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Definitions

• the present invention relates to induction therapy for treating newly diagnosed neuroblastoma, particularly involving induction chemotherapy and therapy with an anti-GD2 antibody.
• BACKGROUND TO THE INVENTION Neuroblastoma, after brain cancer, is the most frequent solid cancer in children under 5 years of age. In high-risk neuroblastoma, more than half of the patients receiving standard therapy have a relapse and ultimately die from the disease. Approximately 90% of cases occur between ages 0 to 6 years. The worldwide incidence in industrialized countries is around 2000 cases per year.
• the disialoganglioside GD2 is a glycosphingolipid expressed primarily on the cell surface. GD2 expression in normal tissues is rare and primarily restricted to the central nervous system (CNS), peripheral nerves, and melanocytes. In cancerous cells, GD2 is uniformly expressed in neuroblastomas and most melanomas and to a variable degree in bone and soft-tissue sarcomas, small-cell lung cancer, renal cell carcinoma, and brain tumors (Navid et al., Curr Cancer Drug Targets 2010). GD2 is also expressed in Ewing sarcoma (Kailayangiri S et al., Br J Cancer. 2012;106(6):1123-1133.
• Antibody 14G2a has been developed as chimeric (murine/human) forms known as ch14.18, in particular, dinutuximab beta (Qarziba ® ) and dinutuximab (Unituxin ® ).
• An independently generated murine antibody 3F8 has been humanized as naxitamab.
• humanized 3F8 has an apparent kD of 7.7 nM for binding to GD2, a binding preference for GD2 versus the related glycan structure GT2 of 1500, and a binding preference for GD2 versus the related glycan structure GQ2 of 200, whereas Unituxin has an apparent kD of 60 nM for binding to GD2, a binding preference for GD2 versus GT2 of >5000 and a binding preference for GD2 versus GQ2 of 1000. These differences reflect the different binding regions of the antibodies.
• Dinutuximab beta which is produced in Chinese Hamster Ovary (CHO) cells, and Unituxin, which is produced in SP2/0 murine hybridoma cells, differ in their glycosylation patterns.
• Dinutuximab beta has a single N-linked glycosylation site (Asn 293), and mass spectrometry analysis revealed that the heavy chain contains the typical IgG diantennary fucosylated N-glycans with 0, 1, or 2 galactose residues, with a smaller fraction of glycans with sialic acid and oligomannose residues, and no Gal- ⁇ - 1,3 Gal, typical for IgG expression in CHO cells (European Public Assessment Report (EPAR) of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for Dinutuximab beta Apeiron (EMA/263814/2017, 23 March 2017).
• CHMP Committee for Medicinal Products for Human Use
• EMA European Medicines Agency
• ch14.18 known as hu14.18K322A is described in WO2005/070967 and has a point mutation in the Fc region in order to reduce complement-dependent cytotoxicity (CDC) but still maintain antibody-dependent cellular cytotoxicity (ADCC).
• CDC complement-dependent cytotoxicity
• ADCC antibody-dependent cellular cytotoxicity
• US 9,777,068B2 it is shown in US 9,777,068B2 that the cytolysis capacity of an anti-GD2 antibody as measured by a CDC assay is essential for the anti-tumour effect.
• Dinutuximab beta also referred to as ch14.18/CHO or APN311 is licensed in the European Union (EU) subject to additional monitoring as Qarziba ® and is administered at 10 mg/m 2 /day as an 8-hour or 24-hour infusion (Dinutuximab Beta Investigator’s Brochure. Version 3.0 dated 14 May 2019).
• Dinutuximab beta is indicated for the treatment of high-risk neuroblastoma in patients aged 12 months and above, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation, as well as patients with history of relapsed or refractory neuroblastoma, with or without residual disease.
• Dinutuximab beta is also authorised as a medicinal product in Australia and Israel.
• Various patents cover methods of using Dinutuximab beta, particularly US 9,777,068 B2 which discloses a continuous intravenous infusion regimen which reduces the side-effect of pain; and US 9,840,566 B2 and US 10,294,305 B2 which disclose treatment regimens in which IL-2 is not administered in the same treatment cycle or overall treatment period.
• Toxicity profiles of chemotherapy drugs and monoclonal antibodies may overlap, and there may be a risk of unacceptable toxicity in combining treatments. For this reason, clinical trials of combination chemotherapy and monoclonal antibody therapy have tended to focus on relapsed and refractory neuroblastoma patients, who have fewer treatment options and worse outcomes.
• a clinical trial of irinotecan hydrochloride, temozolomide, and dinutuximab with or without eflornithine in treating patients with relapsed or refractory neuroblastoma recruitment has suspended patient recruitment because of a higher than expected incidence of hearing loss (https://clinicaltrials.gov/ct2/show/NCT03794349).
• response rates would not necessarily predict response in newly diagnosed patients because previously treated tumors generally acquire additional mutations enabling them to become more resistant to further anticancer treatment than lesser treated or previously untreated tumors.
• Individual anti-GD2 antibodies have different toxicity profiles, with different dosing and supportive medication requirements.
• a first aspect of the invention provides a method of treating a newly diagnosed neuroblastoma in a patient by administering chimeric anti-GD2 antibody dinutuximab beta to the patient in combination with induction chemotherapy, wherein the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy at a cumulative dose of up to 500 mg/m 2 , wherein a newly diagnosed neuroblastoma is treated in the patient.
• a second aspect of the invention provides a method of treating a newly diagnosed neuroblastoma in a patient by administering chimeric anti-GD2 antibody dinutuximab beta to the patient in combination with induction chemotherapy, wherein the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient in a dose of up to 100 mg/m 2 per cycle during one or more cycles of induction chemotherapy, wherein a newly diagnosed neuroblastoma is treated in the patient.
• a third aspect of the invention provides a method of treating a newly diagnosed neuroblastoma in a patient by administering chimeric anti-GD2 antibody dinutuximab beta to the patient in combination with induction chemotherapy, wherein the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy at a treatment density of up to 5 mg/m 2 /day, wherein a newly diagnosed neuroblastoma is treated in the patient.
• DESCRIPTION OF THE FIGURES Figure 1 Schema for combination induction chemotherapy (COJEC and GPOH) and combination dinutuximab beta immunotherapy.
• COJEC cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide
• Cycle A vincristine, carboplatin, etoposide
• Cycle B vincristine, cisplatin
• Cycle C vincristine, cyclophosphamide, etoposide
• GPOH German Pediatric Oncology and Hematology
• HDC BuMel high-dose chemotherapy busulfan and melphalan
• Cycle N5 cisplatin, etoposide, vindesine
• Cycle N6 vincristine, dacarbazine, ifosfamide, doxorubicin
• PBSC peripheral blood stem cells.
• the present invention provides methods of treating a newly diagnosed neuroblastoma in a patient and compositions for use in the methods.
• Neuroblastomas are cancers that start in early nerve cells (called neuroblasts) of the sympathetic nervous system, and they can be found anywhere along this system. Most primary tumors (65%) occur within the abdomen with at least half of these arising in the adrenal medulla. Other common sites of disease include the neck, chest, and pelvis. Presenting signs and symptoms are highly variable and dependent on site of primary tumor as well as the presence or absence of metastatic disease and/or paraneoplastic syndromes.
• IRGSS International Neuroblastoma Risk Group Staging System
• a new International Neuroblastoma Risk Group (INRG) classification system has been proposed in 2009 with 4 broad categories —very low risk, low risk, intermediate risk, and high risk — based on the assessment of the following prognostic factors: age at diagnosis (2 cutoffs, 12 and 18 months), INRG tumour stage (L1, L2, M, MS), histologic category, grade of tumour differentiation, DNA ploidy (hyperploidy/diploidy), MYCN oncogene status (amplified or not), aberrations at chromosome 11q (presence/absence) (Cohn SL et al, Journal of Clinical Oncology 2009 27:2, 289-297).
• This system uses combinations of the seven prognostic risk factors to define 16 pretreatment groups stratified by the prognostic markers within four categories, namely very low–, low-, intermediate- and or high-risk group, the categories based on the 5-year event-free survival (EFS) rates of the 16 pretreatment groups.
• the pretreatment groups (labeled A to R) and risk categories are summarized in Pinto NR et al, J Clin Oncol. 2015 Sep 20; 33(27): 3008–3017, as shown in Table 1. 6
• By newly diagnosed neuroblastoma we mean a first diagnosis of neuroblastoma within a patient, for which the patient has yet to receive any neuroblastoma treatment.
• the newly diagnosed neuroblastoma may fall within any of the INRGSS disease classifications, or it may have been diagnosed by any other clinically accepted means.
• a newly diagnosed neuroblastoma patient will commence treatment within a few weeks from diagnosis, but we do not intend the term “newly diagnosed” to imply any limit on the interval between diagnosis and treatment.
• the methods may suitably be used for treatment of high-risk neuroblastoma, according to the high-risk classification of the International Neuroblastoma Risk Group (INRG) classification system, as described in Pinto NR et al, supra.
• INRG International Neuroblastoma Risk Group
• pretreatment groups K, N, O, P, Q and R are identified as belonging to the high-risk classification, and the methods may be used to treat patients in any of these groups, which may be defined as any patient with MYCN amplified neuroblastoma (other than stage L1 according to INRGSS) or any patient older than 12 months of age at diagnosis with stage M disease.
• Suitable patients may be pretreatment group P (i.e. stage M, according to INRGSS, age ⁇ 18 months), and typically ⁇ 18 years.
• the methods involve administering chimeric anti-GD2 antibody dinutuximab beta to the newly diagnosed neuroblastoma patient in combination with induction chemotherapy.
• dinutuximab beta consists of 2 light chains (220 amino acids) and 2 heavy chains (443 amino acids) and is of the IgG1 subclass.
• the monoclonal antibody incorporates human constant regions for the heavy chain IgG1 and the kappa light chain, along with the mouse variable regions targeted specifically against human GD2.
• the relative molecular mass of the intact antibody is approximately 150,000 daltons.
• the encoding nucleotide sequences and the amino acid sequences of chimeric anti-GD2 antibody dinutuximab beta are provided in US 9,777,068 B2.
• the light-chain nucleotide sequence is provided as SEQ ID NO.1
• the heavy- chain nucleotide sequence is provided as SEQ ID NO.2
• the light-chain amino acid sequence as SEQ ID NO. 3 and the heavy-chain amino acid sequence as SEQ ID NO. 4.
• the first 60 nucleotides of SEQ ID NO. 1 or SEQ ID NO. 2 encode the signal peptide of the heavy or light chain respectively.
• the first 20 amino acids of SEQ ID NO.3 or 4 are the signal peptide of the heavy or light chain respectively.
• the signal peptides are cleaved off during post-translational processing, and are not part of the final recombinant protein.
• a preparation comprising a dinutuximab beta may further comprise salts and WFI.
• the preparation comprising dinutuximab beta may further comprise a buffer, e.g., phosphate-buffered saline, comprising said salts and WFI.
• a preparation comprising dinutuximab beta may further comprise stabilizing agents, preservatives and other carriers or excipients.
• the preparation comprising a dinutuximab beta may be freeze-dried and reconstituted for use. In one embodiment, the preparation comprising dinutuximab beta does not comprise preservatives and other excipients.
• the preparation comprising dinutuximab beta may be added to an infusion bag, e.g., an infusion bag containing 100 mL NaCl 0.9% and 5 mL human serum albumin 20%.
