A Phase I/II Dose Schedule Finding Study of ch14.18/CHO Continuous Infusion

Chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese Hamster Ovary (CHO) cells (ch14.18/CHO) specifically recognizes the target antigen GD2, which is expressed on virtually all neuroblastoma tumours. This antibody has already been tested in stage 4 neuroblastoma patients as a bolus infusion in phase I/II clinical trials with encouraging response rates. Aldesleukin (IL-2, (Proleukin)) has been shown to augment natural killer cell mediated antibody dependent cellular cytotoxicity in vitro and in vivo which is the main mechanism of ch14.18/CHO mediated anti-neuroblastoma activity. The feasibility to combine ch14.18/CHO therapy with aldesleukin (IL-2) has been demonstrated in patients with neuroblastoma. However, side effects of ch14.18/CHO bolus infusions (e.g. 20 mg/m2 on 5 consecutive days as 8h infusions) and intravenous infusion of aldesleukin (IL- 2) (e.g. 3 x 106 IU/m2/day, continuous infusion for 4 days) are neuropathic pain requiring intravenous (i.v.) morphine applications and inflammatory responses including shock and capillary leak syndrome, requiring inpatient care. Clinical experience with bolus infusions of ch14.18/CHO indicates that a decrease of the infusion rate is associated with a reduction of neuropathic pain in treated patients. Furthermore, the feasibility of subcutaneous (s.c.) aldesleukin (IL-2) therapy (e.g. 6x106 IU/m2 ) in an outpatient setting has been demonstrated in children with stage 4 neuroblastoma. The primary objective is to find a tolerable treatment schedule which reduces the pain-toxicity profile of ch14.18/CHO whilst maintaining immunomodulatory efficacy in patients (1-21 years old) with either primary refractory (= 2 lines of conventional treatment) or relapsed neuroblastoma by using a prolonged continuous infusion in combination with a fixed dose of s.c aldesleukin (IL-2). The secondary objectives are: To assess pain intensity and relief by appropriate medication with a validated self- report tool To validate, during the first course, the correlation between activated NK cells and ch14.18/CHO level with ADCC by using MNC and serum from patients on day 15. To determine systemic immune modulation/response resulting from the combined treatment of ch14.18/CHO and s.c. aldesleukin (IL-2) by repeated analysis of NK-cell activation, soluble IL-2 receptor, ADCC, CDC and anti-idiotype response (HAMA and HACA). To achieve an increase in absolute lymphocyte counts and absolute NK cell numbers after the respective cycles as a measurement of response to s.c. aldesleukin (IL-2). To determine the pharmacokinetics of ch14.18/CHO. To evaluate anti-tumour responses resulting from this treatment regimen through clinical assessments in patients with measurable disease. The chosen ch14.18/CHO infusion schedule will be examined in an expansion cohort of 20 patients to confirm the results.

The current study was assessed to address a need in paediatric drug development in an orphan disease indication by establishing an efficacious immunotherapy approach with improved tolerance for paediatric high risk neuroblastoma (HR-NBL) patients after intensive multimodal treatments. Survival rates for children with HR-NBL are low and have only shown modest improvement despite treatment intensification reaching only 20 to 30% cure rates in long term observation. Hence, the concept of an additive tumour specific immunotherapy for HR-NBL was introduced to improve outcome. Therefore standard therapy including the addition of a combination therapy of a chimeric mononuclear antibody (mAB), ch14.18/CHO addressing GD2 with interleukin 2 (IL2), which has been shown to augment natural killer cell- mediated cancer cell cytotoxicity was a promising option to increase event free survival. However, such a tumour-specific immunotherapy is associated with considerable side effects and pain leading to the use of high doses of intravenous (iv) morphine. However, it could be shown that a decrease in the infusion rate of ch18.14 alleviates neuropathic pain and an administration of IL2 not iv but subcutaneously (sc) reduces IL2 associated side effects. Based on these considerations, the continuous infusion of ch14.18/CHO in combination with IL2 sc was developed anticipating an ameliorated anti-neuroblastoma activity with an acceptable pain-toxicity profile. The primary objective of this study was to find a tolerable treatment schedule which reduces pain, helping to spare the use of high dose iv morphine whilst maintaining immunomodulatory efficacy in paediatric patients with either primary refractory or relapsed neuroblastoma using a prolonged continuous infusion in combination with sc IL2. As of July 2014, 124 patients between 1 and 21 years of age from 11 European countries were recruited. The dose finding cohort consisted of 24 and the confirmatory cohort consisted of 100 patients. The algorithm result of the dose finding cohort was that the suitable ch14.18/CHO infusion schedule is 10mg/m over 10 days. With this infusion schedule, the efficacy and toxicity endpoints could be reached, the pain toxicity profile could be improved and there are signals of clinical activity related to objective responses. Since this infusion schedule is efficient and beneficial for the patients it has already been implemented in another GD2 SIOPEN study (Amendment 7 of the HRNBL1/SIOPEN study).