Antineoplastic Agents

All Drugs and Chemicals

Etoposide

Carboplatin

Ifosfamide

Etoposide phosphate

Isophosphamide mustard

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Conventional chemotherapy (Ifosfamide, carboplatin, etoposide) with Pazopanib

Pazopanib

Ki Woong Sung, MD, PhD

Ki Woong Sung

The purpose of this study is to evaluate the safety and efficacy of combination chemotherapy with Pazopanib in pediatric patients with relapsed/refractory solid tumor

Combination Chemotherapy With Pazopanib in Children and Adolescents With Relapsed/Refractory Solid Tumors

Safety and Efficacy of Combination Chemotherapy With Pazopanib in Children and Adolescents With Relapsed/Refractory Solid Tumors

Definition of dose-limiting toxicity (DLT)

* Hematologic DLT: delayed recovery of ANC/platelets \> 42 days
* Grade 3 creatinine elevation, proteinuria, hyperbilirubinemia, bleeding
* Grade 2 arterial thrombosis
* Any grade 4 toxicities except hematologic toxicities

* as assessed by International Neuroblastoma Response
* Primary tumor: CT and/or MRI; MIBG scan if available
* Metastatic sites: bone marrow biopsies, CT/MRI, MIBG scan

  * CR (Complete response): No tumor (primary \& metastatic)
  * VGPR (Very good PR): Decreased by 90-99% (primary) \& no tumor (metastatic)
  * PR (Partial response): Decreased by \> 50% (primary \& metastatic)
  * MR (Mixed response): \> 50% reduction of any measurable lesion (primary or metastases) with \< 50% reduction in any other; \< 25% increase in any existing lesion
  * SD (Stable disease): No new lesions; \< 50% reduction but \< 25% increase in any existing lesion.
  * PD (Progressive disease): Any new lesion; increase of any measurable lesion by \> 25%

- as assessed by 2-dimensional measurement (the product of the tumor's longest diameter and its longest perpendicular diameter)

* CR: complete disappearance of all previously measurable tumors.
* PR: greater than 50% decrease in tumor size
* SD: less than 50% reduction in tumor size or less than 25% increase in tumor size
* PD: greater than 25% increase in tumor size or the appearance of a new tumor

- as assessed by The Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

* CR: Disappearance of all target lesions.
* PR: At least a 30% decrease in the sum of diameters of target lesions
* SD: Neither sufﬁcient shrinkage to qualify for PR nor sufﬁcient increase to qualify for PD
* PD: At least a 20% increase in the sum of diameters of target lesions

Ministry of Health, Republic of Korea

Samsung Medical Center

Neoplasms

All Conditions

Digestive System Diseases

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Symptoms and General Pathology

Rare Diseases

Carcinoma

Carcinoma, Hepatocellular

Melanoma

Sarcoma

Osteosarcoma

Wilms Tumor

Neuroblastoma

Sarcoma, Ewing

Rhabdomyosarcoma

Hepatoblastoma

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neoplasms, Glandular and Epithelial

Neoplasms, Connective and Soft Tissue

Neuroectodermal Tumors, Primitive, Peripheral

Neoplasms, Neuroepithelial

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Myosarcoma

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Syndrome

Neoplastic Syndromes, Hereditary

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Genetic Diseases, Inborn

Soft Tissue Sarcoma

Wilms' Tumor

Ewing Sarcoma

Neuroepithelioma

Antibodies

Antibodies, Monoclonal

Nivolumab

Ipilimumab

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Myeloma Proteins

Paraproteins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients less than 40 years old with relapsed/refractory solid tumors and at least 2 sites of measurable disease will receive the current pediatric RP2D of nivolumab and ipilimumab for one cycle and undergo cryoablation therapy of one tumor site. Patients will continue to receive cycles of checkpoint inhibition as long as there is no disease progression of unacceptable toxicity (maximum of 13 cycles \[12 months\]).

