Abstract P4-15-04: Effect of pre-treatment with cyclophosphamide on MM-302 (HER2-targeted liposomal doxorubicin) deposition in HER2-positive metastatic breast cancer patients assessed by 64Cu-MM-302 PET/CT
Authors: Miller Kathy , LoRusso Patricia M , Munster Pamela , Krop Ian , Ma Cynthia , Lee Helen , Reynolds Joe , Campbell Karen , Moyo Victor , Hendriks Bart , Wickham Thomas , Siegel Barry A , Shields Anthony F 
Published: May 2015

Background: Liposomal encapsulation of doxorubicin has addressed the cardiotoxicity of free doxorubicin, but has not achieved an improvement in anti-tumor activity in metastatic breast cancer. MM-302 is a HER2-targeted liposomal doxorubicin, specifically designed to target tumor cells overexpressing HER2 and minimize uptake into normal cells such as cardiomyocytes, which express low levels of HER2. MM-302 and MM-302 plus trastuzumab are being studied in patients as part of an ongoing Phase 1 clinical trial. Published reports indicate that deposition into solid tumors is a rate-limiting step in liposome-mediated delivery of drug to tumor cells. In order to understand drug deposition into solid tumors, we have radiolabeled MM-302 with 64Cu for imaging by PET/CT. Further, preclinical work has demonstrated that pretreatment with cyclophosphamide has the ability to improve liposomal drug delivery by making the tumor microenvironment permissive for deposition and retention of liposomes. This Phase 1 study evaluates the delivery of 64Cu-MM-302 to solid tumors and the ability of cyclophosphamide pretreatment to increase delivery of 64Cu-MM-302 to tumors.

Methods: Patients aged ≥ 18 years with histologically confirmed HER2-positive advanced breast cancer that has progressed or recurred on standard therapy or for which no standard therapy exists, who have adequate performance status, bone marrow reserve and organ function, were eligible for the study. Patients received 30 mg/m2 of MM-302 plus 6 mg/kg trastuzumab, q3w and 400 MBq (10.8 mCi; 3-5 mg/m2, doxorubicin basis) of 64Cu-MM-302 (cycle 1 only) with or without pretreatment of 450 mg/m2 cyclophosphamide. Patients underwent PET/CT on the day of administration and on day 2, day 3 or both. The primary goal of this analysis was to study delivery of 64Cu-MM-302 and the effect of cyclophosphamide pretreatment. Other endpoints being studied include safety, dosimetry, and treatment response.

Results: Combination of MM-302 with cyclophosphamide was well tolerated and no issues were reported related to 64Cu-MM-302 administration or imaging. Uptake of 64Cu-MM-302 in tumor lesions increased over time with significant deposition at 24 and 48 h while activity in the blood decreased over time. Median lesion deposition of 64Cu-MM-302 (as % i.d./kg) in the patients with cyclophosphamide pretreatment was higher than in those without pretreatment: 6.0 (n=5 patients/20 lesions) vs. 4.4 (n=7 patients/36 lesions) at 24 h and 7.6 (n=4 patients/16 lesions) vs. 4.0 (n=4 patients/17 lesions) at 48 h.

Conclusions: PET/CT imaged 64Cu-MM-302 deposition into diverse tumor lesions, including liver, brain and bone metastases. Our preliminary data thus far suggest that cyclophosphamide pretreatment increases delivery of 64Cu-MM-302 to patient tumors, as predicted by preclinical models. Correlation between 64Cu-MM-302 tumor deposition and lesion/patient response is currently being investigated.

Citation Format: Kathy Miller, Patricia M LoRusso, Pamela Munster, Ian Krop, Cynthia Ma, Helen Lee, Joe Reynolds, Karen Campbell, Victor Moyo, Bart Hendriks, Thomas Wickham, Barry A Siegel, Anthony F Shields. Effect of pre-treatment with cyclophosphamide on MM-302 (HER2-targeted liposomal doxorubicin) deposition in HER2-positive metastatic breast cancer patients assessed by 64Cu-MM-302 PET/CT [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-04.