• Chemotherapy for neuroblastoma typically involves multiple cycles of treatments with combinations of drugs. By induction therapy, we mean the first (frontline) or only course of chemotherapy administered to a newly diagnosed neuroblastoma patient. Induction chemotherapy is typically performed in conjunction with surgery.
• Induction chemotherapy may be administered before or after surgery, or surgery may be performed between treatment periods with induction chemotherapy drugs. Surgery may be performed more than once in conjunction with induction chemotherapy. Depending on risk classification, treatment may stop after induction chemotherapy and surgery. Induction therapy is typically used in the treatment of high-risk neuroblastoma, although patients classified as intermediate-risk may also receive chemotherapy and surgery (Pinto NR et al, 2015, supra). Multimodal standard treatment for newly diagnosed high risk neuroblastoma may involve induction chemotherapy, megatherapy, radiation, surgery, and consolidation therapy. For high-risk neuroblastomas, the current treatment can be divided into 3 distinct phases (Maris JM. N Engl J Med. 2010;362(23):2202-2211.
• Suitable platinum compounds may include cisplatin, carboplatin and/or oxaliplatin.
• Suitable alkylating agents may include cyclophosphamide, dacarbazine, mechlorethamine, chlorambucil, temozolamide, melphalan, and/or ifosfamide.
• Suitable topoisomerase agents may inhibit topoisomerase I or topoisomerase II.
• Suitable topoisomerase I inhibitors may include irinotecan, topotecan, and/or camptothecin.
• Suitable topoisomerase II inhibitors may include etoposide, doxorubicin, epirubicin, daunorubicin and/or mitoxantrone.
• Anthracyclines are a class of potent and widely used cytotoxic drugs, derived from antibiotics that inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand. They create iron-mediated free oxygen radicals, damaging the DNA and cell membranes, and inhibit topoisomerase II.
• Suitable anthracyclines may include doxorubicin, epirubicin, daunorubicin and/or mitoxantrone.
• Suitable antimicrotubule agents include vinca alkaloids, which are made from the periwinkle plant (catharanthus rosea), and taxanes, which are derived from the bark of the Pacific Yew tree (taxus).
• Suitable vinca alkaloids are vincristine, vinblastine, vinorelbine, and/or vindesine.
• Suitable taxanes include paclitaxel and/or docetaxel.
• induction chemotherapy we include any chemotherapy including at least one agent selected from at least three of the four classes, namely platinum compounds, alkylating agents, topoisomerase inhibitors and microtubule agents.
• the induction chemotherapy comprises between 1 and 10 cycles, such as between 5 and 8 cycles. Suitable numbers of cycles may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 cycles.
• Induction chemotherapy regimens which have been investigated are summarized in the table below. Of these, the 3 most effective induction chemotherapy regimens have become standard of care in different geographic regions.
• the rapid COJEC regimen is the preferred European induction regimen from the SIOPEN group, described in Ladenstein R et al. J Clin Oncol. 2010;28(21):3516-3524. Rapid COJEC showed an improvement in the Phase 3 HRNBL1 Study against the modified MSKCC/COG N7 (https://clinicaltrials.gov/ct2/show/NCT01704716).
• higher single doses of selected drugs than standard induction schedules are administered over a substantially shorter treatment period, with shorter intervals between cycles (Cochrane Database Syst Rev. 2015 May 19;(5):CD010774. doi: 10.1002/14651858.CD010774.pub2).
• ANBL0532 program The preferred US induction regimen from the Children’s Oncology Group (COG) (ANBL0532 program) is described in Park JR et al, J Clin Oncol 2011;29(33):4351–57; and https://clinicaltrials.gov/ct2/show/NCT00567567.
• ANBL/COG involves 2 cycles of topotecan and cyclophosphamide (400 mg/m 2 /d) for 5 days followed by 4 cycles of multiagent chemotherapy (Memorial Sloan-Kettering Cancer Center [MSKCC] regimen comprising alternating cisplatin/etoposide and cyclophosphamide plus doxorubicin/vincristine).
• a “treatment period” with a specific preparation or treatment as used herein means the period of time in which said specific preparation or treatment is administered to the patient. For example, if a chemotherapy drug is administered for 8 consecutive days, followed by 2 days of no administration of the chemotherapy drug, then the treatment period with the chemotherapy drug is 8 days.
• the term “treatment cycle” as used herein means a course of one or more treatments or treatment periods that is repeated on a regular schedule and may encompass a period of rest. For example, a treatment given for 8 days followed by 2 days of rest is 1 treatment cycle. The treatment cycle may be repeated, either identically or in an amended form, e.g., with a different dose or schedule, or with different additional treatments.
• a “treatment interval” is the interval between starting and completing a treatment cycle.
• the “overall treatment time” means the time period comprising all treatment cycles.
• treatment cycles may comprise time periods of no treatment (intervals in which no treatment is administered to the patient, i.e., no chemotherapy, no antibody, no other drug).
• the overall treatment time may also comprise said intervals of no treatment within treatment cycles. For example, if the patient receives 8 treatment cycles of 10 days, then the overall treatment time is 80 days.
• the overall treatment time may comprise at least 1, or 2 or more cycles, or up to 12 cycles. In one embodiment, the overall treatment time comprises 3, 4, 5, 6, 7, 8, 9, or 10 cycles.
• chimeric anti-GD2 antibody dinutuximab beta in combination with induction chemotherapy, we mean that the anti-GD2 antibody is administered during the overall treatment time of the induction chemotherapy.
• the anti-GD2 antibody and the chemotherapy drug(s) may be administered simultaneously, sequentially, or separately.
• “simultaneously” means that the drugs are to be taken together on at least one treatment day and may or may not be formulated as a single composition. Simultaneously” also encompasses a partial overlap in treatment days upon which the drugs are administered.
• the chemotherapy drug(s) may be administered for one or more consecutive days, and then both the chemotherapy drug(s) and the anti-GD2 antibody may be administered on subsequent consecutive days.
• “Sequentially” means that the drugs are administered on consecutive treatment days, but not on the same treatment day.
• the chemotherapy drug(s) may be administered for one or more consecutive days, and the anti-GD2 antibody may be administered for the immediately following one or more consecutive days.
• “separate” administration means that the anti-GD2 antibody and the chemotherapy drug(s) are administered as part of the same overall dosing regimen, but they are not administered on the same day.
• the chemotherapy drug(s) may be administered for one or more consecutive days, then there may be one or more days during which neither the chemotherapy drug(s) nor the anti-GD2 antibody are administered, and then on one or more subsequent days, the anti-GD2 antibody may be administered.
• the anti-GD2 antibody is administered simultaneously with the chemotherapy drug(s), more typically the treatment periods of the anti-GD2 antibody and the chemotherapy drug(s) are partially overlapping.
• the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy at a cumulative dose of up to 500 mg/m 2 .
• cumulative dose we mean the total dose that is administered during the overall treatment time. The units of dose are expressed in mg/m 2 , where the area (in m 2 ) refers to the patient’s body surface area (BSA). For example, if a patient has a body surface area of 0.7 m 2 , then a cumulative dose of 500 mg/m 2 would be 350 mg.
• the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy at a cumulative dose of at least 100 mg/m 2 , such as from 100 to 200 mg/m 2 , from 200 to 300 mg/m 2 from 300 to 400 mg/m 2 , or from 400 mg/m 2 to 500 mg/m 2 . Any intermediate range is also envisaged, such as from 100 to 400 mg/m 2 , or from 200 to 400 mg/m 2 .
• the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient in a dose of up to 100 mg/m 2 per cycle during one or more cycles of induction chemotherapy.
• Dinutuximab beta is not necessarily administered during all cycles of the induction chemotherapy. It may be administered during all but the first 2 cycles, or all but the first cycle, or all cycles of induction chemotherapy. Omitting the dinutuximab beta from the first cycle or first 2 cycles may improve the tolerability of the treatment regimen, as patients may start to adapt to the toxicity of the chemotherapy drug(s) after 1 or 2 cycles.
• the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy in a dose per cycle that is equal for all cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered.
• dinutuximab beta may be administered in a dose per cycle that is at least 10 mg/m 2 per cycle, such as from 10 to 30 mg/m 2 per cycle, from 20 to 40 mg/m 2 per cycle, from 30 to 50 mg/m 2 per cycle, from 40 to 60 mg/m 2 per cycle, from 50 to 70 mg/m 2 per cycle, or from 60 to 80 mg/m 2 per cycle.
• Suitable doses per cycle may be 20 mg/m 2 , 30 mg/m 2 , 40 mg/m 2 , 50 mg/m 2 , 60 mg/m 2 , or 70 mg/m 2 .
• dinutuximab beta may be administered at a dose per cycle that varies by up to 20 mg/m 2 such as up to 10 mg/m 2 between different cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered.
• the choice to vary the dose of dinutuximab beta between cycles may be based on the toxicity profiles of different cycles of a given induction chemotherapy.
• dinutuximab beta may be administered in a dose per cycle of at least 10 mg/m 2 per cycle for all cycles, such as from 10 to 30 mg/m 2 per cycle for one or more cycles and from 20 to 40 mg/m 2 per cycle for the other cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered; or from 20 to 40 mg/m 2 per cycle for one or more cycles and from 30 to 50 mg/m 2 per cycle for the other cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered; or from 20 to 40 mg/m 2 per cycle for one or more cycles and from 40 to 60 mg/m 2 per cycle for the other cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered; or from 40 to 60 mg/m 2 per cycle for one or more cycles and from 60 to 80 mg/m 2 per cycle for the other cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered.
• the mid-point of the given range may suitably be administered.
• a suitable dose of dinutuximab beta would be 30 mg/m 2 .
• Any of the above features of dose per cycle as defined in relation to the second aspect of the invention may be applied to the first aspect of the invention.
• a cumulative dose of up to 500 mg/m 2 such as at least 100 mg/m 2 , such as from 100 to 200 mg/m 2 , from 200 to 300 mg/m 2 , from 300 to 400 mg/m 2 , or from 400 to 500 mg/m 2 of dinutuximab beta may be provided in doses per cycle according to the embodiments described above.
• the features of cumulative dose as defined in relation to the first aspect of the invention may be applied to the second aspect of the invention.
• the cumulative dose may be up to 500 mg/m 2 , and embodiments described above.
• the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy at a treatment density of up to 5 mg/m 2 /day.
• treatment density we mean the cumulative dose divided by the total duration of combined induction therapy and dinutuximab beta treatment cycles.
• the “overall treatment time for dinutuximab beta” is less than the overall treatment time.
• the “overall treatment time for dinutuximab beta” is measured from the beginning of the first to the end of the last treatment cycle during which the dinutuximab beta is administered. For example, if the induction chemotherapy comprises 8 treatment cycles of 10 days each, and dinutuximab beta is first administered during the third cycle, and last administered during the eighth cycle, then the overall treatment time is 80 days, and the overall treatment time for dinutuximab beta is 60 days.
• “treatment density” may also be defined as the cumulative dose divided by the “overall treatment time for dinutuximab beta”.
• Suitable treatment densities may be at least 1 mg/m 2 /day, such as from 1 to 2 mg/m 2 /day, from 2 to 3 mg/m 2 /day or from 3 to 4 mg/m 2 /day. Any intermediate range is also envisaged, such as a treatment density of from 1 to 4 mg/m 2 /day, or from 2 to 4 mg/m 2 /day. Any of the above features of treatment as defined in relation to the third aspect of the invention may be applied to the first aspect of the invention.
