Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Gaucher Disease Type 2

Neuroepithelioma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Immunomodulating Agents

This is a single arm study. Patients with high risk neuroblastoma who have residual measurable disease will receive a combination of 5 days of anti-GD2 with expanded activated NK cells.

Haploidentical donor NK cells will be expanded over 10 days and infused in combination with anti-GD2. Anti-GD2 will be given as daily infusion for 5 days ; D-1, 0,+1, +2 and +3. NK cells will be infused at single dose on day 0. The patient will receive cyclophosphamide 60mg/kg on day -3 and day -2 prior to the NK cell infusion. IL- 2 will be given subcutaneously for 6 doses every alternate day starting on day -1, for NK cell survival.

Anti-GD2 in combination with NK cells

Miriam Kimpo, MD

Chetan Dhamne, MBBS, MS, MD

Dr. Miriam Kimpo, MD

Dr.Chetan Dhamne, MBBS, MS. MD

Dario Campana, MD, PhD

Neuroblastoma is a neoplasm of the sympathetic nervous system which affects mostly children younger than 5 years of age. It is a heterogeneous disease, with nearly 50% of patients presenting with a high-risk phenotype. After standard treatment, the 2-year event-free survival (EFS) for high risk neuroblastoma (EFS) is only about 50%. Immunotherapy with anti-GD2 antibodies has been shown to improve EFS in Children's Oncology Group and SIOPEN trials.

The anti-GD2 antibody mediates neuroblastoma cell killing primarily through antibody-dependent cell-mediated cytotoxicity (ADCC). Natural killer (NK) cells are the main effectors of ADCC. We postulate that infusion of expanded activated NK cells from healthy haploidentical donors along with anti-GD2 antibody will enhance neuroblastoma killing.

Adoptive transfer of haploidentical NK cells has been shown to be safe in clinical trials at NUH. There is experience combining antibody infusion with autologous NK cells in the clinical trial with good safety data.

The proposed trial is a phase I/II study to determine the safety and efficacy of expanded activated haploidentical NK cells in combination with anti-GD2 (ch14.18/CHO). We plan to enrol patients with high risk or relapsed neuroblastoma with evidence of residual disease who are at high risk of recurrence or progression on current treatment.

In the proposed protocol , we plan to infuse NK cells at escalating dose levels to find the optimum dose tolerated by the patients in combination with anti-GD2 (ch14.18/CHO) . There are 3 NK cell dose levels :

Dose level 1 (1 x 10\^6/kg) , Dose level 2 (1 x 10\^7/kg) , Dose level 3 (1 x 10\^8/kg)

If a partial response or stable disease is observed, further infusions of NK cells can be administered. There will be intra- and inter - patient dose escalation.

The donor will be either parent, based on the best NK cell donor as determined by the study team. The donor will be harvested and NK cells expanded prior to infusion into the patient along with anti-GD2 (ch14.18/CHO).

The study aims to study safety and efficacy of a combination of NK cells and anti-GD2 (ch14.18/CHO).

To determine the feasibility, safety and effectiveness of anti-GD2 in combination with expanded, activated NK cells in research participants with Neuroblastoma

Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells

Pilot Study of Anti-GD2 and Expanded, Activated Natural Killer Cell Infusion for Neuroblastoma

Disease status at primary and metastatic soft tissue sites will be assessed using MIBG scans or PET scan as applicable. RECIST and Curie scoring systems will be used to assess response. Metastatic bone disease will be assessed using MIBG or PET scan. Bone marrow will be assessed by histology or flow cytometry. Disease response will be defined as Complete response/remission (CR), Partial response (PR), Minor response, Stable disease (SD), or Progressive disease(PD).

NK cells will be identified by flow cytometry in peripheral blood and their percentages and absolute numbers will be calculated.

Cytokine panel to assess levels of IL15 serially post lymphodepletion regimen

National University Hospital, Singapore

Skin and Connective Tissue Diseases

Osteosarcoma

Sarcoma

Sarcoma, Ewing

Neoplasms, Connective and Soft Tissue

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Ewing Sarcoma

After a lymphodepleting regimen the patients will receive 1.0 to 10.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells.

Following a lymphodepleting treatment with conventional chemotherapy, patients will be treated with 1.0 to 10.0 x 10⁶/kg GD2 Chimeric Antigen Receptor (CAR) positive T cells as a single dose.

GD2-CART01

Franco Locatelli, MD, PhD

The purpose of this study is to test the safety and efficacy of GD2-CART01, a CAR T cell treatment targeting GD2 in paediatric or young adult patients with High Risk and/or relapsed/refractory Neuroblastoma.

