A phase II trial of gemcitabine, 5-fluorouracil and leucovorin in advanced esophageal carcinoma

BACKGROUND: The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin. PATIENTS AND METHODS: Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m(2). Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria. RESULTS: Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia. CONCLUSION: The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.     

A phase II study of capecitabine and lapatinib in advanced refractory colorectal adenocarcinoma: A Wisconsin Oncology Network study

Background

Prognosis remains poor after progression on first-line chemotherapy for colorectal adenocarcinoma, and inactivation of the EGFR pathway with monoclonal antibodies is an effective treatment strategy in selected patients with metastatic disease. Lapatinib is an oral EGFR and HER-2 dual tyrosine kinase inhibitor that has not shown significant activity in metastatic colorectal cancer. However, lapatinib may act synergistically with capecitabine in anticancer effects.

Methods

This was an open-label, non-randomized phase II study of lapatinib 1,250 mg orally daily and capecitabine 2,000 mg/m² by mouth split into twice-daily dosing for 14 days of a 21 days cycle. Inclusion criteria included metastatic or locally advanced adenocarcinoma of the colon or rectum with progression by RECIST on or within six months of receiving a fluoridopyrimidine-, oxaliplatin- or irinotecan-containing regimen. Prior EGFR monoclonal antibody was permitted. K-ras testing was not routinely performed and was not a part of the study protocol.

Results

Twenty nine patients (16 M; 13 F) were enrolled in this study. There were no complete or partial responses. 41.4% of patients achieved stable disease as a best response. Median overall survival was 6.8 months, with a 1-year survival rate of 22%, and median progression-free survival was 2.1 months. The combination produced few grade 3 and no grade 4 toxicities. No grade 3 toxicity occurred in more than 10% of patients.

Conclusions

Although capecitabine and lapatinib is well tolerated, it is not an effective regimen in patients with refractory colorectal adenocarcinoma.Key Words: Colorectal cancer, capecitabine, lapatinib, EGFR, Her-2     

Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer

Purpose Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer. Methods Eligible women were treated with POH four times daily at 1,200–1,500 mg m⁻² dose⁻¹ on a 28-day cycle. Patients tolerating 1,200 mg m⁻² day⁻¹ four times daily after one cycle were dose-escalated to 1,500 mg/m². The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations. Results Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m². Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29–123 days). Median overall survival was 389 days (95% CI, 202–776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-β1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability. Conclusions Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.     

A Phase II Study of Oxaliplatin, 5-Fluorouracil,Leucovorin, and High-Dose Capecitabine in Patients With Metastatic Colorectal Cancer

PurposeCapecitabine has shown similar efficacy to 5-fluorouracil (5-FU); a regimen containing 2 weeks of capecitabine/oxaliplatin (CapOx) has demonstrated noninferiority to infusional 5-FU/oxaliplatin/leucovorin (FOLFOX) for the treatment of metastatic colorectal cancer (mCRC). This phase II study explores the efficacy and safety of a 2-day course of oxaliplatin/capecitabine (2DOC), with oxaliplatin given on day 1 and capecitabine given orally every 8 hours in high doses over 6 doses, mimicking FOLFOX6.Patients and MethodsThis phase II study was conducted by the University of Wisconsin Carbone Cancer Center. Eligible patients with mCRC received oxaliplatin 100 mg/m² intravenously (I.V.) over 2 hours followed by leucovorin 20 mg/m² I.V. bolus and 5-FU 400 mg/m² I.V. bolus on day 1 and day 15. Capecitabine was administered at 1500 mg/m² orally every 8 hours over 6 doses starting on day 1 and day 15.ResultsA total of 45 patients were enrolled; 44 were evaluated for response. Seventeen patients (39%) had objective responses. Median time to progression was 6.8 months, and median overall survival (OS) was 17.5 months. The most common side effects were grade 1/2 neuropathy, fatigue, and nausea. Severe hand-foot syndrome (HFS) was rare.ConclusionThe overall response rate with the 2DOC regimen is similar to published CapOx regimens, and time to progression and OS are similar. The incidence of HFS, diarrhea, and mucositis were lower compared with published results of 2-week schedules of capecitabine. The 2DOC regimen merits further study as a more convenient regimen than infusional 5-FU with less HFS when compared with a 2-week administration of capecitabine.     

Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS)

The inhibition of histone deacetylase (HDAC) can induce differentiation, growth arrest, and apoptosis in cancer cells. This phase II multicenter study was undertaken to estimate the efficacy of belinostat, a potent inhibitor of both class I and class II HDAC enzymes, for the treatment of myelodysplastic syndrome (MDS). Adults with MDS and ≤2 prior therapies were treated with belinostat 1,000 mg/m² IV on days 1–5 of a 21-day cycle. The primary endpoint was a proportion of confirmed responses during the first 12 weeks of treatment. Responding patients could receive additional cycles until disease progression or unacceptable toxicity. Twenty-one patients were enrolled, and all were evaluable. Patients were a median 13.4 months from diagnosis, and 14 patients (67%) had less than 5% bone marrow blasts. Seventeen patients (81%) were transfusion dependent. Prior therapy included azacytidine (n = 7) and chemotherapy (n = 8). The patients were treated with a median of four cycles (range, 1–8) of belinostat. There was one confirmed response—hematologic improvement in neutrophils—for an overall response rate of 5% (95% CI, 0.2–23). Median overall survival was 17.9 months. Grades 3–4 toxicities considered at least to be possibly related to belinostat were: neutropenia (n = 10), thrombocytopenia (n = 9), anemia (n = 5), fatigue (n = 2), febrile neutropenia (n = 1), headache (n = 1), and QTc prolongation (n = 1). Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual.     

