Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Sarcoma

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Dinutuximab

The treatment phase foresees 5 cycles of Dinutuximab Beta. Dinutuximab Beta administration is restricted to hospital-use only and must be administered under the supervision of a physician experienced in the use of oncological therapies. It must be administered by a healthcare professional prepared to manage severe allergic reactions including anaphylaxis in an environment where full resuscitation services are immediately available. The study treatment will be administered with a continuous intravenous infusion at a dose of 14 mg/mq/day, days 1-5, a total of 60 hours (cumulative dose/cycle: 70 mg/mq). Each cycle lasts 28 days.

The study treatment will be administered with a continuous intravenous infusion at a dose of 14 mg/mq/day, days 1-5, a total of 60 hours (cumulative dose/cycle: 70 mg/mq). Each cycle lasts 28 days.The treatment phase foresees 5 cycles of Dinutuximab Beta.

Dinutuximab beta

Franca Fagioli, MD

Limited progress has been made in identifying novel targets that may be therapeutic for Osteosarcoma(OS) and there remains an urgent need for the development of new agents that are effective in improving survival. From this perspective, repurposing already proven targets in other tumors may offer new opportunities for OS in children and young adults. Anecdotal evidence of anti-GD2 therapy exists in OS from prior Phase 1 trials that included patients with OS.

Anecdotal evidence of anti-GD2 therapy exists in OS from prior Phase 1 trials that included patients with OS. In a Phase 1/1B trial of the murine antibody (14.2G2a) plus IL2, 2/33 patients had OS. One patient had multiple bone metastases and received 1 cycle of therapy. Two months later, repeat scans showed a complete response. This patient remained disease free for 8 months but subsequently relapsed.

The Children's oncology group recently investigated the use of dinutuximab monotherapy in patients with recurrent pulmonary OS in complete surgical remission in a single-arm phase II study (AOST1421). Patients received 5 cycles of dinutuximab 70mg/m2/cycle with GM-CSF in 2 different dinutuximab infusion schedules: 35mg/m2/day over 20 hours (2-day) and 17.5mg/m2/day over 10 hours (4-day) schedule. The primary end point was Disease Control Rate (DCR), defined as the proportion of patients' event-free at 12 months from enrollment and success was defined as ≥16/ 39 patients (\> 40%) event-free at 12 months from enrollment. The preliminary results of this study were showed at ASCO 2020. Thirty-nine patients were eligible and evaluable (median age 15 yr). One of 136 administered therapy cycles met the criteria for unacceptable toxicity when 1 patient receiving the 2-day schedule died after cycle 2 due to an unknown cause and 1 patient experienced grade 4 neurotoxicity (depressed level of consciousness and respiratory depression) attributed as probably related to the protocol therapy. The protocol was revised to allow only the 4-day schedule. Other ≥ Grade 3 toxicities occurring in \> 10 % of participants were predictable dinutuximab toxicities such as pain, diarrhea, hypoxia and hypotension. A DCR of 30.7% (95% CI 17- 47%) was found, as 27/39 patients experienced an event. The final official results have not been published yet, and analyses are ongoing. A humanized version of the anti-GD2 antibody, Naxitamab (hu3F8), developed at Memorial Sloan Kettering Cancer Center, is currently being tested for efficacy against recurrent OS (NCT02502786).

Rationale dose and schedule of Dinutuximab beta in MaQ trial.

The recommended dosage of Dinutuximab (Unituxin, United Therapeutics) is 17.5 mg/m2/day administered IV over 10-20 hours for 4 consecutive days for a maximum of 5 cycles. In AOST1421, patients with recurrent pulmonary OS received 5 cycles of dinutuximab 70mg/m2/cycle with GM-CSF in 2 different infusion schedules: 35mg/m2/day over 20 hours (2-day) (experimental infusion) and 17.5mg/m2/day over 10 hours (4-day) schedule. However, during this trial, 2 serious adverse events (n=1 death, n=1 grade 4 neurotoxicity), possibly related to the experimental infusion schedule of dinutuximab were reported. In light of these events, the protocol was modified for the remainder of the study to allow only the 4-day schedule.

In the EU, Dinutuximab beta is approved for high-risk NB patients at the recommended dosage of 100 mg/m2 per course as either an 8-hour short-term i.v. infusion over 5 consecutive days (STI), or as a long-term i.v. infusion over 10 consecutive days (LTI). A pharmacokinetics study of LTI dinutuximab beta showed that this regimen results in higher plasma exposure at time points preceding subsequent antibody infusions after cycle 1, allowing for a persistent activation of antibody effector mechanisms over the entire treatment period. Moreover, LTI led to a less toxic profile compared with STI regimen. Data on Dinutuximab dosage and safety are based on studies enrolling primary refractory or relapsed NB or first-line NB children with either complete response or at MRD. OS is the most common primary malignant bone tumor in AYA, thus we expect to include older patients than NB patients, that notably experience greater toxicity from antitumor therapies. Moreover, the present trial will enroll patients who have experienced OS R/R and have already received at least one line of standard treatment. Furthermore, so far, PK data are lacking for the adolescent population. For these reasons, the patients enrolled in this study with OS R/R will received Dinutuximab beta (Qarziba) 14 mg/mq/day, for 5 days (total dose: 70mg/sqm/cycle) i.v. continuous infusion. Each cycle will last 28 days.

