Clinical Assessment of 5-Fluorouracil/Leucovorin, Nab-Paclitaxel, and Irinotecan (FOLFIRABRAX) in Untreated Patients with Gastrointestinal Cancer Using UGT1A1 Genotype-Guided Dosing.
ABSTRACT: PURPOSE:5-Fluorouracil (5-FU)/leucovorin, irinotecan, and nab-paclitaxel are all active agents in gastrointestinal cancers; the combination, FOLFIRABRAX, has not been previously evaluated. UDP Glucuronosyltransferase 1A1 (UGT1A1) clears SN-38, the active metabolite of irinotecan. UGT1A1*28 polymorphism reduces UGT1A1 enzymatic activity and predisposes to toxicity. We performed a trial to assess the safety and tolerability of FOLFIRABRAX with UGT1A1 genotype-guided dosing of irinotecan. PATIENTS AND METHODS:Patients with previously untreated, advanced gastrointestinal cancers received FOLFIRABRAX with prophylactic pegfilgrastim every 14 days. UGT1A1 *1/*1, *1/*28, and *28/*28 patients received initial irinotecan doses of 180, 135, and 90 mg/m2, respectively. 5-FU 2,400 mg/m2 over 46 hours, leucovorin 400 mg/m2, and nab-paclitaxel 125 mg/m2 were administered. Doses were deemed tolerable if the dose-limiting toxicity (DLT) rate during cycle 1 was ?35% in each genotype group. DLTs were monitored using a sequential procedure. RESULTS:Fifty patients enrolled, 30 pancreatic, 9 biliary tract, 6 gastroesophageal, and 5 others. DLTs occurred in 5 of 23 (22%) *1/*1 patients, 1 of 19 (5%) *1/*28 patients, and 0 of 7 *28/*28 patients. DLTs were all grade 3: diarrhea (3 patients), nausea (2 patients), and febrile neutropenia (1 patient). The overall response rate was 31%. Response rates in pancreatic, gastroesophageal, and biliary tract cancers were 34%, 50%, and 11%, respectively. Eighteen patients (36%) received therapy for at least 24 weeks. CONCLUSIONS:FOLFIRABRAX with genotype-guided dosing of irinotecan is tolerable in patients with advanced gastrointestinal cancer and UGT1A1*1*1 or UGT1A1*1*28 genotypes. Too few *28/*28 patients were enrolled to provide conclusive results. Responses occurred across multiple tumor types.
Project description:Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m2 , irinotecan 180 mg/m2 , leucovorin 200 mg/m2 , bolus 5-fluorouracil [5-FU] 400 mg/m2 , and continuous 5-FU 2400 mg/m2 ) or a modified FOLFIRINOX (oxaliplatin 85 mg/m2 , irinotecan 150 mg/m2 , leucovorin 200 mg/m2 , and continuous 5-FU 2400 mg/m2 ) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (-/*6, 12 patients; -/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (-/*6, 33 patients; -/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 -/*6 than among those with UGT1A1 -/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 -/*6, tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. However, for patients who received the modified FOLFIRINOX, there was no difference in the frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with WT UGT1A1.
Project description:Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy.Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m(-2) for the *1/*1, 110 mg m(-2) for the *1/*28 and 90 mg m(-2) for the *28/*28 genotypes.The dose of irinotecan was escalated to 450 mg m(-2) in patients with the *1/*1 genotype, to 390 mg m(-2) in those with the *1/*28 genotype and to 150 mg m(-2) in those with the *28/*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities.Our results demonstrated that the recommended dose of 180 mg m(-2) for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 *1/*1 and *1/*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 *28/*28 genotype is 30% lower than the standard dose of 180 mg m(-2).
