James D. Peyton

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

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.

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 FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only

Lessons Learned This regimen is a viable option for patients with liver-only metastatic colorectal cancer. Enrollment criteria for future studies should include testing for the newly identified KRAS mutations. 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/m2, 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m2 i.v.; irinotecan, 125 mg/m2; oxaliplatin, 85 mg/m2 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 had 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.

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

Abstract 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 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

Abstract 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.