Phase II trial of imatinib, bevacizumab and cetuximab plus modified FOLFOX-6 in advanced untreated colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15030-e15030
Author(s):  
A. F. Sobrero ◽  
E. Bennicelli ◽  
A. Pessino ◽  
A. Guglielmi ◽  
S. Mammoliti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Treatment Plan ◽  
Exploratory Laparotomy ◽  
Complete Response ◽  
Structural Support ◽  
Grade 3 ◽  
Colorectal Cancer Patients ◽  
The Cost ◽  
Disease Free

e15030 Background: Imatinib inhibits PDGFR interfering with pericytes, the structural support to newly formed tumor blood vessels. It may thus synergize with bevacizumab. Microenvironment and tumor targeted agents along with chemotherapy could be a promising add-on approach. Methods: cetuximab 500 mg/m2, bevacizumab 5 mg/kg and modified FOLFOX-6 were given i.v. on day 1 and repeated every 2 weeks. Imatinib 400 mg/day per os was given continuously. Due to the cost and potential toxicity of the combination, the endpoint for this phase II study was very ambitious: at least 25% of complete response (medically or surgically achieved), lasting a minimum of 12 months in advanced untreated colorectal cancer patients with clearly unresectable disease. Results: Of 26 patients (16 with 1 site of disease), 17 completed the first 4 months of treatment according to the protocol, while 9 had to discontinue one biologic drug due to side effects (5 cetuximab, 3 imatinib and 1 bevacizumab). Grade 3–4 toxicity: diarrhea 12%, neutropenia 24%, skin rash 24%, hypersensitivity reactions 16%, asthenia 8%, neuro 8%. All patients were evaluable for response. Eleven responses ( 1 CR and 10 PR), 13 SD and 2 PD were observed, corresponding to 42% RR ( 95% CI = 23–61). The minimum follow up is 12 months; median PFS is 10 months. One patient among responders underwent radiofrequency ablation and 17 patients underwent surgery: 8 R-0, 3 R-1, 5 R-2 and one exploratory laparotomy. Major post surgical complications occurred in 5/17 patients. No evidence of macroscopic disease after the entire treatment plan was obtained in 13/26 patients: 12 surgical and 1 medical CR. Seven/13 were disease free at 6 months, but only 3 were still disease free at 12 months. ERCC1, ERCC2/XDP, GSTP1,TS,EGF, COX2, CYCLIN D, FCgR polymorphisms and K-RAS mutations were evaluated on all 26 patients, but no correlations were found with clinical outcome. Conclusions: The triple combination of biologics with modified FOLFOX-6 is feasible and tolerable as initial aggressive treatment. The primary endpoint of the study was not met . In fact the activity, 42% RR, was not outstanding and the high resectability rate, 69%, is misleading in the light of the short duration of the surgically induced CR. [Table: see text]

Randomized Multicenter Phase II Study Comparing a Combination of Fluorouracil and Folinic Acid and Alternating Irinotecan and Oxaliplatin With Oxaliplatin and Irinotecan in Fluorouracil-Pretreated Metastatic Colorectal Cancer Patients

2001 ◽  
Vol 19 (22) ◽  
pp. 4195-4201 ◽  
Author(s):  
Yves Bécouarn ◽  
Erick Gamelin ◽  
Bruno Coudert ◽  
Sylvie Négrier ◽  
Jean-Yves Pierga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Folinic Acid ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Survival Times ◽  
Activity Data ◽  
Randomized Phase Ii ◽  
Grade 3 ◽  
Intent To Treat ◽  
Colorectal Cancer Patients

PURPOSE: To assess antitumor activity and safety of two regimens in advanced colorectal cancer (CRC) patients with proven fluorouracil (5-FU) resistance in a randomized phase II study: 5-FU/folinic acid (FA) combined with alternating irinotecan (also called CPT-11) and oxaliplatin (FC/FO tritherapy), and an oxaliplatin/irinotecan (OC) combination. PATIENTS AND METHODS: Sixty-two patients were treated: arm FC/FO (32 patients) received, every 4 weeks, FA 200 mg/m2 followed by a 400-mg/m2 5-FU bolus injection, then a 600-mg/m2 continuous infusion of 5-FU on days 1 and 2 every 2 weeks administered alternately with irinotecan (180 mg/m2 on day 1) and oxaliplatin (85 mg/m2 on day 15). Arm OC (30 patients) received oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 every 3 weeks. RESULTS: In an intent-to-treat analysis, two partial responses lasting 10.7 and 16 months were observed with the tritherapy regimen, and seven (median duration, 11 months; range, 10.6 to 11.4 months) were observed with the bitherapy regimen. Median progression-free and overall survival times were 8.2 and 9.8 months, respectively, in the FC/FO arm and 8.5 and 12.3 months, respectively, in the OC arm. Main grade 3/4 toxicities were, respectively, neutropenia, 53% and 47%; febrile neutropenia, 13% and 3%; diarrhea, 19% and 10%; vomiting, 6% and 13%; and neurosensory toxicity, 3% and 3%. No treatment-related deaths occurred. CONCLUSION: The every-3-weeks OC combination is safe and active in advanced 5-FU–resistant CRC patients. The lower activity data seen with the tritherapy regimen may be related to the lower dose intensities of irinotecan and oxaliplatin in this schedule.

