Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium

Abstract

Purpose: 131I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate.

Patients and methods: Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m2/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected.

Results: One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%.

Conclusion: Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.

Trial registration: ClinicalTrials.gov NCT02035137.

Conflict of interest statement

Steven G. DuBoisConsulting or Advisory Role: BayerResearch Funding: Merck, Roche/Genentech, Lilly, Curis, Loxo, BMS, Eisai, Pfizer, Turning Point Therapeutics, Bayer, Salarius PharmaceuticalsTravel, Accommodations, Expenses: Roche/Genentech, Salarius PharmaceuticalsUncompensated Relationships: Ymabs Therapeutics Inc Susan GroshenEmployment: Pfizer Scarlett CzarneckiSpeakers' Bureau: United Therapeutics Yael P. MosseConsulting or Advisory Role: ASCO, Pfizer, Lilly, Auron Therapeutics, JumoResearch Funding: Pfizer John M. MarisStock and Other Ownership Interests: Tantigen BIO IncConsulting or Advisory Role: Auron Therapeutics, Illumina Radiopharmaceuticals, Jubilant DraxImagePatents, Royalties, Other Intellectual Property: GPC2 binders and CARs, Neuroblastoma antigens Suzanne ShustermanStock and Other Ownership Interests: Bristol Myers Squibb, GlaxoSmithKline, Intuitive Surgical, Kindred Biosciences, Merck, Nuvasive, OPKO Health, Regeneron, Surgalign, Amgen, BioTelemetry, RTI Surgical Holdings, EFOFEM biosciences, InVitae Susan L. CohnStock and Other Ownership Interests: Merck, Stryker, Amgen, Pfizer, AbbVie, Amgen, Lilly, Sanofi, Accelerated Medical Diagnostics, Novo Nordisk, Gilead Sciences, United Health Group, TevaHonoraria: Y-mAbs TherapeuticsResearch Funding: United Therapeutics, MerckOpen Payments Link: https://openpaymentsdata.cms.gov/physician/46569/summary Brian WeissResearch Funding: Novartis, Genentech, ExelixisTravel, Accommodations, Expenses: Exelixis, RocheOpen Payments Link: https://openpaymentsdata.cms.gov/physician/620363 Gregory A. YanikResearch Funding: Jazz Pharmaceuticals Meredith S. IrwinHonoraria: Bayer Daphne A. Haas-KoganConsulting or Advisory Role: Leidos Biomedical Research, SRA International, Gerson Lehrman Group, Guidepoint Global Araz MarachelianResearch Funding: Pfizer, United Therapeutics Katherine K. MatthayConsulting or Advisory Role: Resonance HealthNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram showing random assignment of 114 patients to yield 105 eligible and evaluable patients. MIBG, 131I-metaiodobenzylguanidine.

FIG 2.

Waterfall plot according to randomized arm showing the sum of relative Curie score (Curie score after first course divided by baseline Curie score) minus 1 such that a value of 0 represents no change from baseline, a value of –1 represents a complete response by Curie score, and positive values represent increases in Curie score. A, B, and C correspond to arms A, B, and C. The heavy red line represents threshold for being considered to have had a partial response or better by Curie score.

FIG A1.

PFS from time of random assignment for 105 patients according to randomized arm. PFS, progression-free survival.

FIG A2.

OS from time of random assignment for 105 patients according to randomized arm. NA, not available; OS, overall survival.