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A Pilot Study of Thermodox and MR-HIFU for Treatment of Relapsed Solid Tumors

Primary Purpose

Solid Tumors, Soft Tissue Sarcoma, Ewing Sarcoma

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Magnetic Resonance-Guided High Intensity Focused Ultrasound
Lyso-thermosensitive Liposomal Doxorubicin
Sponsored by
Children's National Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Solid Tumors focused on measuring Relapsed/refractory solid tumors, High Intensity Focused Ultrasound, Lyso-thermosensitive Liposomal Doxorubicin, ThermoDox

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • AGE: ≥ 12 years of age.
  • DIAGNOSIS: Histologically confirmed malignant solid tumors
  • TUMOR LOCATION: Patient must have at least one tumor located in areas accessible to HIFU, which will be defined as the target lesion(s). Target lesions must be reachable within the normal safety margins of HIFU as specified in the instructions for use.
  • TARGET LESION(S): Radiographically measurable/evaluable solid tumor target lesion(s).
  • THERAPEUTIC OPTIONS:

    - Malignant Tumor: The patient's cancer must have relapsed after or failed to respond to frontline curative therapy and there must not be other potentially curative treatment options available.

  • PRIOR THERAPY:

    • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering on this study.
    • No limitation on the number of prior chemotherapy regimens that the patient may have received prior to study entry.
    • Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry (6 weeks for prior nitrosoureas) Prior treatment with anthracyclines is allowed as long as total cumulative dose is ≤ 450 mg/m2.
    • Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 3 weeks prior to study entry.
    • Biologic (anti-cancer agent): The last dose of all biologic agents for the treatment of the patient's cancer (such as retinoids or tyrosine kinase inhibitors) must be at least 7 days prior to study entry.
    • Radiation therapy: The last dose of radiation to more than 25% of marrow containing bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry. The last dose of all other local palliative (limited port) radiation must be at least 2 weeks prior to study entry.
    • Stem Cell Transplantation. At least 42 days post-autologous stem cell transplant or at least 90 post-allogeneic transplant and recovered from toxicities without evidence of graft versus host disease and on stable doses of immunosuppressive medications if required.
    • Growth Factors. The last dose of colony stimulating factors, such as filgrastim, sargramostim, and erythropoietin, must be at least 1 week prior to study entry, the last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be at least 2 weeks prior to study entry.
  • CONCURRENT THERAPIES:

    - No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted.

  • PERFORMANCE STATUS:

    • Lansky/Karnofsky performance level ≥ 50% (See Appendix I).
    • Patients who are unable to walk because of paralysis or motor weakness, but who are up in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.
  • HEMATOLOGIC FUNCTION:

    • Peripheral absolute neutrophil count (ANC) of ≥ 1000/µL.
    • Platelet count ≥ 75,000/µL (transfusion independent (no transfusion within at least 7 days prior to enrollment)).
  • HEPATIC FUNCTION:

    • Total bilirubin must be ≤ 1.5 times the upper limit of normal (ULN) for age and gender.
    • SGPT (ALT) must be ≤ 3.0 times the upper limit of normal for age.
  • RENAL FUNCTION: Serum creatinine ≤ ULN for age/sex OR a creatinine clearance ≥60 mL/min/1.73 m2.
  • CARDIAC FUNCTION: Adequate Cardiac Function with Ejection Fraction > 50% by echocardiogram.

Exclusion Criteria:

  • Clinically significant unrelated systemic illness, such as serious infections, hepatic, renal or other organ dysfunction, which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate study interventions.
  • Patients who are pregnant or breast-feeding are not eligible for this study due to risks of fetal and teratogenic adverse events seen in animal/human studies with doxorubicin. Negative pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method beginning at the signing of informed consent and until at least 30 days after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or designated associate.
  • Implant or prosthesis within the path of the HIFU beam.
  • Target pathway <1 cm from nerve plexus, spinal canal, or bowel.
  • Target 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.
  • Patients currently receiving other anticancer agents.
  • Patients currently receiving other investigational agents.

Sites / Locations

  • Children's National HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

All Patients

Arm Description

LTLD 50 mg/m2 will be administered intravenously over 30 minutes on day 1 of every 21-day cycle. MR-HIFU hyperthermia will follow infusion (+/- 30 minutes) for one hour to a target area with a target temperature of 40-45°C followed by ablation therapy (>55°C). The HIFU hyperthermia regimen will have a duration of at least 60 minutes and will then be followed by ablation therapy. Patients may receive up to a total of 6 cycles. Subsequent treatment cycles may treat alternative target lesions. Disease status will be evaluated using standard imaging techniques (CT/MR) post each cycle.

