Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3623-TPS3623 ◽  
Author(s):  
Yasutoshi Kuboki ◽  
Akihito Kawazoe ◽  
Yoshito Komatsu ◽  
Tomohiro Nishina ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Sample Size ◽  
Phase Ii ◽  
Alternative Hypothesis ◽  
Objective Response ◽  
Clinical Trial Information ◽  
Egfr Antibody

TPS3623 Background: Immune checkpoint inhibitor (ICI) was reported to show durable responses in patients with MSI-H (Microsatellite Instability-High) metastatic colorectal cancer (mCRC). On the other hand, for patients with MSS (Microsatellite Stable) mCRC, ICI monotherapy achieved no response. Recently, WNT/β-catenin signaling has been reported to be involved in the elimination of tumor-infiltrating lymphocytes and the resistance of anti-PD-L1 antibodies. CRC is representative cancer with WNT/β-catenin pathway activation. Furthermore, STAT3 has also been reported to be a key driver of this immune evasion. Considering these rationales, the blocking of these signaling pathways with ICI may enhance antitumor immune response. Therefore, we initiated phase I/II study to assess efficacy and safety for the combination of BBI608, which blocks STAT3 and WNT/β-catenin signaling, with pembrolizumab in patients with mCRC. Methods: The eligibility criteria were patients with gastrointestinal cancer not responded to or intolerant of standard chemotherapies (SOC) for phase I part, and MSS mCRC refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and anti-EGFR antibody (if wild-type RAS) for Cohort B in phase II part. For Cohort A, MSI-H mCRC refractory or intolerant to the SOC, irrespective of anti-EGFR antibody are investigated. Phase I part was designed to determine the recommended phase II dose in a “3+3” cohort-based dose escalation design of BBI608 (240mg BID every day on level 1 and 480mg BID every day on level 2) with pembrolizumab (200mg/body q3w). Primary endpoint of the phase II part is Immune-related objective response rate (irORR) determined by their Response Evaluation Criteria In Solid Tumors (irRECIST). A null hypothesis and alternative hypothesis for cohort B are irORR = 5% and 20%, respectively. Required sample size for Cohort B was 40 with a one-sided alpha of 5% and power of 90%. Required sample size for Cohort A (10 patients) was determined in an exploratory manner. We also investigate biomarker study using paired samples of both tumor biopsy and blood. The enrollment to phase I part began in November 2016. Clinical trial information: NCT02851004. Clinical trial information: NCT02851004.

Scoop: Multicenter phase I/II trial of BBI608 and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 107-107 ◽  
Author(s):  
Hiroki Hara ◽  
Akihito Kawazoe ◽  
Yasutoshi Kuboki ◽  
Yoshito Komatsu ◽  
Tomohiro Nishina ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Partial Response ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Sample Size ◽  
Phase Ii ◽  
Objective Response ◽  
Alternative Hypotheses ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

107 Background: The anti–PD-1 antibody pembrolizumab (P) provides response rates of 28-57% in patients (pts) with MSI-H metastatic colorectal cancer (mCRC) vs 0% in those with non-MSI-H cancers. STAT3 has been previously reported as a potential key driver of immune evasion. This study investigates efficacy and safety for the combination of BBI608 (napabucasin), which blocks phosphorylated STAT3 and downregulates IDO1 and PD-L1, with P, in pts with mCRC. BBI608 480 mg BID with P was determined as the recommended phase II dose in phase I. Methods: Phase II included Cohorts A (MSI-H) and B (non-MSI-H). Pts with mCRC not responding to or intolerant of standard chemotherapies were enrolled. The primary endpoint was immune-related objective response rate (irORR), according to irRECIST. The sample size for Cohort A (10 pts) was derived in an exploratory manner. In Cohort B, assuming null and alternative hypotheses of irORR = 5% and 20% led to an estimated required sample size of 40 pts, with a 1-sided alpha of 5% and power of 90%. Genomic profiles and the consensus molecular subtypes (CMS) of colorectal cancer were determined by whole exome sequencing and RNA sequencing as previously described. Results: From Feb/2017 to Jun/2018, 10 pts were enrolled in Cohort A and 40 in Cohort B. The irORR was 50% (5 of 10 pts) in Cohort A and 10% (95% CI 2.8 to 23.7) (4 of 40 pts) in Cohort B. Of evaluable 19 pts for CMS classification in Cohort B, CMS1, CMS2, CMS3, and CMS4 were detected in 3, 6, 4, and 6 cases, respectively. The irORR was 33% (1 of 3 pts), 0% (0 of 6 pts), 25% (1 of 4 pts), 33% (2 of 6 pts) in CMS1, CMS2, CMS3, and CMS4, respectively. One CMS3 patient with partial response had POLE mutation, while 1 CMS1 and 2 CMS4 pts with partial response did not. The most common grade 3 or higher treatment-related adverse events included fever (10%) in Cohort A, and diarrhea (5%) and appetite loss (7.5%) in Cohort B, without unexpected safety signals. No treatment-related deaths occurred. Conclusions: BBI608 with P showed encouraging anti-tumor activity with acceptable toxicity for non-MSI-H mCRC pts as well as MSI-H mCRC pts. Impact of CMS on the efficacies of this combination warrants further investigation in the additional cohort of this study. Clinical trial information: NCT02851004.

Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3506-3506
Author(s):  
Andrea Sartore-Bianchi ◽  
Filippo Pietrantonio ◽  
Sara Lonardi ◽  
Benedetta Mussolin ◽  
Francesco Rua ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Liquid Biopsy ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Type I ◽  
Tumor Dna

3506 Background: Despite advances in molecular segmentation of metastatic colorectal cancer (mCRC), beyond RAS status therapeutic actionability remains confined to the limited subgroups of ERBB2 amplified, BRAF mutated and MSI-H patients. Optimization of available treatments is therefore warranted. Rechallenge with anti-EGFR monoclonal antibodies is often empirically used with some benefit as late-line therapy. We previously found that mutant RAS and EGFR ectodomain clones, which emerge in blood during EGFR blockade, decline upon antibody withdrawal leading to regain drug sensitivity. Based on this rationale, we designed CHRONOS, a multicenter phase II trial of anti-EGFR therapy rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in circulating tumor DNA (ctDNA). To our knowledge, this is the first interventional clinical trial of liquid biopsy for driving anti-EGFR rechallenge therapy in mCRC. Methods: Eligible patients were PS ECOG 0-2 RAS/BRAF WT mCRC having first achieved an objective response and then progression in any treatment line with an anti-EGFR antibody containing regimen, displaying RAS, BRAF and EGFR ectodomain WT status in ctDNA at molecular screening after progression to the last anti-EGFR-free regimen. Clonal evolution in ctDNA was analyzed by ddPCR and next generation sequencing. Panitumumab 6 mg/kg was administered IV every two weeks until progression. The primary endpoint was objective response rate (ORR) by RECIST version 1.1 with independent central review. 27 total patients and 6 responses were required to declare the study positive (power = 85%, type I error = 0.05). Results: Between Aug 19, 2019 and Nov 6, 2020 52 patients were screened by liquid biopsy and 36 (69%) were negative in ctDNA for RAS/BRAF/EGFR mutations. Of these, 27 patients were enrolled in 4 centers. Median age was 64 years (range: 42-80). PS ECOG was 0/50%, 1/46%, 2/4%. Previous anti-EGFR was administered in 1st line in 63%, 2nd in 15% and > 2nd in 22%. Median number of previous treatments was 3. The primary endpoint was met, with 8/27 partial responses (PR) observed (2 unconfirmed) (ORR = 30%, 95% CI: 12-47%). Stable disease (SD) was obtained in 11/27 (40%, 95% CI: 24-59%), lasting > 4 months in 8/11. Disease control rate (PR plus SD > 4 months) was therefore obtained in 16/27 (59%, 95% CI: 41-78%). Median progression-free survival was 16 weeks. Median duration of response was 17 weeks (1 ongoing). Maximal grade toxicity was G3, limited to dermatological and occurring in 19% of patients. ctDNA dynamics were studied in all patients. Conclusions: Liquid biopsy-driven rechallenge with anti-EGFR antibodies leads to further objective responses in one third of patients. Genotyping tumor DNA in the blood to direct therapy can be effectively incorporated in the management of advanced CRCs. Clinical trial information: 2016-002597-12.

