TY - JOUR
T1 - Alpha particle radium 223 dichloride in high-risk osteosarcoma
T2 - A phase i dose escalation trial
AU - Subbiah, Vivek
AU - Anderson, Pete M.
AU - Kairemo, Kalevi
AU - Hess, Kenneth
AU - Huh, Winston W.
AU - Ravi, Vinod
AU - Daw, Najat C.
AU - Somaiah, Neeta
AU - Ludwig, Joseph A.
AU - Benjamin, Robert S.
AU - Chawla, Sant
AU - Hong, David S.
AU - Meric-Bernstam, Funda
AU - Ravizzini, Gregory
AU - Kleinerman, Eugenie
AU - Macapinlac, Homer
AU - Rohren, Eric
N1 - Funding Information:
V. Subbiah reports receiving commercial research grants from Bayer, Novar-tis, GlaxoSmithKline, NanoCarrier, Northwest Biotherapeutics, Genentech/ Roche, Berg Pharma, Incyte, Fujifilm, PharmaMar, D3 Oncology Solutions, Pfizer, Amgen, Multivir, Blueprint Medicines, LOXO Oncology, Vegenics, Alfasigma, Agensys, Idera Pharma, Boston Biomedical, Inhibrx, and Exelixis, and is a consultant/advisory board member for MedImmune/Astra Zeneca. W.W. Huh is a consultant/advisory board member for Lilly. S.P. Chawla is a consultant/advisory board member for, reports receiving other commercial research support and speakers bureau honoraria from Amgen, Roche, Threshold Pharmaceuticals, GlaxoSmithKline, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, SARC, Karyopharm Therapeutics, and Jansen, and holds ownership interest (including patents) in ADI, Cellestia, and Counterpoint. D.S. Hong reports receiving commercial research grants from AbbVie, Adaptimmune, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, Medimmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, and Takeda, speakers bureau honoraria from Bayer, holds ownership interest (including patents) in Molecular Match, OncoResponse, and Presagia Inc, and is a consultant/advisory board member for Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack,
Funding Information:
V. Subbiah would like to thank Dr. Shreyaskumar Patel and Dr. Norman Jaffe for the insightful discussions during protocol development, Dr. Richard Gorlick and Dr. Cynthia Schwartz for their support, and Dr. Emil Freireich and Dr. Razelle Kurzrock for inspiration, guidance, mentorship and motivation to do first-in-human clinical trials in rare diseases. Funding was provided by the Shannon Wilkes Osteosarcoma Research Foundation, the High-Impact Clinical Research Support at The University of Texas MD Anderson Cancer Center, and the National Institutes of Health Cancer Center Support Grant CA016672. The authors acknowledge Bayer HealthCare Pharmaceuticals for providing the radioactive isotopes.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Purpose: The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bonetargeting radium 223 dichloride (223RaCl2) can be safely administered to patients with osteosarcoma and that early signals of response or resistance can be assessed by quantitative and qualitative correlative imaging studies and biomarkers. Patients and Methods: A 3+3 phase I, dose-escalation trial of 223RaCl2 (50, 75, and 100 kBq/kg) was designed in patients with recurrent/metastatic osteosarcoma aged ≥15 years. Objective measurements included changes in standardized uptake values of positron emission tomography (PET; 18FDG and/or NaF-18) and single-photon emission CT/CT (99mTc-MDP) as well as alkaline phosphatase and bone turnover markers at baseline, midstudy, and the end of the study. Results: Among 18 patients enrolled (including 15 males) aged 15-71 years, tumor locations included spine (n = 12, 67%), pelvis (n = 10, 56%), ribs (n = 9, 50%), extremity (n = 7, 39%), and skull (n = 2, 11%). Patients received 1-6 cycles of 223RaCl2; cumulative doses were 6.84-57.81 MBq. NaF PET revealed more sites of metastases than did FDG PET. One patient showed a metabolic response on FDG PET and NaF PET. Four patients had mixed responses, and one patient had a response in a brain metastasis. Bronchopulmonary hemorrhage from Grade 3 thrombocytopenia (N = 1) was a DLT. The median overall survival time was 25 weeks. Conclusions: The first evaluation of the safety and efficacy of an alpha particle in high-risk osteosarcoma shows that the recommended phase II dose for 223RaCl2 in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies.
AB - Purpose: The prognosis of metastatic osteosarcoma continues to be poor. We hypothesized that alpha-emitting, bonetargeting radium 223 dichloride (223RaCl2) can be safely administered to patients with osteosarcoma and that early signals of response or resistance can be assessed by quantitative and qualitative correlative imaging studies and biomarkers. Patients and Methods: A 3+3 phase I, dose-escalation trial of 223RaCl2 (50, 75, and 100 kBq/kg) was designed in patients with recurrent/metastatic osteosarcoma aged ≥15 years. Objective measurements included changes in standardized uptake values of positron emission tomography (PET; 18FDG and/or NaF-18) and single-photon emission CT/CT (99mTc-MDP) as well as alkaline phosphatase and bone turnover markers at baseline, midstudy, and the end of the study. Results: Among 18 patients enrolled (including 15 males) aged 15-71 years, tumor locations included spine (n = 12, 67%), pelvis (n = 10, 56%), ribs (n = 9, 50%), extremity (n = 7, 39%), and skull (n = 2, 11%). Patients received 1-6 cycles of 223RaCl2; cumulative doses were 6.84-57.81 MBq. NaF PET revealed more sites of metastases than did FDG PET. One patient showed a metabolic response on FDG PET and NaF PET. Four patients had mixed responses, and one patient had a response in a brain metastasis. Bronchopulmonary hemorrhage from Grade 3 thrombocytopenia (N = 1) was a DLT. The median overall survival time was 25 weeks. Conclusions: The first evaluation of the safety and efficacy of an alpha particle in high-risk osteosarcoma shows that the recommended phase II dose for 223RaCl2 in osteosarcoma is 100 kBq/kg monthly (twice the dose approved for prostate cancer), with minimal hematologic toxicity, setting the stage for combination therapies.
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U2 - 10.1158/1078-0432.CCR-18-3964
DO - 10.1158/1078-0432.CCR-18-3964
M3 - Article
C2 - 30733229
AN - SCOPUS:85062430470
SN - 1078-0432
VL - 25
SP - 3802
EP - 3810
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -