A Pivotal Study to Evaluate the Effectiveness and Safety of ExAblate Treatment of Metastatic Bone and Multiple Myeloma Tumors for the Palliation of Pain in Patients Who are not Candidates for Radiation Therapy

Bone is the third most common organ involved by metastatic disease behind lung and liver [7]. In breast cancer, bone is the second most common site of metastatic spread, and approximately 85% of patients dying of breast cancer have bone metastasis. Breast and prostate cancer metastasize to bone most frequently, which reflects the high incidence of both these tumors, as well as their prolonged clinical courses.

The increasing longevity of the population coupled with better therapeutic management of cancer patients contributes to the high incidence and prevalence of metastatic bone lesions. Pain from bone metastases is the most common cause of cancer pain and as more patients are living with bone metastases, improving their quality of life becomes a major challenge. In patients who die from breast, prostate, and lung cancer, autopsy studies have shown that up to 85% have evidence of bone metastases at the time of death [7-9].

Current treatments for patients with bone metastases are primarily palliative and include localized therapies [10], systemic therapies (chemotherapy, hormonal therapy, radiopharmaceutical, and bisphosphanates), and analgesics (opioids and non-steroidal anti-inflammatory drugs). Recently, radiofrequency ablation has been tested as a treatment option for bone metastases [11]. The main goals of these treatments are improvement of quality of life and functional level. These goals can be further described:

1. Pain relief
2. Preservation and restoration of function
3. Local tumor control
4. Skeletal stabilization

Treatment with external beam radiation therapy (EBRT) is the standard of care for patients with localized bone pain, and results in the palliation of pain in the majority of these patients. More than 66% of patients with a limited number of well-localized bony metastases can be treated effectively by external-beam irradiation. However, approximately 30% of patients treated with radiation therapy do not experience pain relief [8, 12-16]. Furthermore, there is an increased risk of pathologic fracture in the peri-irradiation period due to an induced hyperemic response at the periphery of the tumor. This weakens the adjacent bone and increases the risk of spontaneous fracture. Adding to this, patients who have recurrent pain at a site previously irradiated may not be eligible for further radiation therapy secondary to limitations in normal tissue tolerance. The speed of response to radiation therapy varies; from the patients that respond most symptomatic bony metastases begin to respond over the course of 10 to 14 days, 70% of patients experience some pain relief within 2 weeks of starting therapy and, within 3 months 90% of patients achieve pain relief.

Patients, who had EBRT and failed to improve, may need to seek other therapies such as radio frequency ablation, surgical resection, etc., which are less efficient and have higher treatment related morbidity. Because the ExAblate system is designed to non-invasively ablate tissue, ExAblate may meet the need of these EBRT failed patients. The ExAblate system has the potential to achieve the first three of the four above mentioned goals, as well as changing the treatment limits and resulting morbidity in accordance with the above-mentioned goals [17]. The palliative effect of ExAblate is achieved by heating the bone periosteum, thus ablating the sensory origin of the pain.

Based on the FDA approved phase-1 initial study (IDE # G050177 ) results and the results of the study that was performed outside the United States that the sponsor has done, palliation effects are significant in terms of mean improvement, the number of treated patients who reported symptomatic improvement and in their potential durability.

Based on the above ExAblate treatment has a potential to be treatment of choice for radiation

• Bone Metastases
• Multiple Myeloma

• Device: ExAblate 2000
  MR guided focused ultrasound.
  Other Names:

  • MRgFUS
  • FUS
  • Focused Ultrasound
  • MR guided Focused Ultrasound
• Device: Sham
  sham comparator

• 1: Experimental
  ExAblate Treatment Test Arm
  Intervention: Device: ExAblate 2000
• 2: Sham Comparator
  ExAblate Sham Control Arm
  Interventions:

  • Device: ExAblate 2000
  • Device: Sham

Inclusion criteria:

1. Men and women age 18 and older
2. Patients who are able and willing to give consent and able to attend all study visits

3. Patients who are suffering from symptoms of bone metastases or multiple myeloma bone lesions and are radiation failure patients:

