A UGT1A1*28 and *6 genotype-directed phase I dose-escalation trial of irinotecan with fixed-dose capecitabine in Korean patients with metastatic colorectal cancer

e15573 Background: Treatment of non-resectable metastatic colorectal cancer (mCRC) involves chemotherapy based on 5-fluorouracil, oxaliplatin and irinotecan and monoclonal antibodies targeting VEGF or EGFR. Rechallenge with oxaliplatin and irinotecan bi fractionation (FOLFIRI3) have previously shown efficacy in chemorefractory patients but desynchronized triplet chemotherapy was never tested. The aim of this study was to evaluate the safety and efficacy of a new regimen so-called: FOLFIRINOX-3 bevacizumab in chemorefractory mCRC. Methods: A phase I study to test bFOLFIRINOX 3 regimen was designed using Standard “3 + 3” design for dose escalation. Patients enrolled, >18years and ECOG 0 or 1, have a pathologically confirmed mCRC and experienced treatment failure after standard chemotherapy that include 5-fluorouracil, oxaliplatin and irinotecan. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg) plus simplified FOLFOX4 (folinic acid (400mg/m2), 5-fluorouracil (400mg/m2 bolus followed by 2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (administered before and after infusional 5-fluorouracil). Three irinotecan levels were planned at 60, 70 and 90 mg/m² (day 1 and day 3). Dose limiting toxicities (DLT) were identified during the first 2 cycles. Primary endpoint was assessment of maximum tolerable dose trough evaluation of acute toxicities (CTCAE v4.03). Secondary endpoints included objective response (RECIST 1.1), progression free survival, overall survival and late toxicity. Results: Thirteen patients received experimental treatment on this study. The RP2D was irinotecan 70mg/m² day 1 and day 3. Two patients experienced DLTs (G3 diarhea ) at dose level 90mg/m² and one DLT occured (G3 diarrhea) at 70mg/m² level. The most common drug-related adverse events (all grades) were fatigue (92.3%), diarrhea (76.9%), nausea (61.5%), peripheral neuropathy (61.5%), thrombopenia (46.1%) and anemia (15.3%). Among 11 response-evaluable patients, we noticed 4 partial responses, 7 stable disease and no progression as best response. Conclusions: The combination of bFOLFIRINOX-3 at the RP2D of 70mg/m² day 1 and day 3. was well tolerated and feseably. The regimen resulted in high response rate in chemorefractory metastatic colorectal cancer. Phase II is ongoing. Clinical trial information: NCT03795311.

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SPICE, a phase I study of enadenotucirev in combination with nivolumab in tumours of epithelial origin: Analysis of the metastatic colorectal cancer patients in the dose escalation phase

Annals of Oncology ◽

10.1093/annonc/mdz246.089 ◽

2019 ◽

Vol 30 ◽

pp. v231

Author(s):

M.G. Fakih ◽

D. Wang ◽

W. Harb ◽

L. Rosen ◽

D. Mahadevan ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase I ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Dose Escalation ◽

Phase I Study ◽

Epithelial Origin ◽

Colorectal Cancer Patients ◽

Origin Analysis

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Pharmacogenomic and Pharmacoproteomic Studies of Cetuximab in Metastatic Colorectal Cancer: Biomarker Analysis of a Phase I Dose-Escalation Study

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.6043 ◽

2010 ◽

Vol 28 (7) ◽

pp. 1181-1189 ◽

Cited By ~ 73

Author(s):

Josep Tabernero ◽

Andres Cervantes ◽

Fernando Rivera ◽

Erika Martinelli ◽

Federico Rojo ◽

...

Keyword(s):

Colorectal Cancer ◽

Phase I ◽

Metastatic Colorectal Cancer ◽

Dose Escalation ◽

Progression Free Survival ◽

Wild Type ◽

Dose Escalation Study ◽

Tissue Samples ◽

First Line Therapy ◽

Biomarker Analysis

PurposeThis study assessed biomarkers for cetuximab efficacy in tissue samples collected during a phase I dose-escalation study exploring every second week administration of cetuximab as first-line therapy in patients with metastatic colorectal cancer (mCRC).Patients and MethodsSixty-two patients received cetuximab monotherapy for 6 weeks, followed by cetuximab plus infusional fluorouracil, leucovorin, and irinotecan until disease progression. Patients in the control arm received cetuximab as a 400 mg/m2initial dose then 250 mg/m2per week; patients in the dose-escalation arms received 400 to 700 mg/m2every second week. Tumor and skin biopsies were taken for immunohistochemical and microarray expression analyses (tumor only) at baseline and week 4. Plasma was collected for proteomic analysis at baseline and week 4. KRAS tumor mutation status was assessed.ResultsIn subsets of paired skin samples from 35 patients, cetuximab treatment was associated with substantial downregulation of phospho(p)-EGFR, p-MAPK and proliferation and substantial upregulation of p27Kip1and p-STAT3 levels. No marked difference in these effects was noted for different schedules of administration and dose levels. In the cetuximab monotherapy phase, responses were seen only in patients whose tumors were wild-type for KRAS (eight of 29 v zero of 19 for KRAS mutant tumors; P = .015). Progression-free survival was longer for patients with KRAS wild-type compared with KRAS mutant tumors (log-rank P = .048). Genomics/proteomics analyses (42 and 45 patients, respectively) identified candidate biomarkers associated with response.ConclusionBiomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.

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