Irinotecan In Advanced Colorectal Cancer Research Articles

O-023 - FOLFOX/bevacizumab +/- irinotecan in advanced colorectal cancer (CHARTA): Long term outcome

O-023 - FOLFOX/bevacizumab +/- irinotecan in advanced colorectal cancer (CHARTA): Long term outcome

LBA-007 - FOLFOX/Bevacizumab +/− Irinotecan in advanced colorectal cancer (AIO) “CHARTA”: Final results and multivariate prognostic factor analysis

LBA-007 - FOLFOX/Bevacizumab +/− Irinotecan in advanced colorectal cancer (AIO) “CHARTA”: Final results and multivariate prognostic factor analysis

CHARTA: FOLFOX+bevacizumab +/- irinotecan in advanced colorectal cancer (CRC)—Final results of the randomized phase II trial of the AIO (KRK 0209).

658 Background: The 4-drug-regimen FOLFOXIRI+Bevacizumab (Bev) was superior to FOLFIRI+Bev (TRIBE F.Loupakis, NEJM 2014). CHARTA investigates the same 4-drug-regimen vs. FOLFOX+Bev. Methods: 250 patients were randomized from 7/11 to 12/14 to standard FOLFOX+Bev (A) vs. FOLFOXIRI+Bev (B), with dose/schedule as in TRIBE, 25% dose reduction in cycle 1 + 2, if necessary. Incl.criteria: ECOG 0-2, ≥ 1 measurable lesion > 1cm; stratified by ESMO-Group 1, 2, 3 (HJ Schmoll et. al., Ann Oncol 2012). Induction: 6 months, maintenance Capecitabine+Bev until progression or max. of 12 months, with reinduction by individual decision. Primary EP: significant improvement of PFS-rate at 9 months (p<0.1, 2-sided Fisher’s-exact test); secondary EP: RR- rate, PFS, OS, sec. resection. Results: Evaluable 241 pts. (1 not elig., 8 prot. violation); m/f: 65%/35%, age 61 yrs. (21-82), left/right: left A: 51, 5%, B: 48, 5%; right A: 45%, B: 55%; ECOG 0-1/2: 96% / 4%, ESMO-group 1/2/3: 29%/ 55%/ 16%. Primary endpoint was met: significantly improved PFS at 9 months 56% vs. 68% (p= 0,086). Preliminary PFS 9,76 vs. 12,0 months (HR 0.77, p=0.61), identical to TRIBE: 9.7 vs. 12.1. Response (A/B): CR: 5/5%, CR/PR 60/70%, SD 25/21%, PD 14/9%; sec. resection: 21/23%. Subgroup - analyses did not show significant differences, except CR / PR left/right (A/B): left 59/68%, right 63/73%; PFS (months) left 10.4/12 (HR 0.69, p=0.03), right: 8.2 /10.7); non-significant improvement in ESMO-group 3 (HR 0.51), RAS-wt (HR 0.67), Koehne-Score High risk HR 0.58; ECOG 1: HR 0.69. QL-Global- Health-Score: slightly worse in A, vs. improved in B. Dose-intensity <70%/ 70-90%/ >90% (A/B): 39/37%/ 18/26%/ 41%/36%; initial dose-reduction 17% of pts. Toxicity: low to moderate without major differences between A &B, except grade ¾ diarrhea 12/16%, neutrophils 14/20%, GI 12/20%. Conclusions: The 4-drug-regimen has superior activity with the same outcome as TRIBE and is well tolerated, without a negative effect of initial dose-reduction, and an improvement of global QoL-Score. Final PFS, OS data and detailed subgroup/multivariate analysis, including Quality of life data, will be presented. Clinical trial information: NCT01321957.

LBA22 - FOLFOX / Bevacizumab (Beva) +/- Irinotecan in advanced colorectal cancer (CRC): A randomized phase II trial (AIO KRK 0209, CHARTA)

