Phase I dose escalation and pharmacokinetics study of intravenous aflibercept plus irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) in patients with metastatic colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 538-538 ◽  
Author(s):  
K. Yamazaki ◽  
T. Yoshino ◽  
K. Yamaguchi ◽  
N. Boku ◽  
N. Machida ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Safety Issue ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Ecog Ps

538 Background: Aflibercept (AF), a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor. This study assessed the safety, dose limiting toxicities (DLTs), recommended dose (RD), and the pharmacokinetics (PK) of AF in combination with FOLFIRI. Methods: This was an open-label, sequential-cohort, dose-escalation study of intravenous AF administered every 2 weeks, in combination with FOLFIRI (fixed doses) in patients (pts) with metastatic colorectal cancer (MCRC). Two dose levels (DL) of AF (2 and 4 mg/kg) were set, and 3-6 pts were to be recruited in each DL. DLTs were to be evaluated in the first 2 cycles. RD was defined as the highest AF dose at which <33% of all evaluable pts experienced DLTs. After establishment of RD, 10 additional pts were treated at RD. PK of AF, irinotecan, SN38, and 5-FU were studied in cycle 1. Results: 16 pts (3 at 2 mg/kg and 13 at 4 mg/kg) with MCRC were treated (M/F, 10/6; median age, 57.0 [47-69]; and ECOG PS 0/1, 9/7), and all had received prior chemotherapies. A total of 131 cycles of AF + FOLFIRI were administered at the two DLs of AF (2 and 4 mg/kg). No DLT was observed. The most common all-causality grade 3/4 adverse events were neutropenia (75.0 %) including one febrile neutropenia after DLT evaluation period and hypertension (25.0%). There was no major safety issue at the RD. Response rate and progression free survival at RD (N=13 pts) was 7.8% and 7.6 month, respectively. Conclusions: RD was determined as 4 mg/kg in this first clinical study of AF in Japanese pts with MCRC. The combination of AF (4 mg/kg) and FOLFIRI was well tolerated in line with results of prior overseas studies. The PK results in Japanese patients showed similar tendency to those reported in patients from other regions of the world. [Table: see text]

A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: The SOFT study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3519-3519 ◽  
Author(s):  
Daisuke Takahari ◽  
Yasuhide Yamada ◽  
Hiroshi Matsumoto ◽  
Hideo Baba ◽  
Kazuhiro Yoshida ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Open Label ◽  
Phase Iii Trial ◽  
Open Label Phase ◽  
Grade 3 ◽  
Ecog Ps

3519 Background: Several studies of oxaliplatin plus S-1 combination therapy (SOX) conducted in Asia have shown promising efficacy and safety for metastatic colorectal cancer (mCRC), suggesting the potential to replace mFOLFOX6. We performed a randomized phase III trial to determine whether SOX plus bevacizmab (SOX+Bev) is non-inferior to mFOLFOX6 plus bevacizmab (mFOLFOX6+Bev) in terms of progression-free survival (PFS). Methods: The SOFT study was a randomized, open-label, phase III trial. Chemotherapy-naïve patients (pts) with mCRC, an ECOG PS of 0-1, and adequate organ functions were randomized to receive either mFOLFOX6+Bev (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2,400 mg/m2 of 5-FU over 46 h, every 2 weeks) or SOX+Bev (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1, and 40−60 mg of S-1 twice daily for 2 weeks, followed by a 1-week rest). The primary endpoint was PFS. A sample size of 225 pts per group was estimated to be necessary based on a median PFS of 10.0 months in each group and an 80% power to demonstrate non-inferiority of SOX+Bev with a 2.5-month margin (hazard ratio, HR = 1.33) and a 2-sided alpha of 0.05. Results: A total of 512 pts were enrolled from February 2009 to March 2011. Data were analyzed after confirming >388 events as planned. Demographic factors were well balanced. Pts received a median of 12 cycles (1 cycle = 2 weeks) of mFOLFOX6+Bev and 8 cycles (1 cycle = 3 weeks) of SOX+Bev (range: 1−16). Median PFS was 11.5 months (95% CI: 10.7−13.2) with mFOLFOX6+Bev and 11.7 months (95% CI: 10.7−12.9) with SOX+Bev. The adjusted HR for PFS was 1.043 (95% CI: 0.860−1.266), and the p value for non-inferiority was 0.0139. Response rate was 62.7% with mFOLFOX6+Bev and 61.5% with SOX+Bev. Grade 3/4 toxicities (%) with mFOLFOX6+Bev/SOX+Bev were leukopenia 8.4/2.4, neutropenia 33.7/8.8, anorexia 1.2/5.2, and diarrhea 2.8/9.2. Conclusions: SOX+Bev is non-inferior to mFOLFOX6+Bev with respect to PFS as 1st-line treatment for mCRC and thus can replace mFOLFOX6+Bev. Clinical trial information: JapicCTI-090699.