• a cumulative dose of up to 500 mg/m 2 such as at least 100 mg/m 2 , such as from 100 to 200 mg/m 2 , from 200 to 300 mg/m 2 , from 300 to 400 mg/m 2 , or from 400 to 500 mg/m 2 of dinutuximab beta may be provided at a treatment density according to the embodiments described above. Any of the above features of treatment density as defined in relation to the third aspect of the invention may be applied to the second aspect of the invention.
• the treatment density may be up to 5 mg/m 2 /day, and embodiments described above.
• the features of cumulative dose as defined in relation to the first aspect of the invention may be applied to the third aspect of the invention.
• the dinutuximab beta is administered at a treatment density of up to 5 mg/m 2 /day, such as described in any of the embodiments above, the cumulative dose may be up to 500 mg/m 2 , and embodiments described above.
• the features of defined in relation to the second aspect of the invention may be applied to the third aspect of the invention.
• the dinutuximab beta when the dinutuximab beta is administered at a treatment density of up to 5 mg/m 2 /day, such as described in any of the embodiments above, the dinutuximab beta may be administered in doses per cycle according to the embodiments described above.
• the dinutuximab beta dose may be selected such that the incidence of dose-limiting toxicity (DLT) falls within a target range.
• the incidence of DLT may be expressed either as the percentage of patients who experience DLT during combination chemotherapy and dinutuximab beta therapy, or as a rate where 0 is no patients and 1 is all patients.
• the incidence of DLT may be determined in a clinical trial and may be expected to also apply to subsequent patients who receive the therapy.
• a target DLT rate may be set for a clinical trial and a permitted range of DLT rates.
• a suitable target DLT rate is ⁇ 33% of patients, and a permitted range of DLT rates is ⁇ 39.5%, such as 26.9% ⁇ 39.5%.
• a DLT is defined as a dinutuximab beta-related adverse event occurring during the DLT assessment period in a clinical trial that leads to treatment discontinuation or which meets certain criteria of Grade ⁇ 3 or 4 toxicity using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Suitable criteria are described in the Example.
• the chimeric anti-GD2 antibody dinutuximab beta may be administered to the patient as a continuous intravenous infusion over 24 hours per day, at a daily dose of 10 mg/m 2 .
• it may be administered over fewer than 24 hours per day, such as over between 8 and 24 hours, or over 8 hours, or over 4 hours. It may be administered at a daily dose of less than 10 mg/m 2 , such as 5 mg/m 2 .
• the antibody should be prepared under sterile conditions. The appropriate volume of dinutuximab beta should be withdrawn from the vials.
• the antibody solution is filtered (0.2 to 1.2 ⁇ m) before injection into the patient either by using an in-line filter during infusion or by filtering the solution with a particle filter (e.g., filter Nr. MF1830, Impromediform, Germany).
• the volume of the antibody is typically added to an infusion bag containing 100 mL NaCl 0.9% and 5 mL human serum albumin 20%.
• the chimeric anti-GD2 antibody dinutuximab beta may be administered to the patient on consecutive days of a cycle until the entire dose per cycle of the chimeric anti-GD2 antibody dinutuximab beta has been administered.
• Pain is an anticipated side effect of dinutuximab beta administration, which has been managed by standard pain prophylaxis, including intravenous morphine.
• morphine is administered only for some but not all days on which the antibody is administered, e.g., only on the first 1, 2, 3, 4, 5, 6, or 7 days of continuous antibody infusion. Further information on management of pain using morphine and other drugs is described in US9,777,068B2.
• Other drugs may be included in induction chemotherapy cycles, such as isotretinoin (13-cis- retinoic acid), suitably after the completion of the dinutuximab beta infusion.
• Granulocyte- colony stimulating factor may be included as supportive therapy for chemotherapy, such as described in relation to the exemplified COJEC and GPOH protocols.
• the first, second, and third aspects of the invention have been particularly exemplified in relation to an induction chemotherapy regimen comprising consecutive chemotherapy cycles of A (vincristine, carboplatin and etoposide), B (vincristine and cisplatin), C (vincristine, cyclophosphamide and etoposide), B, A, B, C, and B, wherein the cycles are of at least 10 days.
• a suitable regimen is rapid COJEC, also referred to herein simply as COJEC (Ladenstein R et al. J Clin Oncol.
• the chemotherapy cycles in rapid COJEC are of 10 day duration, but the cycles may be up to 14 days duration, according to Smith and Foster, 2018, supra. Cycle durations of 10, 11, 12, 13 and 14 days are encompassed.
• the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient at (i) a cumulative dose of from 120 to 160 mg/m 2 and/or a treatment density of from 2.00 to 2.67 mg/m 2 /day; or (ii) at a cumulative dose of from 160 to 200 mg/m 2 and/or a treatment density of from 2.67 to 3.33 mg/m 2 /day; or (iii) at a cumulative dose of from 190 to 230 mg/m 2 and/or a treatment density of from 3.17 to 3.83 mg/m 2 /day; or (iv) at a cumulative dose of from 220 to 260 mg/m 2 and/or a treatment density of from 3.67 to 4.30 mg/m 2 /day.
• a suitable cumulative dose of 140 mg/m 2 may be provided in 4 cycles at 20 mg/m 2 per cycle and 2 cycles at 30 mg/m 2 per cycle (amounting to a treatment density of 2.33 mg/m 2 /day).
• a suitable cumulative dose of 180 mg/m 2 may be provided in 6 cycles at 30 mg/m 2 per cycle (amounting to a treatment density of 3.00 mg/m 2 /day).
• a suitable cumulative dose of 210 mg/m 2 may be provided in 3 cycles at 30 mg/m 2 per cycle and 3 cycles at 40 mg/m 2 per cycle (amounting to a treatment density of 3.50 mg/m 2 /day).
• a suitable cumulative dose of 240 mg/m 2 may be provided in 6 cycles at 40 mg/m 2 per cycle (amounting to a treatment density of 4.00 mg/m 2 /day).
• the dinutuximab beta is suitably administered during all but the first 2 cycles of the induction chemotherapy.
• the first, second, and third aspects of the invention have been particularly exemplified in relation to an induction chemotherapy regimen comprising 6 alternating chemotherapy cycles of N5 (cisplatin, etoposide, and vindesine) and N6 (ifosfamide, vincristine, dacarbazine, and doxorubicin), wherein the cycles are of at least 21 days.
• a suitable regimen is GPOH (Simon T et al. Klin Padiatr. 2017;229(3):147-67.6; Berthold F, Lancet Oncol. 2005;6(9):649-58).
• the chemotherapy cycles in GPOH are of 21 days duration, but the cycles may be longer. Cycle durations of 21, 22, 23, 24, 25, 26, 27 or 28 days are encompassed.
• the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient at (i) a cumulative dose of from 160 to 220 mg/m 2 and/or a treatment density of from 1.52 to 2.10 mg/m 2 /day; or (ii) at a cumulative dose of from 220 to 280 mg/m 2 and/or a treatment density of from 2.10 to 2.67 mg/m 2 /day; or (iii) at a cumulative dose of from 280 to 340 mg/m2 and/or a treatment density of from 2.67 to 3.24 mg/m 2 /day; or (iv) at a cumulative dose of from 320 to 380 mg/m 2 and/or a treatment density of from 3.05 to 3.62 mg/m 2 /day.
• a suitable cumulative dose of 190 mg/m 2 may be provided in 2 cycles at 30 mg/m 2 per cycle and 3 cycles at 50 mg/m 2 per cycle (amounting to a treatment density of 1.81 mg/m 2 /day).
• a suitable cumulative dose of 250 mg/m 2 may be provided in 5 cycles at 50 mg/m 2 per cycle (amounting to a treatment density of 2.38 mg/m 2 /day).
• a suitable cumulative dose of 310 mg/m 2 may be provided in 2 cycles at 50 mg/m 2 per cycle and 3 cycles at 70 mg/m 2 per cycle (amounting to a treatment density of 2.95 mg/m 2 /day).
• a suitable cumulative dose of 350 mg/m 2 may be provided in 5 cycles at 70 mg/m 2 per cycle (amounting to a treatment density of 3.33 mg/m 2 /day).
• the dinutuximab beta is suitably administered during all but the first cycle of the induction chemotherapy.
• the therapeutic effect of the combination induction chemotherapy and dinutuximab beta therapy may be defined as stable disease (i.e., no further increase in lesions, tumor tissue and/or size), partial response (i.e., reduction in lesions, tumor tissue and/or size), and/or complete response (i.e., complete remission of all lesions and tumor tissue).
• the therapeutic effect of dinutuximab beta administration may be an increase in immune response to the tumor, as determined, for example, by an increase in immune system biomarkers (e.g., blood parameters, such as lymphocyte counts and/or NK cell numbers; and/or cytokines).
• the therapeutic effect may be a reduction in tumor markers (e.g., catecholamines).
• the therapeutic effect may be determined by methods such as metaiodobenzylguanidine scintigraphy (mIBG), magnetic resonance imaging (MRI), or X-ray computed tomography (CT), and/or bone marrow histology (assessed by aspirate or trephine biopsy).
• the administration of the chimeric anti-GD2 antibody dinutuximab beta improves one or more clinical parameters compared to the induction chemotherapy administered without the chimeric anti-GD2 antibody dinutuximab beta.
• International neuroblastoma response criteria are described in Park JR et al J Clin Oncol. 2017;35(22):2580.
• Suitable clinical parameters are selected from overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, primary tumour volume reduction, Curie score, event-free survival (EFS), and overall survival (OS), overall response during and after induction (primary tumor, metastases), and metastatic CR and PR rates.
• EFS and OS may be determined at 3 or 5 years.
• ORR includes CR, and PR.
• Clinical improvement may also be characterized by changes in immune parameters during induction therapy for patients also treated with dinutuximab beta. Suitable immune parameters are Immunophenotype, complement-dependent cytotoxicity (CDC) and ADCC.
• Complete Response (CR) may be further defined as follows: Complete disappearance of all measurable and evaluable disease, no new lesions, no disease-related symptoms, and/or no evidence of evaluable disease, including, e.g., normalization of markers and/or other abnormal laboratory values. In some embodiments, all measurable, evaluable, and non-evaluable lesions and sites must be assessed using the same technique as baseline.
• Partial Response may be further defined as follows: Applies only to patients with at least 1 measurable lesion. Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions.
• a fourth aspect of the invention provides a chimeric anti-GD2 antibody dinutuximab beta for use in the method of the first aspect of the invention.
• a fifth aspect of the invention provides a chimeric anti-GD2 antibody dinutuximab beta for use in the method of the second aspect of the invention.
• a sixth aspect of the invention provides a chimeric anti-GD2 antibody dinutuximab beta for use in the method of the third aspect of the invention.
• 4. The method of Paragraph 3, wherein the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during all but the first 2 cycles, or all but the first cycle, or all cycles of the induction chemotherapy. 5.
• chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy in a dose per cycle that is at least 10 mg/m 2 per cycle, such as from 10 to 30 mg/m 2 per cycle, from 20 to 40 mg/m 2 per cycle, from 30 to 50 mg/m 2 per cycle, from 40 to 60 mg/m 2 per cycle, from 50 to 70 mg/m 2 per cycle or from 60 to 80 mg/m 2 per cycle. 7.