Outcomes

Primary Outcome Measures

Primary objective 1: Response of treated target lesion(s) assessed by CT or MRI
The Response Evaluation Criteria in Solid Tumors (RECIST v1.1) will be used
Primary objective 2: The number of participants with treatment-related adverse events as assessed by the Common Terminology Criteria of Adverse Events (CTCAE) v.5
CTCAE v.5 will be used

Secondary Outcome Measures

Full Information

First Posted
February 22, 2021
Last Updated
August 9, 2023
Sponsor
Children's National Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT04791228
Brief Title
A Pilot Study of Thermodox and MR-HIFU for Treatment of Relapsed Solid Tumors
Official Title
A Pilot Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) and Magnetic Resonance-Guided High Intensity Focused Ultrasound (MR-HIFU) for Treatment of Relapsed or Refractory Solid Tumors
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 10, 2022 (Actual)
Primary Completion Date
December 1, 2025 (Anticipated)
Study Completion Date
December 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Children's National Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a pilot study of LTLD with MR-HIFU hyperthermia followed by ablation in subjects with refractory/relapsed solid tumors.
Detailed Description
LTLD is a heat-activated formulation of liposomal doxorubicin that releases the drug when exposed to hyperthermic conditions (40-45°C). This novel agent has been well tolerated in adults with similar toxicity profile to doxorubicin. MR-HIFU offers a non-invasive and non-ionizing ability to selectively heat large tissue volumes. Thus, MR-HIFU is a promising technology for triggering doxorubicin release from LTLD. The investigator's approach involves continuous maintenance of the target at mild hyperthermia with MR-HIFU following LTLD infusion. Following hyperthermia, the investigators will deliver ablation therapy (>55°C) to targeted areas of tumor where feasible and safe. Addition of this ablation therapy after mild-hyperthermia-triggered drug delivery with LTLD has the potential to significantly potentiate chemotherapy with minimal additional adverse effects to improve local control and drug delivery without increasing toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Solid Tumors, Soft Tissue Sarcoma, Ewing Sarcoma, Malignant Epithelial Neoplasm, Rhabdomyosarcoma, Wilms Tumor, Hepatic Tumor, Germ Cell Tumor, Bone Metastases
Keywords
Relapsed/refractory solid tumors, High Intensity Focused Ultrasound, Lyso-thermosensitive Liposomal Doxorubicin, ThermoDox

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
All Patients
Arm Type
Experimental
Arm Description
LTLD 50 mg/m2 will be administered intravenously over 30 minutes on day 1 of every 21-day cycle. MR-HIFU hyperthermia will follow infusion (+/- 30 minutes) for one hour to a target area with a target temperature of 40-45°C followed by ablation therapy (>55°C). The HIFU hyperthermia regimen will have a duration of at least 60 minutes and will then be followed by ablation therapy. Patients may receive up to a total of 6 cycles. Subsequent treatment cycles may treat alternative target lesions. Disease status will be evaluated using standard imaging techniques (CT/MR) post each cycle.
Intervention Type
Device
Intervention Name(s)
Magnetic Resonance-Guided High Intensity Focused Ultrasound
Other Intervention Name(s)
MR-HIFU
Intervention Description
Magnetic resonance (MR)-guided high intensity focused ultrasound (HIFU) provides precise and controlled delivery of heat by focusing ultrasound energy inside a lesion using an external applicator without the need for a scalpel or needle. Additional therapeutic advantages of this modality include its range of bioeffects, including both high temperature tumor ablation via coagulative necrosis, and effects of lower temperature, mild hyperthermia that can help to enhance local drug delivery to tumors. Both tumor ablation and hyperthermia may be employed to potentiate the effects of chemotherapy.
Intervention Type
Drug
Intervention Name(s)
Lyso-thermosensitive Liposomal Doxorubicin
Other Intervention Name(s)
LTLD, ThermoDox
Intervention Description
LTLD combines doxorubicin with lyso-thermosensitive liposomes that can selectively deliver drug to tumors and when exposed to temperatures greater than 40°C, rapidly and locally releases doxorubicin in high concentrations from systemically administered LTLD. If combined with hyperthermia, doxorubicin will be released in the heated tumor margins and in any areas within the tumor that were not completely ablated and increase the likelihood of complete tumor necrosis. LTLD will extend tumor cell death to the hyperthermic regions in the peri-ablation zones and minimize the possibility of incomplete ablation or tumor recurrence.
Primary Outcome Measure Information:
Title
Primary objective 1: Response of treated target lesion(s) assessed by CT or MRI
Description
The Response Evaluation Criteria in Solid Tumors (RECIST v1.1) will be used
Time Frame
At the end of every 21-day cycle
Title
Primary objective 2: The number of participants with treatment-related adverse events as assessed by the Common Terminology Criteria of Adverse Events (CTCAE) v.5
Description
CTCAE v.5 will be used
Time Frame
Up to thirty days after last dose of protocol therapy
Other Pre-specified Outcome Measures:
Title
Exploratory objective 1: Response of non-target lesion(s) assessed by CT or MRI
Description
Lesions that are evaluable or measurable but not in the treated location(s) will be collected
Time Frame
At the end of every 21-day cycle
Title
Exploratory objective 2: Participant reported target tumor pain intensity assessed using the Numerical Rating Scale-11 (NRS-11)
Description
The NRS-11 consists of a 11-point numeric scale to assess pain intensity from 0 (no pain) to 10 (worst pain)
Time Frame
At the end of every 21-day cycle
Title
Exploratory objective 3: Participant reported impact of pain on daily activities assessed using the PROMIS Pain Interference Scale (PROMIS-PI)
Description
The PROMIS-PI consists of 8 questions on pain. Each question will be rated from 0 (never), 1 (almost never), 2 (sometimes), 3 (often), and 4 (almost always)
Time Frame
At the end of every 21-day cycle
Title
Exploratory objective 4: Blood samples taken to see adaptive immune response and immune suppression
Description
To determine changes in pharmacodynamics of immune markers
Time Frame
At 1 day and 1 week after MR-HIFU treatment on first 21-day cycle

