NCI 6896: a phase I trial of vorinostat (SAHA) and isotretinoin (13-cis retinoic acid) in the treatment of patients with
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PHASE I STUDIES
NCI 6896: a phase I trial of vorinostat (SAHA) and isotretinoin (13-cis retinoic acid) in the treatment of patients with advanced renal cell carcinoma Ana M. Molina 1 & Johannes C. van der Mijn 2,3 & Paul Christos 4 & John Wright 5 & Charlene Thomas 1 & Janice P. Dutcher 6,7 & David M. Nanus 1 & Scott T. Tagawa 1 & Lorraine J. Gudas 2 Received: 17 July 2019 / Accepted: 14 November 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumor sensitivity to retinoids and have synergistic anti-tumor activity when combined. We performed a Phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor vorinostat and isotretinoin in patients with advanced renal cell carcinoma (RCC). Vorinostat was administered at 300 mg orally twice daily in combination with escalating doses of isotretinoin for 3 consecutive days per week. A standard 3 + 3 dose escalation design was used. Dose limiting toxicities (DLT) were assess during the first cycle to determine the maximum tolerated dose (MTD). Fourteen patients enrolled on the trial of which 12 were evaluable for toxicity (6 cohort 1; 3 cohort 2; 3 cohort 3) and 11 for tumor response. One patient in cohort 1 experienced a DLT (grade 3 depression). Common grade 1–2 toxicities included fatigue and GI effects (nausea, diarrhea, anorexia). MTD was established as vorinostat 300 mg with isoretinoin 0.5 mg/kg twice daily 3 days per week. Best responses in evaluable patients included 1 partial response and 9 stable disease, lasting a median of 3.7 months (range 1.8–10.4 months). The combination of vorinostat and isotretinoin is safe, tolerable and associated with responses in patients with refractory metastatic RCC. Keywords Renal cell carcinoma . Histone deacetylase . Vorinostat . Isotretinoin . SAHA
Introduction Ana M. Molina and Johannes C. van der Mijn are Co-primary authors * Ana M. Molina [email protected] 1
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, 520 East 70th Street, New York, NY 10021, USA
2
Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
3
Department of Medical Oncology, Amsterdam University Medical Center, Amsterdam, The Netherlands
4
Department of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY, USA
5
Division of Cancer Treatment & Diagnosis, National Cancer Institute, Bethesda, MD, USA
6
Our Lady of Mercy Cancer Center, Bronx, NY, USA
7
Present address: Cancer Research Foundation of NY, Chappaqua, NY, USA
Multiple systemic therapies have been developed in the past decade for patients with metastatic renal cell carcinoma (RCC). VEGF targeted therapy, immune checkpoint- and mTOR-inhibitors have become the mainstay in the treatment of patients with metastatic disease. Most patients however acquire resistance against these agents, after which few treatment options are available. Molecular profiling studies h
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