Successful multifold dose escalation of anti-GD2 monoclonal antibody 3F8 in patients with neuroblastoma: a phase I study

Abstract

Purpose: Pain can hinder immunotherapy with anti-G(D2) monoclonal antibodies (MoAbs) like 3F8. Heat-modified 3F8 (HM3F8) lacks effector functions and could mask G(D2) or cross-reactive epitopes on nerves, thereby preventing a subsequent dose of unmodified 3F8 from activating pain fibers. We hypothesized that 3F8 dose escalation is possible without increased analgesic requirements in patients pretreated with HM3F8.

Patients and methods: Thirty patients with resistant neuroblastoma (NB) received one to two cycles of 3F8 plus granulocyte-macrophage colony-stimulating factor. 3F8 dosing began at 20 mg/m(2)/d and increased by 20 mg/m(2)/d in the absence of dose-limiting toxicity (DLT). Premedication included analgesics, antihistamines, and 5-minute infusions of HM3F8. On the basis of experience with 3F8 10 mg/m(2)/d in prior protocols, the DLT of pain was defined as more than seven doses of opioids administered within 2 hours. Opioid use was compared with a contemporary control group treated with 3F8 20 mg/m(2)/d but no HM3F8. Disease response was assessed.

Results: Treatment was administered in the outpatient setting. Dose escalation stopped at 160 mg/m(2)/d because of drug supply limitations; even through this dosage level, analgesic requirements were similar to historical controls, and there were no DLTs. Analgesic requirements at 3F8 dosage levels through 80 mg/m(2)/d were significantly less compared with controls. Anti-NB activity occurred at all dosages.

Conclusion: Multifold dose escalation of 3F8 is feasible. The findings can be interpreted as compatible with the possibility that HM3F8 can modify toxicity without blunting anti-NB activity. This pain control strategy may help achieve dose escalation with other anti-G(D2) MoAbs.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig A1.

Results in mice xenografted with human neuroblastoma. The biodistribution of 25 mg/m2 (0.8 mg/kg) of 131I-3F8 was not altered by prior administration of 30 mg/m2 (0.9 mg/kg) of heat-modified 3F8 (HM3F8; a ratio of HM3F8:3F8 of approximately 1:1), as reflected in the (A) tumor-to-nontumor ratio and (B) percent injected dose (ID) per gram of tumor. st, stomach; cont, contents; sm int, small intestine; lg int, large intestine.

Fig A2.

Results in rats xenografted with human neuroblastoma. Treatment with 3F8 (160 mg/m2, or 4.8 mg/kg) produced tumor shrinkage with or without prior administration of heat-modified 3F8 (HM3F8; 40 mg/m2, or 1.2 mg/kg; a heated-to-native ratio of 1:4).