Actuate 1901: 9-ING-41 in Myelofibrosis

NCT04218071 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: 1901
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 9

Brief Summary

9-ING-41 has anti-cancer clinical activity while not causing myelosuppression, and has both pre-clinical anti-fibrotic activity and activity against myelofibrosis. This Phase 2 study will study its efficacy in patients with advanced myelofibrosis.

Conditions

Myelofibrosis

Keywords

primary myelofibrosis; post polycythemia vera myelofibrosis; post essential thrombocythemia myelofibrosis; Ruxolitinib; Jak2 inhibitors; glycogen synthase kinase 3 beta; GSK3beta; 9-ING-41

Outcome Measures

Primary Outcomes (1)

• Response rate

  The percent of patients with response will be assessed at the protocol specified timepoints according to the Revised IWG-MRT and ELN Response Criteria for MF (2013)

  3-24 months

Study Arms (2)

9-ING-41

EXPERIMENTAL

9-ING-41 is administered by intravenous infusion twice weekly at a dose of 9.3 mg/kg. Cycle duration is 28 days.

Drug: 9-ING-41

9-ING-41 plus Ruxolitinib

EXPERIMENTAL

9-ING-41 9.3 mg/kg will be administered by intravenous infusion twice weekly for cycle durations of 28 days with Ruxolitinib at doses specified in the protocol as appropriate for patient's platelet count.

Drug: Ruxolitinib; Drug: 9-ING-41

Interventions

Ruxolitinib DRUG

Ruxolitinib at protocol-specified doses for given platelet count

Also known as: Jakafi

9-ING-41 plus Ruxolitinib

9-ING-41 DRUG

9-

Also known as: 9-ING-41 Compound

9-ING-41; 9-ING-41 plus Ruxolitinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient -
• Is able to understand and voluntarily sign a written informed consent and is willing and able to comply with the protocol requirements including scheduled visits, treatment plan, laboratory tests and other study procedures
• Is aged ≥ 18 years
• Has documented diagnosis of symptomatic primary MF, PPV-MF or PET-MF as defined by the World Health Organization classification
• Is ineligible or unwilling to undergo stem cell transplantation at time of study entry
• Has laboratory function within specified parameters per local laboratory (may be repeated):
• Absolute neutrophil count (ANC) ≥ 100/mL; platelets ≥ 20,000/mL
• Transaminases (AST/ALT) and alkaline phosphatase ≤ 3 (≤ 10 X the upper limit of normal (ULN) if considered to be MF-related) x ULN; bilirubin ≤ 1.5 x ULN (unless patient has Gilbert's Syndrome)
• Serum amylase and lipase ≤ 1.5 x ULN
• Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2
• Has received the final dose of any of the following treatments/procedures with the specified minimum intervals before first dose of 9-ING-41 (unless in the opinion of the investigator and the study medical coordinator the treatments/procedures will not compromise patient safety or interfere with study conduct:
• Chemotherapy, immunotherapy, or systemic radiation therapy - 14 days maximum, or ≥ 5 half-lives (whichever is shorter)
• Surgery with general anesthesia - 7 days
• Patients who are to receive 9-ING-41 plus Ruxolitinib must have attempted ≥12 weeks of Ruxolitinib therapy and required dose reductions/interruptions and/or had an inadequate response
• Women of childbearing potential must have a negative baseline blood or urine pregnancy test within 72 hours of first study therapy. Women may be neither breastfeeding nor intending to become pregnant during study participation and must agree to use effective contraceptive methods (hormonal or barrier method of birth control, or true abstinence) for the duration of study participation and in the following 100 days after discontinuation of study treatment

You may not qualify if:

• Patient -
• Is pregnant or lactating
• Is known to be hypersensitive to any of the components of 9-ING-41 or to the excipients used in its formulation
• Has \>10% blasts in peripheral blood or bone marrow biopsy
• Has had a myocardial infarction within 12 weeks of the first dose of 9-ING-41
• Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation
• Is considered to be a member of a vulnerable population (for example, prisoners)
• Herbal preparations / medications are prohibited throughout the study. These herbal medications include, but are not limited to St. John's wort, Kava, ephedra (ma huang), Gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and Ginseng. Patients should stop using cannabinoids or herbal preparations/medications at least 7 days prior to first dose of study treatment -

Sponsors & Collaborators

• Actuate Therapeutics Inc.: lead

Study Sites (9)

University of Southern California

Los Angeles, California, 90033, United States

Location

University of California Los Angeles

Los Angeles, California, 90095, United States

Location

Georgia Cancer Center

Augusta, Georgia, 30912, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Siteman Cancer Center

St Louis, Missouri, 63100, United States

Location

Weill Cornell Medicine | NewYork-Presbyterian Meyer Cancer Center

New York, New York, 10065, United States

Location

Duke Cancer Center

Durham, North Carolina, 27710, United States

Location

Brown University

Providence, Rhode Island, 02912, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

Related Publications (11)

• Jeffers A, Qin W, Owens S, Koenig KB, Komatsu S, Giles FJ, Schmitt DM, Idell S, Tucker TA. Glycogen Synthase Kinase-3beta Inhibition with 9-ING-41 Attenuates the Progression of Pulmonary Fibrosis. Sci Rep. 2019 Dec 12;9(1):18925. doi: 10.1038/s41598-019-55176-w.

