A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG Oncology/Gynecologic Oncology Group study 0283 Journal Article
| Authors: | O'Cearbhaill, R. E.; Miller, A.; Soslow, R. A.; Lankes, H. A.; DeLair, D.; Segura, S.; Chavan, S.; Zamarin, D.; DeBernardo, R.; Moore, K.; Moroney, J.; Shahin, M.; Thaker, P. H.; Wahner-Hendrickson, A. E.; Aghajanian, C. |
| Article Title: | A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG Oncology/Gynecologic Oncology Group study 0283 |
| Abstract: | Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. Methods: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. Results: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. Conclusions: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype. © 2023 Elsevier Inc. |
| Keywords: | immunohistochemistry; adult; clinical article; human tissue; protein expression; treatment outcome; treatment response; aged; gene mutation; clinical trial; constipation; fatigue; neutropenia; paresthesia; diarrhea; drug safety; hypertension; hypophosphatemia; side effect; antineoplastic agent; anorexia; ovarian cancer; gene; progression free survival; peritoneum cancer; phase 2 clinical trial; sensory neuropathy; anemia; nausea; thrombocytopenia; vomiting; dehydration; myalgia; cohort analysis; creatinine; creatinine blood level; dasatinib; hematuria; abdominal pain; arthralgia; backache; coughing; dyspnea; fever; hyperglycemia; alkaline phosphatase; hypermagnesemia; hypoalbuminemia; hypokalemia; hyponatremia; depression; immunotherapy; thromboembolism; urinary tract infection; ovary carcinoma; peripheral edema; limb pain; anxiety disorder; recurrent disease; pleura effusion; weakness; headache; hot flush; leukocyte count; clear cell carcinoma; lung infection; flatulence; alopecia; tremor; pik3ca gene; hemorrhoid; hypocalcemia; abdominal distension; clear cell cancer; bloating; fallopian tube carcinoma; retinoblastoma binding protein 2; high throughput sequencing; human; female; article; patient history of surgery; endometrial clear cell carcinoma; arid1a mutation; baf250a; alkaline phosphatase level |
| Journal Title: | Gynecologic Oncology |
| Volume: | 176 |
| ISSN: | 0090-8258 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2023-09-01 |
| Start Page: | 16 |
| End Page: | 24 |
| Language: | English |
| DOI: | 10.1016/j.ygyno.2023.06.021 |
| PUBMED: | 37418832 |
| PROVIDER: | scopus |
| PMCID: | PMC10529107 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Roisin E. O'Cearbhaill -- Source: Scopus |
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