TRIBE has shown superiority of adding Oxaliplatin to FOLFIRI / Bev (F. Loupakis, NEJM 2016); STEAM (J. Bendell, ASCO GI 2014) and CHARTA investigate the addition of Irinotecan to FOLFOX + Bev in a randomized Phase II trial. 7/11 to 12/14 250 patients were randomized to standard FOLFOX / Bev (A) vs. FOLFOXIRI / Bev (B), with dose / schedule as in TRIBE, with exception of 25% dose reductions in cycles 1 and 2 if necessary. Incl.- criteria: ECOG 0-2, ≥ 1 measurable lesion > 1cm. Stratification: ESMO-Group 1,2,3 (Schmoll et. al., Ann Oncol 2012). Treatment-duration: 6 months induction, 12 months maintenance or until progression. Primary Endpoint: Improvement of PFS-rate @ 9 months with p < 0.1 (2-sided, Fisher's-exact test), secondary endpoint: RR- rate, PFS, OS, sec. resection. 241 pts. evaluable (1 not elig., 8 protocol violation); pts. characteristics: m/f: 65%/35%, age 61yrs. (21-82), left/right: left A: 51,5%, B:48,5%; right A: 45%, B: 55%, ECOG 0-1/2: 96% / 4%, ESMO-group 1/2/3: 29%/ 55%/ 16%, Koehne-Score: low/ intermed./high 9% /75%/ 16%; no difference for A vs.B in all subgroups. Primary endpoint was met: PFS-rate @ 9 months of 56% vs. 68% (p= 0,086); median PFS 9,76 vs. 12,0 months, HR 0.77, p = 0.61 (TRIBE-Trial: 9,7 vs. 12,1). Response-rates (A/B): CR 5% vs. 5%, CR + PR 60% vs. 70%, SD 25% vs. 21%, PD 14% vs. 9%. Mets resection: 23% vs. 26%. OS 24.9 vs 27.9 months (prelim.). PFS-Subgroup - analysis did not show significant differences, except left vs. right location: 10.4 vs. 12 months (HR 0.69, p = 0.03). Beyond this, a non-significant improvement was seen in ESMO-Group 3 (HR 0.51), RAS-wt (HR 0.67), Koehne-score High risk (HR 0.58), ECOG 1 (HR 0.69). The QL-Health-Score after induction was slightly reduced in A and improved in B without major changes. Dose-intensity <70%/ 70-90%/ >90% (A vs. B): 39% vs 37%/ 18% vs. 26% / 41% vs. 36%; initial dose-reduction 17% of pts. Toxicity: was low to moderate without major differences between A &B, except grade ¾ diarrhea 12% vs. 16%, neutrophils 14% vs. 20% & GI 12% vs. 20%. CHARTA reproduces response- & PFS-data of TRIBE and further supports the use of the 4-drug-regimen 1st-line-treatment for most pts.

A phase II study of oxaliplatin reintroduction in patients pretreated with oxaliplatin and irinotecan for advanced colorectal cancer (RE-OPEN study).

758 Background: Re-introduction of oxaliplatin (L-OHP) for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy regimens including L-OHP, irinotecan (CPT-11), and fluorouracil was thought to be effective approach. We performed a single arm, open-label phase II study (UMIN ID: 000004884), and the reported results of interim analysis were promising. Methods: Patients with prior chemotherapy including L-OHP and CPT-11 achieved tumor response or stable disease during prior L-OHP based therapy, and 6 months or over from confirmed progression disease during previous L-OHP based therapy was eligible for this study. Patients received FOLFOX regimens every two weeks. Primary endpoint was disease control rate (DCR) after 12 weeks of treatment start. Tumor response was evaluated by RECIST v1.1, and DCR was defined as complete response (CR), partial response (PR) or stable disease. This trial followed a Simon’s two-stage minimax design. Assuming the expected and threshold DCR after 12 weeks of treatment start would be 40% and 20%, 33 patients (18 in Step I and 15 in Step II) were required with a one sided α-level of 5% and a power of 80%. Results: Between February 2011 and August 2013, 33 patients were enrolled in this study. Characteristics of patients were as follows (n=33): median age of 62 years (35-77); male/female: 19/14; ECOG PS0: 84.8%; and colon/rectum: 14/19. All patients received mFOLFOX6 regimen. The DCR after 12 weeks of treatment start was 39.4% (95% CI: 21.8-57.0%), and the primary endpoint was met. The response Rate (CR or PR) was 6.1%. The median number of courses of chemotherapy was five, and the median total dose of L-OHP was 366.9 mg/m2. The median progression free survival was 98 days and the median overall survival was 300 days. The incidence of allergic reaction was 24.4% and peripheral neuropathy was 90.9%, graded as mild to moderate events. There were no other severe adverse events and treatment related deaths. Conclusions: Reintroduction of L-OHP was effective and could be a new salvage option for patients with mCRC refractory to previous L-OHP based therapy. Clinical trial information: 000004884.

