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
Thomas F. Cash, Araz Marachelian, Steven G. DuBois, Yueh‐Yun Chi, Anahit Baregamyan, Susan Groshen, Hunter C. Jonus, Anasheh Shamirian, Mary F. Crowley, Fariba Goodarzian, Patricia T. Acharya, Bruce Pawel, Amy K. Erbe, Ankita Shahi, Jen Zaborek, Eleanor Kennedy, Shahab Asgharzadeh, Judith G. Villablanca, Navin Pinto, Brian Weiss, Yaël P. Mossé, Ami V. Desai, Margaret E. Macy, Meaghan Granger, Kieuhoa T. Vo, Paul M. Sondel, Katherine K. Matthay, Julie R. Park, Kelly C. Goldsmith
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.