• the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy in a dose per cycle of at least 10 mg/m 2 per cycle for all cycles, such as from 10 to 30 mg/m 2 per cycle for one or more cycles and from 20 to 40 mg/m 2 per cycle for the other cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered; or from 20 to 40 mg/m 2 per cycle for one or more cycles and from 30 to 50 mg/m 2 per cycle for the other cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered; or from 20 to 40 mg/m 2 per cycle for one or more cycles and from 40 to 60 mg/m 2 per cycle for the other cycles during which the chimeric anti-GD2 antibody dinutuximab beta is administered; or from 40 to 60 mg/m 2 per cycle for one or more cycles and from 60 to 80 mg/m 2 per cycle for the other cycles during which the chimeric anti-GD
• a treatment density of up to 5 mg/m 2 /day wherein a newly diagnosed neuroblastoma is treated in the patient.
• chimeric anti-GD2 antibody dinutuximab beta is administered to the patient as a continuous intravenous infusion over 24 hours per day, in a daily dose of 10 mg/m 2 . 19. The method of any one of the preceding paragraphs wherein the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient on consecutive days of a cycle until all of the dose per cycle of the chimeric anti-GD2 antibody dinutuximab beta has been administered. 20.
• the induction chemotherapy comprises 6 alternating chemotherapy cycles of N5 (cisplatin, etoposide, and vindesine) and N6 (ifosfamide, vincristine, dacarbazine, and doxorubicin), wherein the cycles are of at least 21 days. 21.
• the induction chemotherapy comprises consecutive chemotherapy cycles of A (vincristine, carboplatin and etoposide), B (vincristine and cisplatin), C (vincristine, cyclophosphamide and etoposide), B, A, B, C and B, wherein the cycles are of at least 10 days. 23.
• a chimeric anti-GD2 antibody dinutuximab beta for use in a method of treating a newly diagnosed neuroblastoma in a patient by administering chimeric anti-GD2 antibody dinutuximab beta to the patient in combination with induction chemotherapy, wherein the chimeric anti-GD2 antibody dinutuximab beta is administered to the patient during the induction chemotherapy at a treatment density of up to 5 mg/m 2 /day, wherein a newly diagnosed neuroblastoma is treated in the patient. 29.
• a chimeric anti-GD2 antibody dinutuximab beta for use of Paragraph 26, 27, or 28 wherein the method of treating a newly diagnosed neuroblastoma in a patient has any of the additional features of Paragraphs 1 to 25.
• Example 1 Phase 1 study combining dinutuximab beta with induction chemotherapy regimens in patients with newly diagnosed high-risk neuroblastoma Rationale: This study is designed to identify safe and effective infusion durations for and cumulative dose levels of dinutuximab beta when combined with different induction chemotherapy regimens (German Pediatric Oncology and Hematology [GPOH] or cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide [COJEC]) for the treatment of newly diagnosed patients with high-risk neuroblastoma without substantially exceeding the treatment density previously established for dinutuximab beta monotherapy.
• the information will be used in the planning of future studies of an established induction chemotherapy regimen randomized to GPOH or COJEC with or without dinutuximab beta.
• This study is a multicenter, open-label, dual-cohort, Phase 1 study of dinutuximab beta combined with 1 of 2 different induction chemotherapy regimens (GPOH or COJEC) in 2 cohorts of up to 25 evaluable patients each.
• Newly diagnosed high-risk neuroblastoma patients as defined by Stage M, according to the International Neuroblastoma Risk Group Staging System (INRGSS), age ⁇ 18 months and ⁇ 18 years will be included in the trial.
• the planned cumulative dinutuximab beta doses (mg/m 2 ) are based on the variable number of treatment days of GPOH or COJEC.
• a confirmation cohort of 10 evaluable patients per cohort may be enrolled.
• the maximum number of patients to be enrolled in the dose escalation and dose confirmation parts of the study combined will be 35 evaluable patients for each induction chemotherapy regimen.
• the dose escalation and de-escalation process, including the number of patients dosed, process will follow a Bayesian Optimal Interval (BOIN) design to determine a recommended cumulative dinutuximab beta dose level as new patients enroll.
• BOIN Bayesian Optimal Interval
• the maximum number of patients to be enrolled in the dose escalation and dose confirmation parts of the study combined will be 35 evaluable patients for each induction chemotherapy regimen (GPOH or COJEC).
• Treatment Groups and Duration For each patient, there will be a screening period of up to 21 days, a treatment period consisting of approximately 126 days (GPOH cohort) or 80 days (COJEC cohort), and an end- of-treatment visit at the end of induction treatment.
• the end-of-study is 100 days after high- dose chemotherapy (HDC)/autologous stem cell transplant (ASCT) or the patient has started a new neuroblastoma treatment instead of HDC/ASCT, whichever is earlier.
• the planned total duration of the study for each patient enrolled is approximately 3 years.
• Dinutuximab beta will be administered at a fixed daily dose of 10 mg/m 2 given as a 24-hour continuous infusion a scheduled number of days within each treatment cycle (Table 10 and Table 11).
• the combination of dinutuximab beta with chemotherapy cycles will start in the second (GPOH cohort in combination with dinutuximab beta) or third (COJEC cohort combined with dinutuximab beta) chemotherapy cycle.
• Patients in the GPOH cohort will receive a total of 5 dinutuximab beta infusions and patients in the COJEC cohort will received a total of 6 dinutuximab beta infusions with their scheduled chemotherapy cycles.
• Table 4 Statistical Methods The sample size is not based on statistical considerations but is typical for studies of this nature and is considered adequate to characterize the distribution of the planned endpoints. Any statistical testing will be considered exploratory and descriptive. All proportions will be estimated with 95% confidence intervals. Data Monitoring Committee: Yes 1.1 Schedule of Activities Study procedures and their timing are summarized in Table 5 (GPOH) and Table 6 (COJEC).
• Dinutuximab beta is a chimeric monoclonal antibody produced in Chinese hamster ovary cells (CHO) targeting the disialoganglioside GD2 antigen highly expressed by neuroectodermal tumors such as neuroblastoma, melanoma cells, and several other tumors.
• Dinutuximab beta is licensed in the European Union (EU) subject to additional monitoring as Qarziba administered at 10 mg/m 2 /day as an 8-hour or 24-hour infusion [4].
• Dinutuximab beta is indicated for the treatment of high-risk neuroblastoma in patients aged 12 months and above, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation, as well as patients with history of relapsed or refractory neuroblastoma, with or without residual disease. Prior to the treatment of relapsed neuroblastoma, any actively progressing disease should be stabilized by other suitable measures.
• the current guideline for the treatment of children with high-risk neuroblastoma in Germany refers to the N5/N6 induction chemotherapy (7).
• an additional randomization (R3) was introduced into the SIOPEN HR-NBL1 study, to compare COJEC with the modified N7 induction chemotherapy regimen (8 to 10), developed at Memorial Sloan-Kettering Cancer Center; this regimen had also been adopted by the COG.
• the original regimen with 7 cycles was modified reducing the number to 5 cycles, with a lower dosage of vincristine (VCR) and using granulocyte-colony-stimulating factor (G-CSF).
• VCR vincristine
• G-CSF granulocyte-colony-stimulating factor
• DMC data monitoring committee
• dinutuximab beta target Due to the expression of the dinutuximab beta target (GD2) on neuronal tissues especially during embryofetal development, the cytotoxic potential of dinutuximab beta and the potential of placental transfer of antibodies, dinutuximab beta may cause fetal harm when administered to pregnant women.
• Female patients of childbearing potential will be required to have a negative pregnancy test before enrollment, pregnancy tests will be conducted during the study and the patients will be required to agree to follow contraceptive guidance.
• no drug-drug interaction studies have been performed with dinutuximab beta, the effect of dinutuximab beta on any other drugs that the child might take cannot be predicted. Prohibited concomitant medications on this study are described in Appendix 2.
• dinutuximab beta in children aged ⁇ 12 months have not yet been established and no data are available. Patients enrolled in the study will be aged between ⁇ 18 months and ⁇ 18 years. As only patients with adequate renal and hepatic function have been investigated to date, patient enrollment will be restricted to those with confirmed adequate renal and kidney function. More detailed information about the known and expected benefits and risks and reasonably expected adverse events (AEs) of dinutuximab beta may be found in the Investigator’s Brochure. The Sponsor will immediately notify the Investigators if any additional safety or toxicology information becomes available during the study.
• AEs adverse events
• AE adverse events
• ADCC antibody-dependent cellular cytotoxicity
• ASCT autologous stem cell transplantation
• BuMel busulfan and melphalan
• CDC complement-dependent cytotoxicity
• COJEC cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide
• CR complete response
• DLT dose-limiting toxicity
• EFS event-free survival
• FDG [ 18 F]-fluorodeoxyglucose
• GPOH German Pediatric Oncology and Hematology
• HACA human anti-chimeric antibody
• HDC high-dose chemotherapy
• INRC International Neuroblastoma Response Criteria
• INRGSS International Neuroblastoma Risk Group Staging System
• mCR metastatic complete response
• MD minimal disease
• MIBG ( 123 I) metaiodobenzylguanidine
• mPR metastatic partial response rate
• MTD maximum tolerated dose
• OS overall survival
• PET positron emission to
• This study is a multicenter, open-label, dual-cohort, Phase 1 study of dinutuximab beta combined with 2 different induction chemotherapy regimens (GPOH or COJEC) in 2 cohorts of up to 25 evaluable patients each.
• Study centers will enroll patients in 1 cohort at a time (ie, only recruit patients scheduled to receive the GPOH or COJEC induction chemotherapy regimen); the allocation of study centers to a treatment cohort may change during the study depending on the recruitment per cohort. If one induction chemotherapy regimen cohort has completed recruitment, then centers may activate the other induction chemotherapy regimen cohort in order to contribute to the recruitment of the slower recruiting cohort after approval by the Sponsor or Medical Monitor.
• a confirmation cohort of 10 evaluable patients per cohort may be enrolled.
• the maximum number of patients to be enrolled in the dose escalation and dose confirmation parts of the study combined will be 35 evaluable patients for each induction chemotherapy regimen.
• Newly diagnosed high-risk neuroblastoma patients as defined by Stage M, according to the International Neuroblastoma Risk Group Staging System (INRGSS), age ⁇ 18 months and ⁇ 18 years will be included in the trial.
• IRGSS International Neuroblastoma Risk Group Staging System
• GPOH cohort a treatment period consisting of approximately 126 days
• COJEC cohort a treatment period consisting of approximately 126 days
• COJEC cohort a treatment period consisting of approximately 126 days
• ASCT autologous stem cell transplant
• the planned total duration of the study for each patient enrolled is approximately 3 years.
• Assessments performed during the study are specified in Table 5 (COJEC) and Table 6 (GPOH).
• the GPOH induction chemotherapy regimen will be administered in 21-day cycles (total of 6 cycles).
• the combination of dinutuximab beta with induction chemotherapy cycles will start in the second chemotherapy cycle ( Figure 1).
• Dinutuximab beta will be administered at a fixed daily dose of 10 mg/m 2 given as a 24-hour continuous infusion a scheduled number of days within each treatment cycle (Table 10).
• the COJEC induction chemotherapy will be administered over 10 weeks in 10-day cycles (total of 8 cycles).
