Mistletoe extract/gemcitabine combination treatment: An interim report from the NCCAM/NCI phase I study in patients with advanced solid tumors

Abstract

3098 Background: European Mistletoe (viscum album L.) extracts (ME) are used in varying doses and schedules as herbal adjunct treatment for solid tumors in Europe. Clinical efficacy remains controversial. Controlled data on safety, toxicity and drug interactions are lacking. Methods: Subjects with stage IV cancer (average age 51 years; breast 5, pancreas 4, colorectal 3, NSCLC 4) enrolled on a 2 stage dose escalation phase I trial of toxicity profile, dose limiting toxicity (DLT), MTD, and gemcitabine (GEM) pharmacokinetics (with and without ME) on s.c.qd ME (HELIXOR A, Helixor GmbH, KG, Rosenfeld, Germany) combined with GEM 750mg/m2i.v. on a weekly x 2 q 21d schedule for 3 cycles. We report on stage I (fixed dose GEM). Starting target ME dose level was 20mg (n=3), with escalations to 50 (n=3), 100 (n=3), 200 (n=5), and 250 mg (n=2). DLT for GEM is neutropenia. GEM and 2’,2’-difluorodeoxyuridine (dFdU) plasma concentrations (Cp) at baseline and week 8 (stable ME dose for 7 days) were determined by HPLC with UV detection o 12 subjects who completed 3 cycles (ME dose 20–200mg). The area under the curve (AUC) was determined using WinNonLin version 4.0. This project was approved by the Navy Clinical Investigation Program Project Number: 02–074 Results: No ME DLT was observed. Ten ME related grade 2 adverse events (AE, injection site reaction 4, flu-like syndrome 4, other local reaction 2), 30 grade 3 GEM-related AE (lymphopenia 12, neutropenia/low WBC 10, thrombocytopenia 2, nausea/vomiting 2, other 4) and 1 GEM related grade 4 lymphopenia were observed. Median baseline and week 8 AUC (664/670 min*nmol/ml, p=0.97) and Cp (47.7/49.7 nmol/ml, p=0.85) of GEM and dFdU (AUC 1038/1099 min*nmol/ml, p= 0.46, Cp 75.7/84 nmol/ml, p=0.67) were equivalent (signed rank test). 1038 of 1059 scheduled ME doses were given (compliance 98.2%). Tow subjects had partial clinical responses (PR) by RECIST (pancreas 1, NSCLC 1) and four subjects had stable disease > 18 wks (pancreas 1, NSCLC 2, rectal 1). Conclusions: The ME/GEM combination has been well tolerated. GEM Cp during infusion was unaffected by ME. Two subjects had a PR. Stage II (GEM dose escalation) will determine if addition of ME alters GEM toxicities and MTD. No significant financial relationships to disclose.