A Pilot Study of Thermodox and MR-HIFU for Treatment of Relapsed Solid Tumors
A Pilot Study of Thermodox and MR-HIFU for Treatment of Relapsed Solid Tumors
This is a pilot study of LTLD with MR-HIFU hyperthermia followed by ablation in subjects with
 refractory/relapsed solid tumors.
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.
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.