• the combination of dinutuximab beta with chemotherapy cycles will start in the third chemotherapy cycle ( Figure 1).
• Dinutuximab beta will be administered at a fixed daily dose of 10 mg/m 2 given as a 24-hour continuous infusion a scheduled number of days within each treatment cycle (Table 11) for a total of 6 infusions. Cumulative dose levels are defined by the total amount of dinutuximab beta the patient is expected to receive over the entire course of therapy.
• a higher cumulative dose levels reflect that the patient will receive more total days of therapy (although not higher infusion rates).
• the planned cumulative dinutuximab beta doses (mg/m 2 ) based on the variable number of treatment days of GPOH or COJEC are presented in Table. See Section 0 for more details.
• the DMC will be responsible for safety oversight and for dose selection and modification decisions.
• the recommended Phase 2 dose (RP2D) will be determined by the MTD or the maximum administered cumulative dose level if no MTD dose is reached.
• 4.2 Scientific Rationale for Study Design Neuroblastoma the most common pediatric extracranial tumor, remains a leading cause of death from cancer in children. Long-term survival of children with high-risk neuroblastoma remains below 60% at 5 years despite improvements in intensive multimodal therapy, including chemotherapy, HDC with autologous hematopoietic stem cell rescue, surgical removal of the primary tumor, radiotherapy, residual disease therapy, and immunotherapy with anti-GD2 monoclonal antibodies.
• Dinutuximab beta will be given at a fixed daily dose of 10 mg/m 2 as a continuous infusion.
• the goal is to identify an appropriate cumulative dose level of dinutuximab beta without substantially exceeding its previously established monotherapy treatment density within each induction chemotherapy regimen for further investigation.
• the starting cumulative dose selected for administration with the GPOH and the COJEC induction chemotherapy regimens was based on the pharmacokinetic (PK) data following administration of dinutuximab beta for 10 days (100 mg/m 2 /course) in 35-day intervals (12).
• Dinutuximab beta infusion durations for the 2 planned treatment induction chemotherapy regimens: ⁇ GPOH: starting dinutuximab beta infusion duration 10 mg/m 2 ⁇ 5 days (50 mg/m 2 /course) in 21-day treatment intervals.
• Escalating starting infusion durations have an increasing number of days with a simultaneous administration of chemotherapy and dinutuximab beta to accommodate the timing within the cycle which will help determine feasibility in combination with hyperhydration.
• 4.3.3 Justification for the Dose Schedules Within an Entire Induction Regimen 4.3.3.1 Rationale for the Starting Dose Schedule
• the rationale for the starting cumulative dinutuximab beta dose levels is derived from the planned treatment density of dinutuximab beta within the GPOH or COJEC induction chemotherapy regimen in comparison to the treatment density used in the SIOPEN monotherapy long-term infusion (LTI) dinutuximab beta study (11).
• Infusion duration of dinutuximab beta will be consistent throughout cumulative dose level 1 during the entire induction regimen. If toxicity is acceptable (estimated DLT probability ⁇ 33%, see Section 6.7.3), then cumulative dose level 2 will be explored.
• the escalation is realized by increasing infusion duration 1 to infusion duration 2 in the second combination cycle.
• the rationale for design of this escalation pattern is an observed decrease in dinutuximab beta toxicity in subsequent cycles of dinutuximab beta therapy (13). Patients will receive the lower infusion duration in the first combination cycle followed by the higher infusion duration in the second combination cycle.
• cumulative dose level 3 all infusion durations are increased to infusion duration 2 and stay consistent throughout the entire induction regimen.
• the infusion durations used in subsequent combination cycles will not be changed, except in the third N6 cycle of cumulative dose level 2 where infusion duration 2 was selected in order to keep a better balance for the total dose planned.
• Dinutuximab beta de-escalation will follow the same strategy.
• De-escalation in cumulative dose level -1 is achieved by decreasing from infusion duration 1 to infusion duration -1 (for GPOH) in the first combination cycle but not the following combination cycle because of an improved toxicity profile of dinutuximab beta in subsequent cycles (13).
• GPOH German Pediatric Oncology and Hematology
• N5 cisplatin, etoposide, vindesine
• N6 vincristine, dacarbazinee, ifosfamide, doxorubicin
• total dose total dose of dinutuximab beta in mg/m 2 .
• the total dose planned for the entire induction regimen is indicated in mg/m 2 .
• Gray-shaded combination cycles represent the primary dose-limiting toxicity (DLT) observation period.
• Patients will receive the lower infusion duration in the first combination cycle followed by the higher infusion duration in the second combination cycle.
• cumulative dose level 3 all infusion durations are increased to infusion duration 2 and stay consistent throughout the entire induction regimen.
• Dinutuximab beta dose de-escalation will follow the same strategy.
• De-escalation in cumulative dose level -1 is realized by decreasing from infusion duration 1 to infusion duration -1 (for COJEC) in the first 2 combination cycles but not in the third combination cycle because of an improved toxicity profile of dinutuximab beta in subsequent cycles (13). After the evaluation of the toxicity to determine dinutuximab beta dose escalation or de-escalation during the first combination cycles, the infusion durations used in subsequent combination cycles are not changed.
• COJEC cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide
• total dose of dinutuximab beta in mg/m 2 The total dose planned for the entire induction regimen is indicated in mg/m 2 .
• Gray-shaded combination cycles represent the primary dose-limiting toxicity observation period.
• a patient is considered to have completed the study treatment if he/she has completed all phases of the study including the last scheduled procedure shown in the Schedule of Activities (SoA) table (see Section 1.1).
• the end of the study is defined as 100 days after the last patient has undergone standard- of-care HDC/ASCT or has started a new neuroblastoma treatment regimen instead of HDC/ASCT, whichever is earlier.
• 5.0 STUDY PROPULATION Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as protocol waivers or exemptions, is not permitted.
• 5.1 Inclusion Criteria Patients are eligible for the study if they meet all the following inclusion criteria: 1. Established diagnosis of neuroblastoma Stage M, according to the INRGSS. 2.
• ALT Alanine transaminase
• AST aspartate aminotransferase
• UPN upper limit of normal
• total bilirubin ⁇ 1.5 ⁇ ULN based on age specific reference ranges.
• Creatinine clearance ⁇ 70 mL/min/1.73 m 2 or creatinine ⁇ 1.5 ⁇ ULN corrected for age.
• Shortening fraction ⁇ 27% by echocardiogram or ejection fraction >50% by echocardiogram. 7. Able to comply with scheduled follow-up and with management of toxicity. 8.
• a female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: i) Not a woman of childbearing potential (WOCBP). OR ii) A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 1 year after the last dose of dinutuximab beta. 9. A male patient must agree to use contraception during the treatment period and for at least 1 year after the last dose of dinutuximab beta and refrain from donating sperm during this period. 10. Parent or guardian able to give consent, with the child giving assent when appropriate, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• ICF informed consent form
• Dinutuximab beta will be diluted with 0.9% sodium chloride solution containing 1% human albumin at the site as described in the Pharmacy Manual. The individual dose of 10 mg/m 2 /day will be calculated based on the body surface area of the patient. Dinutuximab beta must be administered according to the procedures described in this study protocol. Only patients enrolled in this study may receive study treatment. Only authorized site staff may supply or administer dinutuximab beta. Continuous infusions of dinutuximab beta will start at time points indicated for each of the chemotherapy cycles (Section 6.2). The start of dinutuximab beta in the morning is recommended for safety reasons.
• the total duration of the infusion will depend on the dinutuximab beta infusion duration planned for each patient and cycle.
• Each IV preparation will contain one, 24-hour dose (10 mg/m 2 dinutuximab beta) for the specific patient.
• Dinutuximab beta will be delivered by continuous infusion using an electronic infusion pump at a flow rate of 2 mL/h ⁇ 0.4 mL/h (see Section 6.7 for details of dinutuximab dose modifications).
• the IV preparation with dinutuximab beta will be replaced approximately every 24 hours. If possible, the patient should receive the planned total dose of dinutuximab beta within each cycle.
• dinutuximab beta Chemical and physical in-use stability of dinutuximab beta has been demonstrated for up to 48 hours at 25°C (50 mL syringe) and for up to 7 days at 37°C (250 mL infusion), after cumulative storage in a refrigerator (2°C to 8°C) for 72 hours.
• the solution for infusion must be prepared under aseptic conditions. Opened vials with remaining antibody solution must be discarded immediately.
• Preparation of dinutuximab beta for administration to the patients will be described in the Pharmacy Manual. Infusion Duration Dose escalation and de-escalation will be accomplished by variation of the number of treatment days with dinutuximab beta at 10 mg/m 2 /day within a given chemotherapy cycle leading to different total infusion durations.
• each IV preparation will contain one, 24-hour dose (10 mg/m 2 )
• the number of IV preparation with dinutuximab beta corresponds to the number of treatment days.
• Cumulative Dose Level The induction chemotherapy regimens consist of 5 (GPOH with dinutuximab beta) or 6 (COJEC with dinutuximab beta) cycles for the assessment of the combination.
• the planned infusion durations are not (always) identical for all cycles of a given induction regimen.
• Variable infusion durations are used between the chemotherapy cycles of a given induction regimen. The reason for that variation is an expected increase in treatment tolerance for dinutuximab beta in subsequent treatment cycles.
• the variation of infusion durations between cycles of a given induction chemotherapy regimen leads to different cumulative dose levels.
• the chemotherapy drugs administered during the GPOH cisplatin, etoposide, vindesine, ifosfamide, dacarbazine, vincristine, and doxorubicin
• COJEC cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide
• the details of all treatments administered including, but not limited to, dose, dose interruptions, and dose modifications will be included in the CRF.
• the induction treatment will be applied over 18 weeks in 21-day cycles. Two different courses will be given every 21 days.
• the GPOH induction chemotherapy regimen is administered in 21-day cycles depending in particular on hematologic recovery and on recovery from other organ toxicities.
• the first cycle with N5 will be without dinutuximab beta.
• the remainder of the cycles will be in combination with dinutuximab beta.
• the induction treatment will be applied over 10 weeks in 10-day cycles and proceed regardless of neutrophil or platelet counts and controlled infection. Three different courses will be given every 10 days. Consult the Sponsor or CRO Medical Monitor if GFR is ⁇ 80 mL/min ⁇ 1.73 m 2 .
• the COJEC induction chemotherapy regimen is administered in 10-day cycles.
• the use of G-CSF 5 ⁇ g/kg/day sc during induction Cycle B is recommended starting 24 hours after the last chemotherapy and stopped the day prior to commencing the next course with an interval of at least 24 hours between the last G-CSF injection and the start of chemotherapy. Use of polyethylene glycol-filgrastim will not be permitted.
• the first 2 cycles, consisting of Cycle A and Cycle B, will be without dinutuximab beta. The remainder of cycles will be in combination with dinutuximab beta.
• Dinutuximab Beta 6.2.2.5 Cycle A with Dinutuximab Beta 6.3 Preparation/Handling/Storage/Accountability 1.
• the Investigator or designee must confirm appropriate temperature conditions have been maintained during transit for all dinutuximab beta received and any discrepancies are reported and resolved before use of the dinutuximab beta.
• Only patients enrolled in the study may receive study treatment and only authorized study center staff may supply or administer study treatment.
• Dinutuximab beta must be stored in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the Investigator and authorized study center staff. 3.
