Qin, Rui

Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway–targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.

Abstract Introduction: Symptom control is an important objective in the care of patients with cancer and a critical goal for long-term survivors of antineoplastic treatments. Commonly used chemotherapies, including paclitaxel, are associated with a toxic effect on the peripheral nervous system in a substantial fraction of patients, termed chemotherapy induced peripheral neuropathy (CIPN), that is often debilitating. CIPN cannot be predicted from clinical parameters in neurologically normal subjects, suggesting a genetic basis as the root cause. Patients with hereditary neuropathy (HN) due to one of ~50 recognized genes are prone to developing severe CIPN even if the hereditary predisposition is clinically silent. Assessment of CIPN has usually been an afterthought of cancer treatment studies using crude symptom measurement instruments. N08C1 and N08CA are recent clinical trials_the latter analyzed only in early 2013_focusing on extensive phenotyping by patient reported outcomes (PRO) to support genetic investigations of paclitaxel-related CIPN. Massively parallel (“nextgen”) DNA sequencing is the genetic technology of choice and represents an as-yet unrealized potential to study cancer symptom control. Methods: Exome sequencing_analysis of 20,794 genes at nucleotide resolution_was performed on blood of CIPN cases (n=73) and controls (n=46) from N08C1. The primary endpoint was the association of HN genes with CIPN. Bioinformatic analysis determined SNV and other genetic variations across 6.2x107 nucleotides. The association of genes with CIPN was statistically examined by the over-dispersion test C-alpha. The role of singleton SNV was assessed by a burden test. N08CA served as validation. Results: 386,644 SNV were detected with an estimated sensitivity of 90% and specificity of 99.9%; the orthogonal validation rate (PCR of >1000 genotypes) was 99.7%. The association of the minor allele (C>T) at rs7349683 in the gene EPHA5, previously reported by Baldwin et al. (2012) for CALGB40101, was confirmed in N08C1. Two hereditary neuropathy genes were identified as new CIPN candidate genes: Firstly, ARHGEF10 was highly significant with p=5x10-4 based on single gene testing and p<0.02 after Bonferroni correction for multiple testing of 41 hereditary neuropathy genes with non-synonymous SNV. Three SNV were predictive, rs17683288, rs2294039 and rs9657362, the latter with an odds ratio (OR)=3.62. Validation in an independent patient group (n=75) from another paclitaxel CIPN trial, N08CA, confirmed the impact of ARHGEF10 on CIPN (p<0.025; rs9657362 OR=2.51). Secondly, peraxin (PRX) was disrupted by non-synonymous singleton SNV in n=8 cases and n=0 controls (OR=6.4; unadjusted p=0.04). 7 of the 8 mutations were also scored as deleterious by both Polyphen 2 and SIFT. Because PRX SNV were non-recurrent validation was performed in N08C1 by Sanger sequencing. Several neuro-genes across the exome were noted as additional CIPN gene candidates. Conclusions: ARHGEF10 and PRX associations with CIPN suggest that CIPN and HN might share genetic roots in a subset of patients. Construct validity of N08C1 is supported by confirmation of a published result from CALGB40101 relating EPHA5 to CIPN. Germline exome sequencing in cancer patients is highly informative for understanding complex pharmacogenomic traits including outcomes in symptom control research. Citation Format: Andreas S. Beutler, Amit Kulkarni, Rahul Kanwar, Rui Qin, Julie M. Cunningham, Terry M. Therneau, Charles L. Loprinzi. Sequencing symptom control: Results from the Alliance N08C1 and N08CA genetics of chemotherapy neuropathy trials. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-196. doi:10.1158/1538-7445.AM2013-LB-196

Purpose Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain. Patients and Methods In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1. Results Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (−9.1) than for placebo (−4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and −2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study. Conclusion A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM.

BACKGROUNDChemotherapy‐induced peripheral neuropathy (CIPN) is a significant side effect of taxane and platinum‐based chemotherapy. Several studies have supported the potential benefit of glutathione for the prevention of platinum‐induced CIPN. The current trial was designed to determine whether glutathione would prevent CIPN as a result of carboplatin/paclitaxel therapy.METHODSIn total, 185 patients who received treatment with paclitaxel and carboplatin were accrued between December 4, 2009 and December 19, 2011. Patients were randomized to receive either placebo (n = 91) or 1.5 g/m2 glutathione (n = 94) over 15 minutes immediately before chemotherapy. CIPN was assessed using the European Organization for Research and Treatment of Cancer Quality‐of‐Life (EORTC‐QLQ) 20‐item, CIPN‐specific (CIPN20) sensory subscale and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.RESULTSThere were no statistically significant differences between the 2 study arms with regard to: 1) peripheral neurotoxicity, as assessed using both the EORTC‐QLQ‐CIPN20 (P = .21) and the CTCAE scales (P = .449 for grade ≥2 neurotoxicity; P = .039 for time to development of grade ≥2 neuropathy, in favor of the placebo); 2) the degree of paclitaxel acute pain syndrome (P = .30 for patients who received paclitaxel every 3‐4 weeks and P = .002, in favor of the placebo, for patients who received weekly paclitaxel); 3) the time to disease progression (P = .63); or 4) apparent toxicities. Subgroup analyses did not reveal any evidence of benefit in any particular subgroup.CONCLUSIONSThe results from this study do not support the use of glutathione for the prevention of paclitaxel/carboplatin‐induced CIPN. Cancer 2014;120:1890–1897. © 2014 American Cancer Society.

