Phase I Study of <sup>131</sup> I-Metaiodobenzylguanidine With Dinutuximab ± Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Trial
Abstract
PURPOSE We conducted a phase I trial to determine the safety, tolerability, and preliminary antitumor activity of 131 I-metaiodobenzylguanidine (MIBG) combined with the anti-GD2 antibody dinutuximab with or without the histone deacetylase inhibitor vorinostat in patients with relapsed/refractory neuroblastoma (rNBL). METHODS In part A, patients with MIBG-avid rNBL received MIBG intravenously (IV) on day 1 at 12, 15, or 18 mCi/kg per the rolling six design and dinutuximab (17.5 mg/m 2 once daily) IV on days 8-11 and 29-32 and granulocyte-macrophage colony-stimulating factor (250 mcg/m 2 once daily) subcutaneously on days 8-17 and 29-38. Autologous stem cells were infused on day 15. In part B, vorinostat at 180 mg/m 2 once daily was given orally on days 0-13 in combination with the part A recommended phase II dose (RP2D). Patients could receive two courses. RESULTS Forty-five eligible patients enrolled, of whom 31 were evaluable. The median age was 7.5 (range, 2.9-24.1) years. For part A (n = 19), no dose-limiting toxicities (DLTs) occurred across all dose levels and courses, establishing the RP2D of MIBG to be 18 mCi/kg. In part B (n = 12), 1 DLT (grade 3 hypokalemia) occurred during course 1, and 3 of 11 patients who received a second course experienced DLT: grade 3 ALT increase, grade 4 hypoxia and grade 5 pneumonitis, and grade 3 fatigue. The best overall response rate (BORR; complete response [CR] + partial response [PR]) on part A was 42% with a CR/PR/minor response (MR) rate of 46%, and 19% progressive disease (PD) rate. For part B, the BORR was 42% with a CR/PR/MR rate of 75% and 0% PD rate. CONCLUSION MIBG combined with dinutuximab was well tolerated with encouraging antitumor activity. Vorinostat added to this combination may augment responses in this heavily pretreated patient population.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (29)
Thomas Cash
Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA
Araz Marachelian
Cancer and Blood Disease Institute, Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles, CA
Steven G. DuBois
Yueh-Yun Chi
3Division of Hematology, Oncology and Blood and Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, United States
Anahit Baregamyan
Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles, CA
Susan G. Groshen
USC Norris Comprehensive Cancer Center, Los Angeles, CA
Hunter C. Jonus
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA
Anasheh Shamirian
Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA
Mary Crowley
Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA
Fariba Goodarzian
Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles, CA
Patricia T. Acharya
Department of Radiology, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA
Bruce Pawel
Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles, CA
Amy K. Erbe
Ankita Shahi
Hematology/ Oncology School of Medicine and Public Health, University of Wisconsin, Madison, WI
Jen Zaborek
Departments of Pediatrics, Human Oncology, or Biostatistics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
Eleanor Kennedy
Departments of Pediatrics, Human Oncology, or Biostatistics, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
Shahab Asgharzadeh
Cancer and Blood Disease Institute Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles California 90027 USA
Judith G. Villablanca
Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA
Navin Pinto
1University of Colorado School of Medicine, Aurora, United States
Brian D. Weiss
Department of Pediatrics, Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Yael P. Mossé
Ami V. Desai
Department of Pediatrics, University of Chicago, Chicago, IL
Margaret E. Macy
Department of Pediatrics, University of Colorado and Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO
Meaghan Granger
Cook Children's Medical Center, Fort Worth, TX
Kieuhoa T. Vo
Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco School of Medicine, San Francisco, CA
Paul M. Sondel
Katherine K. Matthay
Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco School of Medicine, San Francisco, CA
Julie R. Park
Kelly C. Goldsmith
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA