Randomized phase 2 trial of pemetrexed, pemetrexed/bevacizumab, and pemetrexed/carboplatin/bevacizumab in patients with stage IIIB/IV non-small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2.

BACKGROUND: The best treatment for patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status is not well defined. In this phase 2 trial, patients were randomized to receive treatment with either single-agent pemetrexed or 1 of 2 combination regimens. METHODS: Patients with newly diagnosed, histologically confirmed nonsquamous NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 were stratified by age and serum albumin level and were randomized (1:1:1) to 1 of 3 regimens: pemetrexed (arm 1), pemetrexed and bevacizumab (arm 2), or pemetrexed, carboplatin, and bevacizumab (arm 3). The response to treatment was assessed every 2 cycles; responding and stable patients continued treatment until progression or unacceptable toxicity. RESULTS: One hundred seventy-two patients were randomized, 162 patients began the study treatment, and 146 patients completed 2 cycles and were evaluated for their response. The median progression-free survival (PFS) was 2.8 months in arm 1, 4.0 months in arm 2, and 4.8 months in arm 3. The overall response rates were 15% in arm 1, 31% in arm 2, and 44% in arm 3. The overall survival was similar in the 3 treatment arms. All 3 regimens were relatively well tolerated. Patients receiving bevacizumab had an increased incidence of hypertension, proteinuria, and bleeding episodes, but most events were mild or moderate. CONCLUSIONS: All 3 regimens were feasible for patients with advanced NSCLC and an ECOG performance status of 2. The addition of bevacizumab to pemetrexed increased the overall response rate. The efficacy of pemetrexed/carboplatin/bevacizumab (median PFS, 4.8 months) approached the prespecified study PFS goal of 5 months. Larger studies will be necessary to define the role of bevacizumab in addition to standard pemetrexed and carboplatin in this population. Cancer 2018;124:1982-91. © 2018 American Cancer Society.

Bendamustine, bortezomib and rituximab produces durable complete remissions in patients with previously untreated, low grade lymphoma.

This Phase II trial evaluated the efficacy of bendamustine, bortezomib and rituximab in patients with previously untreated low-grade lymphoma. Eligible patients had low grade lymphoma with no previous systemic disease treatment. Treatment for all patients was given in 28-day cycles for a maximum of 6 cycles. Patients received rituximab 375 mg/m2 intravenously (IV) on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6; bendamustine 90 mg/m2 IV on days 1 and 2; and bortezomib 1·6 mg/m2 IV on days 1, 8 and 15. Patients were permitted to begin maintenance treatment with rituximab 6 months after completion of study treatment and after 6-month follow-up assessments had been conducted. Fifty-four eligible patients were enrolled. The most common grade 3/4 toxicities were leucopenia (28%), neutropenia (30%) and lymphopenia (17%). There were no treatment-related deaths and 1 unrelated death on study (embolic stroke). The overall response rate was 94% for all patients. The median follow-up was 54 months. Kaplan-Meier estimates of progression-free survival and overall survival at 36 months were 75% and 88%, respectively. The treatment regimen was well tolerated and produced high response rates. Further study of this regimen in patients with previously untreated lymphoma is warranted.

A Phase 2 Study of the Hsp90 Inhibitor AUY922 as Treatment for Patients with Refractory Gastrointestinal Stromal Tumors.

BACKGROUND: AUY922 is an inhibitor of heat shock protein 90 (Hsp90). Hsp90 inhibitors induce kit degradation in preclinical gastrointestinal stromal tumor (GIST) models. This trial was designed to determine the progression-free survival (PFS) of patients with GIST refractory to or intolerant of imatinib and sunitinib. METHODS: Eligible patients received AUY922 70 mg/mg(2) by intravenous (IV) infusion on days 1, 8, and 15 of 21-day cycles. Treatment continued until progression or unacceptable toxicity. RESULTS: Between December 2011 and January 2015, 25 patients were enrolled (median age, 63 years; 56% male) and received a median of 2 cycles (range: 1-12) of AUY922 treatment. Thirty-four patients were planned, but enrollment was stopped early due to slow accrual. Median PFS was 3.9 months (95% CI: 2.5, 5.3) and median OS was 8.5 months (95% CI: 5.2, 16.7). Radiographic response was evaluated in 21 patients; one patient achieved PR (4%) with another 15 having best response of stable disease (60%). The most common treatment-related adverse event was diarrhea (60% all grades). Reversible ocular toxicities that resulted in drug hold (24%) or reduction (8%) were also observed. CONCLUSION: AUY922 produced a median PFS which compares favorably to historical controls of placebo (6 weeks) for patients refractory to treatment with imatinib. While diarrhea and ocular toxicities were common, the majority of patients received treatment until disease progression.