• the Investigator, institution, or the head of the medical institution (where applicable) is responsible for dinutuximab beta accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 4. Further guidance and information for the final disposition of unused dinutuximab beta are provided in the Pharmacy Manual. The Investigator, a member of the study center staff, or a hospital pharmacist must maintain an adequate record of the receipt and distribution of all study medication using the Drug Accountability Form. These forms must be available for inspection at any time. 6.4 Measures to Minimize Bias: Randomization and Blinding This is a nonrandomized open-label study. 6.5 Study Treatment Compliance Study treatments will be administered to the patients under the supervision of appropriately trained staff at the study center.
• the CRO Medical Monitor should be contacted if there are any questions regarding concomitant or prior therapy.
• a list of excluded medications/therapy is provided in Appendix 2.
• Neuropathic pain is an anticipated side effect of dinutuximab beta. Patients will receive gabapentin and IV morphine. If the patient does not experience significant pain during the first infusion of dinutuximab beta, the use of IV morphine can be modified per Investigator discretion. Inflammatory side effects are anticipated that require co-medication with antipyretic drugs. Anti-histaminergic prophylaxis and prevention of gastritis is recommended. Instructions for the administration of these concomitant medications are included in Appendix 3.
• Dinutuximab beta must be administered by a healthcare professional prepared to manage severe allergic reactions including anaphylaxis. Infusion of dinutuximab beta must be initiated in an environment where full resuscitation services are immediately available. 6.7 Dose Modification The dose modifications for chemotherapy toxicity can be found in Section 6.2. 6.7.1 General Guidance on Dose Modifications for Dinutuximab Beta Previous experience with dinutuximab beta has shown a decrease of dinutuximab beta toxicity in subsequent cycles. Therefore, in this study, dinutuximab beta infusion flow rate may be reduced, or interrupted, in the first treatment cycle in accordance with the dose modifications that are described in this section.
• Dinutuximab beta dose modifications will be performed by changing the flow rate of the infusion or interrupting the infusion. This would usually occur in the event of Grade 3 or 4 toxicity as defined in NCI-CTCAE version 5.0. 6.7.1.1 Dinutuximab Beta Infusion Rate Modifications
• Dinutuximab beta infusion rate modifications for dinutuximab beta related Grade ⁇ 3 toxicities are as follows: ⁇ No modification for Grade ⁇ 3 hematologic toxicity corrected by transfusion and no modification for Grade ⁇ 3 leukocytopenia associated with chemotherapy. ⁇ For dinutuximab beta related Grade ⁇ 3 toxicities, except as noted below, stop dinutuximab beta infusion.
• the infusion should be stopped, and total dose infused at that point recorded. - If toxicity (Grade ⁇ 3) recurs while at 100% flow rate (2 mL/h) administration will be stopped and restarted at a 50% infusion rate (1 mL/h). If toxicity resolves or improves to Grade ⁇ 2 with supportive measures, then the infusion of the prescribed dose at the lower rate will be completed.
• Grade 3 electrolyte imbalance especially hyponatremia ⁇ 130 mmol/L in the absence of central nervous system [CNS] symptoms and sequelae
• CNS central nervous system
• Grade 3 hepatic toxicity that returns to Grade 1 prior to the time for next dinutuximab beta treatment course.
• Grade 3 neurotoxicity with subjective findings only eg, tingling, hot or cold hands, etc.
• Performance (30% to ⁇ 50%, see Section 9.2.4).
• Altered taste Specific product-related toxicities including guidance on early detection and management are described in Appendix 4.
• the dinutuximab beta dose escalation and de-escalation process is based on the evaluation of DLTs that occurred according to the BOIN method (19, 19).
• the decision to dose escalate, de-escalate, or remain at the same cumulative dose level is determined by comparing the observed DLT rate at the current cumulative dose level with a prespecified toxicity tolerance interval. If the observed DLT rate is less than or equal to the lower boundary of the interval, then the cumulative dose level is escalated. If the observed DLT rate is greater than or equal to the upper boundary of the interval, then the cumulative dose is de-escalated.
• the observed DLT rate used for determining whether the dose will escalate, de-escalate, or remain the same for the next cohort will be based on the number of patients experiencing DLTs during the time window defined above at the current dose schedule. If the observed DLT rate is: ⁇ ⁇ 0.260, the dinutuximab beta dose is escalated for the next cohort. ⁇ ⁇ 0.395, the dinutuximab beta dose is de-escalated for the next cohort.
• the dinutuximab beta dose remains the same for the next cohort.
• patients After the first 2 patients are enrolled and evaluated singly, patients will be enrolled and evaluated in cohorts of 3 patients. Note that a minimum of 2 evaluable patients tolerating a given cumulative dose level must be available before deciding to escalate to the next cumulative dose level. Evaluable patients have either completed the primary DLT observation period without a DLT or have experienced a DLT. All patients enrolled at a dose level should be evaluable before making a dosing change decision. No dose skipping will occur with this design.
• the patient will be replaced.
• the replacement patient will be assigned the same cumulative dose level as the non-evaluable patient. Enrollment in the dose escalation phase will continue until the maximum sample size (25 patients in each of the GPOH and COJEC cohorts) is reached, unless required otherwise by the Study Stopping Rules defined below.
• the MTD will be defined as the cumulative dinutuximab beta dose level that in combination with chemotherapy has an estimated DLT rate closest to the target DLT rate.
• Dinutuximab Beta Study Stopping Rules The dinutuximab beta dose-finding process for each chemotherapy regimen will be repeated until one of the following: ⁇ The predefined total number of evaluable patients is included. ⁇ The point estimate of toxicity probability for cumulative dose level -1 is above 33%. ⁇ 10 evaluable patients have been treated at the same cumulative dose level. In case unacceptable toxicity or DLTs are observed early in the DLT assessment period with dinutuximab beta in cumulative dose level 1, cumulative dose level -1 dose modifications will be considered by the DMC. 6.8 Treatment After the End of the Study After the end of the study (as defined in Section 4.4) the patients will continue under the care of their physician.
• a DLT is defined as a dinutuximab beta related AE occurring during the DLT assessment period that leads to treatment discontinuation or meet 1 of the following criteria: ⁇ Grade ⁇ 3 neurological toxicity. ⁇ Grade ⁇ 3 cardiac toxicity. ⁇ Grade 4 severe, unrelenting neuropathic pain unresponsive to continuous infusion of narcotics and other adjuvant measures including lidocaine infusions. ⁇ Grade ⁇ 3 capillary leak. ⁇ Grade 4 hyponatremia ( ⁇ 120 mmol/L) despite appropriate fluid management. ⁇ Grade 4 skin toxicity. ⁇ Grade 3 vision toxicity (ie, subtotal vision loss per toxicity scale).
• Any Grade 4 toxicity (laboratory abnormality or non-hematological toxicity) that leads to change of management defined as: chemotherapy dose reduction or delay of next cycle (>7 days for COJEC regimen with dinutuximab beta or >14 days for GPOH regimen with dinutuximab beta).
• Any death not clearly related to disease progression (Grade 5 toxicity).
• the NCI-CTCAE version 5.0 will be used for all severity grading. Prolongation of induction length and chemotherapy dose reduction (due to Grade ⁇ 3 toxicity) will not be considered a DLT but will be monitored and considered by the DMC to define the RP2D.
• Stopping Rules 8.2.1 Individual Patient Stopping Rules Patients should stop dinutuximab beta and be taken off study treatment if the following toxicities occur: ⁇ Grade 3 (bronchospasm) and 4 (anaphylaxis) allergic reaction. ⁇ Grade ⁇ 3 serum sickness. ⁇ Grade 4 severe, unrelenting neuropathic pain unresponsive to continuous infusion of narcotics and other adjuvant measures including lidocaine infusions. ⁇ Any of the following neurotoxicities: - Grade 3 sensory changes interfering with daily activities >2 weeks after completing dinutuximab beta therapy. - Grade 3 objective motor weakness. - Grade 3 vision toxicity (ie, subtotal vision loss per toxicity scale).
• ⁇ Grade 4 hyponatremia ( ⁇ 120 mmol/L) despite appropriate fluid management.
• Grade 4 capillary leak syndrome (Grade 4 includes ventilator support).
• Grade 4 skin toxicity ⁇ Grade ⁇ 3 cardiac toxicity.
• ⁇ Patients will be taken off protocol if International Neuroblastoma Response Criteria (INRC) defined disease progression occurs, see Appendix 6 (18).
• ⁇ Patients will be taken off protocol if the start of a treatment cycle including dinutuximab beta must be delayed for more than 1 week (COJEC regimen with dinutuximab beta) or more than 2 weeks (GPOH regimen with dinutuximab beta) due to toxicity.
• IRC International Neuroblastoma Response Criteria
• the parent(s) or legal guardian may withdraw the patient from the study, at any time, or may be withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or administrative reasons.
• the parent(s) or legal guardian withdraws consent, for disclosure of future information, the Sponsor may retain and continue to use any data collected before such a withdrawal of consent.
• the parent(s) or legal guardian withdraws a patient, from the study, he/she may request destruction of any samples taken and not tested, and the Investigator must document this in the study center study records.
• Progressive disease according to INRC see Appendix 6).
• the Investigator will maintain a screening log to record details of all patients screened and to confirm eligibility or record reasons for screening failure, as applicable.
• Procedures conducted as part of the patient routine clinical management (eg, blood count) and obtained before signing of the ICF may be utilized for screening or baseline purposes provided the procedures met the protocol specified criteria and were performed within the time frame defined in the SoA table (Section 1.1).
• the maximum amount of blood collected from each patient over the duration of the study will be included in the ICF and Laboratory Manual. 9.1.1 Screening
• the screening period starts with the date of signature of the informed consent and needs to be completed within 21 days. Tests that are required to establish the diagnosis of Stage M neuroblastoma and other examinations done before signature of the consent form that are required in the screening period will not have to be repeated.
• Baseline is important to assess expected cardiac toxicity from anthracyclines and unexpected toxicity.
• ⁇ Hearing test is important at baseline to assess ototoxicity in particular with cisplatin.
• ⁇ Pulmonary function test (PFT) will be done on patients able to comply with the test. Oxygen saturation at room air can replace PFT in patients who cannot comply with the PFT. This important baseline information is also required for long-term toxicity assessment after BuMel high-dose chemotherapy (HDC).
• HDC BuMel high-dose chemotherapy
• ⁇ Full blood count (hemoglobin, platelets, white blood cells with differential [neutrophils, lymphocytes, eosinophils, basophils]) and biochemistry including creatinine and/or cystatin C clearance, sodium, potassium, chloride, ALT, AST, total bilirubin, creatinine and/or cystatin C, C-reactive protein (CRP) will evaluate hematologic, hepatic and renal baseline characteristics.
• C-reactive protein C-reactive protein
• ⁇ Daily pain assessment (see Appendix 5). ⁇ Daily AE assessment. ⁇ Daily documentation of concomitant medication. Daily assessments start on Day 1 and continue until last day of chemotherapy. ⁇ Full blood count and biochemistry on last day of chemotherapy. Full blood count: hemoglobin, platelets, white blood cells with differential (neutrophils, lymphocytes, eosinophils, basophils). Biochemistry: sodium, potassium, chloride, ALT, AST, total bilirubin, creatinine and/or cystatin-C, and CRP. 9.1.3.2 Assessment During Chemotherapy With Dinutuximab Beta ⁇ Daily physical examination. ⁇ Daily vital signs (blood pressure, pulse rate, body temperature). ⁇ Daily body weight. ⁇ Daily documentation of performance status.