Randomized phase II open-label study of mFOLFOX6 in combination with linifanib or bevacizumab for metastatic colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3532-3532
Author(s):  
Bert H. O'Neil ◽  
Calin Cainap ◽  
Eric Van Cutsem ◽  
Vera A. Gorbunova ◽  
Christos Stelios Karapetis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Progression Free Survival ◽  
High Dose ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Bevacizumab Treatment ◽  
Grade 3 ◽  
Weight Decrease ◽  
Ecog Ps

3532 Background: Linifanib is a potent and selective inhibitor of VEGF/PDGF receptors. This trial assessed the efficacy and safety of mFOLFOX6 in combination with linifanib or bevacizumab as second-line treatment for metastatic colorectal cancer (mCRC). Methods: Patients (pts) with measurable mCRC refractory to 1 prior regimen and ECOG PS 0–1, stratified by prior bevacizumab treatment and radiotherapy, were randomized to receive mFOLFOX6 with bevacizumab 10 mg/kg on day (d) 1 of 14-d cycle (Arm A), mFOLFOX6 with daily linifanib 7.5 mg (Arm B), or mFOLFOX6 with daily linifanib 12.5 mg (Arm C). The primary endpoint was progression-free survival (PFS). Severity of adverse events (AEs) was graded using NCI-CTCAE v3.0. Results: 148 pts were randomized at 45 sites in 14 countries. 32 pts (21.6%) had received prior bevacizumab. PFS and response data are shown below (Table). Median survival (OS) was not reached at median follow up 7.6 months. Palmar-plantar erythrodysesthesia (PPE) was the only Grade 3/4 AE significantly higher on linifanib (high dose, 16.3%) vs. bevacizumab (0%). Rate of any Grade 3+ AE was significantly higher on linifanib vs. bevacizumab.Hypertension rates were 41.7% (Arm A), 40.0% (Arm B), and 36.7% (Arm C). AEs dose-related to linifanib were constipation, proctalgia, stomatitis, fatigue, weight decrease, decreased appetite, and PPE. Conclusions: The addition of linifanib to mFOLFOX6, compared to mFOLFOX6 + bevacizumab, did not provide a PFS advantage for mCRC. OS results will be updated for conference presentation. [Table: see text]

Randomized, phase II study of bevacizumab with mFOLFOX6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: Resectability and safety in OLIVIA.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3619-3619 ◽  
Author(s):  
Thomas Gruenberger ◽  
John A. Bridgewater ◽  
Ian Chau ◽  
Pilar Garcia Alfonso ◽  
Michel Rivoire ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Progression Free Survival ◽  
Remnant Liver ◽  
Resection Rate ◽  
Open Label ◽  
R1 Resection ◽  
Unresectable Liver Metastases ◽  
Grade 3 ◽  
Hepatic Lesions ◽  
Ecog Ps

3619^ Background: Patients (pts) with unresectable colorectal cancer liver-only metastases (CLMs) may become resectable after downsizing by chemotherapy (CT) and biologic therapy. Although biologics are thought to improve overall response rate (ORR), the optimal combination of a biologic and CT for resectability remains uncertain. Methods: This open-label, multinational study randomized pts with unresectable CLMs to bevacizumab (BEV) plus mFOLFOX6 or FOLFOXIRI q2w. Resectability was assessed by interdisciplinary review. Unresectability was defined as ≥1 of the following: no possibility of upfront R0/R1 resection of all hepatic lesions, <30% estimated residual liver after resection, or disease in contact with major vessels of the remnant liver. The primary end point was overall resection rate (R0/R1/R2). Results: From 10/2008 to 12/2011, 80 pts were randomized to mFOLFOX6-BEV (n=39) or FOLFOXIRI-BEV (n=41). Pt characteristics were male (46% vs 71%), aged ≥60 y (36% vs 63%), ECOG PS of 1 (23% vs 37%), and ≥5 target CLMs (49% vs 49%) in the mFOLFOX6-BEV and FOLFOXIRI-BEV arms, respectively. Resection rate, ORR, and progression-free survival (PFS) data are shown (Table). Grade ≥3 adverse events (AEs) occurred in 84% and 95% of pts receiving mFOLFOX6-BEV and FOLFOXIRI-BEV, respectively, and included neutropenia (35% vs 48%; febrile, 8% vs 13%) and diarrhea (14% vs 28%). Conclusions: The results suggest that FOLFOXIRI-BEV improves resection rates, ORR, and long-term outcomes vs mFOLFOX6-BEV in pts with initially unresectable CLMs. CT- and BEV-related AEs occurred with the expected incidence and were manageable. FOLFOXIRI-BEV should be evaluated further as an effective regimen to downsize CLMs. Clinical trial information: NCT00778102. [Table: see text]

scholarly journals Safety, efficacy and patient-reported outcomes with trifluridine/tipiracil in pretreated metastatic colorectal cancer: results of the PRECONNECT study

