Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL.

Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.

Phase II Study of First-Line Trebananib Plus Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2. BACKGROUND: Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC). METHODS: Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2. RESULTS: Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts. CONCLUSION: There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

Physical function and quality of life in frail and/or elderly patients with metastatic colorectal cancer treated with capecitabine and bevacizumab: an exploratory analysis.

OBJECTIVES: Optimal treatment strategies in frail and/or elderly patients with metastatic colorectal cancer have not been well defined. Using data from a prospective, phase II study of elderly patients with metastatic colorectal cancer treated with bevacizumab and capecitabine, we explored the differences in functional measure and quality of life (QoL) between patients with ECOG performance status (PS) 1 and 2. MATERIALS AND METHODS: Geriatric functional measures included patient reported limitations in ADLs and IADLs, ECOG PS, 3-item recall, hearing acuity, and the "Get up and Go" test. QoL was assessed by means of the FACT-C questionnaire and the EQ-5D questionnaire. The prognostic impact of baseline characteristics on survival was studied using univariate Cox regression analysis. RESULTS: The majority (62%) of the 45 patients had an ECOG PS of 2. The ECOG PS 2 group had more limitations in IADLs, lower baseline QoL, and a lower patient-rated health score. For all participants, QoL significantly improved from baseline to the start of cycle 2 (FACT-C: 99.9 vs. 105.4, p=0.01) and did not deteriorate when baseline scores were compared to when participants went off study (FACT-C: 99.9 vs. 98.6, p=0.59). In the Cox-regression analysis, a positive "Get up and Go" test was prognostic for improved survival (HR=0.31, p=0.01). CONCLUSION: There is significant heterogeneity in functional measures and quality of life among elderly patients with metastatic colorectal cancer with ECOG PS 1 and 2. The "Get up and Go" test may be a useful prognostic indicator for survival in this population.

A phase II trial of frontline capecitabine and bevacizumab in poor performance status and/or elderly patients with metastatic colorectal cancer.

OBJECTIVES: This study aims to determine the efficacy and tolerability of capecitabine (CAP) plus bevacizumab (BEV) as treatment for frontline metastatic colorectal cancer (mCRC) in frail and/or elderly patients. MATERIALS AND METHODS: This was an open label, multi-site, single arm, phase II study in frontline mCRC. In this study, patients (pts) who were frail (ECOG 2) or older patients with ECOG 1 performance status (PS) received CAP (1000 mg/m(2) bid, 14 days of every 21 days) plus BEV (7.5mg/kg iv once every 21 days). The primary objective was progression free survival (PFS). Secondary objectives were overall response rate (ORR) and toxicity. RESULTS: In terms of patients: 50 were enrolled; 5 withdrew consent prior to treatment; 45 were treated, and 41 were evaluable. The mean age was 75.9 (range 54-93) and 62% had an ECOG 2 PS. The median PFS was 6.87 months (95% CI, 5.1-11.5 months) and median overall survival was 12.7 months (95% CI, 6.9-12.7 months). The most common grades 3-4 toxicities were: diarrhea (17.8%), fatigue (13.3%), hand-foot syndrome (13.3%), dehydration (8.9%), hypertension (6.7%) and vomiting (6.7%). CONCLUSIONS: The results of this trial support the use of CAP plus BEV as first-line treatment for frail/elderly patients with metastatic CRC. The ORR (40%) is comparable to pooled data in elderly on fluorouracil (5-FU)+BEV. The median PFS (7.2 months) in this study is slightly lower than that seen with 5-FU+BEV but this study had a high percentage of ECOG PS 2 patients. Side effects were manageable with no new safety signals.