Charles D. Webb

Prospective randomized study of four novel chemotherapy regimens in patients with advanced nonsmall cell lung carcinoma: a minnie pearl cancer research network trial.

The authors compared the toxicity, response rate, and progression free survival of four chemotherapy regimens for patients with advanced (Stage IIIB and IV) nonsmall cell lung carcinoma.

Phase II Trial of Weekly Docetaxel, Vinorelbine, and Trastuzumab in the First-Line Treatment of Patients with HER2-Positive Metastatic Breast Cancer

BACKGROUND The combinations of trastuzumab/docetaxel and trastuzumab/vinorelbine are highly active in the treatment of patients with HER2-positive metastatic breast cancer (MBC). We investigated the feasibility and safety of a 3-drug combination of trastuzumab, docetaxel, and vinorelbine as first-line therapy in this patient group. PATIENTS AND METHODS Sixty patients with previously untreated, measurable HER2-positive MBC (immunohistochemistry 3+ and/or fluorescence in situ hybridization positive) were treated with docetaxel 30 mg/m2 intravenously (I.V.) and vinorelbine 25 mg/m2 I.V. on days 1 and 8 of each 3-week cycle. Trastuzumab was given weekly (4-mg/kg loading dose followed by 2 mg/kg/week). Patients were evaluated after 6 weeks; responders/stable patients continued treatment until progression. RESULTS Patients received a median of 11 treatment cycles (range, 1-22 cycles). Forty-one of 60 patients (68%) had major responses (16 complete responses [27%], 25 partial responses [42%]). An additional 13 patients (22%) had stable disease for > or = 6 months. After a median follow-up of 58 months, median progression-free survival was 12 months (95% CI, 9.1-16.3 months), and the median overall survival was 40.8 months (95% CI, 25-not reached). Neutropenia (72% grade 4) was the most common hematologic toxicity; 8 patients were hospitalized for febrile neutropenia. A total of 67% of patients required dose modifications for neutropenia during cycles 1 or 2. Other grade 3/4 toxicities included fatigue (12%), hyperglycemia (7%), and myalgias (7%). There were no treatment-related deaths. CONCLUSION The combination of trastuzumab, docetaxel, and vinorelbine is highly active as first-line treatment for patients with HER2-positive MBC. However, this regimen offers no obvious advantages over other less myelosuppressive trastuzumab-containing regimens, and its routine use is not supported by the study.

Phase II Trial of Docetaxal Plus Imatinib Mesylate in the Treatment of Patients With Metastatic Breast Cancer

BACKGROUND Inhibition of the platelet-derived growth factor receptor (PDGFR) might improve the efficacy of chemotherapy by lowering interstitial tumor pressure and allowing increased tumor penetration by cytotoxic agents. In this phase II trial, we added imatinib, a PDGFR inhibitor, to docetaxel in the first-line treatment of women with metastatic breast cancer (MBC). PATIENTS AND METHODS Women with MBC who had received a maximum of 1 previous chemotherapy regimen were eligible for this trial. Initially, patients received oral imatinib 600 mg daily and docetaxel 30 mg/m2 on days 1, 8, and 15 of a 28-day cycle. The imatinib dose was lowered from 600 mg to 400 mg daily because of toxicity (primarily gastrointestinal) observed in the first 15 patients. Patients were evaluated for response (Response Evaluation Criteria in Solid Tumors) after 8 weeks of therapy; treatment continued in responding/stable patients until tumor progression or unacceptable toxicity. The primary endpoint was the overall response rate. RESULTS Thirty-seven patients entered this trial between May 2005 and March 2008. This regimen was relatively poorly tolerated, even after reduction of the imatinib dose, primarily because of gastrointestinal toxicity (nausea, vomiting, and diarrhea). Eight patients (22%) stopped therapy because of toxicity before the 8-week initial evaluation. Six of 37 enrolled patients (16%; 95% CI, 4.3%-28.1%) had partial responses; an additional 4 patients had stable disease for > 6 months. The median progression-free and overall survivals were 9.3 months and 15.4 months, respectively. CONCLUSION When compared with previous results with single-agent docetaxel, the combination of weekly docetaxel plus imatinib was tolerated relatively poorly and produced a low objective response rate. The efficacy of weekly docetaxel is not improved by concurrent administration of imatinib as a PDGFR inhibitor.

Sorafenib and Everolimus in Advanced Clear Cell Renal Carcinoma: A Phase I/II Trial of the SCRI Oncology Research Consortium

Purpose: To evaluate the feasibility and efficacy of sorafenib and everolimus in renal cell carcinoma (RCC). Methods: Patients with advanced RCC and ≤1 previous targeted therapy were treated. Results: Maximum tolerated doses were sorafenib 200 mg PO BID, everolimus 35 mg PO once weekly. Dose-limiting toxicity was hand–foot syndrome. The response rate was 13%; median PFS was 5.45 months (95% CI: 3.8–7.6). Skin toxicity, fatigue, hypertension, proteinuria, and mucositis (usually Grade 2) were common. Conclusions: Fifty percent doses of sorafenib and everolimus were required when these drugs were combined. No increase in efficacy was suggested; toxicity was modestly increased.

