Pharmacodynamic and therapeutic pilot studies of single-agent ribavirin in patients with human papillomavirus–related malignancies. (May 2022)

• Record Type: Journal Article
• Authors: Burman, Bharat; Drutman, Scott B.; Fury, Matthew G.; Wong, Richard J.; Katabi, Nora; Ho, Alan L.; Pfister, David G.
• Is Part Of: Oral oncology. Volume 128(2022)
• Publication Date: 2022-05
• Subjects: 4E-BP1 eIF4E-binding protein–1 -- AML acute myelogenous leukemia -- CTCAE Common Terminology Criteria for Adverse Events -- eIF4E eukaryotic translation initiation factor 4E -- GLI1 glioma-associated protein 1 -- HN head and neck -- HPV human papillomavirus -- p-eIF4E phospho-eIF4E -- POD progression of disease -- RECIST Response Evaluation Criteria in Solid Tumors -- R/M recurrent and/or metastatic -- RP2D recommended phase II dose -- SCCs squamous cell carcinomas -- SD stable disease; Ribavirin -- Human papillomavirus -- HPV-related cancers -- eIF4E -- Cap-dependent translation; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2022.105806
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: Therapies targeting the viral etiology of HPV-related cancers are lacking. HPV E6 and E7 oncogenesis is dependent on eIF4E-mediated cap-dependent translation. Ribavirin effectively reduces eIF4E levels in patients with HPV-related cancers. Ribavirin monotherapy likely has limited clinical efficacy in HPV-related cancers. Rational combinations with ribavirin or other eIF4E inhibitors should be considered. Abstract: Objectives: Ribavirin inhibits eukaryotic translation initiation factor 4E (eIF4E), thereby decreasing cap-dependent translation. In this two-part study, we assessed the pharmacodynamic effects and therapeutic potential of ribavirin in human papillomavirus (HPV)–related malignancies. Methods: In the pharmacodynamic study, ribavirin (400 mg BID for 14 days) was evaluated in 8 patients with HPV-positive localized oropharyngeal carcinoma with phosphorylated-eIF4E (p-eIF4E) ≥ 30%. In the therapeutic study, ribavirin (1400 mg BID in 28-day cycles, continuously dosed) was evaluated in 12 patients with recurrent and/or metastatic HPV-related cancer. Dose interruptions or reductions were allowed according to prespecified criteria. Toxicities were assessed in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4; response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Patients remained on study until disease progression or unacceptable toxicity. Results: Six patients were evaluable in the pharmacodynamic study: 4 had decreased p-eIF4E after 14 days of ribavirin. In the therapeutic study, 12 patients were evaluable for toxicity, and 9 were evaluable for response. Among these, median follow-up was 3.5 months, and best overall response was stable disease in 5 patients and progression of disease in 4 patients. Median progression-free survival was 1.8 months. The most common treatment-related adverse events (grade > 2) were anemia, dyspnea, and hyperbilirubinemia. All patients had anemia (grades 1–3), with 33% having at least 1 dose reduction. Conclusion: Oral ribavirin decreases p-eIF4E levels and is well-tolerated. However, a clear signal of efficacy in patients with recurrent and/or metastatic HPV-related cancers was not observed. (NCT02308241, NCT01268579)