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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