A small exploratory cohort of patients with GD2-positive tumors other than Neuroblastoma has also been included.

The study will consist of 2 phases, a Phase I or dose escalation phase and a Phase II or expansion phase. Paediatric or young adult patients with relapsed High Risk and/or relapsed/refractory Neuroblastoma will be enrolled in the study.

After completion of the phase I portion of the study, a small cohort of patients with GD2-positive tumors other than Neuroblastoma has also been included.

Eligible patients will undergo leukapheresis in order to harvest T cells, which will be manufactured to obtain the autologous CAR T product GD2-CART01, a GD2-targeting CAR T product. Briefly, the patients will be treated with a lymphodepleting regimen containing conventional chemotherapic agents and subsequently will receive a single infusion of GD2-CART01. Moreover, the product contains a suicide gene safety switch (namely inducible Caspase 9): in case of relevant toxicities, the patient will receive the dimerizing agent in order to activate the apoptotic pathway in the infused T cells.

After infusion of CAR T cells, the patients will enter a 5-year active follow-up period.

Anti-GD2 CAR T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors

Phase I/II Study of Anti-GD2 Chimeric Antigen Receptor-Expressing T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors

Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale, version 4 and the number of patients experiencing DLT will be evaluated

Assessment of Best Overall Response (BOR)

Detection of infused CAR T cell in the peripheral and bone marrow blood

Assessment of the seric cytokines profile

Tumor response assessment through the two different criteria

Assessment of the kinetic of CAR T cell elimination after infusion of the dimerizer

Bambino Gesù Hospital and Research Institute

Haematology-Oncology Department Chief

Lutetium Lu 177 dotatate

Radiopharmaceuticals

A total of two doses of 177Lu-DOTATATE will be administered intravenously. The minimum time between treatments is 2 weeks.

A weight-based activity of 200 MBq kg-1 will be used for the first dose. The activity of the second dose will be calculated based on whole body activity scans as well as SPECT CT scans to determine the absorbed kidney dose. The aim is to administer 177Lu-DOTATATE corresponding to a whole-body dose of 1,2 Gy, with a cumulative whole-body dose of about 2,4 Gy over two courses, and not exceeding a cumulative renal dose of 23 Gy, in order to avoid renal toxicity.

177Lu-DOTATATE

Jakob Stenman, MD PhD

Kleopatra Georgantzi, MD

Jesper S Brok, MD PhD

Jelena Rascon, MD PhD

Max M van Noesel, MD PhD

Heidi Knudsen, MD

The LuDO-N Trial is a multi-centre phase II clinical trial on 177Lu-DOTATATE treatment of recurrent or relapsed high-risk neuroblastoma in children. The LuDO-N Trial builds on the experience from the previous LuDO Trial and utilises an intensified dosing schedule to deliver 2 doses over a 2-week period, in order to achieve a maximal effect on the often rapidly progressing disease. This strategy requires a readiness for autologous stem cell transplantation in all patients, but is not anticipated to increase the risk of long-term sequelae, since the cumulative radiation dose remains unchanged. The primary aim of the study is to assess the response to 177Lu-DOTATATE treatment at 1 and 4 months after ende of treatment. Secondary aims are to assess survival and treatment-related toxicity. Additional aim are to correlate tumour dosimetry with response, correlate SSTR-2 expression with 68Ga-DOTATATE uptake and to correlate the uptake with the treatment response.

177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-risk Neuroblastoma

A Phase II Trial of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-risk Neuroblastoma

SSTR-2 expression in the histology samples from primary surgery measured by immunohistochemistry.

Measured by SUVmax (maximum standardized uptake value)

Treatment response assessed in accordance with the Revised International Neuroblastoma Response Criteria (INRC)

Number and severity of treatment-related adverse events

Time to progress or death, whichever occurs first

Advanced Accelerator Applications

Novartis

Jakob Stenman

Consultant Pediatric Surgeon, Associate Professor

Anti-Infective Agents

Natriuretic Agents

Analgesics

Molgramostim

Sargramostim

Aldesleukin

Spironolactone

Interleukin-2

Dinutuximab

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

Dinutuximab beta

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

Micronutrients

Pharmaceutical Solutions

Gastrointestinal Agents

Central Nervous System Depressants

Dermatologic Agents

Vitamins

Herbal and Botanical

Amino Acids

Ascorbic Acid

Irinotecan

Temozolomide

Carboxymethylcellulose Sodium

Sirolimus

Dasatinib

Sorbitol

Ethanol

Immunosuppressive Agents

Titanium dioxide

Temsirolimus

MTOR Inhibitors

Topoisomerase I Inhibitors

Protein Kinase Inhibitors

Alkylating Agents

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Tyrosine Kinase Inhibitors

Vitamin C

Soy Bean

Tyrosine

Patients randomized to the control arm receive irinotecan (I) and temozolomide (T) alone.

