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

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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

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. LTLD has been evaluated with
      ultrasound-guided high intensity focused ultrasound and found to be safe and feasible. In
      this population, patients had a real-time thermometry device implanted intra-tumorally,
      allowing for only a limited spatial sample of temperature at the target. Without more
      complete knowledge of temperature distribution in and around the targeted area, the use of
      ultrasound-guided HIFU for LTLD drug delivery does not provide spatial control over drug
      release. This may result in areas of over or under treatment within the target, and
      potentially even off-target drug delivery or overheating. In contrast, our MR-HIFU device
      provides real-time MR thermometry without additional devices. Building upon recent
      mathematical as well as pre-clinical work we will use an approach that capitalizes on MR-HIFU
      features to optimize drug delivery to the targeted tumor. Similar to many original
      pre-clinical studies and clinical trials with LTLD, our approach involves continuous
      maintenance of the target at mild hyperthermia with MR-HIFU following LTLD infusion.
      Following hyperthermia, we 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, as demonstrated by mathematical modeling as well as pre-clinical
      studies.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Primary objective 1: Response of treated target lesion(s) assessed by CT or MRI


Condition

Solid Tumors

Intervention

Magnetic Resonance-Guided High Intensity Focused Ultrasound

Study Arms / Comparison Groups

 All Patients
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.

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

14

Start Date

June 1, 2021

Completion Date

June 1, 2024

Primary Completion Date

June 1, 2024

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.
      

Gender

All

Ages

12 Years - N/A

Accepts Healthy Volunteers

No

Contacts

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



Administrative Informations


NCT ID

NCT04791228

Organization ID

HIFU Thermodox PII


Responsible Party

Principal Investigator

Study Sponsor

Children's National Research Institute


Study Sponsor

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


Verification Date

March 2021