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

Study Description

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Brief Summary:

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 or disease	Intervention/treatment	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

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	34 participants
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
Study Start Date :	October 2016
Estimated Primary Completion Date :	October 2018
Estimated Study Completion Date :	October 2020

Arms and Interventions

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Arm	Intervention/treatment
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

Outcome Measures

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Primary Outcome Measures :

1. 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
2. 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
3. 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
4. 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 :

1. 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
2. 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
3. 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

Eligibility Criteria

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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

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Contacts

Contact: Emily Stern, RN, BSN	202-476-2802	estern@childrensnational.org
Contact: Stephanie Forlenza		saforlenza@childrensnational.com

Locations

United States, District of Columbia
Children's National Medical Center	Recruiting
Washington, District of Columbia, United States, 20010
Contact: Emily Stern, RN, BSN 202-476-2802 estern@childrensnational.org
Contact: Stephanie Forlenza 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

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Responsible Party:	AeRang Kim, MD, PhD, Children's Research Institute
ClinicalTrials.gov Identifier:	NCT02536183 History of Changes
Other Study ID Numbers:	HIFU Thermodox
First Posted:	August 31, 2015
Last Update Posted:	April 2, 2018
Last Verified:	March 2018

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