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A randomized phase II study of pulsatile high-dose sunitinib versus TAS-102 in patients with metastatic colorectal carcinoma (mCRC).

ABSTRACT: Interventions: A: TAS-102 (Lonsurf) 35 mg per square meter, twice daily, 5 days a week, with 2 days of rest, for 2 weeks, followed by a 14-day rest period. B: Experimental: High Dose Intermittent Sunitinib 700 mg once every 2 weeks. Primary outcome(s): The primary objective of this study is to improve progression free survival (PFS), of patients with metastatic colorectal carcinoma (mCRC) treated with high-dose sunitinib once every 2 weeks to 5 months, compared to the reported 2 months for TAS-102 monotherapy. Study Design: Randomized controlled trial, Open (masking not used), Active, Parallel

DISEASE(S): Metastastic Colorectal Cancer

PROVIDER: 2442614 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Transcriptome analysis was used to identify gene expression changes during development of sunitinib resistance in a renal cell carcinoma patient-derived xenograft (PDX) model. During the response phase, tumors exhibited a 91% reduction in volume, characterized by induction of TNFRSF1A, TNFAIP3, NFKB2, CCL2, CCL20, BIRC3, and MOAP1. Ingenuity Pathway Analysis indicated decreased expression of cell survival genes during tumor response to sunitinib. In this model, after 4 weeks of treatment, tumors developed resistance despite continued administration of the tyrosine kinase inhibitor (TKI) sunitinib (40 mg/kg/d p.o.). Resistance was associated with increased expression of VEGFA, EPO, IL-8, ANGPT2, TNFRSF12, MAPK3/7, MAPKBP1, and increased cell survival genes, suggesting activation of angiogenesis and MAPK/ERK pathways. Tumor lysate mRNA evaluated for murine gene expression to examine the contribution of host effects, indicated that tumor response was associated with downregulation of immune cell trafficking, cellular movement, and inflammatory response genes. During tumor escape, genes associated with cellular movement, inflammatory response, and immune cell trafficking were strongly induced, along with intratumoral accumulation of myeloid derived suppressor cells (MDSC), indicating a role for host factors during emergence of sunitinib resistance. The same PDX model was used to assess anti-tumor efficacy of sunitinib combined with MEK inhibitor (MEKi) PD-0325901 (4 mg/kg/d p.o.) using different schedules. The most effective treatment regimen was either continuous treatment with both drugs or switching from sunitinib to PD-0325901 monotherapy at d30, which reduced tumor volume by 78.6% (p=0.0241) and 88.5% (p=0.0068), respectively. The combination of MEKi with TKI (sunitinib, axitinib, or pazopanib) suppressed levels of phospho-MEK1/2 and phospho-ERK1/2, and decreased intratumoral MDSC. Thus, continuous treatment with sunitinib alone did not maintain tumor response, and addition of a MEKi abrogated resistance leading to prolonged survival.

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A randomized phase II study of pulsatile high-dose sunitinib versus TAS-102 in patients with metastatic colorectal carcinoma (mCRC).

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