High risk neuroblastoma (NB) has widespread metastasis. Current therapy is at toxicity limit with an unacceptably low 30% cure rate. GD2 is an established target for antibody therapy. Effective therapeutic monoclonal antibodies (MoAb) can exploit GD2 binding kinetics (slow koff) and effective ADCC and CMC functions. Armed with these characteristics, mouse anti-GD2 MoAb m3F8 was chosen for clinical studies over the past 2 decades. NB response by marrow histology and MIBG scans, as well as prolonged progression-free survival support the efficacy and safety of this approach. The major limitation of anti-GD2 MoAb therapy is the pain side effect, and specifically for murine MoAb like m3F8, it is the hurdle of immunogenicity. Objective/Hypothesis: The humanized form of 3F8 (hu3F8) can potentially overcome both of these limitations. A phase I dose escalation study of hu3F8 is proposed to explore both ends of dosing schedule. At low dose hu3F8, pain side effects could be much reduced;at high dose hu3F8, anti-tumor effect could be much improved. The primary goal is to establish the maximum tolerated dose (MTD) with minimal/no pain side effects, and MTD with no dose-limiting toxicity (DLT). The secondary goal is to study the pharmacokinetics (PK) of hu3F8. The last goal is to assess anti-tumor activity. Study Design: Six dosage levels of hu3F8 will be tested (0.06, 0.15, 0.3, 0.6, 1.5, 3 mg/kg/dose), given as two injections of hu3F8 each over 30 minutes, 168 hours apart. Using a classic 3+3 phase I design, DLT will be measured by Common Toxicity Criteria (Version 4.0, NCI). Pain side effect will be treated with standardized opioid rescues. DLT of pain is defined as a need for seven or more (mean + 2SD) doses of opioids within two hours. DLT of hypertension is defined as a need for antihypertensive medication for >24 hours. The mean number of rescues required at each dose level will be compared to that for 20 mg/m2 of m3F8 used in concurrent studies at MSKCC. A maximum of 36 patients will be treated on this study;if there are no DLTs, only 21 patients will be needed to complete the study. Serum PK over 168 hours after each injection of hu3F8 will be analyzed. Anti- tumor activity will be monitored using INSS for NB, or RECIST criteria for GD2-positive solid tumors. Impact: This proposal builds on current anti-GD2 MoAb therapy by exploiting kinetically and functionally improved humanized antibodies for metastatic relapsed NB and GD2-positive solid tumors. A painless or pain-"lite" regimen can greatly expand the possibilities of future applications of anti-GD2 MoAb for treating other GD2-positive cancers in children and in adults.

Public Health Relevance

High risk neuroblastoma spreads to bone and bone marrow, and is very difficult to treat;even with strong medicines like chemotherapy and radiation, the chance of cure is unacceptably low. Murine monoclonal antibody (MoAb) m3F8 targeted against the antigen GD2 on neuroblastoma has shown clinical benefits. Next generational anti-GD2 MoAb has been humanized, and hu3F8 has log-fold enhancement in anti-tumor activity even at low doses, with potential for less pain side effects. A phase I study of hu3F8 in patients with neuroblastoma and GD2-positive tumors is proposed.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Clinical Oncology Study Section (CONC)
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Timmer, William C
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Sloan-Kettering Institute for Cancer Research
New York
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Ahmed, Mahiuddin; Cheung, Nai-Kong V (2014) Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy. FEBS Lett 588:288-97
Dobrenkov, Konstantin; Cheung, Nai-Kong V (2014) GD2-targeted immunotherapy and radioimmunotherapy. Semin Oncol 41:589-612
Cheung, Nai-Kong V; Dyer, Michael A (2013) Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer 13:397-411