A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle.

PURPOSE: This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan). PATIENTS AND METHODS: Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2. RESULTS: Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment. CONCLUSIONS: The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.

A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors.

Introduction The PI3 kinase (PI3K) pathway is a commonly dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective dual PI3K/mTOR inhibitor. Methods Patients were enrolled in a 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetics (PK) of BEZ235 when administered twice-daily as an oral sachet. For intrapatient PK comparison, patients were to receive a lead in of the total daily dose in a QD schedule for the first 8 days of the initial 28 day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred. Results Thirty-three patients received BEZ235. Initial dose levels of 200 and 400 mg BID had no DLTs. At the 600 mg BID dose level with 1200 mg QD lead in dose two DLTs of grade 3 mucositis occurred early in the first treatment cycle, the lead-in QD dosing was eliminated. Fatigue and mucositis limited dosing at 600 mg BID in subsequent patients. The 400 mg BID dose level was re-explored, with DLTs of grade 3 hyperglycemia, dehydration, fatigue, and grade 3 thrombocytopenia. Twelve patients were enrolled at an intermediate dose of 300 mg BID; a grade 3 mucositis DLT was reported in 1 patient, and this dose was declared the MTD. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. Fifteen patients experienced stable disease as their best response, including 10 (colorectal [4 patients], endometrial [3 patients], carcinoid NOS, pancreas, and melanoma) who had disease control for ≥16 weeks. Conclusions The recommended dose of BEZ235 administered BID as an oral sachet formulation is 300 mg BID. Toxicities seen have been reported for other dual PI3K/mTOR inhibitors.

Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon Research Institute.

This trial compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin versus paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma. Patients with stage 3 or 4 epithelial ovarian cancer with residual measurable disease or elevated CA-125 levels after maximal surgical cytoreduction were randomized (1:1) to receive treatment with paclitaxel (175 mg/m(2) , 3 h infusion, day 1) and carboplatin (AUC 6.0, IV, day 1) with or without sorafenib 400 mg orally twice daily (PO BID). Patients were reevaluated for response after completing 6 weeks of treatment (two cycles); responding or stable patients received six cycles of paclitaxel/carboplatin. Patients receiving the sorafenib-containing regimen continued sorafenib (400 PO BID) for a total of 52 weeks. Eighty-five patients were randomized and received treatment.Efficacy was similar for patients receiving paclitaxel/carboplatin/sorafenib versus paclitaxel/carboplatin: overall response rates 69% versus 74%; median progression-free survival 15.4 versus 16.3 months; 2 year survival 76% versus 81%. The addition of sorafenib added substantially to the toxicity of the regimen; rash, hand-foot syndrome, mucositis, and hypertension were significantly more common in patients treated with sorafenib. The addition of sorafenib to standard paclitaxel/carboplatin did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer. Based on evidence from this study and other completed trials, sorafenib is unlikely to have a role in the treatment of ovarian cancer.

Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma.

INTRODUCTION/BACKGROUND: Inhibition of tumor angiogenesis by the interruption of VEGF pathway signaling is of therapeutic value in several solid tumors. Preclinical evidence supports similar importance of the pathway in non-Hodgkin lymphoma. In this randomized phase II trial, we compared the efficacy and toxicity of rituximab with bevacizumab versus single-agent rituximab, in patients with previously-treated follicular lymphoma. PATIENTS AND METHODS: Patients (n = 60) were randomized (1:1) to receive rituximab (375 mg/m(2) intravenously [I.V.] weekly for 4 weeks) either as a single agent or with bevacizumab (10 mg/kg I.V. on days 3 and 15). Patients with an objective response or stable disease at week 12 received 4 additional doses of rituximab (at months 3, 5, 7, and 9); patients who received rituximab/bevacizumab also received bevacizumab 10 mg/kg I.V. every 2 weeks for 16 doses. RESULTS: After a median follow-up of 34 months, PFS was improved in patients who received rituximab/bevacizumab compared with patients who received rituximab alone (median 20.7 vs. 10.4 months respectively; HR, 0.40 (95% confidence interval [CI], 0.20-0.80); P = .007). Overall survival was also improved numerically (73% vs. 53% at 4 years), but did not reach statistical significance (HR, 0.40 (95% CI, 0.15-1.05); P = .055). The addition of bevacizumab increased the toxicity of therapy, but both regimens were well tolerated (no grade 4 toxicity). CONCLUSION: The addition of bevacizumab to rituximab significantly improved PFS. The role of angiogenesis inhibition in the treatment of follicular lymphoma requires further definition in larger clinical trials.

