A Phase II Study with Lead-In Safety Cohort of 5-Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2-Positive Esophagogastric Adenocarcinomas.

LESSONS LEARNED: Neoadjuvant 5-fluorouracil, oxaliplatin, and lapatinib in combination with radiation therapy is safe for neoadjuvant treatment for patients with localized human epidermal growth receptor 2-positive esophagogastric adenocarcinoma.Evaluation of this drug combination in a larger patient pool would allow for more accurate analysis of its efficacy. BACKGROUND: The optimal design of neoadjuvant chemoradiation for the treatment of localized esophagogastric cancers is the subject of much debate. In this nonrandomized trial, we evaluated neoadjuvant 5-fluorouracil (5-FU), oxaliplatin, and lapatinib in combination with radiation therapy as neoadjuvant treatment for patients with localized human epidermal growth receptor 2 (HER2)-positive esophagogastric adenocarcinomas. METHODS: Patients received neoadjuvant 5-FU (225 mg/m2 continuous intravenous infusion, days 1-42), oxaliplatin (85 mg/m2 intravenously [IV], days 1, 15, and 29), and lapatinib (six patients, 1,000 mg p.o., days 1-42; six patients, 750 mg p.o., days 1-42) plus radiation (1.8 Gy/day Monday through Friday for 50.4 Gy total). Following restaging, eligible patients underwent definitive resection, and pathologic response to neoadjuvant therapy was assessed. Planned enrollment was 42 patients. The primary endpoint was the pathologic complete response (pCR) rate. RESULTS: Twelve patients (median age 64 years; 67% male) received a median of 5.6 weeks of treatment (range: 1.1-8.4). The pCR rate was 8%; four of the 12 patients underwent tumor resection and one patient had a pCR, with pathologic partial response in the remaining three. The most common lapatinib-related adverse events included (all grades) nausea (67%) and diarrhea (58%), although these were all grade 1 or 2. Enrollment was halted due to low accrual. CONCLUSION: The treatment regimen was determined to be safe. The study was terminated early due to low accrual.

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.

A Phase II Study of FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only.

BACKGROUND: Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis. METHODS: Patients received FOLFOXIRI (5-FU, 3,200 mg/m(2), 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m(2) i.v.; irinotecan, 125 mg/m(2); oxaliplatin, 85 mg/m(2) i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate. RESULTS: Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1-33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all were complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found. CONCLUSION: KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations.

Regorafenib Prior to Selective Internal Radiation Therapy Using 90Y-Resin Microspheres for Refractory Metastatic Colorectal Cancer Liver Metastases: Analysis of Safety, Dosimetry, and Molecular Markers.

Background: This Phase II, open-label, study examined the safety of regorafenib followed by selective internal radiation therapy (SIRT) with regorafenib re-initiation in the treatment of metastatic colorectal cancer (mCRC) patients with liver metastases who are not surgical candidates. Methods: Patients received 160 mg regorafenib daily on a 21-day course followed by a 1 week washout prior to SIRT. Liver function was evaluated at 2 and 4 weeks after SIRT, and regorafenib re-initiated if liver function was normal. Patients were evaluated for safety, and restaged at weeks 6 and 12 following SIRT. In addition, protein and cytokine assays of blood were performed to identify candidate molecular biomarkers associated with outcomes. Individual patient voxel-based dosimetry assessment was performed post-SIRT. Results: Twenty-Five patients were enrolled and received a median 11 weeks regorafenib. Three patients received regorafenib, but not SIRT due to disease progression. The remaining 22 patients received SIRT with a median activity delivered to the liver of 38 mCi, mean normal liver dose of 14.98 Gy and tumor mean dose of 29.0 Gy with a tumor to normal ratio mean of 2.42. There were four treatment-related serious AEs and no treatment-related deaths. Median progression-free survival was 3.7 months and the median overall survival was 12.1 months. The relative densities of several biomolecules changed significantly during the course of treatment, most notably post-treatment increases in levels of sex-hormone binding globulin (SHBG) and decreased levels of the cytokine MIG (CXL9). Decreases in von Willebrand factor (VWF), the ankyrin repeat domain (ANKRD26), and MIG were associated with improved survival times. Post-treatment increases in alpha-2-macroglobulin (A2M) and the cytokine intercellular adhesion molecule (ICAM-1) were associated with reduced overall survival time, while increases in Eotaxin (CCL14) predicted longer overall survival times. Conclusions: The treatment of mCRC patients with liver metastases using regorafenib followed by SIRT was tolerable in this patient population. Further efficacy analysis of this treatment schema and analysis of potential molecular biomarkers using larger sample sizes is merited.

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.

A phase II trial of carboplatin and weekly topotecan in the first-line treatment of patients with extensive stage small cell lung cancer.

BACKGROUND: Carboplatin and topotecan are commonly used in the treatment of small cell lung cancer (SCLC); however, there are no data for this combination in the first-line setting using weekly topotecan. In this multicenter, community-based phase II trial, we evaluated carboplatin and weekly topotecan in the previously untreated patients with extensive stage SCLC. METHODS: This trial was designed to achieve an objective response rate (ORR) of 70% (alpha = 0.05; beta = 0.20); secondary aims were to assess time to progression, toxicity, and overall survival (OS). Patients with Eastern Cooperative Oncology Group performance status 0 to 1, measurable disease, and adequate organ function were eligible. TREATMENT: carboplatin area under the concentration-time curve = 5 (intravenous) on day 1 and topotecan 4 mg/m(2) (intravenous) on days 1 and 8, every 21 days for up to six cycles, with restaging every 6 weeks (per RECIST). RESULTS: Between June 2006 and November 2008, 61 patients were enrolled. The median follow-up is 40 weeks (range 27-109 weeks). Patient characteristics were as follows: median age 67 years (range 40-84 years); male, 53%; and Eastern Cooperative Oncology Group performance status 0, 28%. Complete responses were seen in two patients and partial responses in 33 patients; ORR was 57% (95% confidence interval [CI] 44-70). Stable disease was seen in 12 patients (20%), and progressive disease was seen in two patients (3%). The median time to progression was 5.5 months (95% CI 4.0-6.3 months). The median OS was 8.5 months (95% CI 7.2-11.4 months). One-year OS was 29%. Grade 3/4 toxicity in >5%: neutropenia (66%), thrombocytopenia (48%), leukopenia (40%), anemia (30%), fatigue (13%), dehydration (8%), infection (8%), and pain (7%). CONCLUSIONS: The ORR achieved with carboplatin and weekly topotecan was less than the anticipated rate of 70%; however, it was comparable with historical rates seen with other platinum doublets in the first-line extensive stage SCLC setting. This regimen was generally well tolerated, with myelosuppression as its primary toxicity.

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.