Randomized, double-blinded phase II evaluation of docetaxel with or without doxercalciferol in patients with metastatic, androgen-independent prostate cancer.

PURPOSE: Docetaxel is standard of care for androgen-independent prostate cancer (AIPC). Doxercalciferol (1 alpha-hydroxyvitamin D2) had modest activity in phase I/II trials. Preclinical data support combining vitamin D analogues with docetaxel to treat AIPC. EXPERIMENTAL DESIGN: Chemotherapy-naive men with metastatic AIPC were randomized 1:1 to receive, on a 4-week cycle, docetaxel (35 mg/m2 i.v., days 1, 8, and 15) with or without doxercalciferol (10 microg orally, days 1-28). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were progression-free survival, overall survival, objective response, and toxicity. Survival was analyzed as intent to treat. RESULTS: Seventy patients were randomized. Median follow-up was 17.6 months (range, 3.3-45.2). PSA response rate was 46.7% [95% confidence interval (95% CI), 30-64] in the doxercalciferol arm and 39.4% (95% CI, 25-56) with placebo (P = 0.560). Median progression-free survival in the doxercalciferol arm was 6.17 months (95% CI, 4.20-10.7) versus 6.20 months (95% CI, 4.83-9.07) with placebo (P = 0.764). Median overall survival in the doxercalciferol arm was 17.8 months (95% CI, 14.9-23.6) versus 16.4 months (95% CI, 11.9-23.8) with placebo (P = 0.383). Twenty-four patients in the doxercalciferol arm and 23 in the placebo arm were evaluable for objective response. No complete responses were observed. Partial objective response rate was 12.5% with doxercalciferol versus 8.7% with placebo (P = 0.672). Rate of grade > or =3 toxicity was 46% with doxercalciferol versus 42% with placebo (P = 0.785). CONCLUSIONS: Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival. Toxicity was similar between arms. Despite the disappointing results of this study, other vitamin D analogues remain under active investigation.     

Phase II study of weekly low-dose paclitaxel for relapsed and refractory non-Hodgkin's lymphoma: a Wisconsin Oncology Network Study

This study was performed to determine the clinical activity and safety of weekly low-dose paclitaxel (90 mg/m2) given as a 1-hour infusion in patients with relapsed and refractory non-Hodgkin's lymphoma (NHL). Thirty patients were treated on a phase II protocol conducted at the University of Wisconsin Comprehensive Cancer Center and within the Wisconsin Oncology Network (WON). A cycle of therapy was defined as paclitaxel at 90 mg/m2 weekly for 6 consecutive weeks followed by a 2-week rest period. Cycles were repeated as long as there was no disease progression or unacceptable toxicity. In general, the patients were heavily pretreated with a median of 4 prior therapies (range 2-11), and 73% were refractory to the most recent systemic therapy. The median age was 70 (range 44-97). All NHL histological subtypes were eligible. Of the 30 eligible patients enrolled, 26 were evaluable for response and 28 for toxicity. The overall response rate was 23% (95% confidence interval (CI) 9.0-43.7%). One patient had a complete response, and 5 patients had partial responses. The median response duration was 3.2 months (range 1.4-11.8 months). The median event-free survival was 1.9 months. The major toxicity was neuropathy. Despite the limited marrow reserve in this patient population, myelosuppression was minimal. Paclitaxel given in this dose and schedule has modest activity in previously treated non-Hodgkin's lymphoma. The response rate appears similar to other reports using different doses and schedules. Myelosuppression appears less with this schedule than with other schedules.     

Defects in natural killer cell activity and interferon response in human lung carcinoma and malignant melanoma

The natural killer (NK) activity of peripheral blood mononuclear cells from 25 patients with squamous cell carcinoma of the lung, malignant melanoma, or epitheloid cancers of the gastrointestinal tract was measured by the lysis of 51Cr-labeled K562 target cells. NK activities of many patients with lung cancer or malignant melanoma were decreased relative to normal controls. This abnormality was significantly correlated with advancing stage of disease and the percentage of monocytes in the cell suspensions. Addition of indomethacin or removal of monocytes did not restore depressed NK function to normal levels. Abnormalities of NK function did not appear to be secondary to the presence of mononuclear suppressor cells. The response to interferon was also impaired in patients with advanced disease. The number of effector:target conjugates was normal even in patients with depressed NK function; however, the number of active lytic effectors was decreased. These results imply that the cells which bind tumor targets are present in patients with advanced cancers, but these cells are either immature or functionally inactive.