Resiniferatoxin to Treat Severe Pain Associated With Advanced Cancer

• INCLUSION CRITERIA:

Subject inclusion criteria are based on inadequate control of pain despite best efforts, including appropriate use of analgesic medications. To be enrolled in the study, subjects must meet all of the following criteria:

1. Age 18 years or older.

2. Clinical and histological diagnosis of cancer with disease that has not adequatelyresponded to standard therapies. A pathology report documenting malignancy isrequired.

3. Subject not currently seeking or receiving potentially curative therapies for cancer (e.g., chemotherapy or immunotherapy). Curative cancer therapy may be sought afterthe Day 15 clinic visit, and palliative anti-tumor therapy is allowed as long as thesubject was established on that therapy prior to enrollment (see exclusion criterion 6).

4. Mean daily worst pain NRS score of greater than or equal to 6 for pain at or belowthe 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 dayswithin 3 weeks preceding treatment.

5. Alternative methods of pain control are not sufficiently effective, not indicated,not tolerated, and/or refused by the subject, as determined by the Pain andPalliative Care Service (PPCS). Alternative methods of pain control include, but arenot limited to, the following:

-Opioids (all routes of administration including neuraxial infusions)

-Adjuvant pain medications such as antidepressants, corticosteroids, localanesthetics, and antiseizure medications

-Procedures such as catheter or implantable pump placement for delivery of analgesicmedication

• Prior neurolytic interventions (including intercostal, superior hypogastric, orceliac plexus blocks)

• Complementary medicine approaches

• Transcutaneous electric nerve stimulation

• Radiation therapy

6. Reasonable expectation that the subject will be able to complete the study throughthe 30-day follow-up.

7. Medical clearance from referring physician consisting of a statement indicating anadequate recovery period from other previous trials/medication.

8. Formal review of the subject s medical records and written approval for his/herinclusion in

the study by 3 separate persons:

• Principal Investigator (PI) or an Associate Investigator (AI)

• Medical oncologist or oncologic surgeon.

• A member of the PPCS at the NIH or institution s equivalent at other sites.

10. International normalized ratio (INR; from prothrombin time [PT]) < 1.5 andpartial thromboplastin time (PTT) less than or equal to the upper limit of thereference range. The INR and PTT may be corrected (e.g., by administration ofblood products, vitamin K, etc.), provided a repeat blood draw confirms thatthe values meet this inclusion criterion.

11. Platelet count greater than or equal to 50,000/mm^3. Platelets will betransfused as necessary to raise the platelet count to greater than or equal to 100,000/mm^3 prior to dosing.

12. Ability to stop any anticoagulant (e.g., Coumadin) and antiplatelet therapies (e.g., aspirin) before and during IT catheter placement according to acceptedmedical guidelines.1

13. Ability and willingness to undergo an eye examination.

14. Ability to read, speak, and understand English, and willingness to complete thestudy tools and forms.

15. For women of childbearing potential and men with partners of childbearingpotential, the ability and willingness to use an effective method ofcontraception 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, or

• surgical sterilization (hysterectomy, tubal ligation, or vasectomy).

15. Availability of a responsible adult to assist with activities of daily livingas needed for the subject through the Day 15 visit.

16. Ability to assign a Durable Power of Attorney (DPA) for research and medicalcare at NIH

EXCLUSION CRITERIA:

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

1. Primary pain source from anatomical regions at T5 dermatome or above.

2. Pain due to causes other than cancer or its treatment that is moderate to severe inintensity.

3. Anatomic abnormality or pathology of the spinal cord and/or IT space on magneticresonance imaging (MRI) that could increase the risk of adverse effects of catheterplacement or interfere with CSF flow.

4. Evidence of advanced brain pathology or elevated intracranial pressure as determinedby symptoms, history, physical examination (including neurological and eyeexamination), and/or MRI.

5. Presence of an IT shunt device (e.g., ventriculo-peritoneal and ventriculo-atrialshunts).

6. Anticipating initiation of palliative anti-tumor therapy or significant changes tocurrent palliative anti-tumor therapy before completion of the Day 15 visit.

7. Documented allergy to chili peppers or capsaicin (e.g., hives, wheal).

8. Contraindication to MRI or MRI contrast.

9. Female subjects who are pregnant or lactating.

10. Clinically significant disorder or condition that might interfere with studyparticipation or greatly increase safety risk to the subject, as judged by a studyinvestigator.

11. Planned use of another investigational agent, therapy, or device within 30 daysafter dosing.

12. Have a history of heart failure or unexplained fainting (syncope).

13. Have an EKG abnormality in which the baseline QTc interval exceeds 450 milliseconds.

14. Have a known family history of long QT syndrome.

15. Have abnormal electrolyte levels (i.e., low potassium) that cannot be corrected.

16. Have urinary retention that does not resolve with medical or surgical treatment.

17. Have skin ulceration that does not resolve with medical or surgical treatment.

18. Have a history of seizure activity in the previous month.

19. Have experienced symptoms of opioid toxicity in the past month (i.e. myoclonus,seizures, and/or hallucinations)