A Phase I Study of Napabucasin Plus Paclitaxel for Japanese Patients With Advanced/Recurrent Gastric Cancer

Shitara, Kohei; Yodo, Yasuhide; Iino, Shuichi

doi:10.21873/invivo.11561

Cited by 15 publications

(18 citation statements)

References 18 publications

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“…In one of these patients, even after paclitaxel was discontinued at cycle 7, partial response was maintained until cycle 21 with napabucasin treatment alone. Collectively, this study demonstrates that drug combinations with napabucasin are a viable treatment approach with potential survival benefits and hence a Phase III trial is ongoing for this combination in gastric and gastroesophageal junction cancers (NCT02178956) [98]. In preclinical studies of HCC, napabucasin promoted apoptosis in vitro and suppressed tumor growth in orthotopic mouse models [104].…”

Section: Targeting Stat3mentioning

confidence: 91%

“…Napabucasin is a STAT3 inhibitor that has been found to have preliminary clinical efficacy. In a clinical trial of napabucasin combined with paclitaxel (JapicCTI-142420), the two drugs were shown to be well tolerated in Japanese patients with gastric cancer [98]. Common adverse effects reported were generally mild and gastrointestinal, but concurrent administration with loperamide was able to control these negative effects.…”

Section: Targeting Stat3mentioning

confidence: 99%

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JAK/STAT signaling in hepatocellular carcinoma

et al. 2020

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Liver cancer is the second most lethal cancer in the world with limited treatment options. Hepatocellular carcinoma (HCC), which accounts for more than 80% of all liver cancers, has had increasing global incidence over the past few years. There is an urgent need for novel and better therapeutic intervention for HCC patients. The JAK/STAT signaling pathway plays a multitude of important biological functions in both normal and malignant cells. In a subset of HCC, JAK/STAT signaling is aberrantly activated, leading to dysregulation of downstream target genes that controls survival, angiogenesis, stemness, immune surveillance, invasion and metastasis. In this review, we will focus on the role of JAK/STAT signaling in HCC and discuss the current clinical status of several JAK/STAT inhibitors.

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Section: Targeting Stat3mentioning

confidence: 91%

Section: Targeting Stat3mentioning

confidence: 99%

JAK/STAT signaling in hepatocellular carcinoma

et al. 2020

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“…The small molecule napabucasin (BBI608) was identified as a STAT3 inhibitor that targets cancer stem cells 35 . Combination treatment with napabucasin and conventional chemotherapy is under evaluation in clinical trials, particularly for advanced cancer patients 42 (Table 2).…”

Section: Clinical Evaluation Of Small Molecule Inhibitors Targeting Dmentioning

confidence: 99%

Targeting DNA binding proteins for cancer therapy

et al. 2020

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Yoshitomo Shiroma and Ryou-u Takahashi contributed equally to this work.Abbreviations: AEP, AF4 family/ENL family/P-TEFb; ARNT, aryl hydrocarbon receptor nuclear translocator; BRD4, bromodomain-containing protein 4; CBP, CREB-binding protein; DUX4, double homeobox protein 4; ETO, eight-twenty one; EWS, Ewing's sarcoma; FLI1, friend leukemia virus integration 1; HIF, hypoxia-inducible factor; MLL, mixed-lineage leukemia; SOX2, Sry-related high-mobility box 2; STAT3, signal transducer and activator of transcription 3; TF, transcription factor; TRF, telomere-repeat binding factor. AbstractDysregulation or mutation of DNA binding proteins such as transcription factors (TFs) is associated with the onset and progression of various types of disease, including cancer. Alteration of TF activity occurs in numerous cancer tissues due to gene amplification, deletion, and point mutations, and epigenetic modification. Although cancer-associated TFs are promising targets for cancer therapy, development of drugs targeting these TFs has historically been difficult due to the lack of high-throughput screening methods. Recent advances in technology for identification and selective inhibition of DNA binding proteins enable cancer researchers to develop novel therapeutics targeting cancer-associated TFs. In the present review, we summarize known cancer-associated TFs according to cancer type and introduce recently developed high-throughput approaches to identify selective inhibitors of cancer-associated TFs. K E Y W O R D SDNA binding protein, drug discovery, high-throughput screening, telomere, transcription factor | 1059 SHIROMA et Al.

