A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial.

BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). METHODS: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity. RESULTS: The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months. CONCLUSION: The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting. IMPLICATIONS FOR PRACTICE: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

Amrubicin and carboplatin with pegfilgrastim in patients with extensive stage small cell lung cancer: A phase II trial of the Sarah Cannon Oncology Research Consortium.

PURPOSE: First-line treatment for patients with extensive-stage small cell lung cancer (SCLC) includes treatment with platinum-based combination chemotherapy. Amrubicin is a synthetic anthracycline with single-agent activity in relapsed/refractory SCLC. In an attempt to improve treatment efficacy, we evaluated amrubicin/carboplatin as first-line therapy for extensive-stage SCLC. PATIENTS AND METHODS: In this multicenter phase II trial, patients received amrubicin (30 mg/m2 daily on Days 1, 2, and 3) and carboplatin (AUC = 5 on Day 1); cycles were repeated every 21 days for 4 cycles. Pegfilgrastim (6 mg subcutaneously) was administered on Day 4 of all cycles. Overall survival (OS) proportion at 1 year was the primary endpoint. The target 1-year OS rate was 47%, an improvement of 35% from historical results with carboplatin/etoposide. RESULTS: Eighty patients received study treatment, and 62% completed the planned 4 courses. The overall response rate was 74% (13% complete responses). The 1-year survival rate was 38% (95% CI: 25, 50). The median survival was 10 months. Myelosuppression was severe but manageable. CONCLUSIONS: The combination of amrubicin/carboplatin was an active first-line treatment for extensive stage SCLC, but showed no indication of increased efficacy compared to standard treatments. Severe myelosuppression was common with this regimen, in spite of prophylactic pegfilgrastim. These results are consistent with those of other trials in showing no role for amrubicin in the first-line treatment of SCLC.

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.

Sorafenib and continued erlotinib or sorafenib alone in patients with advanced non-small cell lung cancer progressing on erlotinib: A randomized phase II study of the Sarah Cannon Research Institute (SCRI).

PURPOSE: To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. PATIENTS AND METHODS: Patients with progressive refractory NSCLC who had previously benefitted from erlotinib (objective response or stable disease >8weeks) were randomized to receive treatment with either erlotinib and sorafenib (400mg orally twice daily) or sorafenib alone. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. RESULTS: Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8weeks of treatment. The median PFS was 3.1months for erlotinib/sorafenib versus 1.7months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. CONCLUSIONS: These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804.

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

LESSONS LEARNED: The addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation. BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer. METHODS: Patients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS). RESULTS: One hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen. CONCLUSION: Addition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup.

Phase I/II trial of neoadjuvant sunitinib administered with weekly paclitaxel/carboplatin in patients with locally advanced triple-negative breast cancer.

The purpose of the study is to evaluate the feasibility and efficacy of adding sunitinib to paclitaxel/carboplatin in the neoadjuvant therapy of patients with triple-negative breast cancer (TNBC). Patients had histologically proven, previously untreated, triple-negative adenocarcinoma, with disease limited to the breast and axilla (clinical T1-T3, N0-N2, M0; T1N1M0 excluded). Following determination of the maximum tolerated doses in the phase I portion, patients in the phase II study received paclitaxel 70 mg/m(2) IV days 1, 8, and 15; carboplatin AUC 5.0 IV day 1; sunitinib 25 mg orally daily; treatment was administered for six 28-day cycles followed by definitive surgery. Sunitinib was resumed postoperatively to complete a 52-week course. Pathologic complete response (pCR) rate was the primary endpoint. Fifty-four patients enrolled; 41 received treatment in the phase II study. Sixteen patients (39 %) were able to complete six cycles of neoadjuvant therapy; 18 additional patients had surgery after completing 2-5 cycles of treatment. The pCR rate in these 34 evaluable patients was 35 %. The toxicity of the regimen was considerable, with myelosuppression resulting in numerous dose reductions and/or omissions of paclitaxel and carboplatin. Eleven patients (27 %) discontinued sunitinib during neoadjuvant therapy, and six patients (14 %) completed 52 weeks of single-agent sunitinib. In the neoadjuvant treatment of patients with TNBC, the combination of paclitaxel, carboplatin, and sunitinib was difficult to administer, and produced a pCR rate comparable to other less toxic regimens. This combination is not recommended for further evaluation. At present, sunitinib has no defined role in the treatment of breast cancer.

