Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients.

Abigerges, D; Chabot, Guy G.; Armand, Jean‐Pierre; Hérait, Patrice; Gouyette, Alain; Gandía, Daniel

doi:10.1200/jco.1995.13.1.210

Cited by 265 publications

(96 citation statements)

References 21 publications

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“…Explanations may be that various nutrients in tissue culture medium might inhibit the activation of the enzyme or that the carboxylesterase extract from porcine liver is not a good substitute for the endogenous carboxylesterase converting CPT-11 in other species. Of interest, however, regardless of the dose of CPT-11 administered to patients, the proportion of SN-38 formed was low and varied between 1.3% and 5.8% (Abigerges et al, 1995). An explanation may be the complicated metabolic pathway of CPT-1 1, as at least 15 metabolites have been detected in the bile of a patient (Lokiec et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Jansen

Hulscher²,

Ark-Otte³

et al. 1998

Br J Cancer

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Summary The relevance of P170-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) for the sensitivity to CPT-11 was investigated in human malignant cell lines as well as in human tumour xenografts. In vitro, the P-gp-positive sublines BRO/mdrl.1 (transfected with MDR1) and 2780AD were slightly cross-resistant against carboxylesterase-activated CPT-11. Cross-resistance against SN-38 was present in 2780AD cells, but not in BRO/mdrl.1 cells. The P-gp modulators BIBW22BS, verapamil and dexniguldipine partly reversed the resistance against CPT-11 in the P-gp-positive sublines. BIBW22BS was the most effective modulator in the reversal of the resistance against carboxylesterase-activated CPT-11 as well as against in the 2780AD subline. In contrast to doxorubicin and vincristine, the BRO/mdrl.1 xenografts were at least as sensitive to CPT-11 as the BRO xenografts. The 2780AD xenografts were slightly less sensitive than the parent tumours, but there was no difference in topoisomerase I DNA unwinding activity. Therefore, the high retention of the multidrugresistant phenotype of 2780AD cells in vivo may be the cause of the low cross-resistance against CPT-11. The MRP-positive subline GLC4/ADR was cross-resistant against carboxylesterase-activated CPT-11 and SN-38. GLC4/ADR cells, however, demonstrated a twofold lower topoisomerase I activity than GLC4 cells. Cross-resistance against the camptothecin derivatives was not apparent in the MRPtransfected subline of SW1573/Si. In conclusion, P-gp-positive cells show a low cross-resistance against CPT-11/SN38, which is only apparent with high P-gp expression in vivo. MRP does not seem to play a role in the sensitivity to

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Section: Discussionmentioning

confidence: 99%

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Jansen

Hulscher²,

Ark-Otte³

et al. 1998

Br J Cancer

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“…In a phase I trial by Abigerges et al (1995), there were two recommended doses: 350 mg m À2 without highdose loperamide and 600 mg m À2 with high-dose loperamide. With the exception of one responder treated at 260 mg m À2 , all objective responses were observed at dose levels above 350 mg m À2 .…”

