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Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is seen in 40% to 60% of patients with colorectal cancer. Everolimus, an oral inhibitor of mTOR, showed efficacy in patients with metastatic colorectal cancers in phase I studies. Experimental Design: In sequential phase II studies assessing two dosing schedules, patients with metastatic colorectal cancers refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/wk (n = 99) or 10 mg/d (n = 100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses. Results: Seventy-one patients were included in the per-protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 and 4.9 months and 1.8 and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = 0.008) and lower DCR (P = 0.035) compared with those with wild-type KRAS in exploratory biomarker analyses. Conclusions: Everolimus 70 mg/wk or 10 mg/d was well tolerated but did not confer meaningful efficacy in heavily pretreated patients with metastatic colorectal cancers. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway. Clin Cancer Res; 19(14); 3987–95. ©2013 AACR.

TPS6643^ Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation, significant morbidity, shortened life span and possible evolution to myelofibrosis and acute myeloid leukemia. Splenomegaly, debilitating constitutional symptoms, and frequent phlebotomy requirements are common in advanced disease. HU, an established first-line agent for cytoreduction, can be associated with cytopenias, aphthous and leg ulcers, and other side effects. Control of hematocrit is not always achieved with HU, and many patients are either intolerant of or become resistant to HU. JAK2 plays a key role in the pathophysiology of PV; nearly 100% of patients harbor either the JAK2V617F or JAK2 exon 12 mutations. In a phase 2 study in HU-resistant or -intolerant PV patients, ruxolitinib, a potent and selective inhibitor of JAK1/JAK2, was well tolerated and achieved rapid and durable clinical responses, including phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) and platelet (PLT) counts and disease-related symptoms. Methods: RESPONSE is a randomized (1:1), open-label, global phase 3 study (NCT01243944) designed to compare the safety and efficacy of ruxolitinib with best available therapy (BAT) in adult patients with PV who are resistant to or intolerant of HU (modified European Leukemia Net criteria) and require phlebotomy because of inadequate hematocrit control. Inclusion criteria have been amended to include patients who exhibit palpable splenomegaly with an MRI-confirmed volume of ≥ 450 cm3 (ie, approximately 2.5 x median normal volume; instead of ≥ 5 cm by palpation) and PLT > 100 x109/L; the requirement for either elevated WBC (> 15 x109/L) or PLT count (> 600 x109/L) was removed. The primary efficacy endpoint is the achievement of both phlebotomy independence and a ≥ 35% reduction in spleen volume after 32 weeks of treatment. Patients will be treated for 80 weeks to assess safety and durability of response. Patients randomized to BAT may be eligible to cross over to receive ruxolitinib after week 32. Enrollment is planned for 145 investigational sites (134 currently open), with a target of 200 patients.