Pemigatinib in previously treated Chinese patients with locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusions or rearrangements: A phase II study.

OBJECTIVE: This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. BACKGROUND: Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries. METHODS: In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee. RESULTS: As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly

Characteristic CYP2A6 genetic polymorphisms detected by TA cloning-based sequencing in Chinese digestive system cancer patients with S-1 based chemotherapy.

S-1 is an oral antitumor agent that contains tegafur, which is converted to fluorouracil (5-FU) in the human body. Cytochrome P450 2A6 (CYP2A6) is the principal enzyme responsible for bioconversion of tegafur to 5-FU. A number of CYP2A6 polymorphisms have been associated with variations in enzyme activity in several ethnic populations. The CYP2A6*4C allele leads to deletion of the entire CYP2A6 gene, and is the main finding in patients with reduced CYP2A6 enzymatic activity. Thus, the aim of our study was to evaluate the allele frequencies of CYP2A6 polymorphisms in a population with cancer of the digestive system. We developed a simple screening method, which combined TA cloning and direct-sequencing, to detect CYP2A6 genetic polymorphisms in Chinese patients with cancers of the digestive system. A total of 77 patients with various types of digestive system cancers were screened for CYP2A6 genetic polymorphisms. The allele frequencies of CYP2A6*1A, CYP2A6*1B and CYP2A6*4C in the 77 patients screened were 62, 42 and 13%, respectively. Frequencies of the homozygous genotypes for CYP2A6*1A and CYP2A6*4C were 27 and 12%, respectively. As expected, patients that were determined to be homozygous for CYP2A6*4C exhibited the characteristic chemotherapy efficacy and toxicity profiles. The TA cloning-based direct sequencing method facilitated allele frequency and genotyping determination for CYP2A6*1A, 1B and 4C of cancer patients. The findings indicated that the population carries a high frequency of the CYP2A6*4C homozygous genotype. Thus, the reduced efficacy of standard chemotherapy dosage in Chinese cancer patients may be explained by the lack of CYP2A6-mediated S-1 bioconversion to 5-FU.

Phase II trial of gefitinib in pretreated Chinese women with advanced non-small-cell lung cancer.

A phase II clinical trial was performed to evaluate the efficacy and safety of gefitinib on pretreated Chinese female non-small-cell lung cancer (NSCLC) patients. Chinese female patients with locally advanced or metastatic NSCLC who failed at least one platinum-based chemotherapy received gefitinib monotherapy (250 mg/day) between April 2002 and January 2010. The primary endpoint was overall response rate (ORR), and secondary endpoints were overall survival (OS) and progression-free survival (PFS). Of the 40 evaluable female patients, the ORR was 62.5%. All patients have responded with one (2.5%) complete response, 24 (60%) partial response, 12 (30%) stable disease, and 3 (7.5%) progressive disease. The OS and PFS were 20 months (95% CI: 11.9-28 months) and 13 months (95% CI: 8.0-17.9 months), respectively. Survival (OS and PFS) were longer in patients with good performance status and in patients older than 65 years (P < 0.05). The most frequently observed toxicities were rash/dry skin (80%), diarrhea (42.5%), and vomiting/anorexia (32.5%). Four patients developed grade 3 toxicities (rash and diarrhea) but did not require either dose reduction or discontinuation. Gefitinib is a highly effective and well-tolerated agent for Chinese women with pretreated advanced NSCLC.

Phase II study of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

PURPOSE: To evaluate the efficacy and safety of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin. METHODS: The FOLFIRI regimen consisted of intravenous infusion of irinotecan 180 mg/m(2) on day 1 plus leucovorin (LV) 400 mg/m(2) on day 1 plus 5-fluorouracil (5-FU) 400 mg/m(2) bolus on day 1 plus 46-hour intravenous infusion of 5-FU 2,400 mg/m(2), every 2 weeks as one cycle. The main selection criterion for this study was the advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin. RESULTS: Of the 57 evaluable patients for efficacy, 4 (7.5%) had a partial response, 36 (67.9%) had stable disease, and 13 (24.5%) had progressive disease. Median progression-free survival was 4.8 months (95% CI 3.9-5.7 months), and median overall survival was 7.8 months (95% CI 13.1-16.5 months). Safety analysis was based on the data of 57 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia 16 (27.8%), nausea/vomiting 7 (12.3%), and diarrhea 1 (1.8%). CONCLUSION: FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin in Chinese population.