Phase I/II study of oral fluoropyrimidine S-1 plus oral Leucovorin as first-line treatment for metastatic colorectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4093-4093 ◽  
Author(s):  
T. Yoshino ◽  
W. Koizumi ◽  
K. Yamaguchi ◽  
Y. Miyata ◽  
T. Kato ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Objective Response ◽  
Oral Fluoropyrimidine ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Adequate Organ Function ◽  
Grade 3

4093 Background: The results of phase I portion of the treatment with the oral S-1 (a new oral fluoropyrimidine) plus oral leucovorin (LV) in patients (pts) with untreated metastatic colorectal cancer (mCRC) was reported at ESMO 2006. Dose limiting toxicities (DLTs) were grade 3 stomatitis/pharyngitis, nausea, diarrhea, ileus and exanthema. The recommended doses (RDs) for this phase II portion were determined to be S-1 40 mg/m2 and LV 25 mg/body orally given twice daily on days 1 to 14 of a 28-day cycle. The PK profiles of S-1 plus LV were similar to those of S-1 monotherapy and UFT plus LV, respectively. The main purpose of this phase II portion is to evaluate the efficacy and safety of S-1 plus LV at RD level in pts with untreated mCRC. Methods: Pts were eligible as follows; unresectable mCRC with no prior chemotherapy or receiving adjuvant chemotherapy completed at least 6 months before, histologically proven adenocarcinoma, PS(ECOG) 0–2, age 20 to 75, measurable lesions, adequate organ function and written informed consent. The pts received 40 mg/m2 of S-1 plus 25 mg/body of LV twice daily as RD in this phase II portion. The primary endpoint was the objective response rates (RRs), and secondary endpoints were time to progression (TTP) and toxicities. Results: Between Sep 2004 and Jun 2006, 56 pts of 65 enrolled pts received the treatment at RD level. The objective RRs were 55% (36 of 65) for all pts and 55% (31 of 56) for pts at RD. Disease control rates (DCRs) were 86% (56 of 65) for all pts and 86% (48 of 56) for pts at RD. Median TTP was 5.5 months for pts at RD, with a median follow-up of 5.5 months. The median survival time is under observation. During the 6 months from starting the treatment, the most common grade 3/4 toxicities at RD were as follows: diarrhea, 23%; stomatitis, 20%; anorexia, 18%; and neutropenia 13%. Conclusions: A combination of S-1 plus oral LV is an effective, well tolerated, and convenient regimen in pts with untreated mCRC, without the addition of either oxaliplatin or irinotecan. The updated results of the objective RRs, DCRs, TTP reviewed extramurally, and detailed safety profile will be presented at the meeting. This trial was supported by Taiho pharmaceutical co., Ltd., Tokyo, Japan. No significant financial relationships to disclose.

A phase I/II study of TQ-B2450, a PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC patients failed to prior EGFR TKI therapies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21062-e21062
Author(s):  
Meiqi Shi ◽  
Li Wang ◽  
Shaorong Yu ◽  
Fei Yan ◽  
Wei Peng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Phase I ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Phase 1 ◽  
Objective Response ◽  
Platinum Based Chemotherapy ◽  
Egfr Tki ◽  
Clinical Trial Information

e21062 Background: Platinum-based chemotherapy is the standard therapy for the patients(pts) with EGFR-mutation–positive advanced NSCLC failed to prior EGFR TKI therapies. However, the IMpower150 study subgroup analyses showed Atezolizumab (PD-L1) plus bevacizumab and chemotherapy improved overall survival in EGFR TKI treated NSCLC. This ongoing phase I/II study designed to assess the benefit of the chemo-free combination of TQ-B2450, a humanized PD-L1 mAb, plus anlotinib in EGFR+ advanced NSCLC pts failed to prior EGFR TKI therapies. Methods: Pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies were eligible. Pts with previous received platinum-based chemotherapy were excluded. Anlotinib was given orally at dose of 8mg to 12mg for 2 weeks of a 21-day cycle (days 1-14), with TQ-B2450 given at 1200mg every 3 weeks on day 1. Phase I determined RP2D. In the phase II part, pts were assessed for efficacy and tolerability. The primary endpoint for the phase II part is the progression free survival (PFS). Secondary endpoints were objective response rate (ORR) disease control rate (DCR), overall survival (OS), and safety. Assuming an expected the median PFS of 9 months (5 months in chemotherapy), and a loss to follow-up of 10%, a total of 54 pts were required to have 90% power at a two-tailed alpha of 0.05 at the phase II part. Results: As of 12 Jan 2021, 22 pts were enrolled (9 in phase 1, 14 in phase 2). 18 pts were included in efficacy and safety analysis. The median age was 64.5 years with 61% male. 50% pts harbored EGFR exon19 deletion, 44% pts had exon21 L858R mutation. While 39% pts had T790M mutation who progressed after osimertinib treatment. The dose escalation cohort included 9 pts, no dose limiting toxicity occurred. 13 pts in the phase II part were administered with dose of 12 mg for anolitinib and 1200mg for TQ-B2450. Of the evaluable pts(n = 18), ORR was 11.1%, DCR was 77.8%, median PFS was 8.0 months (95% CI 4.9 to 11.1). Most frequent TRAE included hypertension (27.8%), hand and foot skin reaction (22.2%) and proteinuria (16.7%). Grade 3 TRAE occurred in 16.7% pts(3/18 pts), all were hypertension, and no Grade 4/5 TRAE were observed. Dose delay due to TRAE occurred in 22.2% patients while no one discontinued treatment due to TRAE. Conclusions: The chemo-free combination of TQ-B2450, a PD-L1 mAb, plus anlotinib has shown a promising anti-tumor efficacy with a more favorable safety profile for pts with EGFR+ advanced NSCLC who failed to prior EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (PFS, DOR and OS). Clinical trial information: ChiCTR1900026273. Clinical trial information: ChiCTR1900026273.

Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 760-760
Author(s):  
Akihito Kawazoe ◽  
Yasutoshi Kuboki ◽  
Yoshito Komatsu ◽  
Tomohiro Nishina ◽  
Eiji Shinozaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Objective Response ◽  
Paired Samples ◽  
Level 1 ◽  
Recommended Phase Ii Dose ◽  
Biomarker Research ◽  
Level 2

760 Background: The anti–programmed death 1 (PD-1) antibody, pembrolizumab provided an objective response rate (ORR) of 40% in patients (pts) with Mismatch Repair–Deficient (dMMR) or Microsatellite Instability–High (MSI-H) metastatic colorectal cancer (mCRC) vs 0% in pts with MMR-proficient/Microsatellite Stable (MSS) mCRC. The WNT/β-catenin signaling has been reported to prevent anti-tumor immunity and promote resistance of anti-PD-1/PD-L1 antibodies. This study investigates efficacy and safety of the combination of BBI608, which blocks phosphorylated STAT3 and downregulates WNT/β-catenin signaling, with pembrolizumab in pts with mCRC (both MSS and MSI-H). Here, we present the results of the phase I part. Methods: Phase I part was designed to determine the recommended phase II dose (RP2D) in a “3+3” cohort-based dose escalation design of BBI608 (240mg BID every day on level 1 and 480mg BID every day on level 2) with pembrolizumab (200mg/body q3w). We also conduct biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: Five pts were enrolled in level 1, and 3 pts in level 2. All pts were MSS mCRC. Seven pts were included in the safety analyses. Two pts in level 1 were excluded from dose-limiting toxicity (DLT) evaluation because of disease progression during DLT evaluation period. No DLTs were observed at either level. Grade 3 or worse treatment-related adverse events (TRAEs) were not observed. Grade 1 or 2 TRAEs included diarrhea related to BBI608 (57%), hyperthyroidism (14%), hypothyroidism (14%), and fever (14%) without unexpected safety signals. One patient in level 2 showed a tumor shrinkage lasting more than 12 weeks for lung and lymph node metastases with remarkable decline of CEA level. Analysis of repeated tumor samples from this case demonstrated that CD8+ T-cells infiltration inside the tumor on treatment was observed by immunohistochemistry and flow-cytometry. Conclusions: BBI608 480mg BID with pembrolizumab was tolerable and determined as RP2D. This combination showed a hint of activity and might evoke immunity in MSS mCRC, which will be confirmed by ongoing phase II part. Clinical trial information: NCT02851004..

scholarly journals A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
John H. Strickler ◽  
Christel N. Rushing ◽  
Donna Niedzwiecki ◽  
Abigail McLeod ◽  
Ivy Altomare ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Dose Escalation ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
Phase Ib ◽  
Expansion Cohort

Abstract Background Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. Methods All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Results A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. Conclusion The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. Trial registration This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

A phase I/II study for panitumumab combined with TAS-102 in patients with RAS wild-type metastatic colorectal cancer (APOLLON study): Phase I results.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 770-770 ◽  
Author(s):  
Takeshi Kato ◽  
Yoshinori Kagawa ◽  
Yoshito Komatsu ◽  
Eiji Oki ◽  
Takayuki Yoshino ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Standard Dose ◽  
Performance Status ◽  
Study Phase ◽  
Wild Type ◽  
Combination Drug ◽  
Egfr Antibody