Qarziba for Patients in Relapsed/Refractory High-grade Osteosarcoma

Maintenance Therapy With Qarziba for Patients in Relapsed/Refractory High-grade Osteosarcoma After Induction Multimodal Therapy - a Phase II Multi-center Study

• Disease Control Rate (DCR) at 12 months from the last episode of relapse/refractory patients with CR or PR OS R/R treated with a maintenance therapy with Dinutuximab Beta.

Prof. Franca Fagioli

Professor

Behaviors and Mental Disorders

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Quality of Life

Neuroepithelioma

Anne EL AATMANI, Pharm, PhD

Emilie BERTHON, Pharm, PhD

Emilie BERTHON, PhamD, PhD

Sophie PERRIAT, PhamD, PhD

In this study the investigators wish to describe the cohort of pediatric patients suffering from neuroblastoma and treated with Dinutuximab and to compare the costs and quality of life between the two French centers, the University Hospital of Strasbourg (HUS) and the Oncopole of Toulouse.

Dinutuximab Beta at the HUS and the Toulouse Oncopole

Dinutuximab Beta at the Strasbourg University Hospitals (HUS) and the Toulouse Oncopole: Comparative Analysis of Patient Pathways, Associated Costs and Quality of Life According to Traditional Hospitalization or Hospital at Home (HAD)

This study is retrospective and consists of comparing two methods of treating neuroblastoma in two health establishments and covers the period from January 1, 1998 to December 31, 2023.

University Hospital, Strasbourg, France

Dermatologic Agents

Isotretinoin

Tretinoin

Keratolytic Agents

Patients who received dinutuximab beta as maintenance therapy

Dinutuximab Beta

13 cis retinoic acid

This is an open-label, multi-center, single-arm, Phase 1 study. The purpose of this study is for evaluating the safety and pharmacokinetics of dinutuximab beta as maintenance therapy in Chinese patients with high-risk neuroblastoma

Evaluation of the Safety and Pharmacokinetics of Dinutuximab Beta as Maintenance Therapy in Chinese Patients With High-risk Neuroblastoma

An Open-Label, Multi-Center, Single-Arm, Phase 1 Study Evaluating the Safety and Pharmacokinetics of Dinutuximab Beta as Maintenance Therapy in Chinese Patients With High-Risk Neuroblastoma

Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)

BeiGene

Symptoms and General Pathology

Recurrence

Anti-Infective Agents

Natriuretic Agents

Analgesics

Molgramostim

Sargramostim

Aldesleukin

Immunomodulating Agents

Spironolactone

Interleukin-2

Analgesics, Non-Narcotic

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

Immunologic Factors

Mineralocorticoid Receptor Antagonists

Mineralocorticoids

Hormones

Hormone Antagonists

Diuretics

Diuretics, Potassium Sparing

Natural killer cells isolated from HLA-haploidentical relative donor

Natural killer cell

Interleukin-2 sc alternate day for 6 doses

Granulocyte-macrophage colony-stimulating factor sc daily till ANC \>2,000/mm3

Granulocyte-Macrophage Colony-Stimulating Factor

Naxitamab iv for 4 days (as alternative for dinutuximab)

Naxitamab

Daniel Cheuk

This is a single-arm clinical trial to evaluate the efficacy and safety of quadruple immunotherapy with natural killer (NK) cells, anti-GD2 antibody, cytokines (interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF)) and retinoid X receptor gamma (RXRg) agonist spironolactone for paediatric patients with relapsed or refractory neuroblastoma.

Included patients will receive intravenous infusion of donor NK cells on day 0, and anti-GD2 antibody (dinutuximab) on day -6 to day -2. IL-2 will be given subcutaneously on day -1, day +1, day +3, day +5, day +7, and day +9. Subcutaneous injection of GM-CSF will be started on day 0, given daily till neutrophil count \>1000/mm3. Spironolactone will be started orally on day -1, given three times daily till cessation of GM-CSF.

Alternative anti-GD2 antibody (Naxitamab) can be used instead of dinutuximab, to be given on day -5, day -3, day +1 and day +3.