[Evaluation of interferon-gamma producing-cells using enzyme linked immunospot assay in mice model of acute graft versus host disease].

OBJECTIVE: To investigate IFN-gamma producing-cells (IFN-gamma PCs) in allogeneic mixed lymphocyte reaction (MLR) and acute graft versus host disease (aGVHD) model of mice. METHODS: Enzyme linked immunospot assay (ELISPOT) was applied to study IFN-gamma PCs in MHC mismatched mice spleen cell MLR and aGVHD model of mice. RESULT: IFN-gamma PCs increased significantly in MLR after allogeneic mice spleen cell stimulation. In the experimental mice aGVHD model, IFN-gamma PCs were significantly higher in the severe aGVHD group than those in the moderate aGVHD. In the moderate aGVHD group, mice with GVHD prophylaxis regimen demonstrated significantly lower level of IFN-gamma PCs, compared with those without prophylaxis. IFN-gamma PCs were significantly correlated with the GVHD clinical scores in the group with moderate aGVHD and prophylaxis regimen. CONCLUSION: ELISPOT is a fast, sensitive and specific approach to evaluate alloresponse in allogeneic mice MLR and IFN-gamma PCs are correlated closely with the severity of aGVHD and prophylaxis regimen in the MHC-mismatched mice model.

[Effects of transforming growth factor beta1 on dendritic cells function].

OBJECTIVE: To investigate the effects of transforming growth factor beta1 (TGF-beta1) on dendritic cells (DC). METHODS: Murine bone marrow cells were cultured with different cytokine combinations to develop immature DC (imDC, GM-CSF only) and TGFbeta-DC (GM-CSF + TGF-beta1), and their responses to lipopolysaccharide (LPS) stimulation were observed. The cell ultrastructure was observed by transmission electron microscopy and their phenotypes were assessed by flow cytometry (FCM). The allogeneic stimulating capacity of DC was assayed by mixed lymphocyte reaction (MLR) with BrdU incorporation. IL-12p70 protein was detected by ELISA and the expressions of Toll-like receptor 4 (TLR4) on DCs were analyzed with semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Compared to imDC, the TGFbeta-DC had no significant alterations in ultrastructure after LPS stimulation. The expressions of CD80, CD86 were lower on TGFbeta-DC than on imDC [(4.14 +/- 0.95)% vs (13.90 +/- 7.22)%; (8.60 +/- 0.75)% vs (20.63 +/- 5.03)%, P < 0.05, both]. The TGFbeta-DC kept their immature morphology after LPS stimulation, but the expressions of I-Ab and CD80 were slightly increased. After 96 h MLR, TGFbeta-DC had weaker stimulating capacity than imDC did, especially when DC/T cells ratios were 1:4 and 1:1 (P < 0.05, both). TGFbeta-DC showed impaired IL-12p70 production and down-regulation of TLR4 expression. CONCLUSIONS: TGF-beta1 can inhibit the expression of co-stimulatory molecules on DC. The TGFbeta-DC is resistant to maturation stimulus (LPS) and might be linked with TLR4 down-regulation.

TGF-beta1 treated murine dendritic cells are maturation resistant and down-regulate Toll-like receptor 4 expression.

OBJECTIVE: To explore the effects of transforming growth factor beta1 (TGF-beta1) on dendritic cells (DC). METHODS: Murine bone marrow cells were cultured with GM-CSF and TGF-beta1 to develop TGF-beta1-treated DC (TGFbeta-DC). Then they were stimulated by lipopolysaccharide (LPS). Their phenotypes were assessed by flow cytometry (FCM). The allogeneic stimulating capacity of DC was measured by mixed lymphocyte reaction (MLR) using BrdU ELISA method and IL-12p70 protein was detected by ELISA. The expression of Toll-like receptor 4 (TLR4) was analyzed by semi quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and FCM. RESULTS: Compared to immature DC (imDC) cultured by GM-CSF alone, the TGFbeta-DC express lower CD80, CD86, I-Ab and CD40. The TGFbeta-DC were resistant to maturation with LPS. Maturation resistance was evident from a failure to up-regulate co-stimulatory molecules (CMs), to stimulate larger T cells proliferation and to enhance secretion of IL-12p70. We also found that TGF-beta1 could down-regulate TLR4 expression on TGFbeta-DC. CONCLUSION: TGFbeta-DC are resistant to maturation stimulus (LPS) and might have some correlation with the down-modulation of TLR4 expression.