A phase II study of high-dose cetuximab plus irinotecan in colorectal cancer patients with KRAS-wild type tumors who progressed on prior standard dose cetuximab and irinotecan.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3582-3582
Author(s):  
Ahmad Ali Fora ◽  
Jeanne A McMahon ◽  
Greg Wilding ◽  
Adrienne E. Groman ◽  
Wen Wee Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Standard Dose ◽  
Dose Schedule ◽  
High Dose ◽  
Grade 3 ◽  
Colorectal Cancer Patients

3582 Background: Prior clinical data suggest a dose-related response to cetuximab (cmab) when combined with irinotecan in patients (pts) with KRAS WT tumors who do not develop grade ≥ 2 rash with standard cmab dosing. However, the investigation of higher doses of cmab in the setting of acquired or innate resistance to standard dose cmab has not been previously investigated. We conducted a phase II clinical trial of high-dose cmab plus irinotecan in KRAS WT pts who progressed on standard-dose cmab plus irinotecan. Methods: Pts who progressed within 4 weeks from receiving a minimum of 6 weeks of standard dose cmab plus irinotecan were included in this study. Cmab was administered at 500 mg/m2/week and irinotecan was administered at the same dose/schedule on which each individual patient previously progressed. All pts received doxycyline 100 mg PO bid starting day 1 of treatment. 12-week PFS rate was the primary endpoint. The regimen was considered interesting if 7/36 patients had stable disease or response at 12 weeks. The study was closed early after meeting its primary endpoint. Results: 20 pts were treated on study: median age 65.5 yrs (44-84), 14 pts were males. 8 pts had grade ≥ 2 hypomagnesaemia (3 grade 3 and 2 grade 4), 6 pts had grade ≥ 2 skin rash (1 grade 3, 0 grade 4), and 4 pts had grade ≥ 2 diarrhea (1 grade 3, 0 grade 4). 1 pt had a confirmed PR and 12 pts had a SD (at 6 weeks). In 9 pts, SD was confirmed at 12 weeks (3 pts> 24 weeks). Median PFS and OS were 2.8 and 6.6 months, respectively. The 1-year survival was 25%. Conclusions: High-dose cmab plus irinotecan is well tolerated with an acceptable rate of diarrhea and skin toxicities but with an increased rate of grade 3-4 hypomagnesemia. The prolonged disease stabilization and single response suggest that resistance to standard dose cmab plus irinotecan can be overcome by cmab dose escalation. The identification of predictive markers of response from dose escalation will be necessary to implement this strategy selectively in KRAS WT colorectal cancer patients.

scholarly journals The Efficacy and Safety of Fruquintinib Plus PD-1 Inhibitor in ≥3 line MSS Metastatic Colorectal Cancer Patients

2021 ◽  
Author(s):  
Xiangyi Wang ◽  
li lin ◽  
jun liang
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Complete Response ◽  
Efficacy And Safety ◽  
Once Daily ◽  
Grade 5 ◽  
Grade 3 ◽  
Vegfr Inhibitor ◽  
Colorectal Cancer Patients

