Abstract LB-403: A Phase 0 microdosing clinical trial to identify chemoresistance

Abstract

Abstract BACKGROUND: As alkylating agents, platinum (Pt) analogs kill cancer cells mainly through induction of DNA damage. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon with 10−18∼21 mole sensitivity. By measuring 14C bound to DNA, AMS detects carboplatin-induced DNA damage after patients receive one subtoxic microdose of 14C-labeled carboplatin. METHODS: Cancer cells, mice bearing tumor xenografts and human cancer patients were treated with one microdose (1/100th the therapeutic dose) of [14C]carboplatin. Carboplatin-DNA adducts and other relevant parameters such as pharmacokinetics (PK), drug influx/efflux, intracellular drug inactivation, and repair of DNA damage, were measured and correlated with response to chemotherapy. RESULTS: In preclinical studies, the levels of microdose-induced DNA damage were linearly proportional to those caused by the therapeutic drug dose (R2=0.92, p<0.0001). When compared to the expression of ERCC1 (a gene commonly used to predict chemoresistance in non-small lung cancer in clinic), DNA damage levels were superior in predicting chemoresistance in cell lines. Measuring drug uptake/efflux, intracellular inactivation and DNA repair allowed insight into some of the resistance mechanisms. We have opened a Phase 0 clinical trial because of the microdosing approach of the study. This trial takes a two-stage design. The first stage is similar to a Phase I trial to define the recommended Phase II dose (RP2D) of 14C-carboplatin. The second stage is similar to a Phase II trial to determine if low levels of microdosing carboplatin-induced DNA damage correlate with chemoresistance and determine some of the underlying chemoresistant mechanisms. So far, we have finished the first (Phase I) stage of the Phase 0 trial. One microdose of 14C-carboplatin was administered to human cancer patients. Pt-induced DNA damage and repair, and PK were measured and correlated with the response and toxicity of chemotherapy. The RP2D of 14C-carboplatin is 107 dpm/kg of body weight, less than 1% of the radiation exposure from an abdominal CT scan. The RP2D of carboplatin is 1% of therapeutic dose. No toxicity was observed. The PK of microdosing carboplatin was the same of the therapeutic dose. Slow drug metabolism correlated with high DNA damage. Molecular analysis of genes such as ERCC1 and RRM1 is being analyzed and will be compared with the Phase 0 results. All these results will be correlated with cancer response and patients' toxicity to chemotherapy. A parallel Phase 0 clinical trial in dogs with naturally occurring cancer will also be presented. CONCLUSION: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance in cancer cell lines. The microdosing trial is nontoxic to patients. The second stage of the trial is currently going on. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-403. doi:10.1158/1538-7445.AM2011-LB-403