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 2 Study of 5-Fluorouracil (5-FU), Ziv-Aflibercept, and Radiation for the Preoperative and Adjuvant Treatment of Patients with Stage II/III Rectal Cancer.

BACKGROUND: This phase II study combined aflibercept with preoperative chemoradiation for patients with stage II/III rectal cancer, followed by mFOLFOX6/aflibercept. METHODS: Patients received preoperative 5-FU (days 1-43), radiation (weeks 1-6), and aflibercept (days 1-15) each 28 day cycle for 6 weeks. Six weeks following the last aflibercept dose, patients underwent surgical resection. Four cycles of mFOLFOX6 plus aflibercept began 8 weeks after surgery. RESULTS: Common treatment-related toxicities included diarrhea, fatigue, and mucositis. The pCR rate was 23%. DISCUSSION: Afilbercept plus 5-FU-based chemoradiation was tolerated in patients with localized rectal cancer and showed a pCR rate within range of historical data.

A Phase-2 Trial of Single Agent Axitinib as Maintenance Therapy Following First-Line Treatment With Modified FOLFOX/Bevacizumab in Patients With Metastatic Colorectal Cancer.

This phase-2 trial evaluated the efficacy of axitinib as maintenance therapy for patients with metastatic colorectal cancer (mCRC) following first-line treatment with FOLFOX/bevacizumab. Patients with mCRC received mFOLFOX/bevacizumab followed by axitinib maintenance after four cycles. The primary endpoint was progression-free survival (PFS). Seventy patients were enrolled. Common treatment-related toxicities were fatigue, nausea, diarrhea, and peripheral neuropathy during FOLFOX/bevacizumab treatment; and fatigue, hypertension, diarrhea, and peripheral neuropathy during axitinib treatment. Median PFS was 8.3 months. Treatment with FOLFOX/bevacizumab followed by maintenance axitinib as first-line treatment for mCRC produced a median PFS consistent with historical controls of other first-line regimens.

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 II Study of the Combination of Bevacizumab, Pertuzumab, and Octreotide LAR for Patients with Advanced Neuroendocrine Cancers.

PURPOSE: To evaluate efficacy and safety of bevacizumab, pertuzumab, and octreotide depot for advanced neuroendocrine tumors. METHODS: Patients received bevacizumab 15 mg/kg and pertuzumab 420 mg IV q21 days with octreotide depot 30 mg IM q28 days. RESULTS: Toxicities in 43 patients included diarrhea (63%), fatigue (63%), hypertension (44%), and nausea (44%). Reversible G3 hypertension (26%) and LVEF decline (9%) occurred. 7/43 patients achieved objective response (typical carcinoid, 5; pancreatic NET, 2). Median PFS and OS were 6.5 and 26.4 months, respectively. DISCUSSION: Bevacizumab, pertuzumab, and octreotide depot was well-tolerated with a 16% ORR. Results in the well-differentiated carcinoid tumors are thought provoking.

Sorafenib Plus Ixabepilone as First-Line Treatment of Metastatic HER2-Negative Breast Cancer: A Sarah Cannon Research Institute Phase I/II Trial.

BACKGROUND: The purposes of the present phase I/II trial were (1) to define tolerable doses of ixabepilone and sorafenib when used in combination and (2) to evaluate the efficacy and toxicity of this combination in the treatment of patients with human epidermal growth factor receptor-negative metastatic breast cancer (MBC). PATIENTS AND METHODS: The eligible patients had human epidermal growth factor receptor-negative MBC and had not received previous chemotherapy in the metastatic setting. All patients received ixabepilone intravenously on day 1 of each 21-day treatment cycle; sorafenib was administered orally twice daily. Patients in phase II received the maximum doses identified in phase I. The patients were reevaluated after the completion of 3 treatment cycles; treatment continued until disease progression or intolerable toxicity. A total of 67 patients were required in phase II to demonstrate increased median progression-free survival from 4.2 to 6.2 months (90% power, α = 0.05). RESULTS: Ten patients entered the phase I portion; the maximum tolerated doses were ixabepilone 32 mg/m(2) and sorafenib 400 mg orally twice daily. A total of 76 patients were treated at the phase II dose. The median progression-free survival was 4.8 months (95% confidence interval, 3.5-6.3 months). The overall response rate was 37%. The regimen was difficult to tolerate for many patients; 20 patients discontinued because of toxicity, and dose reductions were frequent. The common toxicities included neutropenia, fatigue, rash, and neuropathy. CONCLUSION: The combination of ixabepilone and sorafenib was poorly tolerated as first-line treatment of patients with MBC. The activity of the combination was similar to the activity previously reported with single-agent ixabepilone or taxanes. Further development of this combination is not recommended.

