This phase 1 study demonstrates that imexon can be safely combined with gemcitabine in patients with advanced pancreatic cancer. The primary DLT is acute abdominal pain and cramping associated with sudden bowel movement(s) or diarrhea occurring at the end of the infusion of imexon. This toxicity is rarely seen at the recommended phase II dose of imexon 875 mg/m2 with gemcitabine 1,000 mg/m2.
Importantly, encouraging evidence of antitumor activity was noted in this large, single arm phase 1 experience. Pharmacokinetic data demonstrate that levels of imexon consistent with preclinical activity can be achieved in patients with pancreatic cancer. There also appears to be no PK interaction between imexon and gemcitabine as the results of this study were similar to those reported for the administration of each drug alone as well as in gemcitabine combinations [9
A phase 1 study of imexon monotherapy administered on days 1–5 and 15–19 every 28 days was recently reported [9
]. The recommended dose on this schedule was 875 mg/m2
with one of two DLTs at 1000 mg/m2
being abdominal pain similar to that seen in this study and occurring in a patient with pancreatic cancer. In another phase 1 study of imexon given daily for 5 days every 3 weeks, the MTD was 1150 mg/m2
. Moulder et al. treated patients with breast, lung, or prostate cancer with imexon days 1–5 combined with docetaxel on day 1 every 3 weeks [11
]. The MTD was imexon 1,300 mg/m2
with docetaxel 75 mg/m2
. The DLT was non-cardiac chest pain. Samlowski et al. treated 68 patients with metastatic melanoma with imexon combined with DTIC both given days 1–5 every 21 days.[12
] The MTD was 1,000 mg/m2
for both imexon and DTIC. The DLT of this regimen was hepatorenal failure in one patient presumably due to the DTIC and myelosuppression, while the most common non-DLT toxicities in the phase 2 portion included nausea, fatigue, and vomiting.
It is noteworthy that abdominal cramping and pain were not major toxicities of these other trials, they were clearly dose limiting in the current trial. One hypothesis is that patients with pancreatic cancer are more prone to the cholinergic effects of imexon, either through compromised pancreatic function or greater incidence of intra-abdominal metastases. Given the discovery of abdominal pain and cramping as DLT, additional laboratory investigation was undertaken in the guinea pig ileum. Imexon resulted in a cholinergic effect similar to that of acetylcholine. We hypothesized that administration of atropine would ameliorate this effect and this was achieved in vivo
in the guinea pig ileum model (Dorr et al. unpublished). Based upon this evaluation, atropine was subsequently utilized at physician discretion for patients experiencing this toxicity with success. Additionally, we have demonstrated in the laboratory that radioactive imexon localizes in the intestine and pancreas in the mouse (Data on file, AmpliMed Corporation). Thus, pancreatic cancer patients may be particularly susceptible to the cholinergic effects of imexon. Alternatively, the weekly schedule evaluated through the majority of this clinical trial may predispose to cholinergic abdominal cramping affects to a greater extent than daily X 5 periodic dosing. The topoisomerase-I inhibitor irinotecan has cholinergic and gastrointestinal promotility effects which are more pronounced with weekly dosing than every 3 week administration.[13
The objective response and stable disease rates are encouraging compared to historic controls. Gemcitabine alone or with erlotinib results in objective response rates of less than 10%.[2
] Studies combining two cytotoxic chemotherapy agents in pancreatic cancer have also rarely resulted in response rates above 10–15%.[14
] Of increasing interest in pancreatic clinical trials is the rate of disease control, typically defined as response plus stable disease. Our rate of disease control of approximately 70% compares favorably to recent large randomized trials,[3
] particularly when recognizing that our study was comprised nearly entirely of metastatic patients while other trials have included 20–25% locally advanced patients with more favourable prognosis. In addition, only 28 of the patients in the current trial received the combination at the MTD. However, our study is a single arm trial and these encouraging results need to be evaluated in subsequent randomized trials.
The pharmacokinetic analysis reveals plasma imexon levels consistent with preclinical antitumor activity.[8
] Gemcitabine pharmacokinetics were in line with prior single agent reports without negative interaction with imexon.[10
] The degree of plasma cystine decrease was slightly less than that seen in the prior single agent study of imexon,[9
] and may reflect a mediating effect of the gemcitabine infusion. Furthermore, while the majority (23/29) of patients evaluated for plasma cystine levels experienced a decrease 8 hours after imexon, there was substantial variability in the degree of change, and six patients (four with SD, two not evaluable), had plasma cystine levels increase. There did not appear to be any impact of dose or clinical outcome on change in cystine levels. However, the patient number was small, and this may have influenced the results.
In summary, this large phase 1 trial demonstrates that imexon and gemcitabine can be safely combined with encouraging clinical activity in advanced pancreatic cancer. The MTD is imexon 875 mg/m2 and gemcitabine 1000 mg/m2 weekly. A randomized phase II trial of gemcitabine with or without imexon is ongoing.