There are 4 patient cohorts:

1. Osteosarcoma
2. Ewing sarcoma
3. Rhabdomyosarcoma
4. All other solid tumors (non-statistical)

Cryoablation therapy is an established method of cancer treatment in adults and pediatrics with certain types of tumors and is standard of care for certain tumors in the setting of progression/relapse.

Percutaneous image-guided Cryoablation (cryosurgery, cryotherapy) is a technique that utilizes successive rapid freeze/thaw cycles to destroy tumor cells. This technique is performed by inserting specialized needles known as cryoprobes into target tumors under imaging guidance with Computed Tomography (CT) and Ultrasound (US), or Magnetic Resonance Imaging (MRI). After the cryoprobe needles are placed within the target tumor, rapid cooling of liquid gas inserted into these probes leads to temperatures reaching -20 to -40 degrees Celsius.

Cryoablation therapy of one disease site will be done starting Day 3 and prior to Day 15 of Cycle 1 only.

Cryoablation Therapy

Nivolumab (Bristol Myers Squibb) is a human monoclonal antibody (immunoglobulin G4) that targets the programmed death-1 cluster of differentiation 279 (CD279) cell surface membrane receptor.

Nivolumab and ipilimumab will be given on day 1 of 21-day cycles for cycles 1-4, followed by nivolumab alone on days 1 and 15 of 28-day cycles for cycles 5+. Patients will receive up to 13 cycles of therapy unless unacceptable toxicity or progression of disease.

Ipilimumab (Bristol Myers Squibb) is a fully human monoclonal immunoglobulin G1Κ specific for human cytotoxic T-lymphocyte antigen 4 (CTLA-4, cluster of differentiation \[CD\]152), which is expressed on a subset of activated T-cells.

Nivolumab and ipilimumab will be given on day 1 of 21-day cycles for cycles 1-4, followed by nivolumab alone on days 1 and 15 of 28-day cycles for cycles 5+. Patients will receive up to 13 cycles of therapy unless unacceptable toxicity or progression of disease.

AeRang Kim, MD, PhD

The is a phase II, single arm, open-label, multi-site trial studying the combination of cryoablation therapy and dual checkpoint inhibition with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) given at the recommended phase 2 dose (RP2D) in pediatric and young adult patients with relapsed or refractory solid tumors.

Patients less than 40 years old with relapsed/refractory solid tumors and at least two sites of measurable disease will receive the current pediatric RP2D of nivolumab and ipilimumab for one cycle and undergo cryoablation therapy of one tumor site. Patients will continue to receive cycles of checkpoint inhibition as long as there is no disease progression of unacceptable toxicity (maximum of 13 cycles \[12 months\]).

Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors

Phase II Study Investigating the Efficacy of Neoadjuvant Dual Checkpoint Inhibition and Cryoablation Therapy in Children, Adolescents, and Young Adults With Relapsed/Refractory Solid Tumors

Patients will undergo consistent imaging prior to every odd cycle of therapy and utilize the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.

Toxicities will be defined using the Common Terminology Criteria for Adverse Events (CTCAE) v. 5.

Patients in the non-statistical cohort will under consistent imaging prior to every odd cycle measured by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1.

Peripheral blood will be collected from patients at baseline, following neoadjuvant immunotherapy/prior to cryoablation, and prior to each cycle of immunotherapy.

Each question will be rated from the following: Excellent (5) to Poor (1), Never (5) to Always (1), or Never (1) to Almost Always (5)

