A Phase II Trial of the Proteasome Inhibitor Bortezomib in Patients With Advanced Biliary Tract Cancers

BackgroundPatients with advanced biliary tract cancers have limited therapeutic options. Preclinical data suggest that proteasome inhibition may be an effective therapeutic strategy. We thus evaluated the clinical efficacy of bortezomib in advanced biliary tract cancers.Patients and MethodsPatients with locally advanced or metastatic cholangiocarcinoma or gallbladder adenocarcinoma who had received 0 to 2 previous therapies received bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day cycle. The primary end point was objective response rate. A Simon 2-stage design was used (null response rate of < 5% and response rate of ≥ 20% of interest).ResultsTwenty patients enrolled (bile duct/gallbladder cancer [14/6] and previous treatments 0/1/2 [10/6/3]). The trial was discontinued early because of lack of confirmed partial responses. No unanticipated adverse events were noted. There was 1 unconfirmed partial response. Ten patients achieved stable disease as best response. Median time to progression was 5.8 months (95% confidence interval [CI], 0.7-77.6 months). Median survival was 9 months (95% CI, 4.6-18.5 months). The 6-month and 1-year survival rates were 70% and 38%, respectively. There was no difference in survival based on primary disease site.ConclusionSingle-agent bortezomib does not result in objective responses in biliary tract cancers. However, the rate of stable disease and time to progression benchmark is encouraging. Further development of bortezomib in combination with other therapies in this disease setting should be considered.     

Phase II study of doxorubicin and paclitaxel as second-line chemotherapy of small-cell lung cancer: a Hoosier Oncology Group Trial

Forty-six evaluable patients with recurrent small-cell lung cancer were entered on a phase II Hoosier Oncology Group (HOG) protocol evaluating bolus doxorubicin 40 mg/m2 followed by paclitaxel 175 mg/m2 over 3 hours. Courses were repeated every 3 weeks for a maximum of 6 courses. Therapy was well-tolerated with grade III neurotoxicity in 5 patients (11%), grade III/IV emesis in 5 (11%), and grade III mucositis in 2 patients. One patient had grade IV myalgias and one patient had grade III cardiotoxicity. The main toxicity was myelosuppression. Twenty-nine patients (63%) had grade IV and 8 (17%) grade III granulocytopenia. Nine patients (20%) were hospitalized for granulocytopenic fever. There was no treatment-related mortality. Nineteen of 46 patients (41%) had an objective response, including 3 complete remissions. Two of 14 patients with refractory disease (progression less than 3 months after initial therapy) responded, compared to 17 of 32 (52%) with sensitive disease (progression beyond 3 months of initial chemotherapy regimen).     

Phase II trial of cimetidine in metastatic melanoma. A Hoosier Oncology Group trial

Fifteen evaluable patients with metastatic malignant melanoma who had received no prior chemotherapy were treated with high-dose cimetidine orally, 600 mg q.i.d. Although three patients had stable disease lasting 2-4 months, there were no objective responses. Median survival was 5.3 months (range 1-18 months). Toxicity was essentially negligible except for severe diarrhea in one patient and worsening liver function abnormalities in another. High-dose cimetidine does not have any significant activity in metastatic melanoma.     

Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: a Hoosier Oncology Group study

OBJECTIVE: To determine the response rate, duration of response and survival with weekly gemcitabine plus docetaxel in metastatic or unresectable pancreatic cancer. METHODS: Forty patients were enrolled, and 38 patients were evaluable for survival and toxicity. Thirty-seven patients were evaluable for response. Nine patients (24%) had locally advanced disease and 29 (76%) had metastatic disease at the time of enrollment. Median Eastern Cooperative Oncology Group performance status was 1. Patients received gemcitabine 750 mg/m(2) i.v. and docetaxel 35 mg/m(2) i.v. weekly for 3 out of 4 weeks for a maximum of 6 cycles. RESULTS: Patients received a median of 4 cycles (range 1-6) of chemotherapy. An objective response was obtained in 10 patients (27%) with a median duration of 17 weeks. Median survival was 7 months, and 1-year survival was 19.3%. Eight patients experienced at least one form of grade 4 toxicity and 27 patients experienced at least one type of grade 3 toxicity. CONCLUSIONS: The combination of gemcitabine and docetaxel is a well-tolerated regimen with clinical efficacy. The ultimate role of this combination versus single-agent gemcitabine can only be determined by a randomized phase III trial.     

