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DNA methyltransferases (DNMTs) methylate DNA, promoting local chromatin condensation and consequent repression of gene expression. The purpose of this two-stage phase II trial was to assess the antitumor activity of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1, in patients with metastatic renal carcinoma (MRC). Untreated adult patients with measurable MRC were treated with MG98 at a dose of 360 mg/m2 via 2-h iv infusion twice weekly for three consecutive weeks out of four. The primary endpoint was objective response or absence of progression for at least eight weeks. Pharmacokinetics and DNMT1 mRNA levels in peripheral blood mononuclear cells (PBMCs) were also analyzed at pre-specified intervals. Seventeen eligible patients received a median of two cycles of treatment (range, 1-7), and no objective responses were seen. Nine patients had progressive disease, six had stable disease, and the study was stopped after the first stage. The most common symptomatic toxicities were rigors, fatigue, fever, and nausea. Hematological toxicity was mild. Seven patients treated with prior nephrectomy had grade 3 or 4 elevations in hepatic transaminases. Significantly higher Cmax and AUC(0-->inf) values were observed in these patients. No conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment. The lack of objective responses observed may be explained by a lack of target effect or the choice of tumor type. Transaminitis was observed in patients with prior nephrectomy and appeared to be associated with altered drug exposure in these patients.

Background. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR‐2) are believed to mediate angiogenesis in colorectal cancer (CRC). Ramucirumab (RAM; IMC‐1121B) is a human IgG1 monoclonal antibody that inhibits VEGF ligand binding to VEGFR‐2, inhibiting VEGFR‐2 activation and signaling. Methods. Patients with metastatic CRC, Eastern Cooperative Oncology Group performance status 0–1, and adequate organ function who had not received chemotherapy for metastatic disease received RAM and the modified FOLFOX‐6 regimen every 2 weeks. Endpoints included progression‐free survival (PFS), objective response rate, overall survival, and safety. The sample size was based on a potentially improved median PFS from 8 months to 11 months. Results. Forty‐eight patients received therapy. Median PFS was 11.5 months (95% confidence interval [CI]: 8.6–13.1 months). The objective response rate was 58.3% (95% CI: 43.21–72.39). The disease control rate (complete or partial response plus stable disease) was 93.8% (95% CI: 82.8–98.7). Median overall survival was 20.4 months (95% CI: 18.5–25.1 months). The most frequent grade 3–4 adverse events included neutropenia (grade 3: 33.3%; grade 4: 8.3%), hypertension (grade 3: 16.7%), and neuropathy (grade 3: 12.5%). Two patients died during the study due to myocardial infarction and cardiopulmonary arrest. Conclusion. RAM may enhance the efficacy of modified FOLFOX‐6 chemotherapy with an acceptable safety profile in metastatic CRC.

BackgroundCheckpoint blockade with ipilimumab provides long-term survival to a significant proportion of patients with metastatic melanoma. New approaches to increase survival and to predict which patients will benefit from treatment are needed. This phase II trial combined ipilimumab with carboplatin/paclitaxel (CP) to assess its safety, efficacy, and to search for peripheral and tumor-based predictive biomarkers.MethodsThirty patients with untreated unresectable/metastatic melanoma were treated with ipilimumab and CP. Adverse events (AEs) were monitored and response to treatment was evaluated. Tumor tissue and peripheral blood were collected at specified time points to characterize tumor immune markers by immunohistochemistry and systemic immune activity by multiplex assays and flow cytometry.ResultsEighty three percent of patients received all 5 cycles of CP and 93% completed ipilimumab induction. Serious AEs occurred in 13% of patients, and no treatment-related deaths were observed. Best Overall Response Rate (BORR) and Disease Control Rate (DCR) were 27 and 57%, respectively. Median overall survival was 16.2 months. Response to treatment was positively correlated with a higher tumor CD3+ infiltrate (immune score) at baseline. NRAS and BRAF mutations were less frequent in patients who experienced clinical benefit. Assessment of peripheral blood revealed that non-responders had elevated baseline levels of CXCL8 and CCL4, and a higher proportion of circulating late differentiated B cells. Pre-existing high levels of chemokines (CCL3, CCL4 and CXCL8) and advanced B cell differentiation were strongly associated with worse patient overall survival. Elevated proportions of circulating CD8+/PD-1+ T cells during treatment were associated with worse survival.ConclusionsThe combination of ipilimumab and CP was well tolerated and revealed novel characteristics associated with patients likely to benefit from treatment. A pre-existing systemic inflammatory state characterized by elevation of selected chemokines and advanced B cell differentiation, was strongly associated with poor patient outcomes, revealing potential predictive circulating biomarkers.Trial registration Clinicaltrials.gov, NCT01676649, registered on August 29, 2012.Electronic supplementary materialThe online version of this article (10.1186/s40425-017-0290-x) contains supplementary material, which is available to authorized users.

