Randomized multicenter phase II trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer.

PURPOSE: Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma. PATIENTS AND METHODS: A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m(2) every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS). RESULTS: The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days. CONCLUSION: Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m(2) once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.

Comparing safety and efficacy of first-line irinotecan/fluoropyrimidine combinations in elderly versus nonelderly patients with metastatic colorectal cancer: findings from the bolus, infusional, or capecitabine with camptostar-celecoxib study.

BACKGROUND: Irinotecan-based chemotherapy regimens are 1 option for treatment of metastatic colorectal cancer (mCRC). The authors report the safety and efficacy of such regimens in elderly patients using a large phase III trial (bolus, infusional, or capecitabine with camptostar-celecoxib [BICC-C]) cohort. METHODS: In period 1, 430 previously untreated patients with mCRC were randomized in a 3-by-2 design to receive irinotecan plus infusional 5-fluorouracil, and leucovorin (FOLFIRI), irinotecan plus bolus 5-fluorouracil/leucovorin (mIFL), and irinotecan plus oral capecitabine (CapeIRI). In period 2, an additional 117 patients were randomized to receive FOLFIRI or mIFL and bevacizumab. In both periods patients were also randomized to a double-blind treatment with celecoxib or placebo. A secondary analysis was conducted examining the safety and efficacy of these regimens in elderly (age >70 years) versus nonelderly (age

Utility of Pretreatment Bilirubin Level and UGT1A1 Polymorphisms in Multivariate Predictive Models of Neutropenia Associated with Irinotecan Treatment in Previously Untreated Patients with Colorectal Cancer.

PURPOSE: Statistical models for predicting hematologic toxicity were evaluated based on UGT1A1 polymorphisms and baseline serum bilirubin. METHODS: Blood DNA samples were collected from 113 patients with untreated metastatic colorectal cancer receiving irinotecan (FOLFIRI, n = 36; mIFL, n = 41; CapeIRI, n = 36). The primary endpoint was absolute neutrophil count nadir during first treatment cycle. Linear regression models, with increased R(2) implying important additional predictive power, sequentially added age, sex, baseline bilirubin level, and UGT1A1 genotype. RESULTS: All models demonstrated low R(2), suggesting unaccounted variables. UGT1A1 genotype added approximately 8-9% during cycle 1 and from approximately 7% [mIFL regimen] to 26% [CapeIRI regimen] after cycle 1. Correlation between genotype and overall ANC nadir without regard to treatment was low (R = -0.201, P = 0.035). Patients with genotype 7/7 may have increased risk for severe neutropenia, but data are insufficient to characterize this. Contribution of baseline bilirubin level was negligible. CONCLUSIONS: Ability of UGT1A1 or baseline bilirubin to predict neutropenia is low and depends on regimen.

Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study.

PURPOSE: This phase III study compared the safety and efficacy of the following three different irinotecan-containing regimens in the first-line treatment of metastatic colorectal cancer: irinotecan plus infusional fluorouracil (FU)/leucovorin (LV) (FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecan plus oral capecitabine (CapeIRI). PATIENTS AND METHODS: A total of 430 previously untreated metastatic colorectal cancer patients were randomly assigned to receive FOLFIRI (n = 144), mIFL (n = 141), or CapeIRI (n = 145). Patients were concurrently randomly assigned to a double-blind treatment with celecoxib or placebo. After a protocol amendment, an additional 117 patients were randomly assigned to either FOLFIRI plus bevacizumab (FOLFIRI+Bev; n = 57) or mILF plus bevacizumab (mIFL+Bev; n = 60), whereas the CapeIRI arm was discontinued. The primary study end point was progression-free survival (PFS), with secondary end points of overall survival (OS), response rate, and toxicity. RESULTS: Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (P = .004 for the comparison with FOLFIRI), and 5.8 months for CapeIRI (P = .015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (P = .09), and 18.9 months for CapeIRI (P = .27). CapeIRI was associated with higher rates of severe vomiting, diarrhea, and dehydration. After the amendment to add bevacizumab, the median survival time has not yet been reached for FOLFIRI+Bev and was 19.2 months for mIFL+Bev (P = .007). FOLFIRI+Bev was associated with a higher rate of > or = grade 3 hypertension than mIFL+Bev. CONCLUSION: FOLFIRI and FOLFIRI+Bev offered superior activity to their comparators and were comparably safe. An infusional schedule of FU should be the preferred irinotecan-based regimen in first-line metastatic colorectal cancer.