• ⁇ Daily pain assessment (see Appendix 5). ⁇ Daily AE assessment. ⁇ Daily documentation of concomitant medication. Daily assessments start on Day 1 and continue until last day of chemotherapy or last day of dinutuximab beta, whichever comes last. ⁇ Start and end of dinutuximab beta infusion: Full blood count and biochemistry: Full blood count: hemoglobin, platelets, white blood cells with differential (neutrophils, lymphocytes, eosinophils, basophils). Biochemistry: sodium, potassium, chloride, ALT, AST, total bilirubin, creatinine and/or cystatin C, CRP.
• ⁇ Immunophenotyping take 2 samples: on first day (prior dosing) and last day of dinutuximab beta infusion (end-of-infusion).
• Samples for PK, CDC and ADCC must be taken on first day (prior dosing) and last day of dinutuximab beta infusion (end-of-infusion).
• HACA 9.1.3.3 Assessment After Chemotherapy Without and With Dinutuximab Beta Adverse event and concomitant medication documentation will be done once after completion of chemotherapy or dinutuximab beta on the visit prior to the next cycle. 9.1.3.4 Mid-Induction Treatment Evaluation Disease evaluations during treatment include the following tests: ⁇ 123 I-MIBG SPECT.
• Full blood count and biochemistry Full blood count: hemoglobin, platelets, white blood cells with differential (neutrophils, lymphocytes, eosinophils, basophils). Biochemistry: sodium, potassium, chloride, ALT, AST, total bilirubin, creatinine and/or cystatin C, CRP. ⁇ Pregnancy test in female patients of childbearing potential. ⁇ HACA. For patients who do not continue on to HDC after induction and proceed with alternative therapy due to refractory disease, the end of induction visit will also serve as the end-of- study visit. Post-study cancer treatment, including but not limited to maintenance treatment, details (normally type and amount/duration of cancer treatment) will be recorded.
• Biochemistry sodium, potassium, chloride, ALT (SGPT), AST (SGOT), total bilirubin, creatinine and/or cystatin C, and CRP.
• ALT SGPT
• AST SGOT
• total bilirubin creatinine and/or cystatin C
• CRP CRP
• Tumor response parameters that will be assessed include the following: ⁇ Best overall response (CR, partial response [PR], minor response [MR], stable disease [SD] [lasting 12 weeks], or disease progression). ⁇ ORR (CR+PR). ⁇ Clinical benefit rate (CBR) (CR or PR or MR or SD [lasting at least 12 weeks]). ⁇ Duration of response or duration of SD. Time-to-event endpoints of time to progression, progression-free survival, and OS during study observation period will also be assessed. 9.2.1 Imaging At screening, patients will undergo a whole-body 123 I-MIBG SPECT scan.
• the 123 I-MIBG SPECT scan will be replaced with [ 18 F]-fluorodeoxyglucose–positron emission tomography in patients at subsequent assessments. These assessments follow according to the revised INRC (see Appendix 6). Brain and primary tumor MRI or CT will be performed as indicated. Contrast enhanced brain MRI is preferred; however, if MRI contrast is contraindicated, then MRI without contrast or CT with/without contrast is acceptable.
• pain assessments scores will be evaluated by the parent or guardian and/or the Investigator by use of the pain assessment scores included in Appendix 5.
• 9.2.4 Performance Status Performance of daily activities will be assessed by use of the Lansky Play-Performance scale for patients ⁇ 16 years-old and the Karnofsky Performance Scale for patient >16 years-old.
• 9.3 Safety Assessments Planned time points for all safety assessments are provided in Table 5 (GPOH) and Table 6 (COJEC).
• 9.3.1 Demographics and Medical History Demographics and relevant medical and surgical history will be recorded in the CRF.
• 9.3.2 Physical Examinations ⁇ At screening a complete physical examination will include at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems.
• ⁇ At subsequent assessments brief physical examination will include at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). ⁇ A hearing test will be conducted to capture ototoxicity. ⁇ Investigators should pay special attention to clinical signs related to previous serious illnesses. 9.3.3 Vital Signs ⁇ Oral temperature, pulse rate, and blood pressure will be assessed. ⁇ Blood pressure and pulse measurements will be assessed with a completely automated device. Manual techniques will be used only if an automated device is not available. ⁇ Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the patient in a quiet setting without distractions (eg, television, cell phones). ⁇ Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 3 blood pressure measurements.
• AEs and SAEs will be collected from the signing of the ICF until end-of-treatment at the time points specified in the SoA table (Section 1.1). Signs and symptoms that begin before the start of study treatment but after obtaining informed consent will be recorded on the medical history/current medical conditions section of the CRF, not the AE section. All SAEs will be recorded and reported to the Sponsor or designee within 24 hours.
• the Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being available. Investigators are not obligated to actively seek AE or SAE after conclusion of the study participation. However, if the Investigator learns of any SAE, including a death, at any time after a patient has been discharged from the study, and he/she considers the event to be reasonably related to the study treatment or study participation, the Investigator must promptly notify the Sponsor. 9.4.2 Method of Detecting AEs and SAEs Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the patient is the preferred method to inquire about AE occurrences.
• the Sponsor will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and Investigators.
• IRB Institutional Review Boards
• IEC Independent Ethics Committees
• Investigator safety reports must be prepared for suspected unexpected serious adverse reactions (SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.
• SUSAR suspected unexpected serious adverse reactions
• An Investigator who receives an Investigator safety report describing an SAE or other specific safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local requirements.
• ⁇ Closely monitor the patient for any AE/SAE and laboratory abnormalities until dinutuximab beta can no longer be detected systemically. ⁇ Obtain a plasma sample for PK analysis if requested by the CRO Medical Monitor (determined on a case-by-case basis). ⁇ Document the quantity of the excess dose as well as the duration of the overdose in the CRF. ⁇ Record the batch number of dinutuximab beta in AE reports and reports of overdose. Decisions regarding dosing interruptions or dose modifications will be made by the Investigator in consultation with the CRO Medical Monitor based on the clinical evaluation of the patient. Any overdose of COJEC and GPOH induction treatment will be recorded.
• NK-cells CD16+/CD56+ NK-cells
• CD8 T-cells CD8+/CD3+ T-cells
• CD4 T-cells CD4+/CD3+ T-cells
• Data will be analyzed locally, and results recorded as absolute cell numbers per ⁇ L of the subpopulations.
• 9.8 Genetics 9.8.1 Fc-gamma Receptor Polymorphisms and KIR/KIR-ligand Analysis A blood sample (2 mL) will be collected in a sample tube containing EDTA on Cycle 1 Day 1 (minimum 2 mL) at the times included in Table 5 and Table 6.
• a BOIN adaptive procedure will be used to assign patients to cumulative dose levels and determine the MTD.
• the function “get.boundary” within the R Package “BOIN” was used.
• the arguments are defined as follows: A maximum sample size of 25 evaluable patients each is planned for the dose escalation phase in each cohort. In the expansion phase, 10 additional patients will be enrolled at the [chosen] cumulative dose level in each cohort.
• the maximum number of patients in this clinical study will be 70.
• the sample size is not based on statistical considerations but is typical for studies of this nature and is considered adequate to characterize the distribution of the planned endpoints. Any statistical testing will be considered exploratory and descriptive.
• 9.3 Populations for Analyses For purposes of analysis, the analysis sets are defined in Table 13. Table 13 Analysis Sets 9.4 Statistical Analyses The SAP will be developed and finalized before database lock and will describe the patient analysis sets to be included in the analyses, and procedures for accounting for missing, unused, and spurious data. This section is a summary of the planned statistical analyses of the primary and secondary endpoints. The analysis and reporting of the exploratory and ancillary endpoints will be described in the SAP.
• the MTD will be the cumulative dose level in combination with chemotherapy which according to DMC assessment is best tolerated and has a DLT rate closest to the target rate of 33%.
• the RP2D will be determined by the MTD or the maximum administered cumulative dose level if no MTD dose is reached.
• Each patient’s outcome with respect to DLTs will be used to update the BOIN algorithm and these results will be used by the DMC to allocate additional patients to a cumulative dose level (see DMC charter).
• safety outcomes will be reported by cumulative dose level, cohort, and regimen within cohort up to the end-of- treatment. Frequency of DLTs (escalation phase only) as used for dose escalation and de-escalation decisions will be tabulated.
• Tolerability assessments will be summarized descriptively by study phase (dose escalation and expansion). For the dose escalation phase, the data will be further categorized by cumulative dose level. Tolerability assessments will include reporting the following-up to the last safety follow-up visit: ⁇ Frequency of study discontinuation and reason. ⁇ Frequency of dose interruption and reduction. ⁇ Mean and median total dose of dinutuximab beta administered over the induction period. All laboratory test results, pain assessments, vital signs measurements, ECG results, weight, and body mass index will be summarized for each treatment group using descriptive statistics at each visit for raw numbers and change from baseline. Screening will serve as baseline for calculating changes from baseline.
• Physical examination findings will be summarized by body system using a shift table from baseline to each subsequent assessment time point and categories of normal, abnormal not clinically significant (NCS), and abnormal CS.
• the performance status and body weight tabular summaries will include mean, standard deviation, median, and range for each assessment time point, as well as for the calculated changes from baseline to each subsequent time point.
• Daily pain assessment scores will be summarized in both tabular and graphic format.
• the tabular summaries will include mean, standard deviation, median, and range for each assessment time point, as well as for the calculated changes from baseline to each subsequent time point.
• the figures will include mean and standard deviation over time. Vital signs will be summarized in both tabular and graphic format.
• the tabular summaries will include mean, standard deviation, median, and range for each assessment time point, as well as for the calculated changes from baseline to each subsequent time point.
• the figures will include mean and standard deviation for each vital sign over time.
• the tabular summary of 12-lead ECG data, ie, ventricular rate, RR interval, PR interval, QRS interval, QT interval, and corrected QT interval, will include mean, standard deviation, median, and range for each assessment time point, as well as for the calculated changes from baseline to each subsequent time point.
• the categorical data, ie, diagnoses will be summarized using a shift table from baseline to each subsequent assessment time point and categories of normal, abnormal NCS, and abnormal CS.
• Tabular summaries of safety laboratory tests will include descriptive statistics (ie, mean, standard deviation, median, and range for continuous data and frequency for categorical data) for each assessment time point, and for the calculated changes from baseline to each subsequent assessment time point. Summaries of the safety laboratory tests relative to laboratory reference ranges will be prepared using shift tables from baseline to each subsequent assessment time point and categories of low, normal, and high for continuous data and abnormal and normal for categorical data. The incidence of treatment-emergent abnormal laboratory, vital sign, and ECG values will also be summarized using descriptive statistics.
• Efficacy endpoints will be analyzed for the full efficacy analysis set as described in Table 14. All proportions will be estimated with 95% confidence intervals.
• LTI Long-term infusion
• NB neuroblastoma
• Mody R Naranjo A, Van Ryn C, Yu AL, London WB, Shulkin BL, et al. Irinotecan- temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol. 2017. 4.
