23 cancer research highlights from the past year
Elraglusib Granted FDA Orphan Drug Status In Soft Tissue Sarcoma
The FDA granted orphan drug designation for elraglusib, a novel drug for treating advanced soft tissue sarcoma.
This article first appeared with Targeted Oncology™.
An orphan drug designation (ODD) was granted by the FDA to elraglusib for the treatment of patients with soft tissue sarcoma (STS).1
Currently, a phase 2, open-label, 2-strata trial is evaluating the combination of elraglusib with gemcitabine and docetaxel in patients 10 years or older with unresectable or metastatic STS or bone sarcomas.2 In this study, investigators are evaluating the primary end point of disease control rate and the secondary end point of progression-free survival (PFS).
Daniel Schmitt, MBAImage Credit: Actuate Therapeutics
"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, MBA, president and CEO 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."
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 the 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.
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 more than 12 weeks, and adequate organ and marrow function. A Lansky score of at least 50 is required for patients younger than 16 years or an Eastern Cooperative Oncology Group performance status of 2 or less for patients 16 years and older.
Patients in stratum A with advanced STS who have received 0 to 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 lines 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.
Key TakeawaysElraglusib 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 also shows 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 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 has so far shown 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.4 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://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. 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
FDA Grants Elraglusib Orphan Drug Designation In Soft Tissue Sarcoma
The FDA granted orphan drug designation for elraglusib, a novel drug for treating advanced soft tissue sarcoma.
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.
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-23-1916Testicular Germ Cell Tumors With Somatic-type Malignancy
(a) Overgrowth of round cells with eosinophilic cytoplasm in a sheet-like growth pattern. Note the residual teratomatous (glandular) component in the right upper corner. (b) High-power view of the tumor showing medium-to-large round cells with eosinophilic cytoplasm, eccentric atypical nuclei, and prominent nucleoli. (c) The tumor cells are strongly positive for myogenin.
Testicular germ cell tumors (GCTs) are the most common malignancies in young men aged 15–35. Despite the high cure rate of over 90%, the prognosis drastically worsens when somatic-type malignancy (SM) arises within these tumors. This review explores the diagnostic criteria, histopathology, molecular features, and clinical management of GCTs with SM, emphasizing the importance of recognizing and treating these rare yet aggressive tumors.
Histopathology
Diagnostic CriteriaGCT with SM is diagnosed when there is an expansile or infiltrative growth of epithelial or mesenchymal components measuring at least 5 mm. The tumor must exhibit a pure population of atypical cells, occupying at least one low-power field (4× objective). If the overgrowth involves less than one low-power field, it is considered a teratoma rather than SM. However, clinical practice may apply less stringent criteria, focusing on the overall amount of tumor exceeding 5 mm in contiguous sections.
Histological SubtypesGCTs with SM exhibit a broad spectrum of histological types resembling non-GCT malignancies in other organs. These include sarcomas, carcinomas, and other rare tumors.
SarcomaSarcomas are the most common type of SM, with various forms including rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, and myxofibrosarcoma. Rhabdomyosarcoma, characterized by rhabdomyoblasts at various stages of myogenesis, is the most frequently reported. Leiomyosarcoma exhibits a fascicular growth pattern with high-grade atypical spindle cells, while angiosarcoma shows pleomorphic atypical cells with irregular vascular spaces.
CarcinomaApproximately 90% of carcinomas in SMs are adenocarcinomas. These can present as enteric, mucinous, endometrioid-like, or not-otherwise-specified types, characterized by high-grade cytologic atypia and an infiltrative growth pattern. Differentiating SM adenocarcinoma from yolk sac tumor (YST) is crucial due to differences in prognosis and treatment. Adenocarcinoma typically shows strong expression of carcinoembryonic antigen and caudal-type homeobox 2, but is negative for alpha-fetoprotein.
Embryonic-Type Neuroectodermal Tumor (ENT)ENTs, previously known as primitive neuroectodermal tumors, result from malignant transformation along mesodermal lines. They are characterized by small, round, blue malignant cells in diffuse sheets, occasionally forming tubules or pseudorosettes. Differentiating ENT from other small round cell tumors like Ewing sarcoma is critical.
Neuroglial NeoplasmsNeuroglial neoplasms in GCTs are extremely rare. They include low-grade astrocytoma, ganglioglioma, and anaplastic astrocytoma, among others. These tumors are confirmed by immunohistochemistry for glial fibrillary acidic protein.
Molecular Features
The molecular features of GCTs with SM remain under investigation. Recent studies suggest that the presence of SM in GCT metastasis may be a high-risk factor for prognosis. Molecular analyses have shown various genetic alterations, including those involving the p53 pathway, which are associated with poor outcomes.
Management and Outcomes
Surgical TreatmentThe primary treatment for GCT with SM is radical surgical extirpation. The feasibility of complete resection significantly impacts the prognosis. In cases where SM is confined to the testis or retroperitoneum, surgical resection can lead to favorable outcomes.
Chemotherapy and RadiotherapyThe role of chemotherapy and radiotherapy in treating GCT with SM is less well-defined. While traditional GCTs respond well to platinum-based chemotherapy, SM components may be resistant, necessitating alternative therapeutic strategies. Radiotherapy may be considered for certain histological subtypes, such as sarcomas and neuroglial tumors.
PrognosisThe prognosis for patients with GCT and SM is generally poor, with cancer-specific survival rates of 50–60%. The extent of the disease at onset and the feasibility of radical resection are critical factors influencing outcomes. Regular follow-up and monitoring for late recurrences are essential for managing these patients.
Conclusions
GCTs with SM represent a rare and aggressive subset of testicular tumors. Early recognition and appropriate management are crucial for improving patient outcomes. Ongoing research into the molecular characteristics and treatment responses of these tumors will likely provide new insights and therapeutic options in the future.
Full text
https://www.Xiahepublishing.Com/2771-165X/JCTP-2022-00028
The study was recently published in the Journal of Clinical and Translational Pathology.
Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.
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