Actuate 1901: 9-ING-41 in Myelofibrosis

Sponsor

Actuate Therapeutics Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04218071

Collaborator

(none)

Enrollment

Locations

Arms

30.3

Anticipated Duration (Months)

6.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis	Drug: Ruxolitinib Drug: 9-ING-41	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

58 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients will receive either single agent 9-ING-41 or 9-ING-41 plus RuxolitinibPatients will receive either single agent 9-ING-41 or 9-ING-41 plus Ruxolitinib

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Aug 20, 2020

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: 9-ING-41 9- Other Names: 9-ING-41 Compound
Experimental: 9-ING-41 plus 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.	Drug: Ruxolitinib Ruxolitinib at protocol-specified doses for given platelet count Other Names: Jakafi Drug: 9-ING-41 9- Other Names: 9-ING-41 Compound

Arm

Intervention/Treatment

Experimental: 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.

Drug: 9-ING-41

Other Names:

9-ING-41 Compound

Experimental: 9-ING-41 plus 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.

Drug: Ruxolitinib

Ruxolitinib at protocol-specified doses for given platelet count

Other Names:

Jakafi

Drug: 9-ING-41

Other Names:

9-ING-41 Compound

Outcome Measures

Primary Outcome Measures

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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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
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
Must not be receiving any other investigational product

Exclusion Criteria:

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 -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern California	Los Angeles	California	United States	90033
2	University of California Los Angeles	Los Angeles	California	United States	90095
3	Georgia Cancer Center	Augusta	Georgia	United States	30912
4	Mayo Clinic	Rochester	Minnesota	United States	55905
5	Siteman Cancer Center	Saint Louis	Missouri	United States	63100
6	Weill Cornell Medicine \| NewYork-Presbyterian Meyer Cancer Center	New York	New York	United States	10065
7	Duke Cancer Center	Durham	North Carolina	United States	27710
8	Brown University	Providence	Rhode Island	United States	02912
9	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109