pci-32765 and Colorectal-Neoplasms

MMR proficient (pMMR) colorectal cancer (CRC) is usually unresponsive to immunotherapy. Recent data suggest that ibrutinib may enhance the anti-tumour activity of anti-PD-1 immunotherapy. In this study, we evaluated the safety and efficacy of ibrutinib plus pembrolizumab in refractory metastatic CRC.. This was a phase 1/2 study in patients with refractory metastatic pMMR CRC. The primary endpoints for phases 1 and 2 were maximum tolerated dose (MTD) and disease control rate, respectively. The secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS).. A total of 40 patients were enrolled. No dose-limiting toxicity was observed, and MTD was not identified. The highest tested dose of ibrutinib, 560 mg once daily, was combined with a fixed dose of pembrolizumab 200 mg every 3 weeks for the phase 2 portion. The most common grade 3/4 treatment-related adverse events were anaemia (21%), fatigue (8%) and elevated alkaline phosphatase (8%). Among 31 evaluable patients, 8 (26%) achieved stable disease, and no objective response was observed. The median PFS and OS were 1.4 and 6.6 months, respectively.. Ibrutinib 560 mg daily plus pembrolizumab 200 mg every 3 weeks appears to be well tolerated with limited anti-cancer activity in metastatic CRC. CLINICALTRIALS.. NCT03332498.

Topics: Adenine; Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; DNA Mismatch Repair; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Piperidines; Progression-Free Survival; Treatment Outcome; Young Adult

Ibrutinib is a drug that inhibits the protein Burton's tyrosine kinase and thereby the nuclear translocation of Nrf2, which played a key role in mediating the activation of antioxidants during stress conditions and ferroptosis resistance. This study aimed to identify the effect of Ibrutinib and ferroptosis inducer on colorectal cancer (CRC) treatment and its underlying mechanism. In our study, we found the upregulation of Nrf2 was correlated with CRC progression and antioxidant proteins. Ibrutinib sensitized CRC to ferroptosis inducers, suggested by further reduced CRC cell viability, proliferation and decreased antioxidant protein levels in CRC cells after combination treatment of Ibrutinib and RSL3 or Ibrutinib and Erastin both in vivo and in vitro. Knockout of Nrf2 diminished the regulatory effect of Ibrutinib on CRC sensitivity to ferroptosis inducers. Altogether, this study demonstrated that Ibrutinib increases the sensitivity of CRC cell to ferroptosis inducers by inhibiting Nrf2.

Topics: Antioxidants; Cell Line, Tumor; Colorectal Neoplasms; Ferroptosis; Humans; NF-E2-Related Factor 2; Protein-Tyrosine Kinases

Colorectal cancer (CRC) is the second most leading cause of cancer-related deaths worldwide. Ibrutinib (IBR), the first in class bruton tyrosine kinase (BTK) inhibitor has promising anticancer activity. In this study, we aimed to develop a hot melt extrusion based amorphous solid dispersions (ASD) of IBR with enhanced dissolution at colonic pH and assess the anticancer activity against colon cancer cell lines. Since colonic pH is higher in CRC patients compared to healthy individuals, Eudragit® FS100 was used as pH dependent polymeric matrix for colon enabled release of IBR. Poloxamer 407, TPGS and poly(2-ethyl-2-oxazoline) were screened as plasticizer and solubilizer to improve the processability and solubility. Solid state characterization and filament appearance confirmed that IBR was molecularly dispersed within FS100 + TPGS matrix. In-vitro drug release of ASD showed > 96% drug release within 6 h at colonic pH with no precipitation for 12 h. Contrary, crystalline IBR showed negligible release. ASD with TPGS showed significantly higher anticancer activity in 2D and multicellular 3D spheroids of colon carcinoma cell lines (HT-29 and HT-116). The outcomes of this research suggested that ASD with a pH dependent polymer is a promising strategy to improve solubility and an effective approach in colorectal cancer targeting.

Topics: Colorectal Neoplasms; Drug Carriers; Drug Compounding; Humans; Hydrogen-Ion Concentration; Polymers; Solubility

Ibrutinib is a Bruton tyrosine kinase inhibitor used in the treatment of chronic lymphocytic leukemia (CLL). Panitumumab, an mAb for epidermal growth factor receptor, is used in the treatment of metastatic colorectal cancer (CRC). We wanted to present our case where we used ibrutinib and panitumumab in combination in a patient with metachronous CLL and CRC. A 58-year-old male patient with a diagnosis of CLL was receiving ibrutinib treatment and primary rectal cancer was detected. FOLFOX + panitumumab were started when metastasis was detected in the lung after neoadjuvant chemoradiotherapy for rectal cancer. The patients used ibrutinib and panitumumab in combination. There was no cumulative or unexpected toxicity due to the combination of both antineoplastic agents. The most important point to be considered in the use of combined drugs is the evaluation of drug-drug interactions. Toxic effects of the combination of ibrutinib and cetuximab have been reported in a patient with metastatic CRC. We used ibrutinib together with panitumumab in our case and we did not encounter any cumulative or unexpected side effects during the treatment.

Topics: Adenine; Colorectal Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Panitumumab; Piperidines; Protein Kinase Inhibitors; Rectal Neoplasms