A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin and MR-HIFU for Pediatric Refractory Solid Tumors - Full Text View

Purpose

This study is looking to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lyso-thermosensitive liposomal doxorubicin (LTLD) administered in combination with MR-HIFU in children with relapsed/refractory solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, and germ cell tumors.

Condition	Intervention	Phase
Pediatric Cancer Solid Tumors Rhabdomyosarcoma Ewing Sarcoma Soft Tissue Sarcomas Osteosarcoma Neuroblastoma Wilms Tumor Hepatic Tumor Germ Cell Tumors	Device: Magnetic resonance high intensity focused ultrasound Drug: Lyso-thermosensitive liposomal doxorubicin	Phase 1


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment
Official Title:	A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) and Magnetic Resonance-Guided High Intensity Focused Ultrasound (MR-HIFU) for Relapsed or Refractory Solid Tumors in Children, Adolescents, and Young Adults

Resource links provided by NLM:

Genetics Home Reference related topics: Ewing sarcoma neuroblastoma

Drug Information available for: Doxorubicin Doxorubicin hydrochloride

Genetic and Rare Diseases Information Center resources: Soft Tissue Sarcoma Osteosarcoma Neuroblastoma Ewing Sarcoma Ewing's Family of Tumors Wilms' Tumor Neuroepithelioma

U.S. FDA Resources

Further study details as provided by AeRang Kim, Children's Research Institute:

Primary Outcome Measures:

Maximum tolerated dose of LTLD [ Time Frame: 3 weeks ]
To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of LTLD administered in combination with MR-HIFU ablation in children with relapsed/refractory solid tumors by examining blood samples collected from participants
Toxicity profile of LTLD [ Time Frame: up to 18 weeks ]
To define and describe the toxicities of LTLD administered in combination with MR-HIFU as measured by reportable adverse events of participants as per the CTCAE v 4.0
Pharmacokinetics of LTLD [ Time Frame: 8 days ]
Analyze blood samples of participants to characterize the pharmacokinetic properties of LTLD administered in combination with MR-HIFU
Feasibility of treatment [ Time Frame: up to 18 weeks ]
To determine the feasibility of LTLD administered at the recommended dose in combination with MR-HIFU induced mild hyperthermia (MHT) as determined by patient outcomes and adverse events

Secondary Outcome Measures:

Antitumor Activity of the Treatment [ Time Frame: up to 18 weeks ]
To preliminarily determine the antitumor activity of LTLD with MR-HIFU within the confines of a phase 1 study by examining the response of target lesions using RECIST criteria v1.1
Social Impact of the Treatment on Participants [ Time Frame: up to 18 weeks ]
To determine changes in symptoms and quality of life in children treated with LTLD and MR-HIFU by administering the Symptom Distress Scale and Peds QL v4.0 to participants
Determine the Changes in Pharmacodynamic Immune Markers in Participants [ Time Frame: 3 weeks ]
To determine the changes in immune markers in children treated with LTLD and MR-HIFU by examining blood samples from participants


Estimated Enrollment:	34
Study Start Date:	October 2016
Estimated Study Completion Date:	October 2020
Estimated Primary Completion Date:	October 2018 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Part A LTLD will be administered intravenously in combination with MR-HIFU ablation on day 1 of every 21 day cycle. There will be two potential dose escalation of LTLD with highest dose not to exceed the adult recommended MTD. Patients may receive up to a total of 6 cycles.	Device: Magnetic resonance high intensity focused ultrasound Magnetic resonance (MR)-high intensity focused ultrasound (HIFU) provides precise controlled delivery of heat by focusing ultrasound energy inside a lesion using an external applicator that is completely non-invasive and non-ionizing. Other Name: MR-HIFU Drug: Lyso-thermosensitive liposomal doxorubicin A heat-activated formulation of liposomal doxorubicin with unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. Other Name: LTLD; ThermoDox
Experimental: Part B LTLD at dose determined from Part A will be administered intravenously on day 1 of every 21 day cycle. MR-HIFU induced MHT will follow immediately post LTLD infusion for one hour to target area with target temperatures of 40-45°C. Patients may receive up to a total of 6 cycles	Device: Magnetic resonance high intensity focused ultrasound Magnetic resonance (MR)-high intensity focused ultrasound (HIFU) provides precise controlled delivery of heat by focusing ultrasound energy inside a lesion using an external applicator that is completely non-invasive and non-ionizing. Other Name: MR-HIFU Drug: Lyso-thermosensitive liposomal doxorubicin A heat-activated formulation of liposomal doxorubicin with unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. Other Name: LTLD; ThermoDox

Arms

Assigned Interventions

Experimental: Part A

LTLD will be administered intravenously in combination with MR-HIFU ablation on day 1 of every 21 day cycle. There will be two potential dose escalation of LTLD with highest dose not to exceed the adult recommended MTD. Patients may receive up to a total of 6 cycles.