High-dose bevacizumab in the treatment of patients with advanced clear cell renal carcinoma: a phase II trial of the Sarah Cannon Oncology Research Consortium.

BACKGROUND: The dose of bevacizumab necessary to optimally inhibit tumor angiogenesis in advanced renal cell carcinoma is unknown. In this phase II trial, we evaluated the efficacy and safety of 2 escalated doses of bevacizumab in patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS: Eligible patients had metastatic or locally advanced unresectable clear cell renal carcinoma. Patients who were previously untreated or who had previously received vascular endothelial growth factor receptor (VEGFR)-targeted therapy were eligible and were considered separately in the efficacy evaluation. Two doses of bevacizumab were evaluated in sequential cohorts: 15 mg/kg every 2 weeks and 15 mg/kg weekly. The initial reevaluation was at 8 weeks; responding and stable patients continued treatment, with reevaluations every 8 weeks until tumor progression or unacceptable toxicity occurred. RESULTS: One hundred nineteen eligible patients were enrolled and received bevacizumab 15 mg/kg every 2 weeks (n = 61) or bevacizumab 15 mg/kg weekly (n = 58). Seventy patients were previously untreated with VEGFR-targeted therapy. In previously untreated patients, the overall response rate was 19%, with a median progression-free survival (PFS) of 7.8 months. Less activity was seen in patients previously treated with VEGFR-targeted agents (overall response rate, 4%; median PFS, 3.7 months). There was no suggestion of any difference in efficacy between the 2 dose levels tested. Both dose levels were tolerated well by most patients, with a spectrum of toxicity typical for bevacizumab. Grade 3/4 proteinuria was more frequent with both of these escalated doses, particularly with 15 mg/kg weekly. CONCLUSION: Although administration of escalated doses of bevacizumab was feasible in patients with advanced clear cell renal carcinoma, there was no suggestion that these doses were more efficacious than bevacizumab administered at the standard dose of 10 mg/kg every 2 weeks.

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 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.

A randomized phase II trial of pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab in the first-line treatment of elderly patients with advanced non-small cell lung cancer.

PURPOSE: To assess time to progression (TTP) in elderly patients with previously untreated nonsquamous non-small cell lung cancer treated with pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab. METHODS: Eligible patients were aged 70 years or older with newly diagnosed stage IIIB/IV nonsquamous non-small cell lung cancer; Eastern Cooperative Oncology Group performance status 0 to 1; adequate organ function; and no active central nervous system metastasis. Patients were randomized 1:1 to cohort A (pemetrexed 500 mg/m2 IV, gemcitabine 1500 mg/m2 IV, and bevacizumab 10 mg/kg IV; days 1 and 15 of 28-day cycles) or cohort B (pemetrexed 500 mg/m2 IV, carboplatin area under the concentration-time curve =5 IV, and bevacizumab 15 mg/kg IV; day 1 of 21-day cycles). After six cycles, stable/responding patients continued bevacizumab until disease progression. RESULTS: Between March 2007 and December 2009, 110 patients (median age, 76 years; 88% stage IV) were treated for medians of 2.5 cycles (cohort A) and 6 cycles (cohort B). Overall response rate was 35% in both cohorts, with stable disease rates of 33% (A) and 45% (B). TTP by cohort was 4.7 and 10.2 months with median OS 7.5 and 14.8 months, respectively. Severe toxicities included the following: neutropenia (A, 51% and B, 45%), fatigue (A, 36% and B, 18%), anemia (A, 22% and B, 7%), infection (A, 25% and B, 7%), thrombocytopenia (A, 11% and B, 31%), and thromboembolism (A, 7% and B, 7%). Three potential treatment-related deaths occurred in cohort A (sepsis, thrombocytopenia, and myocardial infarction) and two in B (sepsis and pulmonary hemorrhage). CONCLUSIONS: Treatment with pemetrexed/carboplatin/bevacizumab was associated with improved TTP and OS in this elderly population and should be further evaluated. Treatment-related toxicities were expected and usually manageable, although deaths occurred with both regimens.

