival were 6.1 and 10.2 months, respectively. One- and 2-year survival rates were 43% and 25%. CONCLUSION: Compared with a previous SWOG trial in a similar patient population, the addition of consolidation paclitaxel after chemoradiotherapy resulted in increased toxicity without a survival advantage. More PS 2 patients (43% v 18%) enrolled onto S9712, which may explain increased toxicity and lack of benefit. The optimal chemoradiotherapy approach for poor-risk patients remains to be defined.

Locally advanced prostate cancer treated with concomitant radiation and 5-fluorouracil: Southwest Oncology Group Study 9024.

PURPOSE: Radiation is considered the standard treatment for locally advanced (T3 and T4) prostate cancer but cure with radiation alone is infrequent. Studies have shown that adding androgen ablation improves the results but there is still much room for improvement. We performed a phase II multi-institutional study to explore the feasibility of concomitant chemoradiotherapy. MATERIALS AND METHODS: Eligible patients had prostate cancer with clinical evidence of invasion through the prostatic capsule or into the seminal vesicles without evidence of nodal or distant metastasis. Prior prostatectomy was not allowed and patients could not be candidates for surgical resection due to medical reasons or refusal of surgery. Radiation consisted of 7,020 cGy in 39 fractions. Continuous infusion 5-fluorouracil at a dose of 200 mg/m2 daily was started on day 1 and continued 7 days weekly until the last day of radiation. RESULTS: All 30 eligible patients were evaluated for toxicity. Diarrhea was the most common toxicity with grade 3 and 4 diarrhea in 2 and 1 patients, respectively. The only other grade 4 toxicity was hemorrhagic cystitis in 1 patient. There was 1 incident each of grade 3 stomatitis, congestive heart failure, edema, proctitis and hematuria. No patient with grade 3 or 4 toxicity required treatment delay. Ten patients (33%) achieved a negative biopsy and 13 (43%) achieved prostate specific antigen less than 1.0 ng/ml. Six patients (20%) achieved a complete response, defined as negative biopsy and prostate specific antigen less than 1.0 (95% CI 8 to 39). Patients without any biopsies or without prostate specific antigen followup were assumed to be nonresponders. CONCLUSIONS: Toxicity was acceptable. The modest response rate indicates that better chemotherapy that improves local and systemic failure is necessary to improve the results. This study confirms the feasibility of a combined chemoradiotherapy approach.

Phase II trial of paclitaxel, carboplatin, and topotecan with G-CSF support in previously untreated patients with extensive stage small cell lung cancer: Southwest Oncology Group 9914.

PURPOSE: This phase II study (S9914) evaluated the efficacy and toxicity of the three-drug combination of paclitaxel, carboplatin, and topotecan with granulocyte colony-stimulating factor support in previously untreated patients with extensive stage small cell lung cancer. PATIENTS AND METHODS: Patients with newly diagnosed extensive stage small cell lung cancer received topotecan 1.0 mg/m intravenously on days 1 through 4; paclitaxel 175 mg/m intravenously on day 4, and carboplatin AUC = 5 intravenously on day 4, treatments were repeated every 21 days for a maximum of six cycles. All patients also received granulocyte colony-stimulating factor 5 mug/kg/day beginning on day 5 of each cycle. RESULTS: A total of 88 patients were enrolled on the study; 79 patients were assessable for survival and toxicity and 74 patients for response. Objective response was observed in 50 patients (68%; 95% confidence interval [CI]: 56%-78%) with nine patients (12%) achieving a complete response. Median progression-free survival was 7 months (95% CI: 6-8 months) and median overall survival was 12 months (95% CI: 11-14 months). The 1- and 2-year survival rates were 48% (95% CI: 37%-59%) and 20% (95% CI: 11%-29%), respectively. The most common toxicities were hematologic. Grade 3 and 4 neutropenia was noted in 17 (22%) and 27 (34%) patients, respectively. Febrile neutropenia developed in only four patients. Two patients (3%) died of treatment-related causes. CONCLUSION: The combination of paclitaxel, carboplatin, and topotecan combined with granulocyte colony-stimulating factor support is an active and reasonably well-tolerated regimen for the treatment of extensive stage small cell lung cancer.

A phase II clinical trial of oral bropirimine in combination with intravesical bacillus Calmette-Guérin for carcinoma in situ of the bladder: a Southwest Oncology Group Study.

OBJECTIVES: To estimate the probability of response when intravesical bacille Calmette-Guérin (BCG) is given in combination with oral bropirimine for bladder carcinoma in situ, and to evaluate toxicity when the 2 agents are combined. METHODS: A total of 51 patients with histologic evidence of carcinoma in situ and no prior treatment with BCG or bropirimine were enrolled in a cooperative group multicenter phase II trial. Initial treatment included Tice BCG 50 mg weekly for 6 weeks and oral bropirimine 3.0 g/day for 3 consecutive days each week for 12 weeks. Response was assessed after 12 weeks by cystoscopy, biopsy, and barbotage cytology. Most patients received a second course followed by an identical assessment. Toxicity was recorded according to the Southwest Oncology Group toxicity criteria. RESULTS: A total of 51 patients were enrolled and treated. There were 42 patients who were eligible and valuable for response and toxicity. There were 28 complete responders (67%, 50% to 80% 95% confidence interval). The 5-year progression-free survival estimate is 53%, and the 5-year survival estimate is 80%. There were no deaths, 2 patients had grade 4 toxicity, 14 grade 3 toxicity, 17 grade 2 toxicity, 6 grade 1 toxicity, and only 3 had no toxicity reported as their worst toxicity grade. CONCLUSIONS: The combination failed to show an estimated response higher than 80%. It is not recommended that further evaluation of this combination be conducted.

Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer.

PURPOSE: Modest toxicity and possibly enhanced activity makes continuous-infusion fluorouracil (FU) an attractive alternative to FU plus leucovorin (FU/LV) for the adjuvant treatment of colorectal cancer. Intergroup trial 0153 (Southwest Oncology Group trial 9415) was developed to compare the efficacy of continuous-infusion FU (CIFU) plus levamisole to FU/LV plus levamisole in the adjuvant treatment of high-risk Dukes' B2 and C1 or C2 colon cancer. PATIENTS AND METHODS: After surgery, patients were randomly assigned to CIFU 250 mg/m(2)/d for 56 days every 9 weeks for three cycles or FU 425 mg/m(2) and LV 20 mg/m(2) daily for 5 days every 28 to 35 days for six cycles. All patients received levamisole 50 mg tid for 3 days every other week. The primary end point was overall survival (OS). RESULTS: The study closed in December 1999 after an interim analysis demonstrated little likelihood of CIFU showing superiority to FU/LV within the stipulated hazard ratio. A total of 1,135 patients were registered. At least one grade 4 toxicity occurred in 39% of patients receiving FU/LV and 5% of patients receiving CIFU. However, almost twice as many patients receiving CIFU discontinued therapy early compared with those receiving FU/LV. The 5-year OS is 70% (95% CI, 66% to 74%) for FU/LV and 69% (95% CI, 64% to 73%) for CIFU. The corresponding 5-year disease-free survival (DFS) is 61% (95% CI, 56% to 65%) and 63% (95% CI, 59% to 68%), respectively. For all patients, 5-year OS is 83%, 74%, and 55%; 5-year DFS is 78%, 67%, and 47% for N0, N1, and N2-3, respectively. CONCLUSION: CIFU had less severe toxicity but did not improve DFS or OS in comparison with bolus FU/LV.

Phase II trial of vinorelbine for relapsed ovarian cancer: a Southwest Oncology Group study.

OBJECTIVES: To assess the activity of vinorelbine in women with recurrent or resistant epithelial ovarian cancer following treatment with platinum and paclitaxel in terms of survival rate at 6 months, objective response rate (in the subset of patients with bidimensionally measurable disease), and health-related quality of life. METHODS: Seventy-nine evaluable patients with progressive ovarian cancer following platinum and taxane therapy received vinorelbine 30 mg/m(2) days 1 and 8 of a 21-day treatment cycle. RESULTS: Six-month survival rate for the entire group was 65% (95% CI: 54-75%) and median survival was 10.1 months (95% CI: 7.7-13.6 months). In the 71 women with measurable disease, 0 complete and 2 partial responses were observed (RR = 3%) (95% CI: 0.3-10%). Patients reported substantial symptom-related distress at baseline, which persisted, but did not worsen, during treatment. Patients also had impaired physical functioning at baseline and this continued to decline during treatment. CONCLUSIONS: The 6-month survival rate achieved with salvage vinorelbine is comparable to the results obtained with other salvage therapies in patients with relapsed ovarian cancer. During the initial 10 weeks of treatment, vinorelbine did not appear to be effective in alleviating the symptom-related distress or progressive impairment of physical functioning associated with this disease.

Randomized phase II trial of sequential chemotherapy in advanced non-small cell lung cancer (SWOG 9806): carboplatin/gemcitabine followed by paclitaxel or cisplatin/vinorelbine followed by docetaxel.

PURPOSE: Improving chemotherapeutic efficacy in non-small cell lung cancer (NSCLC) will require the development of new drugs or new strategies to better use currently available agents. Sequential administration offers an opportunity to increase drug diversity while maintaining dose intensity. On the basis of the data indicating the activity of taxanes as second-line therapy and the lack of efficacy for more than three cycles of platinum-based therapy, this randomized Phase II study tested the concept of planned sequential chemotherapy in advanced NSCLC. EXPERIMENTAL DESIGN: Patients with selected stage IIIb (pleural effusion)/stage IV NSCLC, performance status of 0-1 and normal organ function were eligible. THERAPY: arm 1, carboplatin (area under the curve = 5.5 mg/ml x min day 1) and gemcitabine (1000 mg/m(2) days 1 and 8 every 21 days x 3) followed by paclitaxel (225 mg/m(2) every 21 days x 3) or arm 2, cisplatin (100 mg/m(2) day 1), vinorelbine (25 mg/m(2) days 1 and 8 every 21 d x 3) followed by docetaxel (75-100 mg/m(2) every 21 days x 3). RESULTS: Two-hundred four patients were accrued, of whom, 178 were eligible and evaluable. Eighty percent of patients were stage IV on arm 1 and 85% on arm 2. Response rates were 21 and 28% on arms 1 and 2, respectively. Median, 1-year and 2-year survivals were 9 months, 34 and 13%, and 9 months, 36 and 8%, on arms 1 and 2, respectively. CONCLUSIONS: Sequential therapy, as used in this study, resulted in comparable efficacy to previous Southwest Oncology Group trials of two drug combinations in this population; however, it failed to meet criteria for further study.