ESMO Open ◽  
2020 ◽  
Vol 5 (3) ◽  
pp. e000698
Author(s):  
Jean-Baptiste Bachet ◽  
Lucjan Wyrwicz ◽  
Timothy Price ◽  
Chiara Cremolini ◽  
Jean-Marc Phelip ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
Open Label ◽  
Patient Reported ◽  
Registration Number ◽  
Grade 3

BackgroundIn RECOURSE (, trifluridine/tipiracil significantly improved overall survival and progression-free survival (PFS) versus placebo in patients with pretreated metastatic colorectal cancer (mCRC). PRECONNECT was designed to further characterise safety and clinical use of trifluridine/tipiracil.MethodsIn this ongoing, international, multicentre, open-label trial, patients with pretreated mCRC received oral trifluridine/tipiracil 35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle. The primary endpoint was safety; secondary endpoints included PFS and quality of life (QoL).Results793 patients (median age 62 years) from 13 countries received trifluridine/tipiracil for a median of 2.84 months (IQR 2.64). Adverse events (AEs) were experienced by 96.7%; the most common (≥20% of patients) were neutropaenia, asthenia/fatigue, nausea, anaemia and diarrhoea. Grade ≥3 AEs occurred in 73.9% of patients, with the most common being neutropaenia (39.1% of patients), anaemia (9.8%) and asthenia/fatigue (5.0%). Median PFS was 2.8 months (95% CI 2.7 to 2.9). Median time to Eastern Cooperative Oncology Group performance status deterioration (≥2) was 8.9 months (range 0.03–14.72). There was no clinically relevant change from baseline in QoL.ConclusionsPRECONNECT showed consistent results with the previously demonstrated safety and efficacy profile of trifluridine/tipiracil, with no new safety concerns identified. QoL was maintained during treatment.Trial registration numberNCT03306394.

Phase I dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3045-3045 ◽  
Author(s):  
Takashi Seto ◽  
Taito Esaki ◽  
Fumihiko Hirai ◽  
Shuji Arita ◽  
Kaname Nosaki ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Troponin T ◽  
Geometric Mean ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Primary Tumor Site ◽  
Grade 3

3045 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients (pts) with advanced solid tumors (NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at doses of 6 (n=3), 9 (3), 21 (6), and 30 mg (8). The most common primary tumor site was lung (n=14). All pts had received ≥1 prior chemotherapy and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated AST and ALT (Cycle 1; combination therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs resolved following treatment discontinuation. The most frequently reported adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia (50%), hypertension (25%) and fatigue (15%). Overall, the most common AEs were bradycardia (55%), neutropenia (45%), and hypertension, fatigue, and rash (30% each). AEs grade ≥3 were reported in 11 pts, the most common being neutropenia (45%) and leukopenia (25%). No pt died due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately linear manner. Gemcitabine did not appear to affect AZD7762 PK. Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in combination with gemcitabine. There were no objective responses; five pts (all lung cancer) had stable disease. Conclusions: The maximum tolerated dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was determined as 21 mg in Japanese pts.

A phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in metastatic colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3626-TPS3626 ◽  
Author(s):  
Antoine Hollebecque ◽  
Guillem Argiles ◽  
Thierry Andre ◽  
Andres Cervantes ◽  
Catherine Leger ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Activity ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Nude Mouse Model

TPS3626 Background: Trifluridine/tipiracil, also known as TAS‐102, is a combination of an antineoplastic thymidine‐based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride). The antitumor activity of combined trifluridine/tipiracil and oxaliplatin has been studied in gastrointestinal tumor xenografts, including a 5‐FU resistant subline, using a nude mouse model. This study demonstrated increased antitumor activity for the combination compared to trifluridine/tipiracil or oxaliplatin alone (p < 0.001) (Nukatsuka et al., Anticancer Res 2015). These data support the rationale for clinical use of the combination. We describe a phase 1, international, dose-escalation study of the combination in metastatic colorectal cancer (mCRC). Methods: This trial includes mCRC patients pretreated with at least one line of standard chemotherapy. The 14‐day administration schedule of trifluridine/tipiracil differs from current clinical practice to avoid overlapping toxicity, notably decreased neutrophils due to oxaliplatin or trifluridine/tipiracil. Trifluridine/tipiracil is administered orally (cohort 1: 25 mg/m² bid; cohort 2: 30 mg/m² bid; cohort 3: 35 mg/m² bid) from day 1 to 5; and oxaliplatin at 85 mg/m² (with a possibility to reduce to 65 mg/m²) on day 1. The primary objective is to determine the maximum tolerated dose (MTD) through a 3+3 design. Secondary objectives include safety, pharmacokinetics, and preliminary efficacy (overall survival, progression‐free survival, overall response rate and biomarkers). As of December 2016, no dose‐limiting toxicities had been reported in cohorts 1 or 2. The MTD has not yet been reached and dose‐escalation continues with enrollment in cohort 3 at full dose for both drugs (trifluridine/tipiracil 35 mg/m² bid and oxaliplatin 85 mg/m²). Once established, the MTD will be confirmed in 6 additional patients to define the recommended dose to be used in the expansion part of the study planned in the same patient population. The results of the dose‐escalation part are expected in 2017. (NCT02848443). Clinical trial information: NCT02848443.