Project description:Purpose: To evaluate safety and preliminary efficacy of metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with newly diagnosed metastatic pancreatic cancer (MPC). Methods: A total of 12 treatment-naive patients (aged 18-65 years, Eastern Cooperative Oncology Group performance status [ECOG PS] ?1) with MPC received 5-fluorouracil 180?mg/m2 per day (days 1-14 continuous infusion); nab-paclitaxel 75?mg/m2, leucovorin 20?mg/m2, and oxaliplatin 40?mg/m2 (days 1, 8, and 15); and bevacizumab 5?mg/kg (days 1 and 15) administered intravenously in each 28-day cycle. The primary end-point was incidence of dose-limiting toxicities (DLTs) in cycle 1. Safety was further evaluated as a secondary end-point; preliminary efficacy was also examined. Results: Two DLTs (grade 3 anemia requiring transfusion and grade 3 mucositis unresponsive to treatment within 4 days of onset) were observed in one of six patients enrolled in dose cohort 1. Cohort 1 was expanded from 6 to 12 patients to further evaluate safety, per the investigators' recommendation. All patients discontinued treatment. The most common grade ?3 adverse events were abdominal pain, fatigue, mucositis, and decreased neutrophil count. Objective response rate was 33% (four partial responses). Median progression-free survival (PFS) and overall survival (OS) were 5.6 (95% confidence interval [CI], 1.7-11.3) and 9.9 (95% CI, 4.4-13.2) months, respectively; 1-year PFS and OS rates were 12.2% (95% CI, 0.7-40.8) and 38.9% (95% CI, 12.6-65.0). Conclusion: FABLOx is feasible and tolerable in patients newly diagnosed with MPC. However, preliminary efficacy data are inconclusive for continued investigation in a phase II trial.
Project description:BACKGROUND:Patients harbouring the UGT1A1*28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1*1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients. METHODS:Eighty-two patients with the UGT1A1*1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1*28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300?mg/m2 for UGT1A1*1/*1 and 260?mg/m2 for *1/*28 patients. In the control group, the dose was 180?mg/m2. We analysed the overall response rate (ORR), toxicity, and survival. RESULTS:The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p?=?0.001 OR: 1.73 [95% CI:1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3-4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found. CONCLUSIONS:Patients with the UGT1A1*1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events.
Project description:Background:In our previous dose-escalation study, we uncovered the maximum tolerated dose (MTD) of weekly irinotecan was escalated to 80 mg/m2 and 65 mg/m2 for UDP glucuronosyltransferase family 1 member A1 (UGT1A1) *1*1 and *1*28 rectal cancer patients in neoadjuvant chemoradiotherapy (nCRT). This is an expansion study for *1*1 patients. Methods:Patients with clinical stage T3-4, N0-2 rectal cancer eligible for preoperative chemoradiotherapy were screened for the UGT1A1*28 genotype. A total of 52 patients with the *1*1 genotype were enrolled. Whole-pelvic intensity-modulated radiation therapy was given in 50 Gy/25 fractions. Concurrently, irinotecan of 80 mg/m2 and capecitabine of 625 mg/m2 twice daily from Monday to Friday were administered weekly. Primary endpoint was toxicities; secondary endpoints included pathological complete response (pCR), tumour-regression grading, treatment compliance, overall survival, local recurrence and disease-free survival. Results:All patients completed capecitabine-based radiotherapy as scheduled, and 42 (81%) patients completed more than three cycles of weekly irinotecan. Overall, grade 3/4 toxicities were observed in 20 cases, including 11 leucopenia, 10 neutropenia and 12 diarrhoea. Forty-three patients (83%) underwent a radical surgery, and 12 were evaluated as pCR. Another four patients accepted a watch-and-wait strategy because of clinical complete response (CCR). Conclusions:Our data demonstrated manageable toxicities and an encouraging CCR rate for UGT1A1 *1*1 genotype in an enhanced neoadjuvant therapy. A phase III trial is ongoing to evaluate the value of irinotecan in neoadjuvant therapy (CinClare) [ClinicalTrials.gov identifier: NCT02605265].
