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

Shinozaki, Eiji; Kawazoe, Akihito; Kuboki, Yasutoshi; Nishina, Tomohiro; Hara, Hiroki; Yuki, Satoshi; Shitara, Kohei; Bando, Hideaki; Kotani, Daisuke; Takahashi, Koji; Mikamoto, Yuichi; Hasegawa, Hiromi; Hirano, Nami; Nomura, Shosaku; Togashi, Yosuke; Nishikawa, Hiroyoshi; Sato, Akihiro; Ohtsu, Atsushi; Yoshino, Takayuki

doi:10.1200/jco.2018.36.15_suppl.3530

Cited by 10 publications

(4 citation statements)

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“…As CSCs are resistant to conventional therapies [4], we hypothesize that concomitant treatment with napabucasin (targeting both tumor and CSCs) may have higher antitumor activity than napabucasin or conventional therapies alone. One study of napabucasin in combination with paclitaxel showed tolerability and signs of anti-cancer activity in breast cancer [23], and several Phase 1b/2 studies have reported complete or partial tumor responses when administering napabucasin in combination with monoclonal antibodies or chemotherapy [19,22,24]. Additionally, one study of napabucasin plus FOLFIRI (folinic acid [leucovorin], fluorouracil, and irinotecan) showed the potential of napabucasin to sensitize cancer cells to FOLFIRI in colorectal cancer [20].…”

Section: Discussionmentioning

confidence: 99%

Phase 1 study of napabucasin, a cancer stemness inhibitor, in patients with advanced solid tumors

Kawazoe

Kuboki

Bando

et al. 2020

Cancer Chemother Pharmacol

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Purpose Napabucasin is a cancer stemness inhibitor that targets a number of oncogenic pathways, including signal transducer and activator of transcription 3 (STAT3). Phase 1/2 studies suggest tolerability and anti-tumor activity in various types of cancer; a Phase 3 study of napabucasin plus standard therapy in colorectal cancer is ongoing. This is a Phase 1 dose-escalation study in patients with advanced solid tumors, and the first study of napabucasin in Japanese patients. Methods Patients received napabucasin 480, 960, or 1440 mg daily in 28-day cycles until disease progression or intolerable toxicity. Primary objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and the pharmacokinetic (PK) profile of napabucasin. Blood samples were taken for PK analysis on Days 1, 2, 8, and 15 of Cycle 1, and Days 29 and 30 of Cycle 2. Secondary objectives were to assess napabucasin antitumor activity, and the relationship between biomarkers and antitumor activity. JapicCTI-No: JapicCTI-132152. Results Enrolled were 14 patients (480 mg [n = 3], 960 mg [n = 4], 1440 mg [n = 7]). One patient experienced a DLT (Grade 3, anorexia). MTD was 1440 mg/day. Most common drug-related adverse events were diarrhea (n = 9), nausea (n = 4), vomiting (n = 3), and anorexia (n = 3). Napabucasin showed a similar PK profile to previous studies and no abnormal accumulation was observed. Following treatment, two patients had stable disease; the remaining 12 had progressive disease. Conclusion Napabucasin was well-tolerated at doses up to 1440 mg/day in Japanese patients with advanced solid tumors; the PK profile was comparable to that reported previously.

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Section: Discussionmentioning

confidence: 99%

Phase 1 study of napabucasin, a cancer stemness inhibitor, in patients with advanced solid tumors

Kawazoe

Kuboki

Bando

et al. 2020

Cancer Chemother Pharmacol

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“…113 In addition, a phase I trial of regorafenib and nivolumab showed remarkable objective response (33%, 8/24) in patients with MSS mCRC, which spurred a phase III trial in refractory settings. Other early-phase studies of combination strategies, which showed anecdotal objective responses in MSS mCRC, are also intriguing and worth following for updated results, including BBI-608, a STAT3 inhibitor, combined with pembrolizumab 114 as well as monalizumab, an anti-NKG2A (checkpoint of NK cell) antibody, with durvalumab+cetuximab. 115 ConCluSIon Even in the current era of precision medicine, there remain significant unmet needs for patients with mCRC.…”

Section: Strategies Targeting Braf-mutant Crcmentioning

confidence: 99%

Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer

Kim

2020

ESMO Open

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Over the last few decades, molecularly targeted agents have been used for the treatment of metastatic colorectal cancer. They have made remarkable contributions to prolonging the lives of patients. The emergence of several biomarkers and their introduction to the clinic have also aided in guiding such treatment. Recently, next-generation sequencing (NGS) has enabled clinicians to identify these biomarkers more easily and reliably. However, there is considerable uncertainty in interpreting and implementing the vast amount of information from NGS. The clinical relevance of biomarkers other than NGS are also subjects of debate. This review covers controversial issues and recent findings on such therapeutics and their molecular targets, including VEGF, EGFR, BRAF, HER2, RAS, actionable fusions, Wnt pathway and microsatellite instability for comprehensive understanding of obstacles on the road to precision oncology in metastatic colorectal cancer.

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“…Tumor cells with pathway activation showed poor responses to immune checkpoint inhibitors contrary to tumor cells without beta-catenin mutations [ 94 ]. The SCOOP Study, which is an ongoing phase I/II trial in metastatic colon cancer, is investigating the safety and efficacy of combining pembrolizumab with BBI608, a downregulator of WNT/β-catenin signaling; the preliminary results are promising [ 95 ].…”

Section: Mechanisms Of Resistance To Immunotherapy and Ways To Ovementioning

confidence: 99%

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

Haibe

Husseini

Sayed

et al. 2020

IJMS

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The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

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

Cited by 10 publications

References 0 publications

Phase 1 study of napabucasin, a cancer stemness inhibitor, in patients with advanced solid tumors

Phase 1 study of napabucasin, a cancer stemness inhibitor, in patients with advanced solid tumors

Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

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