North Central Cancer Treatment Group N0543 (Alliance): A phase 2 trial of pharmacogenetic‐based dosing of irinotecan, oxaliplatin, and capecitabine as first‐line therapy for patients with advanced small bowel adenocarcinoma

Abstract

Background Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used as first line therapy for small bowel adenocarcinoma. The addition of irinotecan improves survival in other gastrointestinal tumors but at the cost of hematologic toxicity. We performed a phase II, cooperative group study (NCCTG N0543, Alliance) using genotype-dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX), with dosing assigned based on UGT1A1 genotype in order to 1) test whether the addition of irinotecan would improve outcomes and whether 2) UGT1A1 genotype-based dosing could optimize tolerability. Methods Previously untreated patients with advanced small bowel adenocarcinoma received irinotecan (day 1), oxaliplatin (day 1), and capecitabine (days 2–15) in a 21-day cycle and were dosed with gCAPIRINOX according to UGT1A1*28 genotypes (6/6, 6/7, and 7/7). Results 33 pts (17-6/6, 10-6/7, 6-7/7) were enrolled [73% male, mean age 64 (range 41–77)] from October 2007 to November 2013. Location of primary tumor included: duodenum (58%), jejunum (30%), and ileum (9%). The regimen yielded a confirmed response rate of 37.5% (95% CI 21–56) with median progression-free survival of 8.9 months and median overall survival of 13.4 months. Neither hematologic toxicity (grade 3+ 52.9%, 30.0%, 33.3%, respectively) nor tumor response rate (41.2% 33%, 33%) differed significantly by UGT1A1 genotype (6/6, 6/7, and 7/7 groups). Conclusions UGT1A1 genotype-directed dosing (gCAPIRINOX) is feasible with favorable rates of hematologic toxicity compared with prior three drug studies in unselected patients. Larger studies would be needed to determine comparability to CapeOx alone or if response/toxicity differs among genotypes.

Small Bowel Adenocarcinoma, Version 1.2020, NCCN Clinical Practice Guidelines in Oncology

“…Although the role of FOLFOXIRI for treatment of SBA has not been formally evaluated, CAPIRINOX (capecitabine, irinotecan, oxaliplatin) has been tested as first-line treatment in a phase II trial of 33 patients with advanced SBA. 124 In this trial, CAPIRINOX-dose-adjusted according to UGT1A1 genotype-showed a response rate of 37.5% (95% CI, 21%-56%), with a median PFS and OS of 8.9 and 13.4 months, respectively. Neither hematologic toxicity nor tumor response rate differed significantly by UGT1A1 genotype, supporting the feasibility of genotype-directed dosing for CAPIRINOX.…”

Anti epidermal growth factor receptor therapy in small bowel adenocarcinoma

“…Few small prospective phase-2 studies have directly tested chemotherapy in patients affected with advanced SBA. [ 2 – 5 ] Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used in the frontline setting. [ 2 , 3 ] The combination of mitomycin C, doxorubicin, and 5-fluorouracil has showed minimal efficacy [ 4 ] and it is not usually employed.…”

“…[ 16 ] Recently, following the survival benefit reached with the use of drug triplets in both CRC and pancreatic cancer, the North Central Cancer Treatment Group performed the first pharmacogenetic-based phase-2 study (N0543) in patients with advanced untreated SBA, using a genotype-dosed combination of capecitabine, irinotecan, and oxaliplatin. [ 5 ] Although the toxicity profile seemed to be favorable, conclusions about benefits of the addition of irinotecan to oxaliplatin and fluorouracil could not be achieved. The lack of clinical studies due to the rarity of SBA has implied for the therapeutic decision-making the adoption of clinical guidelines created for large bowel adenocarcinoma.…”

“…Clinical studies regarding systemic treatment of advanced SBA are limited. [ 2 – 5 ] The lack of high-level data has prevented from writing practical guidelines. Based on either retrospective or phase-2 studies, the combination of fluoropyrimidines and oxaliplatin is regarded as the standard regimen for advanced and metastatic disease.…”

The evolving management of small bowel adenocarcinoma

“…UGT1A1 genotype-guided drug dosage, i.e., standard irinotecan dosage for 6/6 UGT1A1 genotype and lower irinotecan dosage for heterozygous 6/7 UGT1A1 genotype and homozygous 7/7 UGT1A1 genotype may result in overall decreased systemic toxicity, while the exposure to SN-38 remains similar in all genotype groups [69,70]. In a most recent study [71], doses of capecitabine, irinotecan and oxaliplatin (CAPIRINOX) were administered according to the UGT1A1 genotype in 33 patients with advanced SBA. While, 17 patients had the common 6/6 UGT1A1 genotype, in 10 patients the 6/7 genotype was found and in 6 the 7/7 genotype.…”