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“…Napabucasin exerts its antitumor activity by increasing levels of ROS beyond a cytotoxic threshold, causing cancer cell death 1–3 . Treatment of several cancers with napabucasin alone or in combination with other cancer therapies has been assessed in a number of ongoing clinical trials (congress abstracts, 4–16 and completed clinical trials 17,18 ). An ongoing phase 3 study is assessing napabucasin in combination with 5‐fluorouracil, leucovorin, and irinotecan (i.e., FOLFIRI) in patients with previously treated metastatic colorectal cancer (Clinicaltrials.gov identifier: NCT02753127) 19 …”

Section: Introductionmentioning

confidence: 99%

Mass balance and pharmacokinetics of an oral dose of ¹⁴C‐napabucasin in healthy adult male subjects

Dai

Karol

Hitron

et al. 2021

Pharmacology Res & Perspec

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This phase 1, open‐label study assessed 14 C‐napabucasin absorption, metabolism, and excretion, napabucasin pharmacokinetics, and napabucasin metabolites (primary objectives); safety/tolerability were also evaluated. Eight healthy males (18–45 years) received a single oral 240‐mg napabucasin dose containing ~100 μCi 14 C‐napabucasin. Napabucasin was absorbed and metabolized to dihydro‐napabucasin (M1; an active metabolite [12.57‐fold less activity than napabucasin]), the sole major circulating metabolite (median time to peak concentration: 2.75 and 2.25 h, respectively). M1 plasma concentration versus time profiles generally mirrored napabucasin; similar arithmetic mean half‐lives (7.14 and 7.92 h, respectively) suggest M1 formation was rate limiting. Napabucasin systemic exposure (per C max and AUC) was higher than M1. The total radioactivity (TRA) whole blood:plasma ratio (AUC last : 0.376; C max : 0.525) indicated circulating drug‐related compounds were essentially confined to plasma. Mean TRA recovery was 81.1% (feces, 57.2%; urine, 23.8%; expired air, negligible). Unlabeled napabucasin and M1 recovered in urine accounted for 13.9% and 11.0% of the dose (sum similar to urine TRA recovered); apparent renal clearance was 8.24 and 7.98 L/h. No uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites, suggesting napabucasin was mainly cleared by reductive metabolism. All subjects experienced mild treatment‐emergent adverse events (TEAEs), the majority related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Napabucasin was absorbed, metabolized to M1 as the sole major circulating metabolite, and primarily excreted via feces. A single oral 240‐mg dose was generally well tolerated.

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A Phase I Study of Napabucasin Plus Paclitaxel for Japanese Patients With Advanced/Recurrent Gastric Cancer

Cited by 15 publications

References 18 publications

JAK/STAT signaling in hepatocellular carcinoma

JAK/STAT signaling in hepatocellular carcinoma

Targeting DNA binding proteins for cancer therapy

Mass balance and pharmacokinetics of an oral dose of ¹⁴C‐napabucasin in healthy adult male subjects

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A Phase I Study of Napabucasin Plus Paclitaxel for Japanese Patients With Advanced/Recurrent Gastric Cancer

Cited by 15 publications

References 18 publications

JAK/STAT signaling in hepatocellular carcinoma

JAK/STAT signaling in hepatocellular carcinoma

Targeting DNA binding proteins for cancer therapy

Mass balance and pharmacokinetics of an oral dose of 14C‐napabucasin in healthy adult male subjects

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Product

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Mass balance and pharmacokinetics of an oral dose of ¹⁴C‐napabucasin in healthy adult male subjects