Project description:Evolving intensiveness of colorectal cancer (CRC) treatment, including chemotherapeutics and targeted agents associations, in adjuvant and metastatic CRC (MCRC) settings, increased overall survival (OS) with individual variability of toxicity. Pharmacogenomic guidelines recommended pre-treatment identification of at-risk patients suggesting dose adjustment of fluoropyrimidines based on dihydropyrimidine dehydrogenase (DPYD), and irinotecan on UDP glucuronosyl-transferase 1 family polypeptide A1 (UGT1A1) genetic variants, but they are poorly applied in clinical practice. This review highlighted clinically validated pharmacogenetic markers, to underline the need of their implementation in the multidisciplinary molecular board for individual CRC patients in clinical practice. Five clinically relevant DPYD variants with different prevalence impair enzymatic effectiveness and significantly increase toxicity: c.1236 G>A (c.1129-5923 C>G, HapB3), 4.1-4.8%; c.1679 T>G (DPYD*13), c.1905+1G>A (DPYD*2A), c.2846 A>T, c.2194 A>T (DPYD*6) 1% each. c.1679T>G and c.1905+1G>A are most deleterious on DPD effectiveness, moderately reduced in c.1236/HapB3 and c.2846A>T. Cumulatively, these variants explain approximately half of the estimated 10-15% fluoropyrimidine-related gastrointestinal and hematological toxicities due to DPD. Prevalent UGT1A1 gene [TA]7TAA promoter allelic variant UGT1A1*28, characterized by an extra TA repeat, is associated with low transcriptional and reduced enzymatic effectiveness, decreased SN38 active irinotecan metabolite glucuronidation, vs wild-type UGT1A1*1 [A(TA)6TAA]. Homozygote UGT1A1*28 alleles patients are exposed to higher hematological and gastrointestinal toxicities, even more than heterozygote, at >150 mg/m2 dose. Dose reduction is recommended for homozygote variant. Wild-type UGT1A1*28 alleles patients could tolerate increased doses, potentially affecting favorable outcomes. Implementation of up-front evaluation of the five validated DPYD variants and UGT1A1*28 in the multidisciplinary molecular tumor board, also including CRC genetic characterization, addresses potential treatments with fluoropyrimidines and irinotecan associations at proper doses and schedules, particularly for early CRC, MCRC patients fit for intensive regimens or unfit for conventional regimens, requiring treatment modulations, and also for patients who experience severe, unexpected toxicities. Integration of individual evaluation of toxicity syndromes (TS), specifically limiting TS (LTS), an innovative indicator of toxicity burden in individual patients, may be useful to better evaluate relationships between pharmacogenomic analyses with safety profiles and clinical outcomes.
Project description:Over 50% of colorectal cancer (CRC) patients develop metastases. The aim of this study was to evaluate efficacy and tolerance of first-line FOLFIRI® + bevacizumab (B) treatment for metastatic CRC, and to assess genetic polymorphisms as potential markers.Adult patients with histologically-proven, non-resectable metastatic CRC and ECOG ≤ 2 were included. 14-day cycles consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m2), bolus FU (400 mg/m2) and leucovorin (400 mg/m2), followed by 46-hour FU infusions (2400 mg/m2). Primary endpoint was response rate according to RECIST criteria. Secondary endpoints were overall (OS) and progression-free (PFS) survivals, response duration, and toxicity. Associations between clinical data, UGT1A1, thymidylate synthase, VEGFA polymorphisms and PFS, OS and toxicity were analyzed.Sixty-two patients were enrolled (median age 68y). 59/62 patients were eligible and evaluable for response at 6 months: 28 showed partial response (47.5%; 95% CI; 34.3-60.9), 20 stable disease (33.9%) and 11 progression (18.6%). Grade 3/4 toxicities were as follows: neutropenia 16.1%; diarrhea 11.3%; nausea-vomiting 1.6%. Median response duration was 9.5 months (range 2.7-20); median PFS 10.3 months (range 8.8-11.7); and median OS 25.7 months (range 20.2-29.7). 11/59 initially unresectable patients were resectable after treatment. VEGFA polymorphism (rs25648) was associated with better OS (HR: 3.61; 95% CI: 1.57-8.30).FOLFIRI® + bevacizumab is active with good response rate, long median OS, and a good safety profile. A VEGFA polymorphism might have a prognostic value in this malignancy.Clinicaltrials.gov: NCT00467142 (registration date: April 25, 2007).