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.

A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors.

PURPOSE: To determine the maximum tolerated doses and dose-limiting toxicities of oral panobinostat in combination with paclitaxel and carboplatin when administered to patients with advanced solid tumors. PATIENTS AND METHODS: Patients initially received panobinostat twice weekly. Following amendment #1, patients received panobinostat three times weekly. Paclitaxel and carboplatin were administered intravenously on day 1 of each 21-day treatment cycle. Dose escalation continued until the maximum tolerated dose was determined. A total of 10 patients were treated at the recommended phase II dose to further assess safety. RESULTS: Twenty-one patients were enrolled across four different dose levels. The dose-limiting toxicity of the combination regimen was myelosuppression (neutropenia and thrombocytopenia), which often warranted panobinostat dose omissions or reductions. Nearly two-thirds of the patients experienced grade 4 neutropenia or grade 3 or 4 thrombocytopenia. Non-hematologic toxicities consisted primarily of diarrhea, fatigue, and vomiting, which were mild to moderate in intensity. No QTc prolongation was reported. Three partial responses were confirmed in patients with carcinoma of unknown primary (two patients) and non-small-cell lung cancer (one patient). Eleven additional patients reported stable disease as their best response to treatment. CONCLUSIONS: The recommended phase II dose is panobinostat 10 mg orally three times weekly in combination with paclitaxel 175 mg/m(2) and carboplatin AUC 5 administered intravenously on day 1 of every 21-day cycle.

Phase II study of maintenance sunitinib following irinotecan and carboplatin as first-line treatment for patients with extensive-stage small-cell lung cancer.

BACKGROUND: Inhibition of angiogenesis may be effective in the treatment of small-cell lung cancer (SCLC). Sunitinib, an oral agent that inhibits the VEGF signaling pathway, may delay progression in sequence with chemotherapy. This phase II trial was designed to evaluate the role of sunitinib monotherapy following 6 cycles of irinotecan and carboplatin in patients with newly diagnosed extensive-stage (ES) SCLC. METHOD: Patients aged ≥18 years with previously untreated ES-SCLC were eligible. Additional criteria included: ECOG PS 0-1, no active brain metastases, and adequate organ function. Patients received 28-day cycles of irinotecan (60 mg/m(2), days 1, 8, 15) and carboplatin (AUC=4, day 1), and were assessed for response every 8 weeks. After 6 cycles of chemotherapy, patients with stable disease or responding disease proceeded to sunitinib monotherapy (25 mg orally daily) until disease progression or unacceptable toxicity. The primary endpoint was 1-year overall survival (OS). RESULTS: Between 2/09 and 10/09, 34 patients (median age 65 years [range, 41-80]) were enrolled. 53% of patients were male, 47% had ECOG PS 0.21 patients (62%) completed 6 cycles of chemotherapy, and 17 (50%) initiated sunitinib monotherapy (median duration: 9 weeks; range, 2-28+weeks). After a median follow-up of 50 weeks (range: 37-68 weeks), 22 (62%) of the patients remain alive. The objective response rate with chemotherapy was 59%, and an additional 20% had stable disease. 1-year OS was 54% and median time to progression was 7.6 months. Grade 3/4 toxicity was rare during sunitinib monotherapy. CONCLUSIONS: This phase II trial provides support for further study of sunitinib maintenance therapy following platinum-doublet chemotherapy in patients with ES-SCLC. The 1 year OS of 54% is encouraging, and a randomized trial would be appropriate to assess sunitinib's impact following chemotherapy.

Phase 1 results from a study of romidepsin in combination with gemcitabine in patients with advanced solid tumors.

