Phase 1/2 Study of Elraglusib (9-ING-41) as Monotherapy and in Combination with Chemotherapy in Refractory Hematologic Malignancies or Solid Tumors

The primary objective of this study is to determine the 1-year **survival rate** of patients treated with the 9-ING-41 schedule, selected from the run-in stage of the study, compared to the control arm. This objective is clinically relevant as it aims to assess the efficacy of 9-ING-41, a **Glycogen Synthase Kinase-3 Beta (GSK-3β) inhibitor**, in improving survival outcomes in patients with refractory hematologic malignancies or solid tumors.

Secondary objectives include:

• To determine the rate of disease control of the combination of 9-ING-41 and gemcitabine/nab-paclitaxel (GA) in patients with pancreatic cancer without prior systemic therapy for advanced disease.
• To correlate disease control rate with tumor molecular profiles.

The clinical trial involves a total of **287 participants** diagnosed with **refractory hematologic malignancies or solid tumors**. The study population includes both male and female subjects, aged 18 years and older, who are considered part of a vulnerable population. Participants were selected based on their ability to understand and sign informed consent, and their willingness to comply with protocol requirements. Key lifestyle considerations include the requirement for women of childbearing potential to have a negative pregnancy test and use highly effective contraceptive methods during and after the study. Male participants with partners of childbearing potential must also use appropriate contraception. Participants must not be receiving any other investigational medicinal product and should have adequate bone marrow, liver, and renal function. The trial specifically targets individuals with pathologically or cytologically confirmed metastatic pancreatic cancer who have not been previously treated with systemic agents in the recurrence/metastatic setting and are candidates for gemcitabine/nab-paclitaxel as a first-line treatment. The study ensures that participants have at least one measurable lesion per RECIST v1.1 and an Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1.

The clinical trial is designed to evaluate the efficacy and safety of **elraglusib** (9-ING-41) in patients with refractory hematologic malignancies or solid tumors. This is a Phase 1/2, randomized, double-blind, controlled study. The primary objective is to determine the 1-year survival rate of patients treated with the 9-ING-41 schedule selected from the run-in stage compared to a control arm. Secondary endpoints include disease control rate, objective response rate, duration of response, progression-free survival, overall survival, time to treatment failure, and monitoring of adverse events using the Common Terminology Criteria for Adverse Events (CTCAE), v5.0.

The trial is expected to run until December 31, 2025, with recruitment having commenced on July 6, 2020. Participants will be involved in the study for the duration of their treatment and follow-up, which may vary depending on individual response and progression. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. Participants must meet specific inclusion criteria, such as being 18 years or older, having confirmed metastatic pancreatic cancer, and not receiving any other investigational medicinal product. Conditions for early termination from the study include non-compliance with protocol requirements or adverse events that necessitate withdrawal.

Participants will receive the investigational product via **intravenous administration**. The study will ensure that all participants provide informed consent and comply with protocol requirements, including scheduled visits, treatment plans, and laboratory tests. Women of childbearing potential must have a negative pregnancy test before starting the study and agree to use effective contraception during and after the study. Male participants with partners of childbearing potential must also use appropriate contraception. The trial aims to provide valuable data on the potential benefits of 9-ING-41 in treating refractory hematologic malignancies or solid tumors, contributing to the advancement of therapeutic options for these conditions.

The clinical trial involves the administration of **9-ING-41**, an investigational medication developed by Actuate Therapeutics Inc. The active substance in 9-ING-41 is **elraglusib**, a chemical compound that functions as a Glycogen Synthase Kinase-3 Beta (GSK-3β) inhibitor. The pharmaceutical form of 9-ING-41 is an **injection**, and it is administered via **intravenous administration**. The specific dosage, frequency of administration, and dosing schedule are determined based on the protocol established during the run-in stage of the study. The trial aims to evaluate the efficacy of 9-ING-41 as a single agent and in combination with chemotherapy in patients with refractory hematologic malignancies or solid tumors.

In addition to the experimental treatment, the study may include standard-of-care therapies or comparator treatments as deemed necessary by the study protocol. These non-experimental treatments serve as control measures to assess the relative effectiveness of 9-ING-41. The trial does not utilize a placebo, as the focus is on comparing the investigational drug with existing therapeutic options. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the treatment protocol and to accurately assess the outcomes related to the investigational medication.

Efficacy in the clinical trial titled "Actuate 1801: Phase 1/2 Study of 9-ING-41, a Glycogen Synthase Kinase-3 Beta (GSK-3β) Inhibitor, as a Single Agent and Combined with Chemotherapy, in Patients with Refractory Hematologic Malignancies or Solid Tumors" will be assessed using several primary and secondary endpoints. The primary endpoint is the 1-year survival rate of patients treated on the 9-ING-41 schedule chosen from the run-in portion of the study compared to the control arm.

Secondary endpoints include the Disease Control Rate (DCR), defined as stable disease for ≥16 weeks, confirmed complete response, or confirmed partial response. The Objective Response Rate (ORR) will be evaluated as the percentage of patients with Complete Response (CR) or Partial Response (PR) according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) criteria relative to the efficacy population. Additional secondary endpoints include Duration of Response (DOR), defined as the time from documentation of tumor response to disease progression, and Progression-Free Survival (PFS), defined as the time from study enrollment until objective tumor progression or death. Overall Survival (OS) will be measured as the time from study entry to death from any cause, and Time to Treatment Failure (TTF) will also be assessed.

Adverse events will be monitored from the date of first administration of 9-ING-41 and ending 30 days after the final administration using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Additionally, the correlation of disease control rate with tumor molecular profiles will be explored. These efficacy parameters will be collected and analyzed at specified intervals throughout the study to determine the therapeutic impact of 9-ING-41 in the target patient population.