Device: Magnetic resonance high intensity focused ultrasound

Magnetic resonance (MR)-high intensity focused ultrasound (HIFU) provides precise controlled delivery of heat by focusing ultrasound energy inside a lesion using an external applicator that is completely non-invasive and non-ionizing.

Other Name: MR-HIFU

Drug: Lyso-thermosensitive liposomal doxorubicin

A heat-activated formulation of liposomal doxorubicin with unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors.

Other Name: LTLD; ThermoDox

Experimental: Part B

LTLD at dose determined from Part A will be administered intravenously on day 1 of every 21 day cycle. MR-HIFU induced MHT will follow immediately post LTLD infusion for one hour to target area with target temperatures of 40-45°C. Patients may receive up to a total of 6 cycles

Device: Magnetic resonance high intensity focused ultrasound

Magnetic resonance (MR)-high intensity focused ultrasound (HIFU) provides precise controlled delivery of heat by focusing ultrasound energy inside a lesion using an external applicator that is completely non-invasive and non-ionizing.

Other Name: MR-HIFU

Drug: Lyso-thermosensitive liposomal doxorubicin

A heat-activated formulation of liposomal doxorubicin with unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors.

Other Name: LTLD; ThermoDox

Detailed Description:

This is phase 1 trial of LTLD with MR-HIFU induced heating in children and young adults with relapsed/refractory solid tumors.

Part A of the trial will be a traditional dose escalation study to determine the pediatric MTD/RP2D of LTLD combined with MR-HIFU ablation which allows for release of doxorubicin in the ablation zone and peri-ablation margins.

Part B of the trial will combine LTLD at the MTD/RP2D with MR-HIFU induced mild hyperthermia (MHT) in an expanded cohort.

Eligibility


Ages Eligible for Study:	up to 30 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Part A: ≤21 years of age
Part B: ≤ 30 years of age.
Histologically confirmed malignant solid tumor.
Patient must have at least one tumor located in areas accessible to HIFU, which will be defined as the target lesion(s).
Radiographically evaluable or measurable solid tumor target lesion(s).
Malignant tumor that is relapsed or refractory and with no other potentially curative treatment options available.
Must have completed an appropriate washout period from prior therapy.
Karnofsky or Lansky performance level ≥ 50%.
Must have appropriate hematologic, hepatic and renal function.
Adequate cardiac function with ejection fraction > 50%

Exclusion Criteria:

Clinically significant unrelated systemic illness.
Patients who are pregnant or breast-feeding.
Target lesions that are pulmonary primary tumors or metastases.
Implant or prosthesis or scar tissue within the path of the HIFU beam.
Target lesion <1 cm from nerve plexus, spinal canal, and bowel.
Lesion in the skull.
Inability to undergo MRI and/or contraindication for MRI.
Inability to tolerate stationary position during HIFU.
Previous history of hypersensitivity to doxorubicin or its liposomal formulations.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02536183

Contacts


Contact: Stephanie Forlenza	202-476-6841	saforlenza@childrensnational.org

Locations


United States, District of Columbia
Children's National Medical Center	Recruiting
Washington, District of Columbia, United States, 20010
Contact: Stephanie A Forlenza 202-476-6841 saforlenza@childrensnational.org
Principal Investigator: AeRang Kim, MD, PhD

Sponsors and Collaborators

AeRang Kim

Investigators


Principal Investigator:	AeRang Kim, MD, PhD	Children's Research Institute

More Information


Responsible Party:	AeRang Kim, MD, PhD, Children's Research Institute
ClinicalTrials.gov Identifier:	NCT02536183 History of Changes
Other Study ID Numbers:	HIFU Thermodox
Study First Received:	August 13, 2015
Last Updated:	February 14, 2017

Keywords provided by AeRang Kim, Children's Research Institute:


Solid tumors relapsed pediatric solid tumors high intensity focused ultrasound Lyso-thermosensitive liposomal doxorubicin ThermoDox relapsed sarcoma	Ewing Sarcoma family of tumors Osteosarcoma Neuroblastoma Wilms Tumor Hepatic Tumor Germ Cell Tumors

Additional relevant MeSH terms:


Neoplasms Sarcoma Neuroblastoma Neoplasms, Germ Cell and Embryonal Osteosarcoma Rhabdomyosarcoma Sarcoma, Ewing Wilms Tumor Liver Neoplasms Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neuroectodermal Tumors, Primitive, Peripheral Neuroectodermal Tumors, Primitive Neoplasms, Neuroepithelial Neuroectodermal Tumors	Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Neoplasms, Bone Tissue Neoplasms, Connective Tissue Myosarcoma Neoplasms, Muscle Tissue Neoplasms, Complex and Mixed Kidney Neoplasms Urologic Neoplasms Urogenital Neoplasms Neoplasms by Site Neoplastic Syndromes, Hereditary Kidney Diseases Urologic Diseases Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on August 17, 2017