Romidepsin is a potent histone deacetylase inhibitor; preclinical studies showed potential synergy with the nucleoside analog gemcitabine. This phase 1 trial was conducted to determine the maximum tolerated dose for two schedules of romidepsin plus gemcitabine in patients with advanced solid tumors in which gemcitabine had previously demonstrated clinical activity. The recommended phase 2 dose was 12 mg/m(2) romidepsin plus 800 mg/m(2) gemcitabine on days 1 and 15 every 28 days. Results suggest additive hematologic toxicities of romidepsin plus gemcitabine, but the level of antitumor activity observed warrants more formal trials of this combination to further assess safety and efficacy.

A phase I study of panobinostat in combination with gemcitabine in the treatment of solid tumors.

PURPOSE: To evaluate the safety and tolerability of the combination of orally administered panobinostat with gemcitabine in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral panobinostat administered 2 or 3 times weekly (continuous or intermittent dosing in combination with intravenous gemcitabine administered on days 1, 8, and 15 every 28 days or on days 1 and 8 every 21 days). Toxicity assessments were ongoing, and disease assessments were repeated every 2 treatment cycles. RESULTS: A total of 63 cycles of study treatment were administered to 17 patients over 5 different dose levels. Dose-limiting toxicities occurred at all dose levels. In all instances, dose-limiting toxicities were due to grade 4 myelosuppression or myelosuppression warranting dose modifications during the first treatment cycle. Nonhematologic toxicities were mild to moderate in intensity and consisted of anorexia, constipation, diarrhea, fatigue, nausea, vomiting, and rash. One patient with ovarian cancer had an unconfirmed partial response, and 5 patients had stable disease lasting more than 4 cycles. CONCLUSION: Dosing of the combination regimen of panobinostat and gemcitabine is limited by myelosuppression. The recommended doses for further study are intermittent oral panobinostat administered at a dose of 10 mg 3 times weekly for 2 weeks in combination with gemcitabine 800 mg/m2 administered intravenously on days 1 and 8 every 21 days.

A phase II trial of vinflunine as monotherapy or in combination with trastuzumab as first-line treatment of metastatic breast cancer.

We investigated the microtubulin inhibitor vinflunine­with trastuzumab in human epidermal growth factor receptor-2 (HER2)-positive patients­as first-line metastatic breast cancer therapy. HER2-negative patients received vinflunine on day 1; HER2-positive patients received vinflunine/trastuzumab every 21 days. Forty-eight patients in each treatment group were planned; the sponsor terminated the study early. Thirty-two evaluable patients (vinflunine, 11; vinflunine/trastuzumab, 21) were enrolled. In HER2-positive patients, vinflunine/trastuzumab produced an objective response rate (33%), clinical benefit rate (71%), and progression-free survival (6.2 months). Grade-3/4 neutropenia occurred in 14 (44%) patients; gastrointestinal toxicities were common and six patients were hospitalized for treatment-related toxicity. The vinflunine/trastuzumab combination was active and well tolerated, but our results do not suggest advantages over taxane/trastuzumab or vinorelbine/trastuzumab.

A phase I study of weekly topotecan in combination with pemetrexed in patients with advanced malignancies.

INTRODUCTION: This phase I study evaluated the safety, tolerability, preliminary antitumor activity, and pharmacokinetic interaction of weekly topotecan (days 1 and 8) in combination with pemetrexed (day 1 only) in patients with advanced solid tumors. METHODS: Patients received topotecan (3.0-4.0 mg/m(2) i.v. days 1 and 8) and pemetrexed (375-500 mg/m(2) i.v. day 1) over 21-day cycles. Patients were accrued across five different dose levels and were observed for safety, tolerability, and preliminary activity. RESULTS: Twenty-six patients received 120 cycles of pemetrexed and topotecan, including five patients who received 8, 8, 10, 12, and 17 cycles without dose reductions, confirming a lack of cumulative myelosuppression. Four patients received topotecan (4.0 mg/m(2) i.v.) and pemetrexed (500 mg/m(2) i.v.), but experienced two dose-limiting toxicities (febrile neutropenia, grade 4 thrombocytopenia). As a result, the topotecan (3.5 mg/m(2) i.v.) and pemetrexed (500 mg/m(2) i.v.) group was expanded to 12 patients. The only grade 3 or 4 nonhematologic toxicity was one episode of grade 3 fatigue; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. One non-small cell lung cancer (NSCLC) patient (12 months) and one soft tissue sarcoma patient (6 months) achieved a partial response. CONCLUSIONS: Weekly topotecan plus every-3-week pemetrexed was well tolerated and active. Full doses of topotecan plus pemetrexed caused brief reversible myelosuppression with minimal dose delays/reductions; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. All six NSCLC patients at the recommended phase II dose had at least stable disease as a best response, including one partial response lasting 12 months. There was no evidence of an effect of pemetrexed on topotecan pharmacokinetics. Collectively, these data suggest that further phase II exploration of weekly topotecan plus every-3-week pemetrexed for advanced malignancies is indicated.