Quadruple Immunotherapy for Neuroblastoma

Quadruple Immunotherapy for Paediatric Patients With Relapsed or Refractory Neuroblastoma

Objective response = complete response + partial response + minor response + stable disease

From the date of treatment start until the date of death from any cause, assessed up to 1 year

From date of treatment start until the date of first documented progression or the date of death from any cause, whichever comes first, assessed up to 1 year

relapse = reappearance of tumor after complete response

Adverse events are graded according to Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events version 5 (CTCAEv5)

Percentage of donor natural killer cells in the recipient's blood will be evaluated weekly from the date of NK cell infusion for 4 weeks, then every 2 weeks till donor NK cells are undetectable

The University of Hong Kong

Hong Kong Children's Hospital

Consultant

Antirheumatic Agents

Cyclophosphamide

Bevacizumab

Irinotecan

Temozolomide

Topotecan

Immunosuppressive Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 every 4 weeks

Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks

Bevacizumab Day 1 + Irinotecan Days 1-5 + Temozolomide Days 1-5 every 3 weeks

Temozolomide Days 1-5+ Topotecan Days 1-5 every 4 weeks

Bevacizumab Day 1 and 15 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks

Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 every 4 weeks

Dinutuximab beta Days 1-7 + Temozolomide Days 1-5 + Topotecan Days 1-5 every 4 weeks

Dinutuximab beta Days 1-7 + Topotecan Days 1-5 + Cyclophosphamide Days 1-5 every 4 weeks

10mg/kg IV (in the vein) on Days 1 and 15 of a 4 week cycle, for 6 cycles or until progression

200mg/m2/d PO (capsule taken orally) on Days 1 to 5 of a 4 week cycle, for 6 cycles or until progression

100mg/m2/d PO (capsule taken orally) on Days 1 to 5 of a 3 week cycle, for 6 cycles or until progression

50mg/m2/d IV (in the vein) on Days 1 to 5 of a 3 week cycle, for 6 cycles or until progression

15mg/kg IV (in the vein) on Day 1 of a 3 week cycle, for 6 cycles or until progression

0.75mg/m2/d IV (in the vein) on Days 1-5 of a 4 week cycle, for 6 cycles or until progression

150mg/m2/d PO (capsule taken orally) on Days 1 to 5 of a 4 week cycle, for 6 cycles or until progression

10mg/m2/d IV (in the vein) on Days 1 to 7 of a 4 week cycle, for 6 cycles or until progression

250mg/m2/d IV (in the vein) on Days 1 to 5 of a 4 week cycle, for 6 cycles or until progression

Lucas Moreno, MD

The purpose of this study is to investigate whether Bevacizumab (an anti-VEGF monoclonal antibody) added to a backbone chemotherapy regimen (Temozolomide, Irinotecan-Temozolomide or Topotecan-Temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma. Also, to investigate whether the addition of Irinotecan or Topotecan to Temozolomide increases the activity of chemotherapy.The primary objective of the study is the best response (Complete Response or Partial Response) while trial treatment, within 18 or 24 weeks depending on the arm of the trial the participant is randomised to. Secondary endpoints are assessing the side effects, the length of time before progression (Progression Free Survival) and overall survival (OS).

This trial will address two important questions:

* does targeting blood vessel development using bevacizumab, (a monoclonal antibody against the Vascular Endothelial Growth Factor (VEGF)), add to the effect on a tumour when used with existing chemotherapy, compared to the effect of the existing chemotherapy alone (temozolomide)? NOTE- This question has been completed.
* does the addition of a second chemotherapy drug (irinotecan or topotecan) increase the effect on a tumour compared to the effect of one alone (temozolomide) NOTE - This question has been completed.
* does the addition of dinutuximab beta added to a backbone chemotherapy (temozolomide or temozolomide + topotecan) increase the effect of backbone alone.

Patients aged 1-21 years of age with relapsed or refractory high-risk neuroblastoma are randomised to one of two treatment arms: temozolomide-topotecan (TTo) or dinutuximab beta-temozolomide-topotecan (dBTTo). Temozolomide (T), irinotecan-temozolomide (IT), bevacizumab-T (BT), BIT (bevacizumab-IT), bevacizumab-temozolomide-topotecan (BTTo) and dinutuximab beta-temozolomide (dBT) are now closed to recruitment.

This is an international open-label, randomised, multicentre phase II trial of temozolomide ± irinotecan, with or without bevacizumab, for the treatment of patients with relapsed or refractory neuroblastoma. The study will evaluate the safety and activity of these combinations.

