Multicenter, randomized, double‐blind phase 2 trial of <scp>FOLFIRI</scp> with regorafenib or placebo as second‐line therapy for metastatic colorectal cancer

Sanoff, Hanna K.; Goldberg, Richard M.; Ivanova, Anastasia; O’Reilly, Seamus; Kasbari, Samer S.; Kim, Richard D.; McDermott, Ray; Moore, Dominic T.; Zamboni, William C.; Grogan, William; Cohn, Allen Lee; Bekaii‐Saab, Tanios; Leonard, Gregory D.; Ryan, Theresa; Olowokure, Olugbenga; Fernando, N.; McCaffrey, John; El‐Rayes, Bassel F.; Horgan, Anne M.; Sherrill, Gary B.; Yacoub, George; O’Neil, Bert H.

doi:10.1002/cncr.31552

Cited by 24 publications

(27 citation statements)

References 15 publications

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“…Another study reported that the addition of regorafenib to FOLFIRI as second-line therapy for mCRC only modestly prolonged PFS when compared with FOLFIRI alone. [24] Some preclinical studies showed that apatinib significantly enhanced the cytotoxicity of substrate drugs and increased the intracellular accumulation of chemotherapy drugs by reversing multidrug resistance. [25,26] Further studies were warranted.…”

Section: Discussionmentioning

confidence: 99%

Apatinib as an optional treatment in metastatic colorectal cancer

Li¹,

Wang²,

Xu³

et al. 2019

Medicine

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Antiangiogenic therapy has shown clinical benefit in metastatic colorectal cancer (mCRC). We aimed to evaluate the efficacy and safety of apatinib in patients who failed standard treatment and to explore potential factors related to its efficacy.A total of 47 patients were enrolled in this retrospective study. Patients who received apatinib therapy after failure of standard therapy from December 2014 and February 2018 were included. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events were recorded and evaluated.The median PFS was 3.717 months (95% confidence interval [CI], 3.198–4.235), and the median OS was 7.335 months (95% CI, 6.738–7.932). The disease control rate was 72.34%, and the ORR was 8.51%. The most common grade 3 to 4 adverse reactions were hypertension, proteinuria, hand-foot syndrome, and diarrhea. Multivariate analysis indicated previous antiangiogenic therapy and baseline elevated neutrophil-to-lymphocyte ratio (NLR) as independent prognostic factors.Apatinib might be a reasonable treatment option with a controlled safety profile for patients with mCRC who have failed standard therapy. Patients who previously received antiangiogenic therapy and who have baseline elevated NLR are more likely to benefit from apatinib.

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Section: Discussionmentioning

confidence: 99%

Apatinib as an optional treatment in metastatic colorectal cancer

Li¹,

Wang²,

Xu³

et al. 2019

Medicine

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“…On the other hand, non-receptor kinases are cytosolic proteins that phosphorylate downstream effector proteins [ 96 ]. Combinations of irinotecan with tyrosine kinase inhibitors—apatinib [ 97 ], dasatinib [ 98 ], lapatinib [ 99 ], pazopanib [ 100 ], regorafenib [ 101 ] and sunitinib [ 102 ]—have been recently tested with different efficacies and endpoints.…”

Section: Irinotecan Anitcancer–drug Combinationsmentioning

confidence: 99%

Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

Kciuk

Marciniak

Kontek

2020

IJMS

144

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Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan’s molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells’ resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.

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“…It is also worth noting that a clinical benefit favoring regorafenib over placebo was identified across RAS status [11,12]. As preliminary studies have reported the safety and the efficacy of combining FOLFOX or FOLFIRI with regorafenib in mCRC [13,14], it seems to us that it could be Table 1 Inclusion criteria -Have histological or cytological documentation of adenocarcinoma of the colon or rectum.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, there is no fully accepted biomarker able to predict regorafenib benefit. Two phase II trials also studied the safety and efficacy profile of regorafenib when combined to chemotherapy in patients with mCRC [ 13 , 14 ]. The study from Schultheis et al [ 13 ] was designed to explore whether the addition of regorafenib to FOLFOX or FOLFIRI could be feasible as first- or second-line treatment of mCRC.…”

Section: Introductionmentioning

confidence: 99%

FOLFIRINOX-R study design: a phase I/II trial of FOLFIRINOX plus regorafenib as first line therapy in patients with unresectable RAS-mutated metastatic colorectal cancer

et al. 2021

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Background The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX – a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer. Methods FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1–2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, β = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150–180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle. Discussion FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer. Trial registration EudraCT: 2018-003541-42; ClinicalTrials.gov: NCT03828799.

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Multicenter, randomized, double‐blind phase 2 trial of FOLFIRI with regorafenib or placebo as second‐line therapy for metastatic colorectal cancer

Abstract: The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society.

Cited by 24 publications

References 15 publications

Apatinib as an optional treatment in metastatic colorectal cancer

Apatinib as an optional treatment in metastatic colorectal cancer

Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

FOLFIRINOX-R study design: a phase I/II trial of FOLFIRINOX plus regorafenib as first line therapy in patients with unresectable RAS-mutated metastatic colorectal cancer

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