Periganglionic Resiniferatoxin for the Treatment of Intractable Pain Due to Cancer-induced Bone Pain

1. Male or female subjects must be at least 18 years of age or older.
2. Must be diagnosed with histologically-confirmed cancer-induced bone pain producing intractable chronic pain in the target area (mid thoracic or chest level down to lower extremities) which was poorly responsive to conservative therapies based on patient report, such as analgesic medication management with potent opioids with or without prior radiotherapy, bisphosphonates, or radioisotope therapy. Additionally, pain that is non-responsive to non-opioid drugs in situations where opioids were not tolerated. Conservative therapies do not include invasive treatments, such as neurolytic procedure, including surgical neurolysis, percutaneous regional or neuraxial continuous infusions (whether opioid or local anesthetic), and peripheral neuromodulation or spinal cord stimulation, but may include temporary diagnostic or therapeutic procedures.
3. Not currently seeking or receiving potentially curative therapies for cancer (e.g., chemotherapy or immunotherapy). Curative cancer therapy may be sought after the Outpatient Follow Up visit 14 (D14). Palliative anti-tumor therapy is allowed as long as the subject was established on that therapy prior to enrollment.
4. Must have moderate to severe pain that is not relieved by standard treatments. Mean daily worst pain NRS score of greater than or equal to 6 for pain at or below the T6 dermatome (level of the chest) that is associated with a malignant disease. The mean score must be derived from recordings on at least 4 of 7 consecutive days within 3 weeks preceding treatment.
5. The subject must agree to undergo a diagnostic periganglionic injection(s) with a long-acting local anesthetic (e.g., bupivacaine) under fluoroscopic guidance which resulted in at least a 30% temporary pain reduction in the targeted pain region lasting for the expected duration of the local anesthetic used.
6. Must be healthy enough to tolerate study procedures in the judgment of the investigator.
7. Subjects taking aspirin, non-steroidal anti-inflammatory medications, or vitamin supplements that include vitamin E or any prophylactic anticoagulant (including but not limited to Coumadin, heparin, or Xarelto) will be counseled either to stop taking these at least 7 days before surgery or be given instructions on dosing changes if applicable. In addition, if patients are currently taking a Factor Xa inhibitor (such as Xarelto) a hematology consult will be obtained. Subjects must be willing to comply with this requirement, which is standard clinical practice when undergoing elective surgical procedures to avoid surgical and post-surgical bleeding complications.

8. Formal review of the subject s medical records and written approval for his/her inclusion in the study by 3 separate persons:

   • Principal Investigator (PI) or an Associate Investigator (AI).
   • Medical oncologist or oncologic surgeon.
   • A member of the Pain and Palliative Care Service (PPCS) at the NIH.

9. For women of childbearing potential and men with partners of childbearing potential, the ability and willingness use an effective method of contraception during the study.

   Effective methods of birth control include:

   • hormonal contraception (birth control pills, injected hormones, or vaginal ring).,
   • intrauterine device.
   • barrier methods (condom or diaphragm) combined with spermicide
   • surgical sterilization (hysterectomy, tubal ligation, or vasectomy).
10. Medical clearance from referring physician consisting of a statement indicating an adequate recovery period from other previous trials/medication if known.
11. Must be able and willing to undergo an eye examination.
12. Must be able to read, speak and understand English and willing to complete the study tools and forms.
13. Subjects must have provided written informed consent which includes signing the institutional review board (IRB)-approved consent form prior to participating in any study-related activity.
14. Must have the capacity to provide informed consent.
15. Must have a responsible adult to provide assistance with activities of daily living as needed for the subject through the Day 14 visit.
16. Must have abilityAbility to assign a Durable Power of Attorney (DPA) for research and medical care at NIH.

EXCLUSION CRITERIA:

Subjects will be excluded from the study if they meet any of the following criteria:

1. Subject must not have primary pain source from anatomical regions at T5 dermatome or above.
2. Subject must not have pain due to causes other than cancer or its treatment that is moderate to severe in intensity.
3. Subjects must not be undergoing or have plans to undergo any active treatment for their cancer during the study until after the day 14 assessment timepoint, after the RTX injection.
4. Subject must not be anticipating initiation of palliative anti-tumor therapy or significant changes to current palliative anti-tumor therapy before completion of the Day 14 visit.
5. Subject must not have an ECG abnormality of which the baseline QTc interval exceeds 450 milliseconds.
6. Subjects must not have an allergy or hypersensitivity to chili peppers, capsaicin or radiographic contrast agents.
7. Subject must not have an anatomic abnormality or pathology of the spinal cord and/or PG space on magnetic resonance imaging (MRI) that could increase the risk of adverse effects of placement of the needle.
8. Subject must not have a contraindication to MRI or MRI contrast..

9. Subjects must not have evidence of a coagulopathy or hemostasis problem as

   evidenced by the following blood laboratory values within the week prior to the planned injection:

   • PT/INR (prothrombin time/International normalized ratio) > 1.5 times upper limit of normal range (ULN).
   • PTT (partial thromboplastin time) > 35 seconds.
10. Subjects must not have a platelet count \<50,000/mm3. Platelets will be transfused as necessary to raise the platelet count to greater than or equal to 100,000/mm3 prior to dosing.
11. Subjects must not have a total neutrophil count (TNC) \<1500. The US Clinical Practice Guideline for lumbar puncture is a platelet count of 50,0000, which is higher risk for hemorrhage than periganglionic infection. Patients with TNC\<1500 (neutropenia) may be eligible later if their TNC level becomes greater than 1500 spontaneously or after use of medications stimulating granulocyte production, such as Neupogen (granulocyte colony stimulating factor: G-CSF).
12. Subjects must not have abnormal electrolyte levels (i.e. low potassium) that cannot be corrected.
13. Subjects must not be febrile or have other evidence of an infection within 7 days of the planned periganglionic injection.
14. Subjects must not have an allergy or hypersensitivity to chili peppers, capsaicin, or radiographic contrast agents.
15. Female subjects must not be pregnant or breastfeeding.
16. Subjects with any medical condition that, in the Investigator s opinion, could adversely impact the subject s participation or safety, conduct of the study, or interfere with the pain assessment, such as poorly controlled diabetes or hypertension. Patients can be re-assessed for eligibility if these conditions can be controlled medically.
17. Subjects may not have a history of heart failure or unexplained fainting (syncope).
18. Subjects may not have a known family history of long QT syndrome.
19. Subjects who participated in a clinical trial of an investigational drug or device within 30 days of screening visit or are scheduled to receive an investigational product within 14 days of RTX injection.
20. Subjects must not have received invasive treatments, such as a neurolytic procedure, including surgical neurolysis, percutaneous regional or neuraxial continuous infusions (whether opioid or local anesthetic), peripheral neuromodulation or spinal cord stimulation.