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: AGE: ≥ 12 years of age. DIAGNOSIS: Histologically confirmed malignant solid tumors TUMOR LOCATION: Patient must have at least one tumor located in areas accessible to HIFU, which will be defined as the target lesion(s). Target lesions must be reachable within the normal safety margins of HIFU as specified in the instructions for use. TARGET LESION(S): Radiographically measurable/evaluable solid tumor target lesion(s). THERAPEUTIC OPTIONS: - Malignant Tumor: The patient's cancer must have relapsed after or failed to respond to frontline curative therapy and there must not be other potentially curative treatment options available. PRIOR THERAPY: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering on this study. No limitation on the number of prior chemotherapy regimens that the patient may have received prior to study entry. Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry (6 weeks for prior nitrosoureas) Prior treatment with anthracyclines is allowed as long as total cumulative dose is ≤ 450 mg/m2. Immunotherapy: The last dose of immunotherapy (monoclonal antibody or vaccine) must be at least 3 weeks prior to study entry. Biologic (anti-cancer agent): The last dose of all biologic agents for the treatment of the patient's cancer (such as retinoids or tyrosine kinase inhibitors) must be at least 7 days prior to study entry. Radiation therapy: The last dose of radiation to more than 25% of marrow containing bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry. The last dose of all other local palliative (limited port) radiation must be at least 2 weeks prior to study entry. Stem Cell Transplantation. At least 42 days post-autologous stem cell transplant or at least 90 post-allogeneic transplant and recovered from toxicities without evidence of graft versus host disease and on stable doses of immunosuppressive medications if required. Growth Factors. The last dose of colony stimulating factors, such as filgrastim, sargramostim, and erythropoietin, must be at least 1 week prior to study entry, the last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be at least 2 weeks prior to study entry. CONCURRENT THERAPIES: - No other anti-cancer therapy (chemotherapy, biological therapy, radiation therapy) is permitted. PERFORMANCE STATUS: Lansky/Karnofsky performance level ≥ 50% (See Appendix I). Patients who are unable to walk because of paralysis or motor weakness, but who are up in a wheelchair will be considered ambulatory for the purpose of calculating the performance score. HEMATOLOGIC FUNCTION: Peripheral absolute neutrophil count (ANC) of ≥ 1000/µL. Platelet count ≥ 75,000/µL (transfusion independent (no transfusion within at least 7 days prior to enrollment)). HEPATIC FUNCTION: Total bilirubin must be ≤ 1.5 times the upper limit of normal (ULN) for age and gender. SGPT (ALT) must be ≤ 3.0 times the upper limit of normal for age. RENAL FUNCTION: Serum creatinine ≤ ULN for age/sex OR a creatinine clearance ≥60 mL/min/1.73 m2. CARDIAC FUNCTION: Adequate Cardiac Function with Ejection Fraction > 50% by echocardiogram. Exclusion Criteria: Clinically significant unrelated systemic illness, such as serious infections, hepatic, renal or other organ dysfunction, which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate study interventions. Patients who are pregnant or breast-feeding are not eligible for this study due to risks of fetal and teratogenic adverse events seen in animal/human studies with doxorubicin. Negative pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method beginning at the signing of informed consent and until at least 30 days after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or designated associate. Implant or prosthesis within the path of the HIFU beam. Target pathway <1 cm from nerve plexus, spinal canal, or bowel. Target 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. Patients currently receiving other anticancer agents. Patients currently receiving other investigational agents.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
General HIFU trials
Phone
202-476-5522
Email
HIFUtrials@childrensnational.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
AeRang Kim, MD, PhD
Organizational Affiliation
Children's National Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's National Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
General HIFU Trials
Phone
202-476-5522
Email
HIFUtrials@childrensnational.org

12. IPD Sharing Statement

Learn more about this trial

A Pilot Study of Thermodox and MR-HIFU for Treatment of Relapsed Solid Tumors

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