Phase II study of the histone deacetylase inhibitor vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in recurrent or metastatic transitional cell carcinoma of the urothelium – an NCI-CTEP sponsored: California Cancer Consortium trial, NCI 6879

• Published in: Investigational new drugs Vol. 39; no. 3; pp. 812 - 820
• Main Authors: Quinn, David I., Tsao-Wei, Denice D., Twardowski, Przemyslaw, Aparicio, Ana M., Frankel, Paul, Chatta, Gurkamal, Wright, John J., Groshen, Susan G., Khoo, Stella, Lenz, Heinz-Josef, Lara, Primo N., Gandara, David R., Newman, Edward
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2021; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antitumor activity; Apoptosis; Bladder; Bladder cancer; Cancer; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - mortality; Carcinoma, Transitional Cell - pathology; Computed tomography; Consortia; Cytopenia; Dosage; Female; Histone deacetylase; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - adverse effects; Histones; Humans; Hydroxamic acid; Inhibitors; Kaplan-Meier Estimate; Lymphocytes; Lymphocytes T; Magnetic resonance imaging; Male; Medical imaging; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - mortality; Neoplasm Recurrence, Local - pathology; Oncology; Pharmacology/Toxicology; Phase II Studies; Platinum; Schedules; Survival; Therapy; Toxicity; Transitional cell carcinoma; Treatment Outcome; Tumor cell lines; Urologic Neoplasms - drug therapy; Urologic Neoplasms - mortality; Urologic Neoplasms - pathology; Urothelial cancer; Urothelium; Urothelium - pathology; Vorinostat - administration & dosage; Vorinostat - adverse effects; Urothelial cancer; Clinical trial; Histone deacetylase inhibitor; Bladder cancer
• ISSN: 0167-6997; 1573-0646; 1573-0646
• DOI: 10.1007/s10637-020-01038-6

Summary Background: Until the advent of T cell check point inhibitors standard second-line therapy for patients with metastatic urothelial cancer (mUC) was undefined. Histone deacetylase inhibitors (HDACi) have anti-cancer activity in a variety of tumor models including modulation of apoptosis in bladder cancer cell lines. We evaluated the efficacy and toxicity of the HDACi vorinostat in patients with mUC failing first-line platinum-based therapy either in the adjuvant/neoadjuvant setting or for recurrent/advanced disease. Methods: Vorinostat was given orally 200 mg twice daily continuously until progression or unacceptable toxicity. The primary end point was RECIST response rate (RR); a RR > 20% was deemed interesting in a 2-stage design requiring one response in the first 12 patients to proceed to 2nd stage for a total of 37 subjects. CT or MRI scan imaging occurred every 6 weeks. Results: Fourteen patients were accrued characterized by: median age 66 years (43–84); Caucasian (79%); males (86%); and Karnofsky performance status ≥90 (50%). Accrual was terminated in the first stage as no responses were observed. Best response was stable disease (3 patients). Progression was observed in 8 patients. Two patients came off therapy prior to re-imaging and a 3rd patient died while on treatment and was not assessed for response. Median number of cycles was 2 (range 1–11). Median disease-free survival and overall survival times were 1.1 (0.8, 2.1) & 3.2 (2.1, 14.5) months, respectively. Toxicities were predominantly cytopenias and thrombocytopenic bleeding. Two pts. had grade 5 toxicity unlikely related to treatment. Two pts. had grade 4 and 6 had grade 3 toxicities observed. Two patients with stable disease remained on therapy for 6+ cycles. Conclusions: Vorinostat on this dose-schedule had limited efficacy and significant toxicity resulting in a unfavorable risk:benefit ratio in patients with mUC. NCT00363883.