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

Pamela Munster, Ian E. Krop, Patricia LoRusso, Cynthia Ma, Barry A. Siegel, Anthony F. Shields, István Molnár, Thomas J. Wickham, Joseph Reynolds, Karen Campbell, Bart S. Hendriks, Bambang S. Adiwijaya, Elena Geretti, Victor Moyo, Kathy Miller

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1086-1093
Number of pages8
JournalBritish Journal of Cancer
Volume119
Issue number9
DOIs
StatePublished - Oct 30 2018
Externally publishedYes

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Doxorubicin
Pharmacokinetics
Breast Neoplasms
Safety
Cyclophosphamide
Disease-Free Survival
Fatigue
Febrile Neutropenia
Penetrance
Anthracyclines
Anniversaries and Special Events
Neutropenia
Thrombocytopenia
Nausea
Trastuzumab
Anemia
Neoplasms
Inflammation
Brain
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Munster, Pamela; Krop, Ian E.; LoRusso, Patricia; Ma, Cynthia; Siegel, Barry A.; Shields, Anthony F.; Molnár, István; Wickham, Thomas J.; Reynolds, Joseph; Campbell, Karen; Hendriks, Bart S.; Adiwijaya, Bambang S.; Geretti, Elena; Moyo, Victor; Miller, Kathy.

In: British Journal of Cancer, Vol. 119, No. 9, 30.10.2018, p. 1086-1093.

Research output: Contribution to journalArticle

Munster, P, Krop, IE, LoRusso, P, Ma, C, Siegel, BA, Shields, AF, Molnár, I, Wickham, TJ, Reynolds, J, Campbell, K, Hendriks, BS, Adiwijaya, BS, Geretti, E, Moyo, V & Miller, K 2018, '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', British Journal of Cancer, vol. 119, no. 9, pp. 1086-1093. https://doi.org/10.1038/s41416-018-0235-2
Munster, Pamela ; Krop, Ian E. ; LoRusso, Patricia ; Ma, Cynthia ; Siegel, Barry A. ; Shields, Anthony F. ; Molnár, István ; Wickham, Thomas J. ; Reynolds, Joseph ; Campbell, Karen ; Hendriks, Bart S. ; Adiwijaya, Bambang S. ; Geretti, Elena ; Moyo, Victor ; Miller, Kathy. / 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. In: British Journal of Cancer. 2018 ; Vol. 119, No. 9. pp. 1086-1093.
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title = "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",
abstract = "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-na{\"i}ve 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.",
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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

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.

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