This regimen of high-dose calcitriol with docetaxel may have activity in incurable pancreatic cancer, with a modest increase in TTP when compared to historical findings using single-agent docetaxel. However, results do not appear superior to those seen with gemcitabine, with or without erlotinib.
Background: Based on our pre-clinical data, we hypothesized that sequencing chemotherapy with erlotinib would increase the tumor response rate in patients with metastatic colorectal cancer. Patients and Methods: A phase II trial (planned n=58) using second-line therapy for metastatic colorectal cancer with either oxaliplatin-based (mFOLFOX6) or irinotecan-based (FOLFIRI) combination chemotherapy and 100 mg erlotinib daily on days 3-8 after each infusion (days 1 and 2) every 14 days. The primary endpoint was the response rate compared to the historical response rate. Results: The FOLFIRI/erlotinib arm met the pre-specified response rate criteria of at least 10% to expand accrual to the intended sample size. The trial was halted after an interim safety analysis (n=11) due to excess grade 3 neutropenia, dose reductions and treatment delays. Grade 3 or 4 neutropenia was observed in 64% of patients. The response rate was 18%. Conclusion: In second-line treatment for metastatic colorectal cancer, mFOLFOX6 or FOLFIRI with erlotinib in a sequence-dependent fashion is not feasible despite potential promising activity. Colorectal cancer is the third most common type of adult cancer in the world, with an estimated 1.8 million cases and 881,000 deaths annually by the GLOBOCAN estimate in 2018 (1). While more than 20% of these patients are diagnosed with metastatic disease, advancement in systemic treatment options have improved their expected median survival from 11-12 months with fluoropyrimidine alone to approximately 2.5 years with modern combination therapies (2, 3). Combination chemotherapy of either oxaliplatin, 5-fluorouracil and leucovorin (FOLFOX) or irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) has similar response rates and survival outcomes in the first-line metastatic setting (3-5). Moreover, these chemotherapy platforms have further incorporated biological agents, such as bevacizumab or monoclonal antibodies to epidermal growth factor receptor (EGFR), thereby improving response rates to approximating 60% in the first-line metastatic setting, as well as prolonging survival endpoints (3, 5, 6). However, second-line chemotherapy platforms using the alternate chemotherapy regimen with a biological agent, typically demonstrates less clinical activity and lower response rates of 6-35% (7-9). Given the expanding repertoire of biological agents, tyrosine kinase inhibitors (TKIs), and most recently immune checkpoint inhibitors for the treatment of metastatic colorectal cancer, there is a continued need to optimize second-line treatment options by integrating chemotherapy with more targeted approaches. This is particularly true as our knowledge based on colorectal cancer subtypes increases (10). Indeed, tumor location and molecular biomarkers, such as extended RAS mutations [testing beyond KRAS proto-oncogene, GTPase (KRAS) exon 2 to also include both KRAS and NRAS proto-oncogene, GTPase (NRAS) from exons 2 through 4], B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, and mismatch repair deficiency, ...
BackgroundIn preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.MethodsPreviously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality.ResultsIn the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1–) eomesodermin (EOMES+)) CD8+T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+EOMES+) CD8+T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation.ConclusionIbrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors.Trial registration numberNCT02562898.
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