FDA Grants Orphan Drug Designation to Elraglusib for Soft Tissue Sarcomas

The FDA has granted orphan drug designation (ODD) to the novel GSK-3β inhibitor elraglusib for the treatment of patients with soft tissue sarcoma (STS).¹

“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,” Daniel Schmitt, president and chief executive officer of Actuate Therapeutics Inc, stated in a news release. “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, 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.”

In August 2023, the FDA granted ODD to the agent for the treatment of patients with pancreatic cancer.²

The agent is currently under study in combination with gemcitabine and docetaxel in an open-label, two-stratum, phase 2 trial (NCT04906876). Eligible patients include those at least 10 years of age with unresectable or metastatic soft tissue or bone sarcomas.³

Within the first stratum (stratum A), patients must have histologically confirmed, grade 2 or 3 locally advanced unresectable or metastatic STS that falls into one of the following subtypes: 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. Within the second stratum (stratum B), patients must have histologically confirmed relapsed/refractory osteosarcoma or Ewing sarcoma following frontline therapy.³

For the entire trial population patients must also have at least 1 measurable lesion per RECIST 1.1, life expectancy greater than 12 weeks, adequate organ and marrow function, and a Lansky score of at least 50 for patients under the age of 16 or an ECOG performance of 2 or less for patients at least 16 years of age.³

In stratum A patients with advanced STS who received between 0 and 3 prior lines of systemic therapy will receive 15 mg/kg of elraglusib twice weekly 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. In stratum B patients with relapsed or refractory bone sarcoma with prior exposure to at least 1 line of systemic therapy will also receive 15 mg/kg of elraglusib twice weekly 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.³

Patients will undergo response assessment every 2 cycles for the first 8 cycles, then every 12 weeks thereafter. The primary outcome of the study is disease control rate. Progression-free survival (PFS) will serve as a secondary end point.³

In addition to this phase 2 trial elraglusib is also being studied as monotherapy and in combination with chemotherapy in patients with relapsed/refractory advanced solid tumors or hematologic malignancies in a phase 1 study. In the trial patients received elraglusib alone at doses ranging from 1 mg/kg to 15 mg/kg twice weekly (n = 67) or in combination with one of the following chemotherapy regimens: gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel (Abraxane), paclitaxel/carboplatin, and pemetrexed (Alimta)/carboplatin (n = 171).⁴

Findings from the trial published in Clinical Cancer Research demonstrated that the initial recommended phase 2 dose (RP2D) of elraglusib was 15 mg/kg twice weekly. However, the RP2D was subsequently amended to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other treatment-related adverse effects (AEs) included transient visual changes and fatigue. The rate of grade 3 or greater treatment-emergent AEs was 55.2% in the monotherapy arm and 71.3% in the combination arm.⁴

Among the patients evaluable for response in part 1 (n = 62), 1 patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). Among those evaluable for response in part 2 (n = 138), 7 PRs occurred, and the median PFS and overall survival were 2.1 months (95% CI, 2-2.6) and 6.9 (95% CI, 5.7-8.4) months, respectively.⁴

“Soft tissue sarcomas are a rare but heterogeneous mix of tumors with >70 histological subtypes identified to date making sarcoma difficult to treat. Surgery remains the most effective treatment for localized cancer with median survival approaching 50%. However, patients with metastatic disease have a median overall survival of less than 6 to 12 months and remain a therapeutic challenge. Doxorubicin, approved almost 50 years ago, remains the recommended first-line line systemic treatment despite exhibiting minimal antitumor activity highlighting the unmet medical need for patients with metastatic STS,” Steven D. Reich, MD, senior vice president of clinical development and acting chief medical officer of Actuate, said.¹ “Preclinical studies have demonstrated that elraglusib induces significant STS cell apoptosis and synergistic effects with chemotherapy providing rationale for the clinical evaluation in metastatic STS.”

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 11, 2024. https://www.globenewswire.com/news-release/2024/09/11/2944428/0/en/Actuate-Receives-FDA-Orphan-Drug-Designation-for-Elraglusib-for-Treatment-of-Soft-Tissue-Sarcomas.html
2. Actuate Therapeutics receives FDA orphan drug designation for elraglusib for treatment of pancreatic cancer. News release. Actuate Therapeutics, Inc. August 1, 2023. Accessed September 11, 2024. https://actuatetherapeutics.com/press-releases/actuate-therapeutics-receives-fda-orphan-drug-designation-for-elraglusib-for-treatment-of-pancreatic-cancer/
3. 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 11, 2024. https://clinicaltrials.gov/study/NCT04906876
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