A 28-Day Intrathecal Toxicity Study with Trastuzumab in Nonhuman Primates.

Introduction : Trastuzumab is indicated for the treatment of patients with breast cancer whose tumors overexpress the HER2 protein. Brain metastases have been observed in breast cancer patients, being the highest in women with HER2-overexpressing tumors. The blood-brain barrier, however, may prevent trastuzumab from reaching appropriate concentrations in the cerebrospinal fluid (CSF). Case studies have been reported in which trastuzumab was intrathecally administered for the treatment of metastatic brain cancer in humans. However, no extensive preclinical safety evaluation has been performed for intrathecal application after repeat-dosing in a trastuzumab cross-reactive species using doses equivalent to or higher than those used in patients. To evaluate the potential of local effects, a 28-day toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys, a trastuzumab cross-reactive species. Preservative-free trastuzumab was used in this preclinical safety study, as caution has been raised for the intrathecal use of benzyl alcohol-containing solutions. Methods: Five male and five female monkeys were evaluated per dose group, of which two monkeys/sex/group were evaluated after a 4-week recovery period. Animals were assigned to 3 groups which received 4 weekly 30-minute intrathecal infusions at 0, 3, or 15 mg per dose at an infusion rate of 1.5 mL/hour. Endpoints evaluated included clinical signs, body weight, appetite, neurological examinations, clinical pathology, gross pathology, and histopathology of the brain (with inclusion of meninges), spinal cord, and infusion site. In addition, CSF and serum samples were collected for toxicokinetic evaluations. Results and Discussion: No test article-related effects on clinical signs, body weight, appetite, neurological examinations, clinical pathology, gross pathology or histopathology were noted. Of note is the absence of demyelination as was discussed as an uncertainty of intrathecally administered proteins. The doses used of 3 and 15 mg per dose resulted in 0.051 and 0.24 mg/g brain doses, respectively. Doses administered in clinical case reports ranged from 5 to 100 mg per dose. For a 1500 g human brain weight, these intrathecal doses would be equivalent to 0.0033 and 0.067 mg/g brain weight. At the high dose of 15 mg, maximum CSF concentrations (C max ) were as high as 403 µg/mL. The applied doses and CSF concentrations achieved in the current study greatly exceeded those reported in patients (6.4 µg/mL at an intrathecal dose of 20 mg). Conclusion: The results of this 4-week toxicology study in monkeys with the results of the clinical case studies support future studies to evaluate intrathecal application of trastuzumab in patients with brain metastasis in HER2-positive breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5101.