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Agglutination data from generations 8 through 19 indicate that bidirectional selection for specific SRBC antibody responses was successful in a line cross of ISA x Warren medium heavy layers. After 11 generations titers of the high SRBC selected line (H line) were nearly 1:32,000; those of the low SRBC selected line (L line) were less than 1:2, but titers of the randombred control line remained stable at 1:32. Directional SRBC selection also affected levels of a naturally occurring rabbit cell agglutinating antibody (RRBC), presumably the avian form of alpha-galactose antibody (anti-Gal). This indirect response was biphasic and opposite in direction to the SRBC responses through generation 14 after which anti-Gal titers of all 3 lines increased. At generation 19, line H had the highest agglutinin titers; of both types, control line was intermediate, and line L was lowest. The correlation between SRBC and RRBC titers was 0.43 (P = 0.0). Females had higher titers than males, but the difference was only significant for the SRBC antibody (P = 0.028). Qualitative changes in anti-Gal accompanied SRBC selection. Rabbit agglutinins of 4 types were recognizable: classic, granular, annular, and one negative or very weak reaction. The score type means in line L were highest, in the control line were intermediate, and in line H were lowest, suggesting avidity differences now exist among these lines. The results show integration of natural and acquired immune systems because selection for one temporarily affected the other. Given the importance of anti-Gal in primates, our results should stimulate further study of this antibody in poultry species.

533^ Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) are overexpressed in CRC and mediate angiogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 MAb that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In preclinical CRC models VEGFR-2 inhibition confers antitumor activity. RAM was administered with mFOLFOX-6 as 1st-line therapy (rx) in mCRC. Methods: Eligible pts had mCRC with no prior chemo Rx (prior adjuvant rx was allowed), at least 1 measurable target lesion by RECIST v1.0, ECOG PS 0-1, and adequate organ function. Pts received RAM (8 mg/kg IV on D1), oxaliplatin (85 mg/m² IV on D1), folinic acid (400 mg/m² IV on D1), fluorouracil (5-FU, 400 mg/m² bolus followed by 2400 mg/m² continuous infusion over 46 hours on D1). Rx cycles were q2w and tumor assessments were q8w. Endpoints included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), safety, and pharmacokinetics/immunogenicity. Sample size was based on an improved median (medn) PFS from 8 to 11 months (m). Results: 48 pts received therapy. All were white; 25 M/23 F; median age 60.5 y. ECOG PS was 0/1 in 30/18 pts. 42 pts (88%) had metastatic disease, with liver (79%) and lung (35%) as most frequent sites. 13 (27%) pts had liver-only mCRC. The most frequently observed RAM-related adverse events (AEs) included hypertension 46% (15% Grade [G] ≥3); diarrhea 31% (2% G≥3); and nausea and infusion-related reactions, each 19% (0% G≥3). 2 pts died on study due to acute MI or cardiopulmonary arrest. Medn PFS was 11.5 m (9-13 m 95% CI) with 1-yr PFS of 48% (32-62% 95% CI). ORR: 67% (52-80% 95% CI); disease control rate (DCR: CR+PR+SD): 94% (83-99% 95% CI; 5 pts had CR, 27 had PR and 13 had SD). Medn duration of response was 11.0 m (7-12 m 95% CI). One-year OS was 85% (72-93% 95% CI). As of 4/15/2011, 2 pts continued to receive rx, 20 had died and 28 (58.3%) remained alive. Conclusions: RAM combined with mFOLFOX-6 was reasonably tolerated in pts with mCRC. Median PFS exceeds 11 m. PFS, ORR, and DCR are encouraging and favor investigation of this regimen and of RAM in mCRC.

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