The efficacy and safety of CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy in patients with metastatic colorectal cancer: A multi-center, single-arm, phase II study (CCOG-0902 study).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 795-795
Author(s):  
Yuuki Sunakawa ◽  
Goro Nakayama ◽  
Kiyoshi Ishigure ◽  
Hiroyuki Yokoyama ◽  
Keisuke Uehara ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Maintenance Therapy ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Sensory Neuropathy ◽  
Progression Free Survival ◽  
Japanese Patients ◽  
Efficacy And Safety ◽  
Stop And Go ◽  
Grade 3

795 Background: The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC). Methods: Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety. Results: The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0–14.8) and 30.6 months (95% CI, 27.6–33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy. Conclusions: CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC. Clinical trial information: UMIN000006478.

Phase I dose-escalation study of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15573-e15573
Author(s):  
Jean-David Fumet ◽  
Alice Hervieu ◽  
Audrey Hennequin ◽  
Sylvie Zanetta ◽  
Aurelie Bertaut ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Folinic Acid ◽  
Dose Escalation ◽  
Objective Response ◽  
Experimental Treatment ◽  
Progression Free Survival ◽  
High Response Rate ◽  
Dose Escalation Study

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.

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

2010 ◽  
Vol 28 (7) ◽  
pp. 1181-1189 ◽  
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.

Results of the Quad wild type arm of the AGITG ICECREAM study: A randomised phase II study of cetuximab alone or in combination with irinotecan in patients with refractory metastatic colorectal cancer with no mutations in KRAS, NRAS, BRAF or PIK3CA.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3572-3572 ◽  
Author(s):  
Jeremy David Shapiro ◽  
Subotheni Thavaneswaran ◽  
Craig Underhill ◽  
Kristy Pamela Robledo ◽  
Christos Stelios Karapetis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Single Agent ◽  
Progression Free Survival ◽  
Wild Type ◽  
Response Characteristics ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ecog Ps

3572 Background: Cetuximab (cet) increases survival in RAS wild-type (WT) metastatic colorectal cancer (mCRC) in first-line and chemorefractory patients (pts). Adding irinotecan (iri) to cet in refractory pts who had progressed on iri increased response and delayed progression in the BOND trial, which was conducted prior to recognition that RAS mutations are predictive of EGFR-inhibitor (EGFR-I) resistance. Subsequent trials in chemorefractory pts used single agent EGFR-I as standard. In the era of biomarker selection, the benefit of continuing iri versus single agent EGFR-I had not been resolved. Methods: ICECREAM is a randomised phase II trial evaluating cet v cet + iri in chemotherapy-refractory mCRC, stratified for KRAS G13D mutation (previously reported) or no mutations in KRAS, NRAS, BRAF and PI3KCA (Quad WT ). EGFR-I naïve, ECOG PS 0-1 pts, progressing within 6 months of iri and refractory (or intolerant) to fluoropyrimidine and oxaliplatin were randomised to cet 400mg/m2 IV loading then 250mg/m2 weekly +/- iri 180mg/m2q2 wks. The primary endpoint was progression-free survival at 6 months (6m PFS); secondary endpoints were response rate (RR), overall survival (OS), toxicity and quality of life (QOL). Results: From Nov 2012 to June 2016, 48 Quad WT pts were recruited: 2 ineligible (not iri-refractory, BRAF mutation) wre not included for analyses and a further 2 not evaluable for response. Characteristics were balanced between cet (n = 21) v cet-iri (n = 25), except for sex (male 62 v 72%) and primary site (left 95 v 68%). 6m PFS rate was 14% v 41%; HR 0.39 (95% CI: 0.20–0.78, p = 0.008). RR was 10% (2 PR) v 36% (1 CR, 8 PR); p = 0.04. Toxicities were higher with cet-iri; at least one grade 3/4 adverse event in 50 v 23%. No differences in global or specific QOL were seen. Conclusions: The AGITG ICECREAM trial confirms a significant synergy for the addition of iri to cet and improved PFS in Quad WT chemorefractory mCRC, echoing data in molecularly unselected pts. Clinical trial information: ACTRN12612000901808.

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