Bevacizumab and everolimus in the treatment of patients with metastatic melanoma: a phase 2 trial of the Sarah Cannon Oncology Research Consortium.

BACKGROUND: In this phase 2 study, the activity and tolerability of the combination of bevacizumab, an inhibitor of angiogenesis, and everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), was evaluated in the treatment of patients with metastatic melanoma. METHODS: Patients with metastatic melanoma who had received up to 2 previous systemic regimens (chemotherapy and/or immunotherapy) were eligible. Previous treatment with angiogenesis or mTOR inhibitors was not allowed. All patients received bevacizumab at a dose of 15 mg/kg intravenously every 21 days and everolimus at a dose of 10 mg orally daily. Patients were re-evaluated every 6 weeks; those with an objective response or stable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST]) continued therapy until tumor progression or unacceptable toxicity occurred. RESULTS: Fifty-seven patients with metastatic melanoma received a median of 4 treatment cycles (range, 1-14+ cycles). Seven patients (12%) achieved major responses, whereas 33 patients (58%) were found to have stable disease at the time of first evaluation. The median progression-free and overall survivals were 4 months and 8.6 months, respectively. Approximately 43% of patients were alive after 12 months of follow-up. The treatment regimen was well tolerated by the majority of patients. CONCLUSIONS: The combination of bevacizumab and everolimus was found to have moderate activity and was well tolerated in the treatment of patients with metastatic melanoma. Further exploration of agents with these mechanisms of action is indicated, perhaps in combination with inhibitors of the mitogen-activated protein kinase (MAPK) pathway.

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.

Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial.

PURPOSE: To compare the results of empiric first-line therapy with paclitaxel/carboplatin/etoposide (PCE) versus gemcitabine/irinotecan, both followed by single-agent gefitinib, in patients with carcinoma of unknown primary site. PATIENTS AND METHODS: Patients with previously untreated carcinoma of unknown primary site were randomized to receive either PCE or gemcitabine/irinotecan. Responding and stable patients continued treatment for 4 to 6 cycles. Patients with no evidence of tumor progression at that time received single-agent gefitinib until tumor progression. The trial was designed to detect an improvement in the 2-year survival rate from 20% to 30%. RESULTS: Between September 2003 and July 2008, 198 patients entered this multicenter, community-based trial. Because of slow accrual, the trial was stopped short of its target accrual of 320 patients. Clinical characteristics were comparable for patients receiving PCE (N = 93) and gemcitabine/irinotecan (N = 105). PCE and gemcitabine/irinotecan produced similar 2-year survival (15% vs. 18%), median survival (7.4 months vs. 8.5 months), median progression-free survival (3.3 months vs. 5.3 months), and response rate (18% vs. 18%). Grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia, and red blood cells transfusions were more common with PCE; diarrhea was more common with gemcitabine/irinotecan. The median duration of gefitinib maintenance was 3 months, suggesting no role as a maintenance therapy in this setting. DISCUSSION: The PCE and gemcitabine/irinotecan regimens have comparable efficacy in the first-line treatment of patients with carcinoma of unknown primary site. Gemcitabine/irinotecan is the preferable regimen, due to its favorable toxicity profile. However, the moderate efficacy of both regimens underscores the need for novel treatment approaches in this patient population.

Paclitaxel/carboplatin plus bevacizumab/erlotinib in the first-line treatment of patients with carcinoma of unknown primary site.