• Appendices Appendix 1 Abbreviations Abbreviation Definition AE Adverse event ALT Alanine aminotransferase ANC Absolute neutrophil count AST Aspartate aminotransferase ASCT Autologous stem cell transplant BOIN Bayesian optimal interval CDC Complement-dependent cytotoxicity COJEC Cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide CRF Case report form CRO Contract research organization CR Complete response CS Clinically significant CRP C-reactive protein CT Computed tomography CTCAE Common Terminology Criteria for Adverse Events Cycle A Vincristine, carboplatin, etoposide Cycle B Vincristine, cisplatin Cycle C Vincristine, cyclophosphamide, etoposide Cycle N5 Cisplatin, etoposide, vindesine Cycle N6 Vincristine, dacarbazine, ifosfamide, doxorubicin DMC Data monitoring committee DLT
• Appendix 2 Excluded Medications/Therapy Excluded medications/therapy are listed below.
• the use of an excluded medication/therapy is a protocol violation and must be recorded in the eCRF.
• ⁇ Due to immunosuppressive activity, the concomitant treatment with corticosteroids is not allowed within 2 weeks prior to the first treatment course and until 1 week after the last treatment course with dinutuximab beta, except for life-threatening conditions.
• Vaccinations (including seasonal influenza) will not be allowed during administration of dinutuximab beta until 10 weeks after last treatment course, due to immune stimulation through dinutuximab beta and possible risk for rare neurological toxicities.
• Appendix 3 Instructions for the Administration of Concomitant Medications Gabapentin Prior to each infusion cycle of dinutuximab beta, the patient should be primed with oral gabapentin starting 3 days before the start of the continuous dinutuximab beta infusion.
• the recommended oral dose of gabapentin is 10 mg/kg/dose once daily on Day 3 before the start of dinutuximab beta administration, increasing to 10 mg/kg/dose twice daily on Day 2 before the start of dinutuximab beta administration and 10 mg/kg/dose 3 times a day thereafter on all subsequent days during the antibody infusion, if required by the patient.
• Oral gabapentin shall be tapered off latest after stop of the dinutuximab beta infusion in a reverse order of the priming schedule.
• Morphine To prevent severe visceral and neuropathic pain opioids are the standard pain treatment given with dinutuximab beta. The first day and cycle usually requires more than subsequent days and cycles. Opioids should therefore be started and then gradually weaned. Besides respiratory depression and sedation, the same adverse effects are essentially seen in children as in adults (nausea, vomiting, constipation, pruritus, urinary retention lowered seizure threshold) The safety and efficacy of continuous iv administration of opioids for pain management are well established for all age groups. The risk of dependence is classified as low.
• iv morphine should initially be given, eg, a morphine sulfate loading infusion (30 ⁇ g/kg/h) in 60 minutes prior to the start of the continuous infusion of dinutuximab beta. Thereafter, it is recommended to administer morphine sulfate at a continuous infusion rate of 30 ⁇ g/kg/h on the first day.
• Boluses can be given as required. It is expected that the iv morphine can be rapidly tapered off. Depending on the individual patient’s pain tolerance, subsequent cycles can be started with iv morphine, including the bolus loading dose, and tapered at the discretion of the treating team.
• opioids are allowed in the tapering phase and after continuous morphine infusion: ⁇ Oral morphine; administered at a dose of 0.2 to 0.4 mg/kg every 4 to 6 hours. ⁇ Oral tramadol; if pain is well-controlled on low doses of oral morphine.
• the equivalent morphine to transdermal fentanyl dose rate in ⁇ g/h will be calculated from the current use of iv morphine, according to the manufacturer’s guidance, and the dose gradually decreased according to pain symptoms. It is not advised to use long-acting morphine in this situation, as it takes 48 hours to stabilize the dose, and this is not practical.
• Non-Steroidal Anti-Inflammatory Drugs In the first cycle, to prevent febrile reactions and to support pain prophylaxis, one of the antipyretic drugs listed below should be used during antibody infusion. In subsequent cycles antipyretic drugs should be administered at the Investigators discretion or according to local guidelines. ⁇ Metamizol (ie, Novalgin®) 10 to15 mg/kg po every 6 to 8 hours, if needed, or iv LTI with a dosage of 2.5 to 3.0 mg/kg/h. ⁇ Paracetamol 15 mg/kg po every 6 hours, if needed, or iv (ie, Perfalgan®) every 6 hours 15 mg/kg (100 mg/100mL).
• Ibuprofen eg, Ibuprofen-ratiopharm 2% or 4% Syrup®, Thomapyrin®
• Ibuprofen-ratiopharm 2% or 4% Syrup®, Thomapyrin® 10 to 15 mg/kg po before the treatment is administered and every 8 hours, if needed.
• Other Supportive Care Measures For anticipated potential of dinutuximab beta for allergic reactions, antihistamines as per local policy are recommended. For example: ⁇ Diphenhydramine (ie, DIBONDRIN ® ) 0.5 to 1.0 mg/kg iv/po q4h prn.
• Cetirizine 2 to 6 years: 2.5 mg/12 h po; 6 to 12 years: 5 mg/12 h po; >12 years: 10 mg/24 h po.
• Dinutuximab beta infusion continues providing patient is otherwise clinically stable. Hypotension For Grade 3 (medical intervention indicated) or Grade 4 (life-threatening) not responsive to a 20 mL/kg 0.9% sodium chloride fluid challenge. Dose modifications during current course of immunotherapy: ⁇ Discontinue dinutuximab beta infusion, support blood pressure with iv fluids, and with vasopressors if necessary. ⁇ If hypotension resolves or improves to Grade 1 with fluid boluses, then dinutuximab beta treatment may resume at 50% rate 1 hour later. To complete the administration of the prescribed dose prolongation of the infusion time period is possible according to the 20% rule.
• hypotension requires treatment with inotropic support, then discontinue dinutuximab beta and the patient will be taken off protocol therapy. If hypotension is unresponsive to supportive measures or requires ventilator support, the patient will be discontinued from dinutuximab beta.
• Hyponatremia Associated With Dinutuximab Beta Patients with either symptomatic hyponatremia, persistent (>48 hours) sodium less than 130 mmol/L, or severe hyponatremia without symptoms (sodium less than 120 mmol/L) will be discontinued from study therapy and receive no further dinutuximab beta.
• Grade 3 electrolyte imbalance (especially hyponatremia ⁇ 130 mmol/L in the absence of central nervous system (CNS) symptoms and sequelae) that improves with treatment within 24 hours will NOT require dose modification when observed, provided that these toxicities are judged to be tolerable by the responsible clinician, as well as the patient and family.
• Performance Status Treatment will be stopped for a performance status ⁇ 20%. If performance status improves to ⁇ 20%, dinutuximab beta treatment can be restarted at 50% of the dose, at which this toxicity occurred. Performance status (30% to ⁇ 50%) will NOT need dose modification when observed, provided that these toxicities are judged to be tolerable by the responsible clinician, as well as the patient and family.
• Pain Patients experiencing pain due to dinutuximab beta despite pain prophylaxis will be treated with additional morphine or similar analgesics, as needed, and have their pain graded according to the NCI-CTCAE version 5.0 and, in addition, will be evaluated with a validated self-reporting tool (Appendix 5).
• Patients with severe unrelenting neuropathic pain unresponsive to continuous infusion of narcotics and other adjuvant measures including lidocaine infusions must be discontinued from study therapy and the Sponsor contacted if the patient may continue the study.
• Hematologic Toxicity All patients will be transfused as needed to maintain an adequate hemoglobin level and platelet count.
• Transaminases ALT and AST: In the event of persistent clinically relevant elevation of transaminase levels (Grade 4, >7 days), discontinuation of treatment should be considered.
• Alkaline phosphatase No dosing interruption or dose modifications will be made for elevated alkaline phosphatase since this occurs commonly and, on its own, is not a good indicator of hepatic toxicity.
• Bilirubin If total bilirubin increases to Grade 3 (>3 ⁇ ULN) due to chemotherapy/ch.14.18/CHO toxicity, the dinutuximab beta antibody should be withheld until the total bilirubin returns to normal. Following recovery, the dinutuximab beta antibody should be restarted at the planned dose.
• Nephrotoxicity Adequate renal function is an eligibility requirement. If renal function is worsening, but not yet Grade 3 (creatinine >3 ⁇ baseline), other nephrotoxic drugs should be avoided. Cardiac Toxicity Any evidence of cardiac abnormalities will require an immediate ECG evaluation. Evidence of ischemia will require immediate discontinuation of therapy.
• Patients with evidence of asymptomatic atrial irregularities, related to an elevated temperature, but without any evidence of ischemia or clinically significant hypotension, will be monitored but continue therapy. Patients experiencing Grade ⁇ 3 cardiac toxicity will be taken off protocol therapy. Complications of fluid overload may be seen. Patients with clinical problems related to fluid overload will be treated with furosemide or mannitol provided they have ⁇ 40 mmHg decrease in systolic blood pressure from baseline. Treatment should be stopped for a sustained decrease in blood pressure below 40 mmHg mean arterial blood pressure. This is also the case if blood pressure has not been restored with brief fluid or albumin challenge, ie, 20 mL/kg of 0.9% sodium chloride. Intravenous vasopressor may be used when clinically indicated. Treatment can be restarted at 50% of the dose of the dinutuximab beta that caused the toxicity, once the blood pressure has returned to 40 mmHg mean arterial pressure.
• Dyspnea Patients experiencing dyspnea and whose oxygen saturation is less than 90% may receive oxygen supplementation. Patients with clinical problems related to fluid overload will be treated with diuretics provided they have ⁇ 40 mmHg decrease in systolic blood pressure from baseline. If the oxygen saturation does then not improve to over 90%, treatment will be discontinued and restarted at 50% of the previous dose of the dinutuximab beta dose when toxicity has been resolved. Neurotoxicity Neuropathy associated with dinutuximab beta. Occasional reports of neuropathy with weakness and paralysis and MRI signs of transverse myelitis have been reported mostly with dinutuximab beta given in combination with IL- 2.
• Persistent confusion (>6 hours) of any cause will require the discontinuation of therapy, with subsequent reinitiating of treatment at 50% of the previous dose if reversal of this toxicity occurs within 5 days prior to the next scheduled dose.
• Pruritus and Urticaria Treat with antihistamines (eg, diphenhydramine or chlorpheniramine).
• antihistamines eg, diphenhydramine or chlorpheniramine.
• Preparation of emergency medication corticosteroids and epinephrine
• a free-flowing iv line must be established at all times. Nausea, Vomiting, and Diarrhea Grade 3 nausea, vomiting and diarrhea will NOT need dose modification.
• Hypersensitivity Reactions Mild Symptoms eg, Localized Cutaneous Reactions or Shivering and Rigor
• Antihistamines diphenhydramine or chlorphenamine
• Moderate Symptoms eg, Hypotension
• Interrupt dinutuximab beta infusion administer supportive care, and monitor patient until resolution of symptoms.
• infusion may be resumed at 50% of the initial infusion rate.
• Severe Symptoms Any Reaction Such as Bronchospasm, Angioedema or Anaphylactic Shock
• epinephrine antihistamines (diphenhydramine or chlorphenamine) and corticosteroids, bronchodilator or other medical measures as needed.
• Patients should be monitored as inpatients for at least 24 hours AND until the symptoms have resolved.
• ⁇ Patients should be closely monitored for anaphylaxis and allergic reactions, particularly during Cycles 1 and 2 of treatment. Patients who experience Grade 4 anaphylaxis or allergic reaction should discontinue dinutuximab beta therapy.
• Grade 3 serum sickness patients should be taken off dinutuximab beta.

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