PMID- 30361524
OWN - NLM
STAT- MEDLINE
DCOM- 20190823
LR  - 20220204
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 119
IP  - 9
DP  - 2018 Oct
TI  - Safety and pharmacokinetics of MM-302, a HER2-targeted antibody-liposomal 
      doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: a 
      phase 1 dose-escalation study.
PG  - 1086-1093
LID - 10.1038/s41416-018-0235-2 [doi]
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/m(2) every 
      4 weeks [q4w]); MM-302 (30 or 40 mg/m(2) q4w) plus trastuzumab (4 mg/kg q2w); 
      MM-302 (30 mg/m(2)) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m(2)) plus 
      trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m(2)) 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/m(2), 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-naive patients, ORR 
      was 28.0% and mPFS 10.9 months (95% CI: 1.8-15.3). Imaging with (64)Cu-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/m(2) plus 6 mg/kg 
      trastuzumab q3w.
FAU - Munster, Pamela
AU  - Munster P
AD  - Helen Diller Family Comprehensive Cancer Center, Department of Medicine, 
      University of California, San Francisco, CA, USA. Pmunster@medicine.ucsf.edu.
FAU - Krop, Ian E
AU  - Krop IE
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
FAU - LoRusso, Patricia
AU  - LoRusso P
AD  - Yale Cancer Center, New Haven, CT, USA.
FAU - Ma, Cynthia
AU  - Ma C
AD  - Department of Medicine and the Alvin J. Siteman Cancer Center, Washington 
      University School of Medicine, St. Louis, MO, USA.
FAU - Siegel, Barry A
AU  - Siegel BA
AD  - Mallinckrodt Institute of Radiology and the Alvin J. Siteman Cancer Center, 
      Washington University School of Medicine, St. Louis, MO, USA.
FAU - Shields, Anthony F
AU  - Shields AF
AD  - Department of Oncology, Karmanos Cancer Institute, Wayne State University, 
      Detroit, MI, USA.
FAU - Molnar, Istvan
AU  - Molnar I
AD  - Research and Development, Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
FAU - Wickham, Thomas J
AU  - Wickham TJ
AD  - Research and Development, Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
FAU - Reynolds, Joseph
AU  - Reynolds J
AD  - Research and Development, Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
FAU - Campbell, Karen
AU  - Campbell K
AD  - Research and Development, Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
FAU - Hendriks, Bart S
AU  - Hendriks BS
AD  - Research and Development, Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
FAU - Adiwijaya, Bambang S
AU  - Adiwijaya BS
AD  - Research and Development, Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
FAU - Geretti, Elena
AU  - Geretti E
AD  - Research and Development, Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
FAU - Moyo, Victor
AU  - Moyo V
AD  - Research and Development, Merrimack Pharmaceuticals, Inc, Cambridge, MA, USA.
FAU - Miller, Kathy D
AU  - Miller KD
AD  - Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
LA  - eng
GR  - P30 CA091842/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181026
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Immunoconjugates)
RN  - 0 (Single-Chain Antibodies)
RN  - 80168379AG (Doxorubicin)
RN  - 8N3DW7272P (Cyclophosphamide)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
RN  - S5Z216QNO6 (gancotamab)
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse 
      effects
MH  - Brain/diagnostic imaging
MH  - Breast Neoplasms/diagnostic imaging/*drug therapy/genetics
MH  - Cyclophosphamide/*administration & dosage/adverse effects
MH  - Dose-Response Relationship, Drug
MH  - Doxorubicin/administration & dosage/adverse effects/*analogs & 
      derivatives/pharmacokinetics
MH  - Drug Administration Schedule
MH  - Female
MH  - Humans
MH  - Immunoconjugates/*administration & dosage/adverse effects/pharmacokinetics
MH  - Receptor, ErbB-2/*genetics
MH  - Single-Chain Antibodies/*administration & dosage/adverse effects/pharmacokinetics
MH  - Survival Analysis
MH  - Trastuzumab/*administration & dosage/adverse effects
MH  - Treatment Outcome
PMC - PMC6219487
COIS- 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.
EDAT- 2018/10/27 06:00
MHDA- 2019/08/24 06:00
PMCR- 2019/10/26
CRDT- 2018/10/27 06:00
PHST- 2018/02/08 00:00 [received]
PHST- 2018/07/27 00:00 [accepted]
PHST- 2018/06/28 00:00 [revised]
PHST- 2018/10/27 06:00 [pubmed]
PHST- 2019/08/24 06:00 [medline]
PHST- 2018/10/27 06:00 [entrez]
PHST- 2019/10/26 00:00 [pmc-release]
AID - 10.1038/s41416-018-0235-2 [pii]
AID - 235 [pii]
AID - 10.1038/s41416-018-0235-2 [doi]
PST - ppublish
SO  - Br J Cancer. 2018 Oct;119(9):1086-1093. doi: 10.1038/s41416-018-0235-2. Epub 2018 
      Oct 26.