  PMID: 31831767 RESULT

• Kuroki H, Anraku T, Kazama A, Bilim V, Tasaki M, Schmitt D, Mazar AP, Giles FJ, Ugolkov A, Tomita Y. 9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer. Sci Rep. 2019 Dec 27;9(1):19977. doi: 10.1038/s41598-019-56461-4.

  PMID: 31882719 RESULT

• Ding L, Madamsetty VS, Kiers S, Alekhina O, Ugolkov A, Dube J, Zhang Y, Zhang JS, Wang E, Dutta SK, Schmitt DM, Giles FJ, Kozikowski AP, Mazar AP, Mukhopadhyay D, Billadeau DD. Glycogen Synthase Kinase-3 Inhibition Sensitizes Pancreatic Cancer Cells to Chemotherapy by Abrogating the TopBP1/ATR-Mediated DNA Damage Response. Clin Cancer Res. 2019 Nov 1;25(21):6452-6462. doi: 10.1158/1078-0432.CCR-19-0799. Epub 2019 Sep 18.

  PMID: 31533931 RESULT

• Wu X, Stenson M, Abeykoon J, Nowakowski K, Zhang L, Lawson J, Wellik L, Li Y, Krull J, Wenzl K, Novak AJ, Ansell SM, Bishop GA, Billadeau DD, Peng KW, Giles F, Schmitt DM, Witzig TE. Targeting glycogen synthase kinase 3 for therapeutic benefit in lymphoma. Blood. 2019 Jul 25;134(4):363-373. doi: 10.1182/blood.2018874560. Epub 2019 May 17.

  PMID: 31101621 RESULT

• Ugolkov AV, Bondarenko GI, Dubrovskyi O, Berbegall AP, Navarro S, Noguera R, O'Halloran TV, Hendrix MJ, Giles FJ, Mazar AP. 9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma. Anticancer Drugs. 2018 Sep;29(8):717-724. doi: 10.1097/CAD.0000000000000652.

  PMID: 29846250 RESULT

• Karmali R, Chukkapalli V, Gordon LI, Borgia JA, Ugolkov A, Mazar AP, Giles FJ. GSK-3beta inhibitor, 9-ING-41, reduces cell viability and halts proliferation of B-cell lymphoma cell lines as a single agent and in combination with novel agents. Oncotarget. 2017 Nov 11;8(70):114924-114934. doi: 10.18632/oncotarget.22414. eCollection 2017 Dec 29.

  PMID: 29383130 RESULT

• Ugolkov A, Qiang W, Bondarenko G, Procissi D, Gaisina I, James CD, Chandler J, Kozikowski A, Gunosewoyo H, O'Halloran T, Raizer J, Mazar AP. Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models. Transl Oncol. 2017 Aug;10(4):669-678. doi: 10.1016/j.tranon.2017.06.003. Epub 2017 Jun 30.

  PMID: 28672195 RESULT

• Ugolkov A, Gaisina I, Zhang JS, Billadeau DD, White K, Kozikowski A, Jain S, Cristofanilli M, Giles F, O'Halloran T, Cryns VL, Mazar AP. GSK-3 inhibition overcomes chemoresistance in human breast cancer. Cancer Lett. 2016 Oct 1;380(2):384-392. doi: 10.1016/j.canlet.2016.07.006. Epub 2016 Jul 14.

  PMID: 27424289 RESULT

• Pal K, Cao Y, Gaisina IN, Bhattacharya S, Dutta SK, Wang E, Gunosewoyo H, Kozikowski AP, Billadeau DD, Mukhopadhyay D. Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer. Mol Cancer Ther. 2014 Feb;13(2):285-96. doi: 10.1158/1535-7163.MCT-13-0681. Epub 2013 Dec 10.

  PMID: 24327518 RESULT

• Boren J, Shryock G, Fergis A, Jeffers A, Owens S, Qin W, Koenig KB, Tsukasaki Y, Komatsu S, Ikebe M, Idell S, Tucker TA. Inhibition of Glycogen Synthase Kinase 3beta Blocks Mesomesenchymal Transition and Attenuates Streptococcus pneumonia-Mediated Pleural Injury in Mice. Am J Pathol. 2017 Nov;187(11):2461-2472. doi: 10.1016/j.ajpath.2017.07.007.

  PMID: 29073967 RESULT

• Anraku T, Kuroki H, Kazama A, Bilim V, Tasaki M, Schmitt D, Mazar A, Giles FJ, Ugolkov A, Tomita Y. Clinically relevant GSK-3beta inhibitor 9-ING-41 is active as a single agent and in combination with other antitumor therapies in human renal cancer. Int J Mol Med. 2020 Feb;45(2):315-323. doi: 10.3892/ijmm.2019.4427. Epub 2019 Dec 12.

  PMID: 31894292 RESULT

MeSH Terms

Conditions

Primary Myelofibrosis; Hereditary Sensory and Autonomic Neuropathies

Interventions

ruxolitinib; 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-(1,3)dioxolo(4,5-f)indol-7-yl)-pyrrole-2,5-dione

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Patients will receive either single agent 9-ING-41 or 9-ING-41 plus Ruxolitinib

Study Record Dates

• First Submitted: January 2, 2020
• First Posted: January 6, 2020
• Study Start: August 20, 2020
• Primary Completion: October 13, 2022
• Study Completion: January 18, 2024
• Last Updated: February 7, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)