A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: Results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO)

BackgroundThe main toxicity of irinotecan in advanced colorectal cancer (CRC) is delayed diarrhoea. Intestinal SN-38, released by deconjugation of the parent glucuronide excreted into the bile or produced in situ by intestinal carboxylesterase, is toxic to the intestinal epithelium. The canalicular transport of irinotecan and SN-38G is mediated by ABCC2 (MRP2) and ABCB1 (MDR1) which are both inhibited by ciclosporin. We tested whether irinotecan and ciclosporin was non-inferior for anti-cancer efficacy and superior for toxicity compared with single-agent irinotecan. MethodsSix hundred and seventy-two patients with advanced, measurable CRC following prior fluoropyrimidine-containing chemotherapy were randomised to either irinotecan 3-weekly 350mg/m2 (or 300mg/m2 if age >70 or performance status (PS)=2) or 3-weekly irinotecan at 140mg/m2 (120mg/m2 if age >70 or PS=2) with ciclosporin 3mg/kg t.d.s. for three days by mouth starting on the morning before irinotecan. The primary end-point was the proportion of patients alive and progression-free at 12 weeks. The key secondary end-point was the incidence of grade ⩾3 diarrhoea within 12 weeks of randomisation. ResultsThe proportion of patients progression-free at 12 weeks with irinotecan was 53.4% compared to 47.2% with irinotecan plus ciclosporin (difference=−6.3%, 95% confidence interval (CI) [−13.8%, 1.3%]). Since the lower limit of the 95% CI crossed the pre-specified non-inferiority margin of −10.6%, non-inferiority of irinotecan plus ciclosporin compared to irinotecan alone was not statistically demonstrated. 15.0% patients developed severe diarrhoea on irinotecan compared to 13.8% on irinotecan plus ciclosporin, a non-significant difference. InterpretationThe pharmacokinetic biomodulation of irinotecan using oral ciclosporin does not improve the therapeutic index of irinotecan in advanced CRC. FundingThe trial was funded by Cancer Research UK and supported by Amgen Pharma.

A phase II study of oxaliplatin reintroduction in patients pretreated with oxaliplatin and irinotecan for advanced colorectal cancer (RE-OPEN study): Reports of interim analysis.

580 Background: Re-introduction of oxaliplatin for patients with metastatic colorectal cancer refractory to standard chemotherapy regimens including oxaliplatin, irinotecan and fluorouracil (5-FU) was thought to be effective approach, but has not been prospectively explored. Thus, we performed a single arm, open-label phase II study (UMIN ID: 000004884). Methods: Patients with prior chemotherapy including oxaliplatin and irinotecan, achieved tumor response or stable disease during prior oxaliplatin-based therapy, and six months or over from confirmed progression disease during previous oxaliplatin-based therapy were eligible for this study. Patients received FOLFOX regimens every two weeks. Primary endpoint was disease control rate (DCR) after 12 weeks of treatment. Tumor response was evaluated by RECIST v1.1, and DCR was defined as complete response, partial response or stable disease. This trial followed a Simon’s two-stage minimax design. Interim analysis of efficacy was planned after 12 weeks of treatment in 18 patients (Step I). If disease control were confirmed in more than five patients, 15 patients would be newly enrolled in Step II. Results: Between 01-2011 and 07-2012, 18 patients were enrolled in Step I of this study. Characteristics of patients were as follows (N=18): median age, 61 yrs (range 35-75 yrs); male/female, 11/7; ECOG PS0, 94.4%; and colon/rectum, 8/10. All patients were assigned to receive mFOLFOX6 regimen. Disease control was observed in seven patients. There was no benefit in nine patients. Two patients refused to continue treatment and one patient gave up treatment due to oxaliplatin related allergic reaction. According to the interim analysis, DCR after 12 weeks of treatment was 38.9%. There were no severe adverse events and treatment related deaths. Conclusions: In interim analysis, initial efficacy of reintroduction of oxaliplatin after 12 weeks of FOLFOX regimen was confirmed. Step II part of this study is currently ongoing. Clinical trial information: UMIN000004884.

6003 The correlation between Topoisomerase-I (Topo1) expression and outcome of treatment with capecitabine and irinotecan in advanced colorectal cancer (ACC) patients (pts) treated in the CAIRO study of the Dutch Colorectal Cancer Group (DCCG)

6003 The correlation between Topoisomerase-I (Topo1) expression and outcome of treatment with capecitabine and irinotecan in advanced colorectal cancer (ACC) patients (pts) treated in the CAIRO study of the Dutch Colorectal Cancer Group (DCCG)

Sirolimus, bevacizumab, 5-Fluorouracil and irinotecan for advanced colorectal cancer: A pilot study