Phase II study of bevacizumab and chemoradiation in the preoperative or adjuvant treatment of patients with stage II/III rectal cancer.

BACKGROUND AND PURPOSE: We wanted to evaluate the efficacy, defined as 2-year disease-free survival (DFS), and safety of bevacizumab/chemoradiation in preoperative and adjuvant settings for patients with stage II/III rectal cancer. PATIENTS AND METHODS: Eligible patients had stage II/III rectal adenocarcinoma, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and adequate organ function, and received preoperative (cohort A) or adjuvant (cohort B) treatment at physician discretion. Patients received 5-fluorouracil (5-FU) as an intravenous infusion (IVCI) 225 mg/m(2)/d on days 1-42, bevacizumab 5 mg/kg intravenously (I.V.) on days 1 and 15 (cohort A), or every 2 weeks (cohort B), with radiation therapy to 50.4 Gy. After surgery (cohort A) or chemoradiation (cohort B), FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) and bevacizumab were administered for 4 months and then bevacizumab was given alone for up to 1 year. RESULTS: Sixty-six patients (cohort A = 35; cohort B = 31) were enrolled from August 2006-April 2009: median age was 57 years; male patients, 62%; ECOG PS 0, 75%; stage II/III, 31%/69%. In cohort A, the complete pathologic response (pCR) rate was 29% (11% microscopic residual disease, 49% gross disease). Four patients did not undergo surgery (toxicity, 2 patients; progressive disease, 1 patient; patient decision, 1 patient). One- and 2-year DFS for cohorts A/B were 85%/not reached and 97%/89%, respectively (median survival not reached for either cohort). Frequent grade 3/4 toxicity included diarrhea (A cohort, 14%; B cohort, 29%), neutropenia (A cohort, 14%, B cohort, 23%), mucositis (A cohort, 23%, B cohort, 0%), and fatigue (A cohort, 6%, B cohort, 10%). Other serious toxicity included bowel perforation and pelvic infection (cohort A, 1 patient each), bowel perforation (2 patients), anal wound dehiscence (1 patient), perianal infection (2 patients), and rectovaginal fistula (1 patient) (cohort B), without treatment-related death in either cohort. CONCLUSIONS: Bevacizumab can be added to standard preoperative and adjuvant chemoradiation in most patients with expected and manageable toxicity and may increase treatment efficacy.

Combined modality treatment with chemotherapy, radiation therapy, bevacizumab, and erlotinib in patients with locally advanced squamous carcinoma of the head and neck: a phase II trial of the Sarah Cannon oncology research consortium.

PURPOSE: : The aim of the study was to evaluate the feasibility and efficacy of adding bevacizumab and erlotinib to concurrent chemoradiation therapy for first-line treatment of patients with locally advanced squamous carcinoma of the head and neck. METHODS: : Sixty previously untreated patients with squamous carcinoma of the head and neck (36 with oropharyngeal primaries; 83% men; median age, 56 years; 73% stage IV) received induction chemotherapy with 6 weeks of paclitaxel, carboplatin, infusional 5-fluorouracil, and bevacizumab; this treatment was followed by radiation therapy, weekly paclitaxel, bevacizumab, and erlotinib. RESULTS: : After a median follow up of 32 months, the estimated 3-year progression-free and overall survival rates are 71% and 82%, respectively. Sixty-five percent of patients had major responses after induction therapy; after completion of therapy, 95% of patients had either partial or complete response radiographically. As expected, grade 3/4 mucosal toxicity occurred frequently (88%) during combined modality; no unexpected toxicity resulted from the addition of bevacizumab and erlotinib. CONCLUSIONS: : The addition of bevacizumab and erlotinib to first-line combined modality therapy was feasible in a community-based setting, producing toxicity comparable to other effective combined modality regimens for head and neck cancer. The high level of efficacy suggests that incorporation of these targeted agents into first-line therapy should be further explored.