Abstract Purpose: Based on the suggestion of REGONIVO study, we reviewed the data of 26 MSS mCRC patients to elaborate the efficacy and safety of fruquintinib (a VEGFR inhibitor) plus PD-1 inhibitor and explore the potential predictors for survival in 3+ line microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients.Patients and methods: This retrospective study enrolled 26 MSS mCRC patients who progressed after at least 2 lines of systematic chemotherapy but didn’t receive PD-1 inhibitors. Fruquintinib of 3mg was administered once daily with 21 days on/7 days off plus PD-1 inhibitor 200mg every 3 weeks until intolerable toxicity or disease progression. Results: Median overall survival (mOS) was 6.1m (ranged 1.8m-NR 95%CI: 2.60-9.60); median progression free survival (mPFS) was 2.3m (ranged 1.5m-NR 95%CI: 0.93-3.67). There was one complete response (CR) and no partial response (PR). Stable disease was observed in 11 patients (42%) and progression disease (PD) was observed in 14 patients (54%). The object response rate (ORR) was 4% (1/26) and disease control rate (DCR) was 46 %( 12/26). Grade ≥3 AEs were observed in 5 patients (19.2%). Grade 5 AEs (immune related encephalitis and cardiotoxicity) were observed in 2 patients. Additionally, there was a significant correlation between NLR < 3.06 and longer survival (P=0.000) for MSS mCRC patients treated with fruquintinib plus PD-1 inhibitor. Conclusions: Fruquintinib plus PD-1 inhibitor may be a choice for 3+ line MSS mCRC patients，especially with pretreatment NLR<3.06.

Bevacizumab plus infusional 5-FU, leucovorin and irinotecan (FOLFIRI) for advanced colorectal cancer that progressed after oxaliplatin and irinotecan chemotherapy: A pilot study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14593-14593
Author(s):  
H. Kwon ◽  
D. Lee ◽  
S. Kim ◽  
S. Y. Oh ◽  
H. J. Choi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Median Overall Survival ◽  
Advanced Colorectal Cancer ◽  
Bowel Perforation ◽  
Complete Response ◽  
Time To Progression ◽  
Humanized Monoclonal Antibody ◽  
Grade 3 ◽  
Colorectal Cancer Patients ◽  
Combination Regimens

14593 Background: The humanized monoclonal antibody bevacizumab inhibits angiogenesis, and improves survival when combined with chemotherapy for advanced colorectal cancer. The purpose of this trial is to evaluate the combination of bevacizumab with infusional 5-FU, leucovorin and irinotecan (FOLFIRI) in patients with advanced colorectal cancer pretreated with combination regimens including 5-fluorouracil (5- FU), leucovorin (LV) and irinotecan or 5-FU, LV and oxaliplatin. Methods: A total 14 patients (median age 56 years) with advanced colorectal cancer, all of them had progressed after oxaliplatin and irinotecan based combination chemotherapy, were enrolled in this study. Patients were treated with 2 hour infusion of irinotecan 150 mg/m2 on day 1, plus bevacizumab 5 mg/kg iv infusion for 90 minute on day 2, intravenous (iv) injection of leucovorin 20 mg/m2 followed by a bolus of 5-FU 400 mg/m2 and then 22 hour continuous infusions of 600 mg/m2 given on 2 consecutive days every 14 days. Results: The median cycles of chemotherapy were six (range 3 to 12). The response rate was 28.5%, one patient (7.1%) had a complete response, and three patients (21.4%) had a partial response. Eight patients (57.1%) had stable disease, and two patients (14.3%) progressed. The median time to progression was 3.9 months (95% confidence interval (CI) 2.0–8.7 months), and the median overall survival was 10.9 months (95% CI 9.6–12.1 months). Grade 3/4 neutropenia occurred in 5 patients, among them 2 patients developed neutropenic fever. Grade 3 hematuria and hematochezia occurred in one patient. Grade 2 proteinuria occurred in two patients. However, hypertension, bowel perforation or thromboembolic events were not occurred in total 90 cycles. Conclusions: Bevacizumab with FOLFIRI is well tolerated and improves survival in heavily treated advanced colorectal cancer patients. Further studies are needed to confirm these results. No significant financial relationships to disclose.

FOLFIRI plus bevacizumab (B) as neoadjuvant treatment for potentially resectable colorectal cancer patients (pts) with liver metastasis: A phase II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14130-e14130
Author(s):  
Guglielmo Nasti ◽  
Alessandro Ottaiano ◽  
Carmen Romano ◽  
Francesco Izzo ◽  
Paolo Delrio ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Metabolic Response ◽  
Neoadjuvant Treatment ◽  
Biliary Fistula ◽  
Pet Scan ◽  
Severe Toxicity ◽  
Normal Organ ◽  
Grade 3 ◽  
Colorectal Cancer Patients

