TY - JOUR
T1 - Safety and pharmacokinetics of MM-302, a HER2-targeted antibody–liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer
T2 - a phase 1 dose-escalation study
AU - Munster, Pamela
AU - Krop, Ian E.
AU - LoRusso, Patricia
AU - Ma, Cynthia
AU - Siegel, Barry A.
AU - Shields, Anthony F.
AU - Molnár, István
AU - Wickham, Thomas J.
AU - Reynolds, Joseph
AU - Campbell, Karen
AU - Hendriks, Bart S.
AU - Adiwijaya, Bambang S.
AU - Geretti, Elena
AU - Moyo, Victor
AU - Miller, Kathy D.
N1 - Funding Information:
We thank all the patients, caregivers, and investigators who participated in this study. We also thank Dr. Ty McClure, who provided statistical analysis of the study, and Dr. Helen Lee, who was instrumental in carrying out the 64Cu-MM-302 imaging analysis. We thank Translational Drug Development (TD2), who provided contract research organization support for this study funded by Merrimack Pharmaceuticals. This study used the Siteman Cancer Center Imaging and Response Assessment Core supported in part by an GR NCI Cancer Center Support Grant (#P30 CA91842).
Funding Information:
Funding: This trial was funded by Merrimack Pharmaceuticals, Inc. Merrimack Pharmaceuticals had roles in the study design; collection, analysis, and interpretation of data; writing of the report and decision to submit paper for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Funding Information:
Competing interests: P.M. has nothing to declare. C.M.’s institution received financial support from Merrimack Pharmaceuticals to conduct this trial. P.L.’s former institution received financial support from Merrimack Pharmaceuticals to conduct this trial. Dr LoRusso has provided consultancy for: Agios, Alexion, Ariad, GenMab, Glenmark, Halozyme, Menarini, Novartis, Roche-Genentech, Genentech, CytomX, Omniox, and Ignyta. B.A.S. has received consulting fees from Merrimack Pharmaceuticals and his institution received financial support from Merrimack Pharmaceuticals to conduct this trial. Dr Siegel also received grants from the National Cancer Institute, and personal fees from Beacon Biosciences during the conduct of the study. AFS received consulting fees from Merrimack Pharmaceuticals and his institution received financial support from Merrimack Pharmaceuticals to conduct this trial. IM was an employee of Merrimack at the time of the study, and is a consultant for Ipsen Biosciences outside of the submitted work. J.R. was an employee of Merrimack at the time of the study. K. C. was an employee of Merrimack at the time of the study. B.S.H. was an employee of Merrimack at the time of the study. B.A. is an employee of Merrimack. E.G. was an employee of Merrimack at the time of the study. V.M. was an employee of Merrimack at the time of the study, is an equity owner in L.E.A.F. Pharmaceuticals LLC outside of the submitted work. In addition, Dr Moyo has a patent null pending. K.D.M. received financial support to her institution from Merrimack Pharmaceuticals to conduct this trial. T.J.W. was an employee of Merrimack at the time of the study.
Publisher Copyright:
© 2018, Cancer Research UK.
PY - 2018/10/30
Y1 - 2018/10/30
N2 - Background: This phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody–liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer. Methods: Patients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w. Results: Sixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5–10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8–15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain. Conclusion: MM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w.
AB - Background: This phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody–liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer. Methods: Patients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w. Results: Sixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5–10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8–15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain. Conclusion: MM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w.
UR - http://www.scopus.com/inward/record.url?scp=85055578270&partnerID=8YFLogxK
U2 - 10.1038/s41416-018-0235-2
DO - 10.1038/s41416-018-0235-2
M3 - Article
C2 - 30361524
AN - SCOPUS:85055578270
SN - 0007-0920
VL - 119
SP - 1086
EP - 1093
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 9
ER -