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Gemcitabine in Combination With Pemetrexed Long Term Infusion in the Treatment of Pretreated Metastatic Colorectal Cancer Patients

ABSTRACT: Study Design: Multicenter, non randomized, open label phase II study designed to evaluate the efficacy and safety of Gemcitabine/Pemetrexed combination. Enrollment period: 18 months. Treatment period: maximum for 24 weeks for each patient (12 cycles lasting 2 weeks). Total duration of the study: 24 months. Number of Subjects: Approximately 38 subjects will be enrolled on study: - First stage:12 patients enrolled If 1 or 0 responses were observed, the trial had to be terminated: - Second stage: an additional of 23 patients were to be enrolled. If 5 or less responses were observed in 35 patients, the combination would not be considered worthy of further study, while if 6 or more responses were observed, the combination would be considered sufficiently active to warrant further testing. Taking into account an invalidity rate of 5%, 38 patients will be needed for this step.

DISEASE(S): Metastatic Colorectal Cancer,Pazienti Pretrattati Con Carcinoma Colon Rettale Avanzato,Colorectal Cancer Metastatic,Colorectal Neoplasms,Pretreated Patients With Advanced Colorectal Cancer

PROVIDER: 2149107 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. Here, we demonstrated that the FAK inhibitor, IN10018, and pegylated liposome doxorubicin (PLD) exerted effective antitumor activity preclinically and clinically (clinical trial ID: CTR20200913). The clinical study is a phase Ib trial which includes dose confirmation and expansion sections. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. As of the data cutoff date (30 November 2022), a total of 61 platinum-resistant ovarian cancer (PROC) patients were enrolled and no IN10018-related grade 4 or 5 adverse effects (AEs) were reported. The ORR was 46.3% (95% confidence interval (CI): 32.6%, 60.4%) and the DCR was 83.3% (95% CI: 70.7%, 92.1%). The median PFS was 7.26 months (95% CI: 5.16 - 8.02 months), and the median duration of response (DoR) was 6.93 months (95% CI: 4.17 - 9.13 months). The primary and secondary endpoints were met. The median OS was not reached, and still maturing. Notably, the regimen exhibited response latency and long-lasting effects in the clinical trial, outcomes frequently observed in immunotherapy. Our preclinical study revealed that the 2-drug combination can maximize the immunogenic cell death (ICD) of cancer cells, boosting the maturation of dendritic cells (DCs) and stimulating CD8 T cells to strengthen the antitumor effects. At present, immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of immunogenic niche. Our work confirmed that IN10018 in combination with PLD can prime the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Correspondingly, animal studies validated that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. The preclinical results warrant further clinical exploration for the triplet regimen with IN10018, PLD, and ICB.

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Gemcitabine in Combination With Pemetrexed Long Term Infusion in the Treatment of Pretreated Metastatic Colorectal Cancer Patients

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