Project description:The aim of this retrospective study was to investigate the relationship between UGT1A1 polymorphisms and toxicities in Chinese patients with pancreatic or biliary tract cancer receiving irinotecan-containing regimens as the second- or third-line chemotherapy.A total of 36 patients with unresectable pancreatic cancer and 12 patients with unresectable biliary tract cancer were included. Approximately 33 patients were treated with FOLFIRI regimen, a chemotherapy regimen, where FOL stands for folinic acid, F for fluorouracil, and IRI for irinotecan (irinotecan 180 mg/m(2) at day 1, CF 200 mg/m(2) at day 1-2, 5-FU 400 mg/m(2) at day 1-2, followed by continuous infusion of 5-FU 600 mg/m(2) for 22 hours at day 1-2, every 2 weeks). The other 15 patients were treated with irinotecan monotherapy (180 mg/m(2), every 2 weeks). UGT1A1*6/*28 polymorphisms were detected by direct sequencing.The frequencies of GG, GA, AA genotypes for UGT1A1*6 were 70.8% (n=34), 25.0% (n=12), and 4.2% (n=2), respectively. And those of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 79.2% (n=38), 18.8% (n=9), and 2.0% (n=1), respectively. A total of 22 patients (45.8%) had grade III-IV neutropenia, and six patients (12.5%) experienced grade III-IV diarrhea. The incidence of grade III-IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022). No relationship was found between grade III-IV neutropenia and UGT1A1*28 polymorphism. The statistical analysis between grade III-IV diarrhea and UGT1A1*6/*28 polymorphisms was not conducted in view of the limited number of patients.In Chinese patients with pancreatic or biliary tract cancer administered irinotecan-containing regimens, those with UGT1A1*6 variant may have a high risk of severe neutropenia.
Project description:To predict precisely severe toxicity of irinotecan, we evaluated the association of UGT1A variants, haplotypes and the combination of UGT1A genotypes to severe toxicity of irinotecan. UGT1A1*6 (211G>A), UGT1A1*28 (TA6>TA7), UGT1A1*60 (-3279T>G), UGT1A7 (387T>G), UGT1A7 (622T>C), and UGT1A9*1b (-118T9>T10, also named *22) were genotyped in 123 patients with metastatic colorectal cancer who had received irinotecan-based chemotherapy. Among the 123 patients, 73 were enrolled in either of two phase II studies of the FOLFIRI (leucovorin, 5-fluorouracil and irinotecan) regimen; these patients constituted the training population, which was used to construct the predicting system. The other 50 patients constituted the validation population; these 50 patients either had participated in a phase II study of irinotecan/5'-deoxy-5-fluorouridine or were among consecutive patients who received FOLFIRI therapy. This prediction system used sequential forward floating selection based on statistical pattern recognition using UGT1A genotypes, gender and age. Several UGT1A genotypes [UGT1A1*6, UGT1A7 (387T>G), UGT1A7 (622T>C) and UGT1A9*1b] were associated with the irinotecan toxicity. Among the haplotypes, haplotype-I (UGT1A1: -3279T, TA6, 211G; UGT1A7: 387T, 622T; UGT1A9: T10) and haplotype-II (UGT1A1: -3279T, TA6, 211A; UGT1A7: 387G, 622C; UGT1A9: T9) were also associated with irinotecan toxicity. Furthermore, our new system for predicting the risk of irinotecan toxicity was 83.9% accurate with the training population and 72.1% accurate with the validation population. Our novel prediction system using statistical pattern recognition depend on genotypes in UGT1A, age and gender; moreover, it showed high predictive performance even though the treatment regimens differed among the training and validation patients.