Patients will be registered into the trial and randomised at the same time to one of the following two arms (approximately 30 patients per arm):

TTo: Temozolomide + Topotecan dBTTo: Dinuximab beta + Temozolomide + Topotecan

Arms which have now closed to recruitment:

dBT: Dinutuximab beat + Temozolomide Closed 28 \]Jan 2020 T: Temozolomide - Closed 28 Jan 2020 BT: Bevacizumab + Temozolomide - Closed 7 Feb 2019 IT: Irinotecan + Temozolomide - Closed 21 June 2018 BIT: Bevacizumab + Irinotecan + Temozolomide - Closed 21 June 2018 BTTo: Bevacizumab + Temozolomide + Topotecan - Closed 7 Feb 2019

Randomisation will be via a secure on-line computer-based system at the Cancer Research Clinical Trial Unit (CRCTU), University of Birmingham, United Kingdom (UK) and patients will be allocated in a 2:1 ratio. Minimisation will be used to ensure balance across the arms for the important prognostic factors as described by London et al. \[10\]: a) relapsed, refractory disease, b) early (\< 18 months), late relapse (≥18 months) and c) measurable versus evaluable disease (i.e. disease evaluated according to RECIST versus disease detectable only by MIBG scanning with or without bone marrow involvement as detected by local morphology) Patients will receive treatment for 6 courses, lasting 24 weeks.

Patients with a response (CR, PR) or stable disease (SD) while on the BEACON-Neuroblastoma trial will receive 6 cycles of trial treatment. If the patient has achieved a satisfactory response (i.e. CR, PR or SD) with acceptable toxicity, treatment may be extended beyond 6 cycles (up to 12 cycles) after discussion with the Sponsor and the Chief Investigator (CI).

In addition, patients randomised to TTo may recieve an optional regimen of dinutuximab beta + topotecan + cyclophosphamide (up to 6 cycles).

Activity Study of Bevacizumab With Temozolomide ± Irinotecan for Neuroblastoma in Children

A Randomised Phase IIb Trial of Bevacizumab Added to Temozolomide ± Irinotecan for Children With Refractory/Relapsed Neuroblastoma - BEACON-Neuroblastoma Trial

To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide, irinotecan-temozolomide or topotecan-temozolomide) demonstrates activity in children with relapsed or refractory neuroblastoma To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma

Safety of the regimens: Incidence and severity of Adverse Events (AE)s

Safety of the regimens: Progression-free survival (PFS)

Safety of the regimens: Overall survival (OS)

Safety of the regimens: Event-free survival (EFS)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Qarziba for Patients in Relapsed/Refractory High-grade Osteosarcoma	NCT05558280	Osteosarcoma in...	Dinutuximab bet...	1 Year - 25 Years	Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna
Qarziba for Patients in Relapsed/Refractory High-grade Osteosarcoma	NCT05558280	Osteosarcoma in...	Dinutuximab bet...	1 Year - 25 Years	Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna
Dinutuximab Beta at the HUS and the Toulouse Oncopole	NCT06275334	Neuroblastoma		2 Years - 25 Years	University Hospital, Strasbourg, France
Evaluation of the Safety and Pharmacokinetics of Dinutuximab Beta as Maintenance Therapy in Chinese Patients With High-risk Neuroblastoma	NCT05373901	High-risk Neuro...	Dinutuximab Bet... 13 cis retinoic...	12 Months -	BeiGene
Quadruple Immunotherapy for Neuroblastoma	NCT05754684	Neuroblastoma R...	Natural killer ... Dinutuximab bet... Interleukin-2 Granulocyte-Mac... Spironolactone Naxitamab	- 18 Years	Hong Kong Children's Hospital
Qarziba for Patients in Relapsed/Refractory High-grade Osteosarcoma	NCT05558280	Osteosarcoma in...	Dinutuximab bet...	1 Year - 25 Years	Azienda Ospedaliera Ospedale Infantile Regina Margherita Sant'Anna
Evaluation of the Safety and Pharmacokinetics of Dinutuximab Beta as Maintenance Therapy in Chinese Patients With High-risk Neuroblastoma	NCT05373901	High-risk Neuro...	Dinutuximab Bet... 13 cis retinoic...	12 Months -	BeiGene
Activity Study of Bevacizumab With Temozolomide ± Irinotecan for Neuroblastoma in Children	NCT02308527	Neuroblastoma	Bevacizumab Temozolomide Temozolomide Irinotecan Bevacizumab Topotecan Temozolomide Dinutuximab Bet... Cyclophosphamid...	1 Year - 21 Years	University of Birmingham
Quadruple Immunotherapy for Neuroblastoma	NCT05754684	Neuroblastoma R...	Natural killer ... Dinutuximab bet... Interleukin-2 Granulocyte-Mac... Spironolactone Naxitamab	- 18 Years	Hong Kong Children's Hospital
Evaluation of the Safety and Pharmacokinetics of Dinutuximab Beta as Maintenance Therapy in Chinese Patients With High-risk Neuroblastoma	NCT05373901	High-risk Neuro...	Dinutuximab Bet... 13 cis retinoic...	12 Months -	BeiGene

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