mentioning

confidence: 99%

Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

et al. 2005

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Although irinotecan 350 mg m À2 is a standard option for relapsed/refractory advanced colorectal cancer, there is some evidence that suggests that a higher dose may be more effective, with acceptable tolerability, following 5-fluorouracil (5-FU). This study assessed the optimal dosing strategy for irinotecan, along with treatment efficacy and safety. A total of 164 patients with metastatic colorectal cancer progressing after failure on 5-FU or raltitrexed received either 350 mg m À2 irinotecan (Group A; n ¼ 36) or 250, 350 or 500 mg m À2 , according to individual patient tolerance (Group B; n ¼ 62) or based on risk factor optimisation (Group C; n ¼ 66). There were no complete responses. There was a trend towards a higher overall response rate in Group B (13%) than in Groups A (8%) and C (9%). Tumour control growth rate was high in all three groups: 58% in group A, 60% in Group B and 50% in Group C. A total of 34% of patients in Group B and 9% in Group C were able to receive a dose of 500 mg m À2 . Median duration of response and time to progression were significantly longer in Groups A and B compared with Group C. No significant between-group differences for any adverse events were seen, although there was a small trend towards better tolerability in Group B. Individual dose escalation based on patient tolerance may allow more patients to receive a higher irinotecan dose without causing additional toxicity and can be an appropriate patient management strategy. 1999). Median overall survival rates of up to 10 months are achievable when irinotecan is used in relapsed/refractory colorectal cancer (Shimada et al, 1993; Rothenberg et al, 1996 Rothenberg et al, , 1999Pitot et al, 1997;Rougier et al, 1997;Van Cutsem et al, 1999). Two European phase III trials investigating the efficacy and safety of irinotecan, following 5-FU failure in advanced colorectal cancer, have demonstrated significant improvements in survival compared with best supportive care and 5-FU (Cunningham et al, 1998;Rougier et al, 1998). The main adverse events accompanying treatment with irinotecan in these trials were diarrhoea, neutropenia, fatigue, nausea and vomiting.Although 350 mg m À2 as an intravenous infusion every 3 weeks is the standard recommended dosage of irinotecan, pharmacokinetic parameters of irinotecan-lactone and the active metabolite SN-38-lactone vary between individuals (Xie et al, 2002). This may be attributed to differences in the levels of the enzymes that metabolise irinotecan, notably carboxylesterase for SN-38. Furthermore, the variable interindividual patient exposure to SN-38 has been identified as an important determinant of toxicity .At the same time, there is convincing evidence of a doseresponse relationship, and therefore a rationale for increasing doses when possible. In a phase I trial by Abigerges et al (1995), there were two recommended doses: 350 mg m À2 without highdose loperamide and 600 mg m À2 with high-dose loperamide. With the exception of one responder treated at 260 mg m À2 , all objective responses...

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“…Such a low complication rate may be explained by the low daily dose of CPT-11. In fact, a phase I study demonstrated that the gastrointestinal toxicity induced by CPT-11 increased in intensity with greater doses of the drug (Albigerges et al, 1995). Leukopenia grade 3 -4 occurred in six patients (18%).…”

Section: Toxicitymentioning

confidence: 99%

“…The administration of a third line of chemotherapy to our patients has been made possible due to the low-toxicity profile resulting from the bifractionated administration of both L-OHP in first-line chemotherapy and campthotecin in second-line chemotherapy. The lower daily dose of CPT-11 decreases the peak plasma level, thus decreasing the toxicity profile, while efficacy is not altered (Albigerges et al, 1995). In view of the palliative intents that chemotherapy accomplishes in the treatment of pretreated colorectal cancer, current approaches should be designed to find active but less toxic drug combinations.…”

Section: Months)mentioning

confidence: 99%

“…It has been shown that CPT-11 efficacy and toxicity are both schedule and dose dependent (Albigerges et al, 1995;Guichard et al, 1997). In a previous study in a group of 54 patients with MCC, the dose of CPT-11, administered as first-line chemotherapy, was split over 2 days and administered with the 'de Gramont' regimen in order to decrease the toxicity profile and to better exploit the synergistic action of CPT-11, 5-FU and LV (Recchia et al, 2003).…”

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confidence: 99%

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Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX

Recchia

Saggio

Nuzzo³

et al. 2004

Br J Cancer

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This multicentre phase II study was designed to evaluate the antitumour activity and toxicity of bifractionated camptothecin (CPT-11) and 5-fluorouracil/ leucovorin (5-FU/LV) in the treatment of patients with metastatic colorectal cancer (MCC) who had been pretreated with 5-FU/LV-oxaliplatin (FOLFOX regimen). In all, 35 patients were enrolled in a two-stage trial. Treatment consisted of two daily doses of CPT-11, 90 mg m 2 administered over 90 min, followed by LV, 200 mg m 2 administered over 2 h plus 5-FU 400 mg m 2 as a bolus and 600 mg m 2 as a 22-h continuous infusion administered with disposable pumps as outpatient therapy. Toxicity was closely monitored. Response was evaluated by computed tomography scans every 8 weeks. All 35 patients were assessable for toxicity and response to treatment. Seven patients had a partial response, giving an overall response rate of 20%; 11 patients had stable disease (31.4%) and 17 progressed (48.5%). The median progression-free survival was 7.1 months and median survival was 14 months. A total of 10 patients (30%) experienced grade 3 -4 toxicity, including nausea (15%), diarrhoea (12%) and neutropenia (15%), while seven patients (21%) had grade 2 alopecia. The bifractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed substantial antitumour activity and was well tolerated in this group of patients with a poor prognosis, pretreated with the FOLFOX regimen.

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Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients.

Cited by 265 publications

References 21 publications

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

CPT-11 sensitivity in relation to the expression of P170-glycoprotein and multidrug resistance-associated protein

Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX

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