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.

A Phase I Study of the Hsp90 Inhibitor AUY922 plus Capecitabine for the Treatment of Patients with Advanced Solid Tumors.

BACKGROUND: This phase I study determined the maximum tolerated dose (MTD) of AUY922 with capecitabine in advanced solid tumors. METHODS: Capecitabine 1000 mg/m(2) PO BID was administered with escalating doses of AUY922 IV; the MTD of AUY922 was combined with capecitabine 1250 mg/m(2) (DL6). RESULTS: 23 patients were treated at 5 dose levels (22 mg/m(2)-70 mg/m(2)). No DLTs were observed until DL6 (grade 3 diarrhea). Reversible vision darkening was seen in 26%. Four patients had partial response; 2 previously progressed on fluorouracil. Eight patients had stable disease (median 25.5 weeks). CONCLUSION: AUY922 plus capecitabine was well-tolerated up to 70 mg/m(2) with encouraging preliminary efficacy.

Pazopanib and liposomal doxorubicin in the treatment of patients with relapsed/refractory epithelial ovarian cancer: a phase Ib study of the Sarah Cannon Research Institute.

PURPOSE: To investigate the combination of liposomal doxorubicin/pazopanib in advanced relapsed/refractory ovarian cancer. PATIENTS AND METHODS: Twenty-two patients received liposomal doxorubicin/pazopanib. Initial doses (liposomal doxorubicin, 40 mg/m2 monthly; pazopanib, 400 mg daily) were too toxic; three subsequent groups received lower doses/altered schedules. RESULTS: The maximum tolerated doses (MTD) were liposomal doxorubicin, 30 mg/m2, and pazopanib, 400 mg daily. Severe toxicity included neutropenia (18%), rash/desquamation (14%), hypertension (9%), and hand-foot syndrome (9%). Five of the eight patients treated with MTD had grade 3 toxicity during the first two cycles. Dose reductions were frequently required. CONCLUSIONS: Further development of the liposomal doxorubicin/pazopanib combination is not recommended.

A phase Ib study of linsitinib (OSI-906), a dual inhibitor of IGF-1R and IR tyrosine kinase, in combination with everolimus as treatment for patients with refractory metastatic colorectal cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) of the combination of linsitinib (OSI-906), a dual inhibitor of IGFR and IR tyrosine kinase activity, and everolimus as treatment for patients with refractory metastatic colorectal cancer (mCRC). METHODS: Eligible adult patients with refractory mCRC, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate end-organ function received escalating doses of OSI-906 and everolimus in a 3 + 3 design. Treatment continued until disease progression or unacceptable toxicity, with response evaluations every 8 weeks. RESULTS: Eighteen patients with metastatic CRC were treated. There were no dose-limiting toxicities (DLTs) in the first dose level (DL, OSI-906 50 mg BID; everolimus 5 mg QD). At DL2 (OSI-906 100 mg BID; everolimus 10 mg QD, n =6), three patients had DLTs considered related to everolimus (grade 3 mucositis, 2; grade 3 thrombocytopenia, 1). An amendment introduced DL2a (OSI-906 100 mg BID; everolimus 5 mg QD, n =5); DLTs were seen in two patients (one patient each: grade 3 thrombocytopenia with bleeding; inability to receive 75 % of doses due to neutropenia/thrombocytopenia). DL1 was the MTD; a total of 7 patients were treated at this dose. Common adverse events across all DLs included grade 1/2 fatigue (50 %) and anorexia (50 %). There were no objective responses to treatment; median time of study treatment was 7.6 weeks (range: 3.9-53 weeks). CONCLUSIONS: The MTD of OSI-906 and everolimus was 50 mg BID and 5 mg QD, respectively. No indications of clinical activity were observed in refractory mCRC patients.