A phase II study of vorinostat (NSC 701852 ) in patients (pts) with relapsed non-small cell lung cancer (NSCLC)

Abstract

18044 Background: Vorinostat is a small molecule inhibitor of histone deacetylase (HDAC). HDAC inhibitors have shown preclinical activity in lung cancer and are postulated to have an antitumor effect by alteration in acetylation status of histone and non-histone proteins. Methods: Pts with relapsed NSCLC who failed no more than 1 prior cytotoxic therapy were eligible. Treatment: vorinostat, 400 mg po daily in a 21 day cycle. Primary objective: response rate (RR), with goal of at least one responder in first 14 evaluable pts. Secondary objectives: time to progression (TTP), overall survival (OS), safety, and correlative assays. Results: 14 pts enrolled from 12/05- 12/06. Median age 59.5 yrs (range 47–79). 11 females. PS 0:1, 10 pts:4 pts. Thirteen of 14 pts had only 1 prior cytotoxic regimen; 1 pt had only prior erlotinib. Best response to prior treatment: stable disease (SD; 11 pts), progressive disease (PD; 3 pts). Median time since last prior therapy: 2.1 mo (range 0.2–78.5). Vorinostat treatment compliance: 95.8 %. Two pts were not evaluable for response due to not completing Cycle 1 of treatment due to PD. No objective antitumor responses have been seen in the first 12 evaluable pts. Seven pts experienced SD (median 4.2 mo, range 2–10.7). Median TTP: 2.8 mo (range 1–10.7+); median OS 6.5 mo (range 1.4–10.7+); estimated 6 mo OS rate 50% (SE 16%). Grade (Gr) 5 toxicity: CVA (1 pt). Gr 3/4 toxicities: neutropenia (Gr 4–1 pt), lymphopenia (Gr 3–2 pts), fatigue (Gr 3–1 pt), elevated alk phos (Gr 3–1 pt), memory impairment (Gr 3–1 pt), PE/DVT (Gr 3–1 pt; Gr 4–2 pts), dehydration (Gr 3–1 pt). Data from the following correlative studies will be updated: p53 status, gene expression, H3 acetylation, transcription of p21, Nur77, Hsp70, erbB1 and 2, and Akt, cell cycle arrest, and assay of isoprostanes generated by treatment with vorinostat. Conclusions: Vorinostat 400 mg daily is tolerable with more than 80% of patients completing Cycle 1. Vorinostat yields TTP in relapsed NSCLC similar to that of other targeted agents. Although 4 of 14 pts experienced vascular events on treatment, these occurrences are common in this disease setting. At least two additional pts are still to be accrued. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents. No significant financial relationships to disclose.

Advances in Targeted Therapy Against Driver Mutations and Epigenetic Alterations in Non-Small Cell Lung Cancer

“…Phase I-II Seven of the 12 patients in the trial experienced SD (median 4.2 months, range 2-10.7). Median TTP: 2.8 months (range 1-10.7+); median OS 6.5 months (range 1.4-10.7+); estimated 6 months OS rate 50% [205].…”

Stochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat

“… Methods Key results Mechanisms Tumor phases Ref. Previously untreated NSCLC patients Well tolerated combination Not determined Phase I trial [ 105 ] Orally administered vorinostat was prescribed either once daily for a duration of 14 days or twice daily for a week, with a three-week interval between doses Encouraging anticancer activity Once every 3 weeks, Carboplatin and paclitaxel (PTX) were intravenously administered Relapsed NSCLC patients Well tolerated treatment Not determined Phase II trial [ 106 ] 400 mg orally per day, with a cycle of 21 days >80 % of patients completing cycle 1 Compliance = 95.8 % During the treatment, vascular events were encountered by 4 out of 14 patients Recurrent and/or metastatic head and neck cancer patients Well tolerated treatment Not determined Phase II trial [ 107 ] 400 mg of vorinostat taken orally on a daily basis A less effective activity compared to the tumor response observed in heavily pre-treated patients Patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy Significant toxicities limiting the evaluation of treatment efficacy Not determined Phase II trial [ 108 ] 400 mg of vorinostat taken orally on a daily basis Median time to progression = 2.8 months Median overall survival (mOS) = 11.7 months Solid tumor patients consisting of 18 Japanese individuals Well tolerated treatments Not determined …”

“…The encouraging results of this study justify conducting phase II trials specifically targeting the disease. This was achieved in the same year in a phase II study investigating the potential of vorinostat in relapsed NSCLC patients who had failed to respond to more than one prior cytotoxic treatment [ 106 ]. A total of 14 patients were recruited, and although no objective anticancer response was noted in the first twelve evaluable patients, seven patients had stable disease (SD).…”

The Use of Histone Deacetylase Inhibitors for the Treatment of Solid Tumors

“…In addition to the expected toxicities, four of 14 patients evaluable for safety experienced adverse vascular events, including two patients with pulmonary embolism and one patient with a fatal cardiovascular accident (CVA). 18 In addition to a phase III compassionate-use trial of vorinostat for patients with advanced CTCL, there is an ongoing phase III trial of vorinostat in patients with mesothelioma in whom treatment with pemetrexed has failed. 19 Currently, phase II or phase I/II trials are investigating vorinostat as a single agent in melanoma, stage IIIb or IV NSCLC, renal cell carcinoma, and transitional cell carcinoma of the urothelium, and as neoadjuvant therapy in women with stage I-III breast cancer (www.cancer.gov/clinicaltrials).…”