Phase II Trial of Talabostat and Docetaxel in Advanced Non-small Cell Lung Cancer

AimsCurrently available therapies do improve survival in advanced stage non-small cell lung cancer (NSCLC), but only to a limited degree. Talabostat mesilate (PT-100) is an orally available amino boronic dipeptide that specifically inhibits dipeptidyl peptidases (including fibroblast activation protein) and enhances an immune response. The aim of this study was to determine the efficacy and safety of talabostat in NSCLC patients.Materials and methodsA phase II trial was conducted to evaluate talabostat in combination with docetaxel in patients with advanced NSCLC after failure of previous platinum-based chemotherapy. In total, 42 patients were enrolled.ResultsTalabostat was well tolerated. Two patients achieved a partial response and one achieved a complete response.ConclusionThere was no evidence that talabostat enhanced the clinical activity of docetaxel in patients with NSCLC.     

Phase II study of low-dose topotecan in myelodysplastic syndromes: a Hoosier Oncology Group (HOG) study

Topotecan has demonstrable activity in high-risk MDS and CMMoL. However, the significant toxicity of topotecan administered at a dose of 2mg/m2 i.v. daily for 5 days as a continuous infusion limits its use in older patients. Therefore, we studied topotecan 1.5mg/m2 per day i.v. over 2 h for three consecutive days in 20 patients with high-risk MDS (12 RAEB; 4 RAEB-T; 4 CMMoL). Cycles were given every 4-6 weeks. Fifteen patients were evaluable for response. Only one patient achieved a durable complete remission (CR). There were three deaths within the first cycle of therapy. Severe myelosuppression was the most common toxicity. Grades 3-4 infections were documented in four patients. We conclude that topotecan administered at this dose and schedule has no clinically significant activity.     

Phase II and gene expression analysis trial of neoadjuvant capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy for locally advanced rectal cancer: Hoosier Oncology Group GI03-53

Purpose

We designed this study in locally advanced rectal cancer to determine the pathological response, toxicity, and disease-free survival (DFS) with induction capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy (CRT) and analyze the gene expression of enzymes involved in the metabolism of capecitabine and irinotecan for associations with response and toxicity.

Methods

Patients with T3/T4 or node positive rectal cancer were treated with capecitabine 1,000?mg/m² twice daily (BID) days 1?C14, and irinotecan 200?mg/m² on day 1 every 21?days for 2 cycles, followed by capecitabine 825?mg/m² BID days 1?C5 per week with concurrent radiotherapy 50.4?Gy in 28 fractions. Surgical resection occured a median of 7.4?weeks after CRT. Gene expression levels or sequencing were used to analyze carboxylesterase-converting enzymes (CES1, CES2), thymidylate synthase (TS), thymidine phosphorylase (TP), dehydropyrimidine dehydrogenase (DPD), topoisomerase I (TOPO I), and uridine-diphosphate (UDP) glucuronosyl transferase 1A1 in pre- and post-treatment tumor and normal tissue samples.

Results

Twenty-two patients were enrolled, and 18 completed neoadjuvant therapy and underwent R0 resection. Two patients with UGT1A1 7/7 had grade 3 and 4 neutropenic fever and sepsis. Pathological complete response (pCR) occurred in 6 of 18 patients (33?%) and 10 (56?%) had tumor and/or nodal downstaging. The 3-year DFS was 75.5?% (95?% CI, 39.7?C91.8?%). Locoregional control rate was 100?%. We observed higher TP gene expression in pCR patients, but no correlations with toxicity.

Conclusions

This neoadjuvant regimen was safe and demonstrated significant antitumor activity. High TP tumor gene expression was associated with obtaining pCR.     

