Phase 1b study of chemoprevention with green tea polyphenon E (PPE) and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (Erlotinib) in patients (pts) with advanced premalignant (AP) lesions of the head and neck.

Abstract

6049 Background: Based on the strong synergistic effects between green tea polyphenon E (PPE) and EGFR-TKI in our preclinical studies (Int J Cancer, 2008; Cancer Prev Res, 2009; JCO, 2009), we conducted a phase 1b study with PPE and erlotinib combination for APL (mild-, moderate-, severe-dysplasia or carcinoma in situ [CIS]) of the oral cavity and larynx from 2/2011 to 11/2017 at Emory Winship Cancer Institute. Methods: All pts were enrolled after signing the IRB approved Informed Consent Form. Tissue biopsy before and at 6-months (6-M) treatment was mandatory, and cytobrushed samples of the APL and normal buccal mucosa at 3-, 6-, and 12-M were obtained for biomarker studies. Treatment included fixed dose of PPE (200 mg, P.O.,TID) and dose escalation of erlotinib P.O., (50mg [level 1], 75mg [level 2] and 100mg [level 3]) for 6-M. The primary endpoint was safety and toxicity, and secondary endpoints were evaluation of pathologic responses, cancer free survival (CFS) and biomarker modulation. Results: Out of 27 enrolled pts, 6 control subjects for biomarker studies, 2 ineligible, and 19 were treated with PPE and erlotinib for 6-M. Clinical characteristics of treated patients included median age, 63 yrs. (range,33-78); 9 M/10 F; 10 former or current smokers/9 never smokers; 15 severe dysplasia or CIS, 2 moderate dysplasia, 2 mild dysplasia; 13 had surgical resection; 17 oral cavity primary; and 2 at larynx. 3 pts were treated at dose level 1, 4 at level 2, and 12 at level 3. Toxicity (G0 or G1 excluded) were: skin rash (1 G3, 1 G2), pruritus/dry skin (1 G2), fatigue (1 G2), diarrhea (1 G2), epistaxis (1 G2), and hypertension (2 G3, 1 G2). Skin rash (associated with erlotinib) may be DLT and MTD has not been reached. The recommend doses for phase 2 or 3 studies will be PPE 200mg TID plus erlotinib 100mg QD. 17 pts were assessed for pathologic responses at 6-M: pCR 7/17 (41%), pPR 2/17 (12%), pSD 5/17 (29%) and pPD (3/17 (18%). The median follow up was 32 months. Median CFS has not been reached. 16 pts are alive at the time of data analyses and 1 pt died (by noncancerous reason). Biomarker studies are ongoing for tissues and/or cytobrushed samples. Conclusions: The treatment of the combination of green tea PPE plus erlotinib for 6-M was well tolerated in pts with APL of the head and neck, and showed significant pathologic response rates (pCR and pPR, 53%). This combination therefore deserves further investigation for efficacy testing. Clinical trial information: NCT01116336.