A randomized phase I and pharmacological trial of sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide in patients with advanced solid neoplasms.

PURPOSE: O(6)-alkylguanine-DNA alkyltransferase (AGAT) is modulated by methylating agents, which, in turn, abrogates nitrosourea resistance in preclinical studies. The feasibility of administering various sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TEM) in patients with advanced solid neoplasms was evaluated in this Phase I and pharmacological study to assess this premise in the clinical setting. The study also sought to determine the maximum tolerated dose (MTD) levels of BCNU and TEM as a function of Seq, to characterize the pharmacokinetic (PK) behavior of TEM administered both before and after BCNU, assess AGAT fluctuations in peripheral blood mononuclear cells (PBMCs), and seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Sixty-three patients were randomized to receive treatment with oral TEM daily on days 1-5 and BCNU administered i.v., either on day 1 before TEM [Sequence (Seq) B-->T] or day 5 after TEM (Seq T-->B). Treatment was repeated every 6 weeks. Blood sampling for PK studies was performed on both days 1 and 5 of course one. PBMCs were sampled to evaluate major sequence-dependent effects on AGAT levels. RESULTS: Neutropenia and thrombocytopenia were the principal dose-limiting toxicities of the BCNU/TEM regimen. These effects were more prominent in patients receiving Seq T-->B, resulting in a much lower MTD of 80/100 mg/m(2)/day compared with 150/110 mg/m(2)/day for Seq B-->T. Notable antitumor activity was observed in patients with glioblastoma multiforme, sarcoma, and ovarian carcinoma. No sequence-dependent PK effects were noted to account for sequence-dependent toxicological effects. At the MTD level, AGAT activity in PBMCs decreased 3-fold, on average, and AGAT fluctuations did not appear to be sequence-dependent. CONCLUSIONS: The principal toxicities of the BCNU/TEM regimen were neutropenia and thrombocytopenia, which were consistent and predictable, albeit sequence-dependent. Seq T-->B was substantially more myelosuppressive, resulting in disparate MTDs and dose levels recommended for subsequent disease-directed evaluations (150/110 and 80/100 mg/m(2)/day for Seq B-->T and T-->B, respectively). Sequence-dependent differences in TEM PK do not account for this clinically relevant magnitude of sequence-dependent toxicity. The characteristics of the myelosuppressive effects of BCNU/TEM, the paucity of severe nonhematological toxicities, and antitumor activity at tolerable doses warrant disease-directed evaluations on this schedule.

Phase II trial of cisplatin/etoposide and concurrent radiotherapy followed by paclitaxel/carboplatin consolidation for limited small-cell lung cancer: Southwest Oncology Group 9713.

PURPOSE: Limited small-cell lung cancer (LSCLC) is characterized by a high initial response rate to chemoradiotherapy, but local or systemic relapse occurs in the majority of patients. Previous Southwest Oncology Group trials in LSCLC have utilized cisplatin and etoposide (PE) delivered concurrently with thoracic radiotherapy followed by two consolidation cycles. Newer chemotherapy regimens such as paclitaxel and carboplatin are active in small-cell lung cancer and hold the promise of improving both local and systemic control. S9713 evaluated the substitution of paclitaxel and carboplatin for PE consolidation in LSCLC. PATIENTS AND METHODS: Between July 1998 and August 1999, 96 patients were accrued from 43 institutions. Eighty-nine patients were eligible; 87 were assessable for survival and response. Treatment consisted of cisplatin 50 mg/m(2) on days 1, 8, 29, and 36, and etoposide 50 mg/m(2) on days 1 to 5 and days 29 to 33, with concurrent radiotherapy of 61 Gy beginning on day 1. Consolidation therapy was carboplatin (area under the curve = 6) and paclitaxel 200 mg/m(2), both drugs administered on day 1 of a 21 day cycle for three cycles. RESULTS: The response rate was 86% (complete response, 33%; partial response, 53%). Median overall survival was 17 months (95% CI, 12.7 to 19.0). One- and 2-year overall survivals were 61% and 33%, respectively. Median progression-free survival (PFS) was 9 months, 1-year PFS was 40%, and 2-year PFS was 21%. CONCLUSION: Consolidation therapy with paclitaxel and carboplatin in LSCLC resulted in an outcome similar to that seen in prior Southwest Oncology Group trials. This study and others which have tested paclitaxel in small-cell lung cancer dampens enthusiasm for this agent in the primary management of LSCLC.