To evaluate the efficacy and the safety of combined 5-Fluorouracil, irinotecan, bevacizumab and sirolimus in refractory advanced colorectal carcinoma. We initiated a regimen with at day 1 an injection (iv) of bevacizumab at 5 mg/kg, followed by 180 mg/m(2) irinotecan, followed by Leucovorin 400 mg/m(2), followed by a 5-Fluorouracil bolus 400 mg/m(2); and a 46-h infusion 2400 mg/m(2). Sirolimus was given orally as continuous administration of 2 mg twice a day every days. This treatment was repeated every 14 d. A total of 12 patients were enrolled. All patients presented with metastatic disease that had failed at least three lines of chemotherapy that contained oxaliplatin, irinotecan and bevacizumab. Cetuximab failure was also observed in all K-Ras wild-type patients. The median number of cycles was 8.5 (range 2-20) and clinical benefit was observed in eight patients. The median time to progression was 5 mo and the median survival was 8 mo. Grade 3 neutropenia developed in four patients, and grade 3 diarrhea and stomatitis in two. The combination regimen of 5-Fluorouracil, irinotecan, bevacizumab and sirolimus in advanced colorectal carcinoma after failure of classical treatment is feasible and promising. Further evaluation of this combination is required.

Pharmacodynamic study of soluble FAS (sFAS) and FASL (sFASL), in patients (pts) with advanced colorectal cancer (ACRC) after irinotecan and cetuximab treatment in third-line therapy: Results of HCB-05–01 trial

22046 Background: No predictive markers of cetuximab efficacy in ACRC, have been validated prospectively fulfilling REMARK criteria. We have previously observed in ACRC pre-treated pts a decrement of sFAS (sFAS/sFASL) ratio (Nadal et al, Clin Cancer Res., 2005) and in a pharmacodynamic study an increment of sFAS ratio between 24–72 h, after first-line therapy (Carcereny et al Proc. ASCOGI, 2006). We hypothesize that changes of sFAS ratio could be an early biological predictor marker to cetuximab-irinotecan efficacy in third-line therapy. Methods: Pts with ACRC and progressive disease (PD) to oxaliplatin and irinotecan, with WHO PS 0–2 were eligible on a multicenter study. Pts received cetuximab (400 mg/m2 initial dose then 250 mg/m2 (w) plus irinotecan 180 mg/m2 q 2w. Serum analysis of sFAS and sFASL were done by ELISA basally and at 48 hours. Spiral computed tomography were done basally, every 2 months until six months, and every 3 months thereafter until PD. Response was assessed q 4 cycles. Primary end point was progression free survival (PFS). 76 pts were needed assuming α and β errors of 0.05 and 0.2 respectively to detect ≥40% of pts without PD at 4 months in the group of sFAS ratio increment above the median (A) compared with ≤10% of pts with PD in the group with sFAS ratio below the median (B). Results: 93 pts were recruited between May 2005 and July 2007. Median age was 63 (range 38–84) years. PFS was 3.3 (95% CI 1.9–4.8) months in the group B and 3.1 (95% CI 2.5–3.6) months (p=0.86) in the group A. Univariate analysis identified the following variables associated with PFS: PS 1 (HR 1.67, 95% CI 1.01–2.76), PS 2 (HR 2.92, 95% CI 1.16–7.34), LDH (0.02% increase of risk, 95% CI 0.002–0.05) and CEA (0.02% increase of risk, 95% CI 0.002–0.04). Multivariate analysis identified LDH as a prognostic factor for survival. Conclusions: Variation of sFAS ratio after treatment with cetuximab and irinotecan in ACRC, is not predictor of PFS. sFAS ratio ≤ 0.03 sFAS ratio > 0.03 p PFS (95% CI) 3.3 (1.9-4.8) 3.1 (2.5-3.6) 0.864 OS (95% CI) 9.66 (5.65-13.67) 7.66 (6.58-8.73) 0.192 Response rate (%) 6 (15) 5 (11.6) 0.641 No significant financial relationships to disclose.

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

瞄准：与 infusional 评估 bevacizumab 的联合 5 氟尿嘧啶(5-FU ) ，甲酰四氢叶酸(LV ) 和在有先进颜色的病人的 irinotecan (FOLFIRI ) 有包括 irinotecan 和 oxaliplatin 的联合政体的表面的癌症(CRC ) pretreated。方法：十四个病人(中部的年龄 56 年) 与先进 CRC，都在基于 oxaliplatin 、基于 irinotecan 的联合化疗以后进行了，在这研究被注册。病人们与 irinotecan 的 2 h 注入被对待 d 上的 150 mg/m2 1 ，正 bevacizumab 为 d 上的 90 min 的 5 mg/kg iv 注入 2 ，并且 LV 20 mg/m2 的 iv 注射由 5-FU 的一丸大丸药跟随了 400 mg/m2 然后 22 h 在二连续的天给每 14 d 的 600 mg/m2 的连续注入。结果：化疗的周期的中部的数字是六(范围 3-12 ) 。反应率是 28.5% ，一个病人有完全的回答，并且三个病人有部分回答。八个病人有稳定的疾病。前进的中部的时间是 3.9 瞬间(95% CI 2.0-8.7 ) ，并且中部的全面幸存是 10.9 瞬间(95% CI 9.6-12.1 ) 。等级 3/4 嗜中性白血球减少症在五个病人发生了，并且这些中的二个得了 neutropenic 发烧。等级 3 血尿症和便血发生在一个。等级 2 蛋白尿发生在二个病人。然而，高血压，肠穿孔或 thromboembolic 事件没总共 90 个周期的发生。结论：有 FOLFIRI 的 Bevacizumab 很好被容忍并且在有重重地对待的先进 CRC 的病人的可行治疗。

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

To evaluate the combination of bevacizumab with infusional 5-fluorouracil (5-FU), leucovorin (LV) and irinotecan (FOLFIRI) in patients with advanced colorectal cancer (CRC) pretreated with combination regimens including irinotecan and oxaliplatin. Fourteen patients (median age 56 years) with advanced CRC, all having progressed after oxaliplatin- and irinotecan-based combination chemotherapy, were enrolled in this study. Patients were treated with 2 h infusion of irinotecan 150 mg/m2 on d 1, plus bevacizumab 5 mg/kg iv infusion for 90 min on d 2, and iv injection of LV 20 mg/m2 followed by a bolus of 5-FU 400 mg/m2 and then 22 h continuous infusion of 600 mg/m2 given on two consecutive days every 14 d. The median number of cycles of chemotherapy was six (range 3-12). The response rate was 28.5%, one patient had a complete response, and three patients had a partial response. Eight patients had stable disease. The median time to progression was 3.9 mo (95% CI 2.0-8.7), and the median overall survival was 10.9 mo (95% CI 9.6-12.1). Grade 3/4 neutropenia occurred in five patients, and two of these developed neutropenic fever. Grade 3 hematuria and hematochezia occurred in one. Grade 2 proteinuria occurred in two patients. However, hypertension, bowel perforation or thromboembolic events did not occur in a total of 90 cycles. Bevacizumab with FOLFIRI is well tolerated and a feasible treatment in patients with heavily treated advanced CRC.

Benefit-Risk Assessment of Irinotecan in Advanced Colorectal Cancer

Irinotecan exerts its cytotoxic activity through inhibition of the nuclear enzyme topoisomerase I. It has been approved in most countries worldwide for treatment of patients with advanced colorectal cancer (CRC). Activity is seen in previously untreated patients and in patients refractory to fluorouracil treatment, whether it is given alone or in combination with other cytotoxic drugs. Irinotecan was first developed in patients refractory to fluorouracil. Activity in terms of tumour responses and patient benefit was seen in several phase II trials that used either a weekly or a three-weekly schedule. In two randomised trials (irinotecan vs best supportive care, and irinotecan vs an infused fluorouracil-based regimen), irinotecan prolonged median survival by approximately 2.5 months without any deterioration in quality-of-life. It was later studied in previously untreated patients with advanced CRC in combination with fluorouracil/folinic acid (leucovorin). In three large randomised trials, median time to tumour progression was prolonged by approximately 2.5 months and overall survival by about 2.5 months compared with fluorouracil/folinic acid alone. Tumour responses were also seen more frequently in the irinotecan arm (35-40% vs 20%). Again, quality-of-life scores were not deteriorated by the addition of irinotecan. Irinotecan has many acute adverse effects. The most prominent and dose limiting being diarrhoea and neutropenia. With irinotecan monotherapy, diarrhoea was seen in 80% of patients and severe grade 3 to 4 diarrhoea occurred in 30-40% of the patients. The severity of diarrhoea can be diminished by preventive actions. Less risk of diarrhoea is generally seen when irinotecan is combined with fluorouracil. Neutropenia is generally short-lived, but may be severe if diarrhoea is also present. This has been noticed particularly when irinotecan has been given in combination with a bolus fluorouracil/folinic acid regimen. Other toxicities include acute cholinergic-like symptoms, nausea and vomiting, and alopecia. In spite of these adverse effects, irinotecan has been accepted as an important first-line treatment for patients with advanced CRC, in combination with, preferably, an infused fluorouracil-based regimen, and has been approved for use as monotherapy in the second-line indication.