Purpose Cumulative neurotoxicity is a prominent toxicity of oxaliplatin-based therapy. Intravenous calcium and magnesium have been extensively used to reduce oxaliplatin-induced neurotoxicity. This trial was designed to definitively test whether calcium/magnesium decreases oxaliplatin-related neurotoxicity. Patients and Methods In all, 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) were randomly assigned to intravenous calcium/magnesium before and after oxaliplatin, a placebo before and after, or calcium/magnesium before and placebo after. The primary end point was cumulative neurotoxicity measured by the sensory scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 tool. Results There were no statistically significant neuropathy differences among the study arms as measured by the primary end point or additional measures of neuropathy, including clinician-determined measurement of the time to grade 2 neuropathy by using the National Cancer Institute Common Terminology Criteria for Adverse Events scale or an oxaliplatin-specific neuropathy scale. In addition, calcium/magnesium did not substantially decrease oxaliplatin-induced acute neuropathy. Conclusion This study does not support using calcium/magnesium to protect against oxaliplatin-induced neurotoxicity.

Recent therapeutic advances for managing advanced prostate cancer include the successful targeting of the androgen-AR axis with several new drugs in castrate resistant prostate cancer including abiraterone acetate and enzalutamide (MDV3100). This translational progress from “bench to bed-side” has resulted in an enlarging repertoire of novel and traditional drug choices now available for use in advanced prostate cancer therapeutics, which has had a positive clinical impact in prolonging longevity and quality of life of advanced prostate cancer patients. In order to further the clinical utility of these drugs, development of predictive biomarkers guiding individual therapeutic choices remains an ongoing challenge. This paper will summarize the potential in developing predictive biomarkers based on the pathophysiology of the androgen-AR axis in tumor tissue from patients with advanced prostate cancer as well as inherited variation in the patient’s genome. Specific examples of rational clinical trial designs incorporating potential predictive biomarkers from these pathways will illustrate several aspects of pharmacogenetic and pharmacogenomic predictive biomarker development in advanced prostate cancer therapeutics.

Abstract Src transduces activated HER tyrosine kinase and phosphorylates HER to further increase its activity. Src also is involved in osteoclast differentiation. We hypothesized that combining a HER tyrosine kinase inhibitor with a Src inhibitor would result in increased therapeutic activity. To address this hypothesis we performed a phase I trial of D and L to: 1)determine the maximally tolerated dose (MTD) of D combined with L; 2)describe the toxicities associated with this combination; 3)assess the pharmacokinetic (PK) interaction of L and D; 4) assess the effect of the L and D combination on circulating tumor cells (CTC) and on osteoclast precursor activation; 5)study the association of toxicity and/or tumor response with PK, and/or pharmacodynamic parameters; and 6)describe the responses of this combination. Eligibility criteria included ≥ 18 years of age, incurable solid tumors not amenable to other therapies, ANC ≥ 1500/ L, PLT ≥ 100,000/ L, total bilirubin ≤ ULN, AST ≤ 3 × ULN or AST ≤5 × ULN if liver involvement, creatinine ≤ 1.5 × ULN, Hgb ≥ 9.0 g/dL, K+ and Mg++ WNL, life expectancy ≥ 12 weeks, ejection fraction &gt; 50%, ECOG PS 0–2, and able to swallow pills whole. In addition to standard phase I exclusion criteria patients could not have received erlotinib, sunitinib, sorafenib, gefitinib, imatinib ≤ 4 weeks prior to registration. Each agent was administered once daily on a 28 day schedule. At the MTD patients were treated with D day 1, and day 9–28 and L day 2–28 to assess PK interaction. Dose levels (mg) were #1 D 70, L 1000, #2 D 100, L 1000, #3 D 140, L 1000. 12 patients were entered on the dose escalation portion of the trial and 15 were entered at the MTD. 5 patients entered at the MTD are too early to be fully evaluable. Characteristics of evaluable patients were: median age, 63; 46% female; PS 0 (64%) 1 (27%), 1 (9%); ≥ 3 prior chemotherapies (59%). DLT was seen in 2 patients at # 3 (1 patient, grade 3 hypermagnesemia, 1, grade 3 rash) and 1 patient at # 2 (grade 3 dyspnea). The MTD was determined to be # 2. No grade 4 or 5 events have been observed in this study. 6 patients had stable disease in the dose escalation cohort. 1 (RCC) was stable disease for 6 cycles, 2 (colorectal) were stable for 5 cycles, 1 (esophagus) was stable for 3 cycles, and 2 (GIST & leiomyosarcoma) were stable for 2 cycles. Analysis of drug levels, CTCs and circulating osteoclast precursors is ongoing. There was a consistent increase in the percentage of CD11b (monocyte/macrophage/osteoclast lineage marker) positive cells in circulation as treatment progressed. However, the late osteoclast lineage marker c-Fms was not similarly increased, suggesting that the elevated CD11b reflects an inflammatory response and not activation of osteoclastogenesis. D and L is a tolerable combination at nearly full doses of each drug. Funded by a grant from Glaxo Smith Kline and Bristol Myers Squibb. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B56.