Patients with rNB receive on the study arm the experimental combination of rapamycin (R)- mTOR Inhibitor, dasatinib (D)- protein kinase inhibitor irinotecan (I)- cytostatic topoisomerase-I-inhibitor and temozolomide (T)- Antineoplastic agent

Pharmacotherapeutic Group: protein kinase inhibitor ATC-Code: L01XE06 Excipients: Tablet core: Lactose monohydrate, Cellulose, microcrystalline, Croscarmellose sodium, Hydroxypropyl cellulose, Magnesium stearate. Film-coating: Hypromellose, Titanium dioxide, Macrogol 400 Formulation: film coated tablet Route of Administration: orally. Patients should be instructed to swallow the tablets as a whole and not to split, chew, or crush them.

Pharmacotherapeutic Group: Immunosuppressive agents - mTOR Inhibitors ATC-Code: L04A A10 Excipients: Polysorbat 80, Phosal 50 PG ((3-sn-Phosphatidyl)cholin from Soy beans, Propylenglycol, lipid acid mono- and -diglyzeride from Soy oil, Ethanol (1,5% bis 2,5%), Soy liid acid and Palmitoyl ascorbic acid) Formulation: Oral solution Route of Administration:orally

Rapamycin

Pharmacotherapeutic Group: cytostatic topoisomerase-I-inhibitor ATC-Code: L01XX19 Excipients: Sorbitol (E420), lactic acid, sodium hydroxid (to adjust the pH to 3.5), water for injection Formulation: concentrate for solution for infusion Route of Administration: intravenously

Pharmacotherapeutic Group: Antineoplastic agents - Other alkylating agents, ATC-Code: L01A X03 Excipients: Capsule content: Anhydrous lactose, Sodium starch glycolate Type A, Colloida anhydrous silica, Tartaric acid, Stearic acid. Capsule shell: Gelatine, Titanium dioxide (E171).

Printing ink: Shellac Propylene glycol, Titanium dioxide (E171), Sunset yellow FCF Aluminium Lake (E110) Formulation: capsule, hard Route of Administration: orally; Temomedac hard capsules should be administered in the fasting state. The capsules must be swallowed whole with a glass of water and must not be opened or chewed

Selim Corbacioglu, MD

Children, adolescents and young adults with high risk relapsed or treatment refractory neuroblastoma (rNB) represent a group of patients with dismal prognosis for whom a recommended standard salvage therapy is currently not available.

The multimodal metronomic approach combining molecular targeted drugs (rapamycin and dasatinib) with conventional chemotherapy (irinotecan and temozolomide) will be investigated in a randomized fashion as new treatment strategy for patients with rNB. The intention is to assess the therapeutic benefit of molecular targeted drugs for the treatment of rNB.

The combination of irinotecan and temozolomide showed activity in the treatment of several solid organ tumors, brain tumors and neuroblastoma. In one study rNB patients received a median of 5 courses of 5 days irinotecan and temozolomide every 3 to 4 weeks with a cumulative dose of 35% lower than in the RIST design. 33% had disease regression with 8% CR or PR. A phase II study in rNB also using irinotecan and temozolomide with a substantially lower intensity showed a response rate of 15%.

The combination of a mTOR inhibitor with a multi-kinase inhibitor demonstrated in preclinical studies a synergistic effect on cell cycle arrest, apoptosis and sensitization for radio- and chemotherapy. It is assumed that this combination of molecular targeted drugs with a tolerable conventional chemotherapy consisting of irinotecan and temozolomide can substantially improve the outcome of this patient population. A group of 20 rNB patients treated with the RIST therapy approach in a compassionate use setting showed an overall survival of 55% at a median of 80 weeks with a tolerable adverse event profile.

Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma

Prospective, Open Label, Randomized Phase II Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-risk Neuroblastoma

The primary objective of this trial is the evaluation of progression-free survival of rNB in children, adolescents and young adults, comparing a multimodal treatment regimen consisting of temozolomide (T), irinotecan (I), rapamycin (R) and dasatinib (S) against irinotecan (I) and temozolomide (T) (I/T) alone

Assessment according to the latest version of the CTC criteria. In particular due to the expected AE Profile:

* Myelosuppressive measures (RBC, PLT units)
* Infectious complications
* Gastrointestinal problems

University of Regensburg

Prof. Dr. med.

