FDA Grants Elraglusib Orphan Drug Designation in Soft Tissue Sarcoma

• The FDA has granted orphan drug designation (ODD) to elraglusib for the treatment of patients with soft tissue sarcoma (STS).
• Elraglusib is a novel GSK-3β inhibitor.
• A phase 2 trial (NCT04906876) is currently evaluating elraglusib when given in combination with gemcitabine and docetaxel.

An ODD was granted by the FDA to elraglusib for the treatment of patients with STS.¹

Currently, a phase 2, open-label, 2-strata trial is evaluating the combination of elraglusib with gemcitabine and docetaxel in patients aged 10 years or older with unresectable or metastatic soft tissue or bone sarcomas.²

In this study, investigators are evaluating the primary end point of disease control rate and secondary end point of progression-free survival (PFS).

“We are pleased to receive the ODD from the FDA, which underscores elraglusib’s potential to address the significant yet unmet medical needs for patients with advanced cancers,” said Daniel Schmitt, president and chief executive officer of Actuate Therapeutics Inc, in a press release.¹ “Elraglusib is a leading GSK-3β inhibitor that has demonstrated a favorable safety profile and antitumor activity across several solid tumors including melanoma, Ewing sarcoma, [and] colorectal and pancreatic cancers. We look forward to the continued development of elraglusib and working closely with regulators to deliver its promise to cancer patients.”

Photorealistic illustration of sarcoma - Generated with Google Gemini AI

Enrollment in the first stratum of the trial, stratum A, is open to patients with histologically confirmed, grade 2 or 3, locally advanced unresectable or metastatic STS, including subtypes like undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma), myxofibrosarcoma, leiomyosarcoma, liposarcoma (excluding well differentiated), angiosarcoma, synovial sarcoma, rhabdomyosarcoma, spindle cell sarcoma, and high-grade sarcoma not otherwise specified.

For the second stratum, stratum B, patients will be enrolled if they have histologically confirmed relapsed/refractory osteosarcoma or Ewing sarcoma following frontline therapy.²

All patients must have at least 1 measurable lesion as defined by RECIST 1.1, a life expectancy of over 12 weeks, and adequate organ and marrow function. A Lansky score of at least 50 is required for patients under the age of 16 or an ECOG performance of 2 or less is needed for patients 16 years of age or older.

Patients in stratum A with advanced STS who received between 0 and 3 prior lines of systemic therapy will be given elraglusib at a dose of 15 mg/kg twice a week in combination with 900 mg/m² of gemcitabine on days 1 and 8 and 75 mg/m² of docetaxel on day 8 of each 21-day cycle until disease progression or unacceptable toxicity. Those in stratum B, patients with relapsed/refractory bone sarcoma with prior exposure to 1 or more line of systemic therapy, will also be given 15 mg/kg of elraglusib 2 times a week plus 900 mg/m² of gemcitabine on days 1 and 8 and 75 mg/m² of docetaxel on day 8 of each 21-day cycle until disease progression or unacceptable toxicity. Investigators will perform response assessment on the patients every 2 cycles for the first 8 cycles, then every 12 weeks thereafter.

About Elraglusib

Elraglusib is a regulator of tumor signaling and antitumor immune response.³ The agent stops GSK-3β from working in cancer cells. In preclinical studies, elraglusib has shown activity. Clinical evidence has also shown elraglusib demonstrates antitumor activity across multiple types of cancers.

The FDA previously granted ODD to the agent for the treatment of patients with pancreatic cancer in August 2023.

Elraglusib is also being studied in another phase 1 study as monotherapy and in combination with chemotherapy in patients with relapsed/refractory advanced solid tumors or hematologic malignancies.⁴ Here, patients are being treated with elraglusib alone at doses ranging from 1 mg/kg to 15 mg/kg twice weekly (n = 67) or in combination with gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, or pemetrexed/carboplatin (n = 171).

This trial showed that the initial recommended phase 2 dose (RP2D) of elraglusib was 15 mg/kg twice a week, according to findings published in Clinical Cancer Research. This RP2D was later modified to 9.3 mg/kg once weekly to reduce central/peripheral vascular access catheter blockages which were linked with elraglusib treatment.

A total of 61 patients were evaluable for response in part 1. Here, 1 patient with melanoma had a complete response, and 1 patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, 138 patients were evaluable for response, and 7 patients had a PR.

The median PFS was 2.1 months (95% CI, 2-2.6), and the median overall survival was 6.9 months (95% CI, 5.7-8.4).

Additional safety findings showed that patients had other treatment-related adverse events (AEs), including transient visual changes and fatigue. In the monotherapy arm, the rate of grade 3 or greater treatment-emergent AEs was 55.2%. In the combination arm, this rate was 71.3%.

REFERENCES:

1. Actuate receives FDA orphan drug designation for elraglusib for treatment of soft tissue sarcomas. News release. Actuate Therapeutics, Inc. September 11, 2024. Accessed September 12, 2024. https://tinyurl.com/ns69enfa

2. A phase 2 study of 9-ING-41 combined with chemotherapy in adolescents and adults with advanced sarcomas. ClinicalTrials.gov. Updated July 28, 2021. Accessed September 12, 2024. https://clinicaltrials.gov/study/NCT04906876

3. Our science. Actuate Therapeutics. Accessed September 12, 2024. https://actuatetherapeutics.com/our-science

4. Carneiro BA, Cavalcante L, Mahalingam D, et al. Phase I study of elraglusib (9-ING-41), a glycogen synthase kinase-3β inhibitor, as monotherapy or combined with chemotherapy in patients with advanced malignancies. Clin Cancer Res. 2024;30(3):522-531. doi:10.1158/1078-0432.CCR-23-1916