This phase I study established that 3F8 dosing can be significantly escalated with acceptable toxicity; acute adverse effects resembled those in prior and concurrent phase II studies,5,6,9
and no delayed adverse effects were encountered. These observations eased concern that HM3F8 and/or high doses of 3F8 might have unexpected toxicities or that the acute neuropathic symptoms during 3F8 treatment might herald long-term nerve damage. Anti-NB activity occurred at all dosages. The findings support the hypothesis that anti-GD2
MoAbs devoid of ADCC and CMC functions, such as HM3F8, can modify pain adverse effects, without blunting anti-NB activity. A randomized trial would be needed to confirm this hypothesis.
The number of cycles was limited to two because that amount was deemed sufficient to answer the phase I study question regarding MTD. Prior experience with more than 200 patients showed that toxicities of 3F8 did not worsen with multiple cycles. Rather, pain and analgesic use were greatest on day 1 of a patient's initial cycle and diminished thereafter. This welcome finding was attributable in part to less anxiety of patients and parents as they became familiar with the symptoms.
A reluctance to dose escalate 3F8 was a result of pain-related hypertension in the initial phase I trial.1
However, a majority of patients were adults (most with melanoma, with age up to 56 years), an age group later identified as being especially susceptible to toxicity from anti-GD2
With subsequent experience, adverse effects proved more readily manageable. Treatment was safely transitioned to the outpatient setting. The 3F8 infusion was reduced to 30 minutes, without exacerbating toxicity. The shorter infusion time facilitated matters for patients and staff. The number of outpatients treated daily increased to 12. In the current study, despite the interference with general well-being for up to several hours per day of each cycle, no family stopped therapy for their child, and all five adolescents completed the treatment plan.
The goal of ever better control of adverse effects plus the promise of increased anti-NB activity with higher dosing converged when HM3F8 was found to have properties that might promote 3F8 dose escalation. Thus, we learned that HM3F8 did not cause pain; all six patients treated in a single day had no adverse effects when 3F8 was mistakenly thawed in hot water. This clinical mishap (never repeated) prompted laboratory investigations. In vitro, HM3F8 retained affinity to GD2
but lost the ADCC and CMC functions of unmodified 3F8 (see Patients and Methods). In animal studies using xenografts of human NB and prior administration of HM3F8, the latter did not affect the biodistribution of iodine-131–3F8 in mice (Appendix Fig A1
, online only) or reduce the anti-NB activity of unmodified 3F8 in rats (Appendix Fig A2
, online only). Rats pretreated with HM3F8 had less discomfort with a subsequent injection of native 3F8. (Mice remain asymptomatic after 3F8 injection irrespective of dose and are not a good model for pain adverse effects.)
All of the previously mentioned findings—the absence of pain in the clinical mishap, the retention by HM3F8 of GD2
binding despite obliteration of effector functions, and the excellent post-HM3F8 biodistribution and anti-NB activity of native 3F8 in animal models—were considered in the following context: the sharp contrast, in patients treated with 3F8, between the immediacy of pain and the much more delayed timing of tumor uptake (peaks at 24 hours).24
We hypothesized that HM3F8 could be used to block the pain fibers that quickly (within minutes) captured the first wave of MoAb as it was infused and thereby reduce pain adverse effects from a large treatment dose of 3F8 administered subsequently.
On the basis of the preclinical studies showing undiminished targeting of native 3F8 after HM3F8, we reasoned that a ratio of ≤ 1:10 (2 mg of HM3F8 v
≥ 20 mg of native 3F8) would have minimal negative effect on 3F8 localization to NB in patients and, therefore, would not reduce antitumor activity. Response is not usually a major aspect of a phase I study; for example, one notable phase I study of another anti-GD2
MoAb did not encompass antitumor responses.12
In our study, however, antitumor activity was of interest, given the possibility that HM3F8 might mask GD2
on NB and thereby reduce the anti-NB effects of unmodified 3F8. Disease regressions were, in fact, seen in this poor-prognosis patient population, although not in patients enrolled with PD (; similar to prior experience9
). Nevertheless, it remains possible that HM3F8 masks GD2
on tumor. Furthermore, one must always consider that responses are delayed effects of prior therapies.
The protocol treatment had no evident impact on the development of HAMA, allaying concern that HM3F8 and/or high doses of 3F8 might increase the risk of HAMA. Thus, similar to the experience with standard-dose 3F8 and no HM3F8,21
HAMA after one cycle of HM3F8 plus high-dose 3F8 did not emerge when patients were less than 90 days from treatment with high doses of immunosuppressive alkylating agents (). Treatment before starting 3F8 was not standardized in the protocol because extensive prior multimodality therapy precludes safe use of strongly myelosuppressive regimens (eg, with high-dose cyclophosphamide) in many patients with resistant NB.
The critical message from this phase I study is the safe multifold escalation of 3F8 dosage in the outpatient setting. Although possibly attributable in part to pain-modifying effects of HM3F8, this clinical scenario is related to the improved management and alleviation of 3F8 adverse effects that emerged in the 1990s. The results of this phase I trial are serving as the basis for a new treatment program centered on HM3F8 and high dosing of 3F8.