   Radiation failure candidates are those who have received radiation without adequate relief from metastatic bone pain as determined by the patient and treating physician, those for whom their treating physician would not prescribe radiation or additional radiation treatments, and those patients who refuse additional radiation therapy,

4. Patients who refuse other accepted available treatments such as surgery or narcotics for pain alleviation.
5. Patient with NRS (0-10 scale) pain score ≥ 4 irrespective of medication
6. Targeted tumor(s) are ExAblate device accessible and are located in ribs, extremities (excluding joints), pelvis, shoulders and in the posterior aspects of the following spinal vertebra: Lumbar vertebra (L3 - L5), Sacral vertebra (S1 - S5)
7. Targeted tumor (treated) size up to 55 cm2 in surface area
8. Patient whose targeted (treated) lesion is on bone and the interface between the bone and lesion is deeper than 10-mm from the skin.
9. Targeted (treated) tumor clearly visible by non-contrast MRI, and ExAblate MRgFUS device accessible
10. Able to communicate sensations during the ExAblate treatment

11. Patients on ongoing chemotherapy regimen for at least 1 month at the time of eligibility:

    - with same chemotherapy regimen (as documented from patient medical dossier),

    And

    - Worst pain NRS still >= 4

    And

    - do NOT plan to initiate a new chemotherapy for pain palliation should be eligible for the study.

12. No radiation therapy to targeted (most painful) lesion in the past two weeks
13. Bisphosphonate intake should remain stable throughout the study duration.
14. Patients will have from 1 to 5 painful lesions and only the most painful lesion will be treated.
15. Patients with persistent distinguishable pain associated with 1 site to be treated (if patient has pain from additional sites, the pain from the additional sites must be evaluated as being less intense by at least 2 points on the NRS compared to the site to be treated).

Exclusion Criteria:

1. Patients who either

   • Need surgical stabilization of the affected bony structure (>7 fracture risk score, see Section 7.3) OR
   • Targeted tumor is at an impending fracture site (>7 on fracture risk score, see Section 7.3).

   OR

   - Patients with surgical stabilization of tumor site with metallic hardware

2. More than 5 painful lesions, or more than 1 requiring immediate localized treatment
3. Targeted (treated) tumor is in the skull
4. Patients on dialysis
5. Patients with life expectancy < 3-Months
6. patients with an acute medical condition (e.g., pneumonia, sepsis) that is expected to hinder them from completing this study.

7. Patients with unstable cardiac status including:

   • Unstable angina pectoris on medication
   • Patients with documented myocardial infarction within six months of protocol entry
   • Congestive heart failure requiring medication (other than diuretic)
   • Patients on anti-arrhythmic drugs
8. Severe hypertension (diastolic BP > 100 on medication)
9. Patients with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations (weight >250 pounds), etc.
10. Patients with an active infection or severe hematological, neurological, or other uncontrolled disease.
11. Known intolerance or allergies to the MRI contrast agent (e.g. Gadolinium or Magnevist) including advanced kidney disease
12. KPS Score < 60 (See "Definitions" below)
13. Severe cerebrovascular disease (multiple CVA or CVA within 6 months)
14. Individuals who are not able or willing to tolerate the required prolonged stationary position during treatment (approximately 2 hrs.)
15. Target (treated) tumor is less then 1cm from nerve bundles, bowels or bladder.
16. Are participating or have participated in another clinical trial in the last 30 days
17. Patients initiating a new chemotherapy regime, or radiation (for the targeted most painful lesion) within the last 2 weeks
18. Patients unable to communicate with the investigator and staff.
19. Patients with persistent undistinguishable pain (pain source unidentifiable)
20. Targeted (treated) tumor surface area >= 55 cm2
21. Patient whose bone-lesion interface is < 10-mm from the skin
22. Targeted (treated) tumor NOT visible by non-contrast MRI,
23. Targeted (most painful) tumor Not accessible to ExAblate
24. The targeted tumor is less than 2 points more painful compared to other painful lesions on the site specific NRS.