Phase II Study of Cetuximab, Docetaxel, and Gemcitabine in Patients With Previously Untreated Advanced Non-Small-Cell Lung Cancer

BACKGROUND Targeting epidermal growth factor receptors (EGFRs) has been a novel strategy in treating non-small-cell lung cancer (NSCLC). This multicenter, community-based trial was designed to examine the role of cetuximab in combination with a nonplatinum regimen. PATIENTS AND METHODS Eligibility criteria were newly diagnosed unresectable stage III/IV NSCLC, all histologies, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Treatment premedication included dexamethasone 20 mg orally 12 and 6 hours before treatment, and 4 mg 12 hours following treatment; diphenhydramine 50 mg intravenously (I.V.) and cimetidine 300 mg I.V. before cetuximab. Treatment medication included docetaxel 30 mg/m2 I.V. days 1 and 8; gemcitabine 1000 mg/m2 I.V. days 1 and 8; and cetuximab 400 mg/m2 I.V. day 1, then 250 mg/m2 I.V. weekly. Patients received up to 6 cycles with restaging every 6 weeks. The primary endpoint was an overall response rate (ORR) > or = 25%. RESULTS Sixty-nine patients enrolled from July 2005 to October 2007. Patients had a median age of 69 years; 70% were male and 30% were female; ECOG PS was 0 in 42%, 1 in 51%, and 2 in 7%; patients had adenocarcinoma (42%), squamous cell (30%), large cell (6%), mixed (1%), and not otherwise specified (20%) disease. The ORR was 17% (95% CI, 9%-29%). Thirty-five patients (54%) had stable disease; 14 patients (22%) had progressive disease. With a median follow-up of 17.8 months, the median progression-free and overall survivals were 4 months and 9.4 months, respectively. The most common (> 10%) grade 3/4 toxicities were neutropenia (25%), rash (22%), and fatigue (12%). Accrual in our middle Tennessee offices was temporarily suspended and ultimately stopped because of a higher-than-anticipated rate of cetuximab-related severe hypersensitivity reactions (HSRs) in 4 patients among the first 12 enrolled, including 1 fatal event. CONCLUSION Cetuximab/docetaxel/gemcitabine was relatively well-tolerated and associated with efficacy similar to chemotherapy alone. Additional study with cetuximab/chemotherapy in NSCLC should focus on new potentially predictive biomarkers. Also, additional study is needed to better understand and prevent the severe HSRs that appear to be endemic to specific regions of the United States.

Phase II trial of ixabepilone and carboplatin with or without bevacizumab in patients with previously untreated advanced non-small-cell lung cancer

BACKGROUND Epothilones, a new class of cytotoxic agents, have demonstrated activity in non-small-cell lung cancer (NSCLC). This phase II study examined ixabepilone/carboplatin (cohort A) and ixabepilone/carboplatin/bevacizumab (cohort B) as first-line therapy for patients with advanced NSCLC. METHOD Patients were enrolled to either cohort A or B at physician discretion and when eligibility met. Eligible patients had newly diagnosed stage III/IV NSCLC, ECOG PS 0-1, adequate organ function, no active CNS metastases, and, in cohort B, bevacizumab treatment criteria. Both cohorts received ixabepilone 30 mg/m2 and carboplatin AUC=6 IV day 1 every 3-weeks for a maximum of 6 cycles. Patients assigned to cohort B also received bevacizumab 15 mg/kg IV day 1 of each cycle, and could continue single-agent bevacizumab for 6 additional cycles. RESULTS Eighty-two patients (median age, 63 years; majority stage IV and former smokers) were enrolled from 11/08 to 10/09 (A-42, B-40) and received medians of 4 and 6 cycles, respectively. The ORRs were 29% and 50%. After median follow up of 17.5 months (A) and 15.7 months (B), median progression free survivals were A-5.3 months (95% CI 2.8-8.6) and B-6.7 months (95% CI 5.1-8.4), with median overall survivals of 9.3 months (95% CI 6.4-16.6) 13.2 months (95% CI 8.9-upper limit not reached), respectively. Grade 3/4 toxicity included: anemia (A-10%, B-27%), neutropenia (A-31%, B-48%), thrombocytopenia (A-19%, B-20%), fatigue (A-10%, B-23%), infection (A-5%, B-20%), and hypersensitivity reaction (A-2%, B-5%). There was one treatment-related death, due to hemoptysis in a cohort B patient with squamous histology. CONCLUSIONS Ixabepilone can be safely combined with carboplatin in newly diagnosed patients with advanced NSCLC. The benefits of treatment appear consistent with those achieved with other modern platinum-doublet regimens. The addition of bevacizumab increases toxicities, however, these are largely expected and reversible. The high ORR and OS observed in the bevacizumab-cohort are encouraging, but would require validation in a larger randomized trial of cohort A versus B.

First-Line Carboplatin, Pemetrexed, and Panitumumab in Patients with Advanced Non-Squamous KRAS Wild Type (WT) Non-Small-Cell Lung Cancer (NSCLC)

ABSTRACT Background: We added panitumumab to standard combination chemotherapy as first-line treatment for patients with advanced KRAS WT non-squamous NSCLC. Methods: Patients received panitumumab 9 mg/kg IV, pemetrexed 500 mg/m2 IV, and carboplatin AUC = 6 IV every 21 days. After 6 cycles, maintenance therapy with panitumumab and pemetrexed was administered every 21 days until progressive disease or unacceptable toxicity. Results: 29 of 66 patients (44%) had objective responses. The median TTP was 6 months; median overall survival (OS) was 17 months. Panitumumab increased treatment-related toxicity, notably skin rash. Conclusions: The addition of panitumumab increased toxicity, and had no discernible impact on efficacy.