Bristol-Myers Squibb

Children's National Research Institute

Oncologist

Blood and Lymph Conditions

Leukemia

Leukemia, Myeloid

Hematologic Diseases

Anti-Infective Agents

Amino Acids

Trastuzumab

Cytarabine

Fludarabine

Fludarabine phosphate

Everolimus

Axitinib

Dasatinib

Crizotinib

Tyrosine Kinase Inhibitors

Sorafenib

Imatinib Mesylate

Erlotinib Hydrochloride

Vemurafenib

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antiviral Agents

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Tyrosine

Conventional chemotherapy (Ifosfamide carboplatin etoposide for solid tumor and fludarabine cytarabine for AML) with matched single-targeted agent (axitinib, crizotinib, dasatinib, erlotinib, everolimus, imatinib, pazopanib, ruxolitinib, sorafenib, vandetanib, vemurafenib, or trastuzumab) or multi-targeted receptor tyrosine kinase inhibitor (pazopanib or sorafenib) according to the result of CancerSCAN™

CancerSCAN™

Erlotinib

Imatinib

Ruxolitinib

Vandetanib

The purpose of this study is to evaluate the efficacy and feasibility of combination chemotherapy with target agents according to the result of targeted deep sequencing in pediatric patients with relapsed/refractory solid tumor or AML.

Outcome of pediatric cancer has been improved substantially over the past few decades, but the prognosis of relapsed/refractory pediatric cancer still remains poor. Advances in genomic technologies have improved the ability to detect diverse somatic and germline genomic aberrations of cancer patients, and it has been incorporated in the clinical management of cancer.

Samsung Genomic Institute developed a targeted next-generation sequencing (NGS) platform, CancerSCAN™, which can detect clinically significant genomic aberrations of tumors. In this study, tumor samples of refractory/relapsed pediatric cancer patients will be tested with CancerSCAN™ and the patients will receive combination chemotherapy with matched single-targeted agent or multi-targeted receptor tyrosine kinase inhibitor according to the result of CancerSCAN™.

I. Relapsed/refractory solid tumor

* Perform CancerSCAN™ at enrollment
* Conventional chemotherapy (ifosfamide, carboplatin, etoposide) with matched single-targeted agent (axitinib, crizotinib, dasatinib, erlotinib, everolimus, imatinib, pazopanib, ruxolitinib, sorafenib, vandetanib, vemurafenib, or trastuzumab) or multi-targeted receptor tyrosine kinase inhibitor (pazopanib or sorafenib) according to the result of CancerSCAN™

II. Relapsed/refractory AML

* Perform CancerSCAN™ at enrollment
* Conventional chemotherapy (fludarabine, cytarabine) with matched single-targeted agent (axitinib, crizotinib, dasatinib, erlotinib, everolimus, imatinib, pazopanib, ruxolitinib, sorafenib, vandetanib, vemurafenib, or trastuzumab) or multi-targeted receptor tyrosine kinase inhibitor (pazopanib or sorafenib) according to the result of CancerSCAN™

Genomics-Based Target Therapy for Children With Relapsed or Refractory Malignancy

Event is defined as relapse, disease progression or treatment-related mortality.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination Chemotherapy With Pazopanib in Children and Adolescents With Relapsed/Refractory Solid Tumors	NCT03628131	Relapsed Pediat... Refractory Pedi...	Pazopanib Ifosfamide Carboplatin Etoposide	2 Years - 22 Years	Samsung Medical Center
Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors	NCT05302921	Osteosarcoma Ewing Sarcoma Rhabdomyosarcom... Relapsed Pediat... Refractory Pedi... Melanoma Hepatoblastoma Hepatocellular ... Neuroblastoma Wilms Tumor	Cryoablation Th... Nivolumab Ipilimumab	1 Year - 39 Years	Children's National Research Institute
Genomics-Based Target Therapy for Children With Relapsed or Refractory Malignancy	NCT02638428	Relapsed Pediat... Refractory Pedi... Relapsed Pediat... Refractory Pedi...	CancerSCAN™ Ifosfamide Carboplatin Etoposide Fludarabine Cytarabine Pazopanib Sorafenib Axitinib Crizotinib Dasatinib Erlotinib Everolimus Imatinib Ruxolitinib Vandetanib Vemurafenib Trastuzumab	- 18 Years	Samsung Medical Center

Spots Global Cancer Trial Database for refractory pediatric solid tumor