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Title: Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases

Abstract

Purpose: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. Methods and Materials: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The (ClinicalTrials.gov) registration number is (NCT01703507). Results: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grademore » 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. Conclusions: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.« less

Authors:
 [1];  [2];  [1];  [2];  [1];  [3];  [4]; ; ; ;  [5]; ; ;  [6]; ; ; ;  [7]; ;  [1] more »; « less
  1. Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania (United States)
  2. Department of Radiation Oncology, Ohio State University, Columbus, Ohio (United States)
  3. Department of Radiation Oncology, Baystate Medical Center, Springfield, Massachusetts (United States)
  4. Department of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)
  5. Department of Medical Oncology, Sidney Kimmel Medical College at Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania (United States)
  6. Division of Medical Oncology, Ohio State University, Columbus, Ohio (United States)
  7. Department of Neurosurgery, Sidney Kimmel Medical College at Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania (United States)
Publication Date:
OSTI Identifier:
22723006
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 99; Journal Issue: 1; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; BRAIN; COMBINED THERAPY; MELANOMAS; PATIENTS; RADIATION DOSES; RADIOTHERAPY; SURGERY; TOXICITY

Citation Formats

Williams, Noelle L., Wuthrick, Evan J., Kim, Hyun, Palmer, Joshua D., Garg, Shivank, Eldredge-Hindy, Harriet, Daskalakis, Constantine, Feeney, Kendra J., Mastrangelo, Michael J., Kim, Lyndon J., Sato, Takami, Kendra, Kari L., Olencki, Thomas, Liebner, David A., Farrell, Christopher J., Evans, James J., Judy, Kevin D., Andrews, David W., Dicker, Adam P., Werner-Wasik, Maria, and others, and. Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. United States: N. p., 2017. Web. doi:10.1016/J.IJROBP.2017.05.028.
Williams, Noelle L., Wuthrick, Evan J., Kim, Hyun, Palmer, Joshua D., Garg, Shivank, Eldredge-Hindy, Harriet, Daskalakis, Constantine, Feeney, Kendra J., Mastrangelo, Michael J., Kim, Lyndon J., Sato, Takami, Kendra, Kari L., Olencki, Thomas, Liebner, David A., Farrell, Christopher J., Evans, James J., Judy, Kevin D., Andrews, David W., Dicker, Adam P., Werner-Wasik, Maria, & others, and. Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. United States. doi:10.1016/J.IJROBP.2017.05.028.
Williams, Noelle L., Wuthrick, Evan J., Kim, Hyun, Palmer, Joshua D., Garg, Shivank, Eldredge-Hindy, Harriet, Daskalakis, Constantine, Feeney, Kendra J., Mastrangelo, Michael J., Kim, Lyndon J., Sato, Takami, Kendra, Kari L., Olencki, Thomas, Liebner, David A., Farrell, Christopher J., Evans, James J., Judy, Kevin D., Andrews, David W., Dicker, Adam P., Werner-Wasik, Maria, and others, and. Fri . "Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases". United States. doi:10.1016/J.IJROBP.2017.05.028.
@article{osti_22723006,
title = {Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases},
author = {Williams, Noelle L. and Wuthrick, Evan J. and Kim, Hyun and Palmer, Joshua D. and Garg, Shivank and Eldredge-Hindy, Harriet and Daskalakis, Constantine and Feeney, Kendra J. and Mastrangelo, Michael J. and Kim, Lyndon J. and Sato, Takami and Kendra, Kari L. and Olencki, Thomas and Liebner, David A. and Farrell, Christopher J. and Evans, James J. and Judy, Kevin D. and Andrews, David W. and Dicker, Adam P. and Werner-Wasik, Maria and others, and},
abstractNote = {Purpose: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. Methods and Materials: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The (ClinicalTrials.gov) registration number is (NCT01703507). Results: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. Conclusions: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.},
doi = {10.1016/J.IJROBP.2017.05.028},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 1,
volume = 99,
place = {United States},
year = {2017},
month = {9}
}