Irinotecan is an active agent in untreated patients with metastatic colorectal cancer.

1996 ◽  
Vol 14 (3) ◽  
pp. 709-715 ◽  
Author(s):  
J A Conti ◽  
N E Kemeny ◽  
L B Saltz ◽  
Y Huang ◽  
W P Tong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Topoisomerase I ◽  
Active Agent ◽  
Response Duration ◽  
Median Response ◽  
Strict Adherence ◽  
Severe Diarrhea ◽  
Grade 3 ◽  
Tumor Biopsies

PURPOSE To determine the response rate, survival, and toxicity of the new anticancer agent, irinotecan (CPT-11), in the treatment of metastatic colorectal cancer. PATIENTS AND METHODS Forty-one chemotherapy-naive patients with measurable metastatic colorectal cancer were treated with a 90-minute infusion of irinotecan 125 mg/m2 administered weekly for 4 weeks every 6 weeks. Pretreatment tumor biopsies to assess topoisomerase-I (Topo-I) activity were obtained from 11 patients. The pharmacokinetics for irinotecan and its active metabolite, SN-38, were determined in 18 patients. RESULTS Thirteen of 41 patients (32%) had a partial response (PR; 95% confidence interval, 18% to 46%). The median response duration was 8.1 months (range, 4.0 to 16.0) and the median survival time was 12.1 months (range, 2.1 to 21.7) for all 41 patients. Grade 3 or 4 toxicities were diarrhea (29% of patients) and neutropenia (22% of patients). Grade 3 or 4 diarrhea was substantially more prevalent in the initial 18 patients on study, with an incidence rate of 56%; a significant reduction in the incidence of severe diarrhea to 9% was noted with strict adherence to an antidiarrheal regimen of loperamide and diphenyldramine. No correlations were seen between pharmacokinetics of irinotecan/SN-38 and the clinical parameters of response, survival, or incidence of diarrhea. CONCLUSIONS Irinotecan has activity in the treatment of patients with metastatic colorectal cancer. Strict adherence to an antidiarrheal regimen of diphenhydramine/loperamide significantly reduced the incidence of diarrhea; the agent was thereafter well tolerated in the majority of patients.

A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4158-4163 ◽  
Author(s):  
Pierre Fenaux ◽  
Azra Raza ◽  
Ghulam J. Mufti ◽  
Carlo Aul ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Myelodysplastic Syndrome ◽  
Active Agent ◽  
Response Duration ◽  
Phase 2 ◽  
Median Response ◽  
Multicenter Phase ◽  
Phase 2 Study ◽  
Grade 3

Abstract This multicenter phase 2 study evaluated the use of tipifarnib (R115777) in patients with poor-risk myelodysplastic syndrome (MDS; French-American-British classification). Patients (n = 82) received tipifarnib 300 mg orally twice daily for the first 21 days of each 28-day cycle. Twenty-six patients (32%) responded to tipifarnib: 12 (15%) complete responses (CRs) and 14 (17%) hematologic improvements; 37 patients (45%) had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis (all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0). Grade 3-4 neutropenia (18%) and thrombocytopenia (32%) were the most common treatment-related adverse events; severe nonhematologic adverse events were rarely reported. In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS.

Multicenter Phase II Study of Bimonthly High-Dose Leucovorin, Fluorouracil Infusion, and Oxaliplatin for Metastatic Colorectal Cancer Resistant to the Same Leucovorin and Fluorouracil Regimen

1999 ◽  
Vol 17 (11) ◽  
pp. 3560-3568 ◽  
Author(s):  
Thierry André ◽  
Mohamed A. Bensmaine ◽  
Christophe Louvet ◽  
Eric François ◽  
Virginie Lucas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Peripheral Neuropathy ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
High Dose ◽  
Median Response ◽  
Grade 3

PURPOSE: To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m2) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone. PATIENTS AND METHODS: One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m2 and continuous 5-FU infusion 1.5 to 2 g/m2/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m2, bolus 5-FU 400 mg/m2, and continuous 5-FU infusion 600 mg/m2/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m2 of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m2 of oxaliplatin day 1 (FOLFOX4). RESULTS: Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P = .02). From the start of treatment, median progression-free survival was 4.7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively. CONCLUSION: This phase II study of oxaliplatin at 85 mg/m2 in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.

Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer.

1996 ◽  
Vol 14 (9) ◽  
pp. 2540-2545 ◽  
Author(s):  
G J Creemers ◽  
C J Gerrits ◽  
J H Schellens ◽  
A S Planting ◽  
M E van der Burg ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Continuous Infusion ◽  
Phase Ii ◽  
Topoisomerase I ◽  
Single Agent ◽  
Locally Advanced ◽  
Specific Inhibitor ◽  
Continuous Exposure ◽  
Median Response