Bortezomib

Eflornithine

Antiprotozoal Agents

Antiparasitic Agents

Ornithine

Subjects will take DFMO by mouth 2 times a day for each day of a 21 day cycle and Bortezomib will be given by IV push on days 1, 4, and 8 of each 21 day cycle.

DFMO

Kathleen Neville, MD

The purpose of this research study is to evaluate an investigational drug (DFMO) in combination with bortezomib, for relapsed and refractory neuroblastoma. DFMO is an investigational drug because it has not been approved by the U.S. Food and Drug Administration (FDA). This study will look at the safety and tolerability of DFMO in combination with bortezomib as well as the tumors response to this study drug.

Study of Difluoromethylornithine (DFMO) in Combination With Bortezomib for Relapsed or Refractory Neuroblastoma

A Phase I/II Trial of DFMO in Combination With Bortezomib in Patients With Relapsed or Refractory Neuroblastoma

Phase I- To determine the safety and tolerability of DFMO in combination with bortezomib at 3 dose levels of DFMO: 1500mg/m2 twice daily, 2000mg/m2 twice daily, and 2500mg/m2 twice daily in subjects with relapsed or refractory neuroblastoma who receive one full cycle of this dose.

Phase II- Study did not enroll to Phase II. Study completed at end of Phase I.

To determine the overall response rate (ORR) by the presence of radiologically assessable disease by cross-sectional imaging and in MIBG (meta-iodobenzylguanidine) or PET (positron emission computed tomography) scans. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI imaging and/or by MIBG or PET scans: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the disease measurements for measurable lesions, Stable Disease, Neither sufficient decrease to qualify for PR or sufficient increase to qualify for PD from study entry. Overall Response (OR) = CR + PR.

Time to progression (PFS), defined as the period from the start of the treatment until the criteria for progression are met taking as reference the screening measurements. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the disease measurements for measurable lesions, taking as reference the smallest disease measurement recorded since the start of treatment (nadir), and minimum 5 mm increase over the nadir or the appearance of one or more new lesions or appearance of positive bone marrow.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells	NCT03242603	Neuroblastoma R...	Anti-GD2 in com...	6 Months - 25 Years	National University Hospital, Singapore
Anti-GD2 CAR T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors	NCT03373097	Neuroblastoma Neuroblastoma R... GD2-positive So... Osteosarcoma Ewing Sarcoma Sarcoma	GD2-CART01	12 Months - 25 Years	Bambino Gesù Hospital and Research Institute
177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-risk Neuroblastoma	NCT04903899	Neuroblastoma R... Neuroblastoma	177Lu-DOTATATE	18 Months - 18 Years	Karolinska University Hospital
Quadruple Immunotherapy for Neuroblastoma	NCT05754684	Neuroblastoma R...	Natural killer ... Dinutuximab bet... Interleukin-2 Granulocyte-Mac... Spironolactone Naxitamab	- 18 Years	Hong Kong Children's Hospital
Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma	NCT01467986	Neuroblastoma R...	Dasatinib Rapamycin Irinotecan Temozolomide Irinotecan Temozolomide	- 25 Years	University of Regensburg
Study of Difluoromethylornithine (DFMO) in Combination With Bortezomib for Relapsed or Refractory Neuroblastoma	NCT02139397	Neuroblastoma R...	DFMO Bortezomib	- 21 Years	Milton S. Hershey Medical Center
Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells	NCT03242603	Neuroblastoma R...	Anti-GD2 in com...	6 Months - 25 Years	National University Hospital, Singapore
Anti-GD2 CAR T Cells in Pediatric Patients Affected by High Risk and/or Relapsed/Refractory Neuroblastoma or Other GD2-positive Solid Tumors	NCT03373097	Neuroblastoma Neuroblastoma R... GD2-positive So... Osteosarcoma Ewing Sarcoma Sarcoma	GD2-CART01	12 Months - 25 Years	Bambino Gesù Hospital and Research Institute
Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma	NCT01467986	Neuroblastoma R...	Dasatinib Rapamycin Irinotecan Temozolomide Irinotecan Temozolomide	- 25 Years	University of Regensburg
Naxitamab and GM-CSF in Combination With IT in Patients With High-Risk Neuroblastoma	NCT04560166	Neuroblastoma R...	Naxitamab and G...	12 Months -	Y-mAbs Therapeutics
Quadruple Immunotherapy for Neuroblastoma	NCT05754684	Neuroblastoma R...	Natural killer ... Dinutuximab bet... Interleukin-2 Granulocyte-Mac... Spironolactone Naxitamab	- 18 Years	Hong Kong Children's Hospital

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