Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I(131) KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma

Abstract

Background: Advanced pancreatic cancer has a poor prognosis, and the current standard of care (gemcitabine based chemotherapy) provides a small survival advantage. However the drawback is the accompanying systemic toxicity, which targeted treatments may overcome. This study aimed to evaluate the safety and tolerability of KAb201, an anti-carcinoembryonic antigen monoclonal antibody, labelled with I(131) in pancreatic cancer (ISRCTN 16857581).

Methods: Patients with histological/cytological proven inoperable adenocarcinoma of the head of pancreas were randomised to receive KAb 201 via either the intra-arterial or intravenous delivery route. The dose limiting toxicities within each group were determined. Patients were assessed for safety and efficacy and followed up until death.

Results: Between February 2003 and July 2005, 25 patients were enrolled. Nineteen patients were randomised, 9 to the intravenous and 10 to the intra-arterial arms. In the intra-arterial arm, dose limiting toxicity was seen in 2/6 (33%) patients at 50 mCi whereas in the intravenous arm, dose limiting toxicity was noted in 1/6 patients at 50 mCi, but did not occur at 75 mCi (0/3).The overall response rate was 6% (1/18). Median overall survival was 5.2 months (95% confidence interval = 3.3 to 9 months), with no significant difference between the intravenous and intra-arterial arms (log rank test p = 0.79). One patient was still alive at the time of this analysis.

Conclusion: Dose limiting toxicity for KAb201 with I(131) by the intra-arterial route was 50 mCi, while dose limiting toxicity was not reached in the intravenous arm.

Figure 1

Dose limiting toxicity. In the intra-arterial arm dose limiting toxicity (DLT) was observed in two of three patients at 50 mCi in the first cohort and in none of the three patients each in both the second cohort (45 mCi) and the third cohort (50 mCi). In the intravenous arm, one out of three patients experienced DLT at 50 mCi and none out of the three patients each in the second (50 mCi) and third cohorts (75 mCi) suffered a DLT. In summary, 2/6 patients experienced DLT in the intra-arterial arm (MTD reached at 50 mCi) and 1/6 patients in the intravenous arm (MTD not reached).

Figure 2

Pharmacokinetics- Post treatment with KAb201. The pharmacokinetics of KAb201 per individual patient (n = 18). After administration of the therapy dose, maximal levels (ng/ml) in blood were seen up to 5 days post treatment, with subsequent gradual decline and undetectable level by 1–2 months.

Figure 3

Pharmacokinetics- Post-therapy dose blood radioactivity of I¹³¹ levels. The pharmacokinetics of I¹³¹ per individual patient (n = 18). Radioactivity levels (MBq = mega bequerel) following administration of the therapy dose were high in the first five days, with levels gradually declining thereafter, to near undetectable levels in blood by 2 months.

Figure 4

Overall survival stratified by Karnofsky Performance Status. This is a Kaplan Meir survival curve of all 19 patients, stratified by their Karnofsky Performance Status i.e. KPS 90/100 versus KPS 70/80. The trend towards improved survival in the higher KPS group was not statistically significant (log rank p = 0.07).