PURPOSE Topotecan is a specific inhibitor of topoisomerase I. Preclinical data have indicated that topoisomerase I inhibitors demonstrate more efficacy and have a greater therapeutic index with prolonged continuous exposure. The feasibility of this concept in humans using a 21-day continuous infusion of topotecan has been reported. We conducted a phase II study of this 21-day continuous topotecan administration schedule in patients with locally advanced, unresectable or metastatic colorectal cancer. PATIENTS AND METHODS Topotecan, initially applied at a dose of 0.6 mg/m2/d, was administered as a continuous infusion via an ambulatory pump for 21 days repeated every 4 weeks. The starting dose was reduced to 0.5 mg/m2/d, because in five of the first 11 patients, the second course had to be delayed due to prolonged myelosuppression. Forty-two patients entered the study; one patient was ineligible and was excluded from further analyses. RESULTS The overall response rate was 10%, with one complete and three partial responses. The median response duration was 7 months (range, 4 to 11). With this schedule, the major toxicity was prolonged cumulative myelosuppression, including a marked inhibition of erythropoiesis. A total transfusion of 250 U of erythrocytes was needed to maintain a hemoglobin level greater than 6.0 mmol/L. Other side effects were mild, and included alopecia (47%), periodic nausea (40%)/vomiting (22%), and fatigue (16%). Pharmacokinetic evaluation showed a mean steady-state plasma concentration (Css) of topotecan of 0.62 ng/mL (range, 0.33 to 1.1), with a significant relationship between the Css of topotecan and common cytotoxicity criteria (CTC) grade of leukocytopenia. CONCLUSION Topotecan administered as a 21-day continuous infusion exerts minor activity as single-agent therapy in patients with metastatic colorectal cancer.

A phase II study of panitumumab plus irinotecan for metastatic colorectal cancer with wild KRAS, resistant to fluoropyrimidine, oxaliplatin, and irinotecan in Japanese (OGSG1001).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 607-607
Author(s):  
Koichi Taira ◽  
Motoki Yoshida ◽  
Naotoshi Sugimoto ◽  
Takayuki Kii ◽  
Shin Kuwakado ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Combination Chemotherapy ◽  
Progression Free Survival ◽  
Response Duration ◽  
Grade 3 ◽  
Egfr Antibody

607 Background: Anti-epidermal growth factor receptor (EGFR) antibody therapy showed to be effective in treatment for metastatic colorectal cancer (mCRC) with wild KRAS. Especially, combination chemotherapy with anti-EGFR antibody plus irinotecan is expected more effective than anti-EGFR antibody alone, resistant to irinotecan. We conducted a phase II trial of panitumumab plus irinotecan for mCRC with wild KRAS resistant to fluoropyrimidine, oxaliplatin, and irinotecan in Japanese. Methods: Subjects were mCRC patients with wild KRAS, who showed resistance to fluoropyrimidine, oxaliplatin, and irinotecan and had measurable disease, ECOG PS 0-2. Panitumumab (6 mg/kg) plus irinotecan (same dose as prior irinotecan) was administered every two weeks. This treatment was provided until progression. The primary endpoint was response rate (RR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), response duration, and adverse event (AE). Results: A total of 31 subjects were enrolled between July 2010 and July 2012. Median age was 64 years old (range 42-74). Nineteen patients had liver metastasis, 11 had lung metastasis, and 3 had lymph node metastasis. An independent review committee evaluated for efficacy in eligible 31 subjects in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The RR of primary endpoint was 29.0% (95% confidence interval (CI), 14.2-48.0 %). DCR was 74.2% (95%CI, 55.4-88.1%) and median PFS was 5.6 months.(95%CI: 3.4-8.7) In 31 subjects for safety evaluation, the incidence of any Grade 3 or greater adverse events was 58.1%. Major adverse events of grade 3 were diarrhea (19.4%), rash acneiform (12.9%), fatigue (9.7%), anorexia (9.7%). A sudden death and an infusion related reaction were occurred. Conclusions: Combination chemotherapy with panitumumab plus irinotecan was demonstarated to be safe and more effective than Japanese single arm phase II of panitumumab alone for mCRC, resistant to fluoropyrimidine, oxaliplatin and irinotecan. This result in Japanese is equal to other reports of panitumumab plus irinotecan. Clinical trial information: UMIN000003819.

Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer.

1996 ◽  
Vol 14 (4) ◽  
pp. 1128-1135 ◽  
Author(s):  
M L Rothenberg ◽  
J R Eckardt ◽  
J G Kuhn ◽  
H A Burris ◽  
J Nelson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Response Duration ◽  
Recurrent Colorectal Cancer ◽  
Median Response ◽  
Severe Diarrhea ◽  
Starting Dose

PURPOSE To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

2021 ◽  
pp. 107815522110179
Author(s):  
Olivia R Court
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Free Survival ◽  
Length Of Treatment ◽  
Common Grade ◽  
Grade 3 ◽  
The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

scholarly journals Topoisomerase I copy number alterations as biomarker for irinotecan efficacy in metastatic colorectal cancer

BMC Cancer ◽  
2017 ◽  
Vol 17 (1) ◽  
Author(s):  
Jesper Andreas Palshof ◽  
Estrid Vilma Solyom Høgdall ◽  
Tim Svenstrup Poulsen ◽  
Dorte Linnemann ◽  
Benny Vittrup Jensen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Copy Number ◽  
Topoisomerase I ◽  
Copy Number Alterations

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 III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer

2000 ◽  
Vol 18 (1) ◽  
pp. 136-136 ◽  
Author(s):  
S. Giacchetti ◽  
B. Perpoint ◽  
R. Zidani ◽  
N. Le Bail ◽  
R. Faggiuolo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Phase Iii ◽  
Line Treatment ◽  
Survival Times ◽  
First Line ◽  
Grade 3 ◽  
First Line Treatment

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)–leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m2/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m2, as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU–LV occurred in ≤ 5% of the patients (≤ 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU–LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P < .001). The median progression-free survival time was 6.1 months with 5-FU–LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU–LV (P = .048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION: By chronomodulating 5-FU–LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.

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