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

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Brief Title

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

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

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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Maximum tolerated dose of LTLD

Secondary Outcome

 Antitumor Activity of the Treatment

Condition

Pediatric Cancer

Intervention

Magnetic resonance high intensity focused ultrasound

Study Arms / Comparison Groups

 Part A
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

34

Start Date

October 2016

Completion Date

October 2021

Primary Completion Date

October 2021

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.
      

Gender

All

Ages

N/A - 30 Years

Accepts Healthy Volunteers

No

Contacts

AeRang Kim, MD, PhD, 202-476-6755, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02536183

Organization ID

HIFU Thermodox


Responsible Party

Sponsor-Investigator

Study Sponsor

AeRang Kim


Study Sponsor

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


Verification Date

February 2021