Actuate 1901: 9-ING-41 in Myelofibrosis

Phase 2

Completed

• Conditions: Myelofibrosis
• Interventions: Drug: 9-ING-41; Drug: Ruxolitinib

• Registration Number: NCT04218071
• Lead Sponsor: Actuate Therapeutics Inc.

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.

Detailed 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.

Study Timeline

• Study First Submitted: 2020-01-02
• Study First Submitted QC: 2020-01-03
• Study First Posted: 2020-01-06
• Study Start: 2020-08-20
• Primary Completion: 2022-10-13
• Study Completion: 2024-01-18
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-05
• Last Update Posted: 2024-02-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 17

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 -

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Response rate	3-24 months	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)

Trial Locations

Locations (9)

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

University of California Los Angeles; 🇺🇸 Los Angeles, California, United States

Georgia Cancer Center; 🇺🇸 Augusta, Georgia, United States

University of Southern California; 🇺🇸 Los Angeles, California, United States

Siteman Cancer Center; 🇺🇸 Saint Louis, Missouri, United States

Weill Cornell Medicine | NewYork-Presbyterian Meyer Cancer Center; 🇺🇸 New York, New York, United States

Duke Cancer Center; 🇺🇸 Durham, North Carolina, United States

Brown University; 🇺🇸 Providence, Rhode Island, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States