Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3b Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies

Benedito A. Carneiro; Ludimila Cavalcante; Devalingam Mahalingam; Anwaar Saeed; Howard Safran; Wen Wee Ma; Andrew L. Coveler; Steven Powell; Bruno Bastos; Elizabeth Davis; Vaibhav Sahai; William Mikrut; James Longstreth; Sheri Smith; Taylor Weisskittel; Hu Li; Brittany A. Borden; R. Donald Harvey; Solmaz Sahebjam; Andres Cervantes; Austin Koukol; Andrew P. Mazar; Neeltje Steeghs; Razelle Kurzrock; Francis J. Giles; Pamela Munster

doi:10.1158/1078-0432.CCR-23-1916

Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3b Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies

Benedito A. Carneiro^*, Ludimila Cavalcante, Devalingam Mahalingam, Anwaar Saeed, Howard Safran, Wen Wee Ma, Andrew L. Coveler, Steven Powell, Bruno Bastos, Elizabeth Davis, Vaibhav Sahai, William Mikrut, James Longstreth, Sheri Smith, Taylor Weisskittel, Hu Li, Brittany A. Borden, R. Donald Harvey, Solmaz Sahebjam, Andres CervantesAustin Koukol, Andrew P. Mazar, Neeltje Steeghs, Razelle Kurzrock, Francis J. Giles, Pamela Munster

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n ¼ 67) or combination therapy (n ¼ 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/ peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n ¼ 62) and part 2 combination (n ¼ 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

Original language	English (US)
Pages (from-to)	522-531
Number of pages	10
Journal	Clinical Cancer Research
Volume	30
Issue number	3
DOIs	https://doi.org/10.1158/1078-0432.CCR-23-1916
State	Published - Feb 1 2024

Funding

grants from AbbVie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Crescendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Bio-therapeutics, Lixte, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicine, Roche, Sanofi, Seattle Genetics, Taiho, and Takeda outside the submitted work (payment to NCI). R. Kurzrock has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, TopAlliance, and the NCI. R. Kurzrock also reports consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, Eisai, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, and X-Biotech; has an equity interest in CureMatch Inc.; serves on the Board of CureMatch and CureMetrix; and is a co-founder of CureMatch. F.J. Giles reports personal fees from Actuate outside the submitted work. P. Munster reports other support from Actuate during the conduct of the study. P. Munster also reports shares and options from Olema, ONkure, Ambagon, AtlasMEDX, AlessaTherapeutics, RasCal, Parthenon, and Hap10; consulting agreements from J&J, AtlasMEDX, Alessa Therapeutics, RasCal, Parthenon, and Hap10; and institutional research support from Amgen, Arvinas, Actuate, BlissBio, Blueprint, Cyteir, Dragonfly, IGM, InventisBio, IQVia, JSI, Genentech, GSK. RevMed, Merck, Novartis, Nurix, Oric Pharmaceuticals, PMV, Relay, Roche, Scorpion, Seagen, Tempest, and Xynomics. No disclosures were reported by the other authors.

ASJC Scopus subject areas

General Medicine

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10.1158/1078-0432.CCR-23-1916

Cite this

Carneiro, B. A., Cavalcante, L., Mahalingam, D., Saeed, A., Safran, H., Ma, W. W., Coveler, A. L., Powell, S., Bastos, B., Davis, E., Sahai, V., Mikrut, W., Longstreth, J., Smith, S., Weisskittel, T., Li, H., Borden, B. A., Harvey, R. D., Sahebjam, S., ... Munster, P. (2024). Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3b Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies. Clinical Cancer Research, 30(3), 522-531. https://doi.org/10.1158/1078-0432.CCR-23-1916

@article{75b76a0f099f4ef4b2027aaf4e87fa1d,

title = "Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3b Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies",

abstract = "Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n ¼ 67) or combination therapy (n ¼ 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/ peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n ¼ 62) and part 2 combination (n ¼ 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.",

author = "Carneiro, {Benedito A.} and Ludimila Cavalcante and Devalingam Mahalingam and Anwaar Saeed and Howard Safran and Ma, {Wen Wee} and Coveler, {Andrew L.} and Steven Powell and Bruno Bastos and Elizabeth Davis and Vaibhav Sahai and William Mikrut and James Longstreth and Sheri Smith and Taylor Weisskittel and Hu Li and Borden, {Brittany A.} and Harvey, {R. Donald} and Solmaz Sahebjam and Andres Cervantes and Austin Koukol and Mazar, {Andrew P.} and Neeltje Steeghs and Razelle Kurzrock and Giles, {Francis J.} and Pamela Munster",

note = "Publisher Copyright: {\textcopyright}2023 American Association for Cancer Research.",

year = "2024",

month = feb,

day = "1",

doi = "10.1158/1078-0432.CCR-23-1916",

language = "English (US)",

volume = "30",

pages = "522--531",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "3",

}

Carneiro, BA, Cavalcante, L, Mahalingam, D, Saeed, A, Safran, H, Ma, WW, Coveler, AL, Powell, S, Bastos, B, Davis, E, Sahai, V, Mikrut, W, Longstreth, J, Smith, S, Weisskittel, T, Li, H, Borden, BA, Harvey, RD, Sahebjam, S, Cervantes, A, Koukol, A, Mazar, AP, Steeghs, N, Kurzrock, R, Giles, FJ & Munster, P 2024, 'Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3b Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies', Clinical Cancer Research, vol. 30, no. 3, pp. 522-531. https://doi.org/10.1158/1078-0432.CCR-23-1916

Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3b Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies. / Carneiro, Benedito A.; Cavalcante, Ludimila; Mahalingam, Devalingam et al.
In: Clinical Cancer Research, Vol. 30, No. 3, 01.02.2024, p. 522-531.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3b Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies

AU - Carneiro, Benedito A.

AU - Cavalcante, Ludimila

AU - Mahalingam, Devalingam

AU - Saeed, Anwaar

AU - Safran, Howard

AU - Ma, Wen Wee

AU - Coveler, Andrew L.

AU - Powell, Steven

AU - Bastos, Bruno

AU - Davis, Elizabeth

AU - Sahai, Vaibhav

AU - Mikrut, William

AU - Longstreth, James

AU - Smith, Sheri

AU - Weisskittel, Taylor

AU - Li, Hu

AU - Borden, Brittany A.

AU - Harvey, R. Donald

AU - Sahebjam, Solmaz

AU - Cervantes, Andres

AU - Koukol, Austin

AU - Mazar, Andrew P.

AU - Steeghs, Neeltje

AU - Kurzrock, Razelle

AU - Giles, Francis J.

AU - Munster, Pamela

PY - 2024/2/1

Y1 - 2024/2/1

N2 - Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n ¼ 67) or combination therapy (n ¼ 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/ peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n ¼ 62) and part 2 combination (n ¼ 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

AB - Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n ¼ 67) or combination therapy (n ¼ 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/ peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n ¼ 62) and part 2 combination (n ¼ 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

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DO - 10.1158/1078-0432.CCR-23-1916

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AN - SCOPUS:85184146802

SN - 1078-0432

VL - 30

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EP - 531

JO - Clinical Cancer Research

JF - Clinical Cancer Research

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ER -

Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3b Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies

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