A Phase II,Single-arm Trial of Sunitinib and Erlotinib in Advanced Renal Cell Carcinoma

BackgroundOverexpression of the epidermal growth factor receptor (EGFR) and its ligands occur frequently in renal cell carcinoma (RCC). Combined vascular endothelial growth factor receptor (VEGF-R) and EGFR inhibition may overcome resistance to VEGF-R inhibitor monotherapy. We performed a dose-escalation phase II study of sunitinib plus erlotinib in advanced renal cell carcinoma.Patients and MethodsPatients with metastatic clear cell or papillary RCC were eligible. Prior therapy was allowed except sunitinib or erlotinib. Three dose levels of erlotinib (50, 100, 150 mg daily) were evaluated in combination with sunitinib 50 mg. Thirty-seven patients were treated at maximum tolerated dose to determine efficacy. The primary endpoint was 8-month progression-free survival (PFS) rate. The trial was powered to assess for a difference between a median PFS of less than 50% with a targeted 70% PFS for the combination.ResultsThe 8-month PFS rate was 40% (95% CI: 23-56). Median PFS was 5.8 months (95% CI: 4.1-9.7) and median overall survival (OS) was 26.3 months (95% CI: 16.1-34.0). The objective response rate was 22% and an additional 59% of patients had stable disease for at least 6 weeks. The most common adverse events for all grades were diarrhea, rash, fatigue, and dysgeusia. Dose reduction in 1 or both of the drugs was undertaken in 17 (46%) patients, while 5 (14%) discontinued study therapy due to toxicity.ConclusionWhile sunitinib and erlotinib are combinable,the 8-month PFS rate did not suggest efficacy improvement over sunitinib monotherapy (NCT00425386).     

Docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer: a Hellenic Cooperative Oncology Group Phase II study

A phase II study was conducted to evaluate the activity and toxicity profile of the combination of docetaxel and gemcitabine in anthracycline-resistant advanced breast cancer (ABC). Thirty-nine eligible patients with a median performance status of I (range, 0-2) were enrolled in the study. Treatment consisted of docetaxel 75 mg/m² in a 1-hr infusion on day 1 preceded by gemcitabine 1000 mg/m² over 30 min on days 1 and 8. One hundred eighty-one treatment cycles were administered, 113 (62.4%) of them at full dose. Relative dose intensity of gemcitabine and of docetaxel was 0.73 and 0.85, respectively. More common grade 3-4 toxicities included neutropenia (49%), anemia (10%), fatigue (10%), nausea/vomiting (8%), and alopecia (77%). Seven patients were hospitalized for febrile neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was required in 90% of patients. Overall, 14 patients (36%) responded, 3 (7.5%) of them completely. Median duration of response was 10.3 months (range, 4.6-17.5+). Median time to progression was 7 months (range, 0.2-17.5+) and median survival 12.7 months (range, 2--20.5+). In conclusion, the combination of docetaxel and gemcitabine, as used in the present study, has moderate activity in anthracycline-resistant ABC. Future studies should incorporate prophylactic administration of G-CSF to reduce the incidence of febrile neutropenia and maintain dose intensity.     

Phase II Evaluation of Amonafide in Advanced Sarcoma: A Southwest Oncology Group Study

Soft tissue sarcomas are generally resistant to most chemotherapeutic agents, and individuals with advanced disease have a poor prognosis. We evaluated amonafide, a new drug that has significant activity against several tumor cell lines, to determine its activity against sarcomas. Amonafide was administered to 18 patients with advanced soft tissue sarcoma (16 of whom had received prior chemotherapy) at a dose of 300 mg/m² over 60 min daily for 5 days. Courses were repeated every 21 days. Toxicity was mild, but no responses were observed. We conclude that amonafide is not an active agent in previously treated, advanced soft tissue sarcomas in the dose and schedule utilized.     

Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

Background.

Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis.

Patients and Methods.

We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks.

Results.

A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors.

Conclusion.

Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients.