e14130 Background: Irinotecan-based chemotherapy plus B was shown to be effective and safe in both first- and second-line treatment for metastatic colorectal cancer (mCRC) pts.We designed this trial to assess whether the combination of FOLFIRI + B given to untreated, potentially resectable mCRC pts was feasible and active. Methods: Phase II, single arm trial with 1-year progression-free rate (PFR) as primary end-point. A sample size of 39 pts was calculated to detect a 70% ± 12% 1-year PFR. The treatment was FOLFIRI q2w (irinotecan 180 mg/m2, leucovorin 200 mg/m2, 5FU 2400 mg/m2 iv in 46 hrs) plus B 5mg/kg q2w. Last cycle before surgery was without B. Potentially resectable, untreated mCRC pts, with liver as unique site of metastases, were eligible. Normal organ function and no contraindications to B were required. Pts were reevaluated for surgery after 6 cycles. PET-Scan were performed at baseline and at the second cycle. Results: Overall 39 pts were enrolled. Median age was 58 (range 30-75), male/female were 24/15. Twenty seven pts (69.2%; 95%CI 52.4% – 83.0%) were progression-free at 1-year. Thirty seven pts (94.9%) underwent surgery. One complete and 22 partial responses were observed (response rate 59.0%; 95% CI 42.1% – 74.4%); 5 pts had disease progression (4 resectable and 1 unresectable). Early PET-scan was assessed according PERCIST criteria [Wahl RL, J Nucl Med 2009] in 29 pts and showed metabolic response (SUV-max decrease > 30%) in 17 (58.6%; 95% CI: 38.9%- 76.5%).Severe toxicity includes grade 3 neutropenia (3 pts, 7.7%) and grade 3 diarrhea (1 pt, 2.6%). Other toxicities include grade 1-2 diarrhea (15.4%), grade 2 nausea (7.8%), grade 2 leucopenia (5.1%), grade 2 asthenia (5.1%), grade 1 anemia (2.6%), grade 2 thrombosis (2.6%). Overall, 16 pts out of 37 experienced surgical complications (43.2%; 95%CI 27.1% - 60.5%): biliary leak (11 pts, 29.7%), biliary fistula (1 pt, 2.7%), other complications (4 pts, 10.8%). All complications were reversible. No peri-operative bleeding was observed. Conclusions: The trial yielded its primary aim and shows that FOLFIRI plus B is feasible and active as neo-adjuvant treatment in patients with resectable liver metastases of CRC.

Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 57-57
Author(s):  
Hideaki Bando ◽  
Daisuke Kotani ◽  
Masahito Kotaka ◽  
Akihito Kawazoe ◽  
Toshiki Masuishi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Braf V600e ◽  
Phase Iii ◽  
Fixed Dose ◽  
Wild Type ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

57 Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.

Phase II Study of Uracil-Tegafur With Leucovorin in Elderly (≥ 75 years old) Patients With Colorectal Cancer: ECOG 1299

2007 ◽  
Vol 25 (34) ◽  
pp. 5397-5402 ◽  
Author(s):  
Howard S. Hochster ◽  
Weixiu Luo ◽  
Elizabeta C. Popa ◽  
Bruce T. Lyman ◽  
Mary Mulcahy ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Elderly Patients ◽  
Survival Time ◽  
Phase Ii ◽  
Performance Status ◽  
Progression Free Survival ◽  
Open Label ◽  
Old Patients ◽  
Gi Toxicity ◽  
Grade 3

Purpose To evaluate the tolerability and effectiveness of uracil-tegafur (UFT) with leucovorin (LV) in the treatment of elderly patients with advanced colorectal cancer. Patients and Methods Patients ≥ 75 years of age with previously untreated colorectal cancer were eligible for this phase II, single-arm, open-label, multicenter cooperative group clinical trial. UFT 100 mg/m2 plus LV 30 mg orally every 8 hours for 28 days every 35 days was administered until progression. Results Fifty-eight patients were enrolled between June 2000 and July 2001, and 55 were treated. The median age of treated patients was 81 years (range, 75 to 90 years), 26 patients were (47%) women, and 80% had good performance status (0 to 1). The observed overall response rate was 22% (95% CI, 11.8% to 35.0%). The estimated median overall survival time was 13.0 months (95% CI, 9.6 to 17.4 months), and median progression-free survival time was 4.6 months (95% CI, 2.6 to 6.7 months). Among the 56 treated patients (including one ineligible patient), 31 (55%) experienced grade 3 to 4 toxicities, most commonly diarrhea (25%) and GI toxicity (36%), with patients older than 85 years of age at highest risk. Conclusion The results of this trial support the efficacy of oral UFT/LV in elderly patients with colorectal cancer. The regimen is tolerated moderately well overall, particularly as compared with other fluoropyrimidine regimens, although there is increased GI toxicity in the most elderly. These results suggest that studies using newer oral fluoropyrimidine analogs should be investigated in this patient population.

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