Actuate 1901: 9-ING-41 in Myelofibrosis

Myelofibrosis Clinical Trial

Official title:

Phase 2 Study of 9-ING-41, a Glycogen Synthase Kinase 3 Beta (GSK 3β) Inhibitor, as a Single Agent or Combined With Ruxolitinib, in Patients With Myelofibrosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04218071
• Other study ID #: 1901
• Status: Completed
• Phase: Phase 2
• Start date: August 20, 2020
• Est. completion date: January 18, 2024

Study information

• Verified date: February 2024
• Source: Actuate Therapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

9-ING-41 is a first-in-class, intravenously administered, maleimide-based, small molecule, potent selective GSK-3β inhibitor with significant pre-clinical and clinical anticancer activity. In the ongoing Actuate 1801 study in a cohort of over 90 patients with advanced refractory malignancies, 9-ING-41 has exhibited no significant toxicity, including no myelosuppression, and significant anti-tumor activity. 9-ING-41 also has significant pre-clinical ability to reverse pathologic fibrosis in multiple models of pulmonary and pleural fibrosis. Reversal of fibrosis by an anti-fibrotic agent in patients with advanced myelofibrosis (MF) has recently been demonstrated to be of clinical benefit. 9-ING-41 has the potential to act both as an anti-neoplastic agent (without causing myelosuppression) and an anti-fibrotic agent in patients with MF. The efficacy of Ruxolitinib is limited in many patients by the inability to tolerate adequate doses for an adequate duration with myelosuppression being a frequent dose limiting toxicity. 9-ING-41 may reduce the dose of Ruxolitinib needed for optimal therapeutic response and/or reverse myelosuppression so than an adequate dose of Ruxolitinib can be tolerated. Pre-clinical data show synergy in MF between 9-ING-41 and Ruxolitinib. This Phase 2 study is designed to evaluate the efficacy of 9-ING-41, as a single agent or in combination with Ruxolitinib, in patients with advanced, poor prognosis MF.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: January 18, 2024
• Est. primary completion date: October 13, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Patient -

1. 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

2. Is aged = 18 years

3. Has documented diagnosis of symptomatic primary MF, PPV-MF or PET-MF as defined by the World Health Organization classification

4. Is ineligible or unwilling to undergo stem cell transplantation at time of study entry

5. 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

6. Has adequate performance status (PS): Eastern Co-operative Oncology Group (ECOG) PS 0-2

7. 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

8. 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

9. 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

10. Male patients with partners of childbearing potential must take appropriate precautions to avoid fathering a child from screening until 100 days after discontinuation of study treatment and use appropriate barrier contraception or true abstinence

11. Must not be receiving any other investigational product

Exclusion Criteria:

Patient -

1. Is pregnant or lactating

2. Is known to be hypersensitive to any of the components of 9-ING-41 or to the excipients used in its formulation

3. Has >10% blasts in peripheral blood or bone marrow biopsy

4. Has had a myocardial infarction within 12 weeks of the first dose of 9-ING-41

5. Has any medical and/or social condition which, in the opinion of the investigator or study medical coordinator would preclude study participation

6. Is considered to be a member of a vulnerable population (for example, prisoners)

7. 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 -

Related Conditions & MeSH terms

• Myelofibrosis
• Primary Myelofibrosis

Intervention

Drug:
• Ruxolitinib
Ruxolitinib at protocol-specified doses for given platelet count
• 9-ING-41
9-

Locations

Country	Name	City	State
United States	Georgia Cancer Center	Augusta	Georgia
United States	Duke Cancer Center	Durham	North Carolina
United States	University of California Los Angeles	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	Weill Cornell Medicine | NewYork-Presbyterian Meyer Cancer Center	New York	New York
United States	Brown University	Providence	Rhode Island
United States	Mayo Clinic	Rochester	Minnesota
United States	Siteman Cancer Center	Saint Louis	Missouri
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Actuate Therapeutics Inc.

Country where clinical trial is conducted

United States, 

References & Publications (11)

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 — View Citation

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 — View Citation

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 Ch — View Citation

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/s41598-019-5 — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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: 10.101 — View Citation

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 P — View Citation

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):717-7 — View Citation

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 — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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