A phase II study of higher dose weekly topotecan in relapsed small-cell lung cancer.

BACKGROUND: Five-day topotecan is approved by the US Federal Drug Administration (FDA) for sensitive relapsed small-cell lung cancer (SCLC). We previously found that 4 mg/m(2) intravenous (I.V.) weekly dosing resulted in low-grade 3/4 toxicity but an overall response rate (ORR) < 10%. We hypothesized that higher topotecan dosing could improve ORR without significantly increasing toxicity. PATIENTS AND METHODS: This multicenter phase II trial sought a 25% ORR (α = 0.04; ß = 0.20). Eligible patients (sensitive or refractory relapsed SCLC; Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1; measurable disease) received weekly topotecan (6 mg/m(2) I.V. for 6 weeks) and were restaged every 8 weeks. RESULTS: Baseline characteristics were N = 38, enrolled 5/2006-10/2007; median age 64 years (range, 35-82), 47% female, 74% ECOG PS 1, 50% refractory relapsed SCLC. The median follow-up was 15 months (range, 12-24 months). No patients received all planned therapy; only 1 patient was able to receive all planned treatment in cycle 1 because of hematologic toxicity and progressive disease (PD). Among all patients, ORR was 8% (95% confidence interval [CI], 2%-21%), 24% had stable disease, and disease in 47% progressed. Among sensitive relapsed patients ORR was 16% (95% CI, 3%-40%) with no complete responses; median response duration was 3.3 months. Five (26%) patients had stable disease; 8 (42%) patients had PD. Among sensitive relapsed patients, the median time to progression (TTP) and overall survival (OS) was 2.5 months and 8.6 months, respectively. Among refractory relapsed patients there were no ORRs, and median TTP and OS were 1.5 months and 3.7 months, respectively. Grade 3/4 toxicities (> 10%) included neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), and pain (13%). There were no treatment-related deaths. CONCLUSION: Weekly topotecan (6 mg/m(2) I.V.) is not feasible because of hematologic toxicity and does not improve efficacy in patients with relapsed SCLC.

Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer.

PURPOSE: Sorafenib, an oral multikinase inhibitor, has shown preliminary activity in non-small-cell lung cancer (NSCLC). Patients with advanced NSCLC were treated with erlotinib with or without sorafenib in this multicenter phase II trial. PATIENTS AND METHODS: Key eligibility criteria included the following: stage IIIB or IV NSCLC; one to two prior regimens; Eastern Cooperative Oncology Group performance status of 0 to 2; and measurable disease. Patients were randomly assigned 2:1 to sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily) or placebo plus erlotinib and stratified by squamous/nonsquamous histology and prior bevacizumab. Treatment efficacy, measured by progression-free survival (PFS) and overall response rate (ORR), was compared. Treatment of 168 patients allowed detection of 40% improvement in the historical PFS of 2.2 months with single-agent erlotinib. RESULTS: One hundred sixty-eight patients enrolled from February 2008 to February 2009. Clinical characteristics of the two groups were similar. ORRs for sorafenib/erlotinib and placebo/erlotinib were 8% and 11%, respectively (P = .56); disease control rates were 54% and 38%, respectively (P = .056). Median PFS was 3.38 months for sorafenib/erlotinib versus 1.94 months for placebo/erlotinib (hazard ratio, 0.86; 95% CI, 0.60 to 1.22; P = .196). Seventy-two patients consented to analyses of tumor epidermal growth factor receptor (EGFR). In 67 patients with EGFR wild-type (WT) tumors, median PFS was 3.38 months for sorafenib/erlotinib versus 1.77 months for placebo/erlotinib (P = .018); median overall survival (OS) was 8 months for sorafenib/erlotinib versus 4.5 months for placebo/erlotinib (P = .019). An OS advantage for sorafenib/erlotinib was suggested among 43 patients with fluorescent in situ hybridization (FISH) EGFR-negative tumors (P = .064). Both regimens were tolerable, with modest toxicity increase with sorafenib. CONCLUSION: Although there was little difference in ORR or PFS, subset analyses in EGFR WT and EGFR FISH-negative patients suggest a benefit for the combination of erlotinib/sorafenib compared with single-agent erlotinib with respect to PFS and OS.

Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.

BACKGROUND: The aim of this study was to compare the efficacy of single-agent weekly docetaxel with the combination of docetaxel and gemcitabine in elderly and/or poor performance status patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Previously untreated patients with stage IIIB/IV NSCLC who were either >65 years old or had an Eastern Cooperative Oncology Group (ECOG) performance status 2 were eligible. Patients were randomized to receive weekly docetaxel (36 mg/m(2)) Days 1, 8, and 15 or docetaxel (30 mg/m(2))/gemcitabine (800 mg/m(2)) Days 1, 8, and 15. Both regimens were repeated on 28-day cycles for 6 cycles or until disease progression. RESULTS: Three hundred fifty patients were randomized, and 345 received treatment. The median age of patients was 74 years; 38% were >75 years old, and 35% had ECOG performance status 2. Intent-to-treat analysis showed median survivals of 5.5 months versus 5.1 months in the groups receiving docetaxel/gemcitabine versus weekly docetaxel, respectively (P = .65). There were no survival differences detected with docetaxel/gemcitabine versus weekly docetaxel in the 223 patients with good performance status (7.2 months vs 8.0 months, respectively) or in the 122 poor performance status patients (3.8 months vs 2.9 months, respectively). Median time-to-progression was longer in patients who received docetaxel/gemcitabine (4.8 months vs 2.9 months; P = .004). Both regimens were generally well tolerated. CONCLUSIONS: Treatment with docetaxel/gemcitabine produced a modest improvement in time-to-progression but had no impact on survival when compared with single-agent weekly docetaxel in this group of patients. Results with both regimens were disappointing, particularly in patients with poor performance status. Improved treatment for these patients will require the introduction of novel, well-tolerated, targeted agents.

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.

Phase I. Trial of irinotecan and temozolomide in patients with solid tumors.

This phase I study was conducted to determine the dose-limiting toxicity, maximum tolerated doses, and recommended phase II doses of the combination of irinotecan (CPT-11, Camptosar) and temozolomide (Temodar). Patients have received irinotecan and temozolomide on one of three different dosing schedules: (1) oral temozolomide on days 1-14 plus a single i.v. dose of irinotecan on day 8 every 28 days (arm 1); (2) weekly i.v. irinotecan on days 1, 8, 15, and 22 plus oral temozolomide on days 1-7 and 15-21 every 42 days (arm 2); and (3) every-other-week i.v. irinotecan on days 1 and 15 plus oral temozolomide on days 1-7 and 15-21 every 28 days (arm 3). A total of 49 patients have received 112+ cycles of therapy on all three dosing schedules to date. Dose-limiting toxicity consisting of diarrhea, neutropenia, and thrombocytopenia was encountered at a temozolomide dose of 125 mg/m2/d and an irinotecan dose of 250 mg/m2 on treatment arm 1. As a result, the protocol has been amended to explore lower doses of temozolomide in combination with higher doses of irinotecan, and patient accrual is currently continuing. Dose-limiting grade 3 diarrhea, nausea, and vomiting were reported in 7/12 patients enrolled on the two dose levels explored on treatment arm 2, so this dosing regimen was considered intolerable. Patient accrual currently continues at dose level 1 of treatment arm 3, so it is too early to determine dose-limiting toxicities and recommended phase II doses for this treatment schedule. Two partial responses have been reported to date in patients with glioblastoma and head and neck cancer, respectively. One evaluable response has also been observed in a patient with metastatic colorectal cancer. Irinotecan weekly x 4 plus temozolomide on days 1-7 and 15-21 is intolerable due to the development of dose-limiting gastrointestinal toxicities. The recommended phase II doses of irinotecan and temozolomide on treatment arms 1 and 3 remain to be determined as patient accrual is currently ongoing.