770 Background: Both panitumumab (Pmab), the anti-EGFR antibody and TAS-102, the combination drug of trifluridine and tipiracil are approved agents for the treatment of metastatic colorectal cancer (mCRC). In preclinical models, the combination of Pmab with TAS-102 demonstrated enhanced activities compared with either drug alone. This phase I/II study is designed to investigate the safety and efficacy of Pmab combined with TAS-102 in patients (pts) with RAS ( KRAS/NRAS) wild-type mCRC refractory to standard chemotherapies. Here we reported the results of phase I part. Methods: Eligible pts are aged 20-74 y, ECOG performance status (PS) 0-1 with confirmed RAS wild-type mCRC, and refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin and anti-angiogenesis therapy, and had no prior treatment with anti-EGFR antibody, TAS-102 or regorafenib. Phase I part is designed to evaluate the incidence of dose limiting toxicities (DLTs) during the first course and to determine recommended phase II dose (RP2D) in the dose de-escalation design (3 + 3 manner) of Pmab (6 mg/kg on days 1 and 15, every 4 weeks per course) combined with TAS-102 (35 mg/m2 BID on days 1-5 and 8-12, every 4 weeks). DLTs were defined as drug-related adverse events (AEs) as follows; febrile neutropenia, G4 neutropenia > 7days, G4 thrombocytopenia, inability to start the 2nd course more than 14 days delay, and G3/4 non-hematological toxicities. Results: Seven pts (3 male, 4 female) with a median age of 68 (range 57-71) were enrolled. Pts were ECOG PS 0 (3/7) or 1 (4/7) with primary tumor located in the colon (3/7) or rectum (4/7). One pt was excluded for the DLT evaluation due to protocol deviation. No DLT was observed in the 6 DLT-evaluable pts. Most frequent drug-related AEs during the DLT evaluation period were G2/3 neutropenia, G1/2 stomatitis, G1 nausea, G1 anorexia and G1/2 rash. Three pts achieved a partial response, and 3 pts had a stable disease. Conclusions: The RP2D for Pmab combined with TAS-102 was determined as the standard dose of Pmab and TAS-102. The enrollment of phase II part is ongoing to evaluate the PFS rate at 6 months by investigator assessment as a primary endpoint with the target number of 46 pts. Clinical trial information: 02613221.

Phase II Trial of Chronomodulated Infusion of High-Dose Fluorouracil and l-Folinic Acid in Previously Untreated Patients With Metastatic Colorectal Cancer

2002 ◽  
Vol 20 (5) ◽  
pp. 1175-1181 ◽  
Author(s):  
H. Curé ◽  
V. Chevalier ◽  
A. Adenis ◽  
N. Tubiana-Mathieu ◽  
G. Niezgodzki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Folinic Acid ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Objective Response ◽  
World Health ◽  
Fixed Dose ◽  
High Dose

PURPOSE: To study tolerability and efficacy of an intensified chronomodulated schedule of fluorouracil (5-FU) and l-folinic acid (l-FA) as first-line treatment of metastatic colorectal cancer, 5-FU was given near individually determined dose-limiting toxicity in a multicenter phase II trial. PATIENTS AND METHODS: One hundred patients (68 men and 32 women, median age 62 years, World Health Organization performance status ≤ 2) with previously untreated and inoperable metastases received chronomodulated daily infusion of 5-FU/l-FA (from 10:00 pm to 10:00 am with peak at 4:00 am). 5-FU dose was escalated from 900 to 1,100 mg/m2/d with fixed dose of l-FA at 150 mg/m2/d for 4 days every 14 days. RESULTS: 5-FU dose escalation was achieved in 66% of the patients. Grade 3 to 4 toxicities mainly consisted of nausea or vomiting (14% of patients and 1.5% of courses), hand-foot syndrome (38% of patients and 8% of courses), mucositis (26% of patients and 4% of courses), and diarrhea (21% of patients and 2.3% of courses). Objective response rate (ORR) was 41% (95% confidence interval, 31.5% to 50.5%). Twenty patients underwent metastases surgery; among these, 12 had a complete resection. Median progression-free survival was 7 months. Median survival was 17 months; 28% of the patients were alive at 2 years and 18.6% at 3 years. CONCLUSION: The ORR achieved with intensified chronomodulated delivery of 5-FU/l-FA was nearly twice as high as that earlier obtained by our cooperative group using less intensive 5-FU/FA chronotherapy.

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