INTRODUCTION: This phase II trial evaluated the efficacy and toxicity of the combination of paclitaxel, carboplatin, bevacizumab, and erlotinib in the first-line treatment of patients with carcinoma of unknown primary site (CUP). METHODS: Patients with previously untreated CUP (adenocarcinoma, poorly differentiated carcinoma, poorly differentiated squamous carcinoma) without clinical or pathologic characteristics of a well-defined treatable subset were eligible. All patients received paclitaxel, carboplatin, bevacizumab, and erlotinib. Treatment cycles were repeated at 21-day intervals. After four cycles, paclitaxel and carboplatin were discontinued; bevacizumab-erlotinib treatment was continued until tumor progression. Patients were initially evaluated for response after completion of two treatment cycles; re-evaluations occurred every 6 weeks thereafter. RESULTS: Forty-nine of 60 patients (82%) completed four cycles of therapy, and 44 patients (73%) subsequently received maintenance bevacizumab and erlotinib. Thirty-two patients (53%) had major responses to treatment; an additional 18 patients had stable disease. After a median follow-up of 19 months, the median progression-free survival time was 8 months, with 38% of patients progression free at 1 year. The median survival time and 2-year overall survival rate were 12.6 months and 27%, respectively. Treatment was generally well tolerated, with a toxicity profile as predicted based on the known toxicities of each treatment component. CONCLUSIONS: Empiric treatment with paclitaxel, carboplatin, bevacizumab, and erlotinib is effective and well tolerated as first-line treatment for patients with CUP. Further development of this regimen is warranted.

Paclitaxel/Carboplatin/gemcitabine versus gemcitabine/vinorelbine in advanced non-small-cell lung cancer: a phase II/III study of the Minnie Pearl Cancer Research Network.

PURPOSE: This prospective randomized study compared overall survival (OS) in patients with previously untreated advanced non-small-cell lung cancer (NSCLC) when treated with the platinum agent-based triple drug combination of paclitaxel/carboplatin/gemcitabine (PCG) versus the nonplatinum agent-based doublet drug combination of gemcitabine/vinorelbine. PATIENTS AND METHODS: Advanced (stages IIIB, IV, and recurrent) chemotherapy-naive patients with NSCLC and performance status 0-2 were randomly assigned to the PCG arm (paclitaxel 200 mg/m(2) on day 1, carboplatin area under the concentration-time curve of 5 on day 1, and gemcitabine 1000 mg/m(2) on days 1 and 8, every 21 days) or to the gemcitabine/vinorelbine arm (gemcitabine 1000 mg/m(2) on days 1, 8, and 15 and vinorelbine 25 mg/m(2) on days 1, 8, and 15, every 28 days). RESULTS: A total of 337 patients were randomly assigned to the 2 arms. The median time to progression was 6 months for PCG and 3.9 months for gemcitabine/vinorelbine with 1- and 2-year progression-free survival rates of 13% and 2% versus 14% and 4% (P = .324 log rank). Median OS for PCG was 10.3 months versus 10.7 months for gemcitabine/vinorelbine with 1-, 2-, and 3-year OS rates of 38%, 12%, and 2% versus 45%, 12%, and 6%, respectively (P = 0.269 log rank). Grade 3/4 thrombocytopenia, nausea/vomiting, myalgia/arthralgia, and neuropathy were significantly greater in the PCG arm. CONCLUSION: There was no difference in OS or progression-free survival when comparing PCG and gemcitabine/vinorelbine, and gemcitabine/vinorelbine was significantly less toxic. Gemcitabine/vinorelbine is a reasonable nonplatinum agent-based doublet therapy for patients with advanced NSCLC.

Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network.

PURPOSE: Treatment remains poor for many patients with carcinoma of unknown primary site (CUP), and no effective second-line treatment has been identified. Combination inhibition of vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) with bevacizumab and erlotinib has proved efficacious and well tolerated in other solid tumors. We therefore have evaluated the efficacy and toxicity of this combination in patients with CUP. PATIENTS AND METHODS: Patients with CUP who either had received previous chemotherapy or were previously untreated with poor-prognosis clinical features were eligible for this study. All patients received bevacizumab 10 mg/kg IV every 2 weeks, along with erlotinib 150 mg orally daily. Patients were re-evaluated after 8 weeks of treatment; those with objective response or stable disease continued treatment until disease progression. RESULTS: Forty-seven (92%) of 51 patients received at least 8 weeks of treatment. Five patients (10%) had partial responses, and 29 patients (61%) had stable disease as the best response. The median survival for the entire group was 7.4 months, with 33% of patients alive at 1 year. This regimen was well tolerated by most patients. CONCLUSION: The combination of bevacizumab and erlotinib has substantial activity in the treatment of patients with CUP. The median survival is superior to survival previously reported with second-line chemotherapy, and is similar to the results of many first-line chemotherapy trials in this setting. This regimen merits further evaluation in patients with CUP.