Implications for Practice:

Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy has proven clinical efficacy as a standalone therapy in renal cell carcinoma and glioblastoma multiforme. Also, enhancement of conventional cytotoxic chemotherapy efficacy has been observed in colorectal, non-small-cell lung, breast, and ovarian cancers. Optimal strategies to cotarget angiogenic cytokines combined with VEGF have not been defined. It was found that bevacizumab could be safely combined with imatinib, which was used as a platelet-derived growth factor receptor inhibitor in our study. High-dose imatinib-related edema was not observed when paired with bevacizumab. This regimen might be suitable for further investigation in other cancers but apparently not in melanoma.     

Southwestern Oncology Group Phase II Trial (S0526) of Pemetrexed in Bronchioloalveolar Carcinoma Subtypes of Advanced Adenocarcinoma

BackgroundPemetrexed, a multitargeted antifolate drug, is an active agent in non–small-cell lung cancer (NSCLC), especially adenocarcinomas. Based on preclinical data supporting the relevance of alpha-folate receptors in adenocarcinoma of the bronchioloalveolar carcinoma (BAC) subtype, this trial was designed to assess pemetrexed in patients with this pathologic subtype of lung adenocarcinoma.Patients and MethodsPatients with histologically confirmed stage IIIB (with malignant pleural effusion) or stage IV adenocarcinoma with BAC features or pure BAC were eligible. Treatment consisted of pemetrexed, 500 mg/m², administered intravenously every 21 days.ResultsOf 27 patients enrolled, 24 were eligible and assessable for adverse events: Toxicity was primarily hematologic, consisting of leukopenia/neutropenia, thrombocytopenia, and anemia. The median follow-up among patients still alive (n = 8) was 35 months (range, 26-47 months). Among 17 patients with measurable disease, the response rate was 23% (all partial responses; 95% confidence interval [CI], 10%-56%). The median progression-free survival (PFS) and overall survival (OS) were 6 and 25 months, respectively.ConclusionPemetrexed is active and well tolerated and, in patients with adenocarcinoma BAC subtypes, likely related to its underlying mechanism of action as a multitargeted antifolate drug.     

Phase II Trial of Docetaxel (Taxotere®) for Untreated Advanced Colorectal Carcinoma

The antimicrotubule agent docetaxel (Taxotere®), a semisynthetic taxoid, has demonstrated antitumor activity against colorectal cancer cell lines in vitro, and in murine tumor models. We sought to characterize its activity in a group of previously untreated patients with colorectal carcinoma. Eighteen previously untreated patients with advanced, measurable colorectal carcinoma were treated with a 60-min intravenous infusion of docetaxel with a dose of 100 mg/m² administered every 21 days. Routine premedication with diphenhydramine was given. Patients were required to have normal organ function and a Karnofsky performance status (KPS) ≥ 60%. No complete responses (CR) or partial responses (PR) were observed. Median survival was 13 months, despite a median time to progression of only 1.3 months. Neutropenia was the most common dose-limiting toxicity, resulting in 5 episodes of febrile neutropenia requiring hospitalization and intravenous antibiotics. One patient experienced a grade 4 hypersensitivity reaction (HSR) requiring treatment termination. No toxic deaths occurred. Despite encouraging preclinical data, docetaxel is an inactive drug in advanced colorectal cancer when given in the dose and on the schedule examined in the present study, and has significant, although reversible, toxicities.     

Docetaxel and Oxaliplatin as First-Line Therapy for Advanced Non-Small Cell Lung Cancer: A Phase II Trial

Abstract

We sought to evaluate the safety and efficacy of docetaxel and oxaliplatin combination as first-line therapy for patients with stage IV or wet III_B non small cell lung cancer. Patients received oxaliplatin at 85 mg/m² intravenously over 2 hours on days 1 and 15 along with docetaxel at 30 mg/m² intravenously on days 1 and 8; both given every 28 days. Cycles were repeated every 4 weeks for a maximum of 6. Fifteen patients were enrolled for an overall response rate of 50% (95% CI 21-74%). Median progression-free survival was 2.4 months with a 1-year progression free survival of 10%. Median overall survival was 7.9 months with 49% of patients alive at 1 year. Most common toxicities were nausea, vomiting, and dehydration. This combination has notable activity in advanced non-small cell lung cancer with a favorable toxicity profile.