No abstract

Allelic exclusion operates in B and T lymphocytes to ensure clonal expression of antigen receptors after V(D)J recombination. Germline transcription, which proceeds V(D)J recombination, has been postulated to provide an instructive signal for allelic exclusion. Here, we use a genetic marker to track germline transcription from a Vb gene within the TCRb locus. We find that developing thymocytes exhibit uniformed, bi-allelic activation of the Vb gene before V-DJ recombination, a process subject to allelic exclusion. We further show that V-DJ rearrangement promotes activation rather than silencing of germline transcription from the remaining Vb genes on either the functionally or non-functionally rearranged chromosome. Results presented here suggest that germline transcription, although necessary for V(D)J recombination, is not sufficient to instruct allelic exclusion.

Purpose To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus and panobinostat (LBH-589) when administered in combination in patients with advanced solid tumor malignancies. Experiment Design Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily and bevacizumab at 10 mg/kg every two weeks. Dose limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on-treatment. Results Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50%), headache (33%), mucositis/stomatitis (25%), hyperlipidemia (25%), and thrombocytopenia (25%). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared to baseline. Conclusions Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile, and did not consistently inhibit HDAC activity; therefore we do not recommend further evaluation.

Lessons Learned Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long‐term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted. Background The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c‐MET, and may delay or reverse anti‐EGFR resistance. Methods In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. Results Twenty‐five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3–7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5–14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib. Conclusion The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.