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

NCT ID: NCT02536183

Last Updated: 2023-08-29

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-10-31
• Study Completion Date: 2022-10-31

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.

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.

Conditions

Pediatric Cancer; Solid Tumors; Rhabdomyosarcoma; Ewing Sarcoma; Soft Tissue Sarcomas; Osteosarcoma; Neuroblastoma; Wilms Tumor; Hepatic Tumor; Germ Cell Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Magnetic resonance high intensity focused ultrasound

Intervention Type: DEVICE

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.

Lyso-thermosensitive liposomal doxorubicin

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

Magnetic resonance high intensity focused ultrasound

Intervention Type: DEVICE

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.

Lyso-thermosensitive liposomal doxorubicin

Intervention Type: DRUG

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

Interventions

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.

Intervention Type: DEVICE

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.

Intervention Type: DRUG

Other Intervention Names

MR-HIFU; LTLD; ThermoDox

Eligibility Criteria

Inclusion Criteria

Part A: ≤21 years of age Part B: ≤ 30 years of age.

DIAGNOSIS:

Histologically confirmed malignant 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, germ cell 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 evaluable or measurable 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. 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 4 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 2 months post-autologous stem cell transplant or at least 3 months 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 peg-filgrastim, 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:

Patients > 16 years old must have a Karnofsky performance level ≥ 50%, and children ≤ 16 years old must have a Lansky performance level ≥ 50%.

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:

Age-adjusted normal serum creatinine OR a creatinine clearance ≥ 60 mL/min/1.73 m2.

CARDIAC FUNCTION:

Adequate Cardiac Function with Ejection Fraction > 50% by echocardiogram or cardiac MRI within 14 days prior to starting therapy.

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 methods 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 or scar tissue within the path of the HIFU beam.

Target lesion <1 cm from nerve plexus, spinal canal, and bowel.

Target lesion in contact with hollow viscera.

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.

• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AeRang Kim

OTHER

Sponsor Role: lead

Responsible Party

AeRang Kim

MD, PhD

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

AeRang Kim, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Children's National Research Institute

Locations

Children's National Medical Center

Washington D.C., District of Columbia, United States

Countries

United States

References

Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.

Reference Type: DERIVED

PMID: 31401903 (View on PubMed)

Other Identifiers

HIFU Thermodox

Identifier Type: -

Identifier Source: org_study_id