Resiniferatoxin to Treat Severe Pain Associated With Advanced Cancer

Pain continues to be a major problem in patients with advanced cancer. Resiniferatoxin (RTX),
a potent member of the family of drugs that includes capsaicin, selectively and irreversibly
destroys the neurons (or their axons) transmitting chronic pain sensation. Intrathecal
injection of RTX in several animal species has demonstrated a high level of safety,
specificity, and efficacy in treating severe pain. This first-in-human, dose-escalation study
will investigate the intrathecal administration of RTX in cancer patients with severe pain.

PRIMARY OBJECTIVE:

To investigate the safety and efficacy of RTX administered intrathecally in subjects with
severe refractory pain associated with advanced cancer.

STUDY POPULATION:

Up to 45 subjects will be accrued. Eligible subjects will be greater than or equal to 18
years of age, have a clinical and histological diagnosis of advanced malignancy, and have
severe pain due to malignancy that is at or below the level of the chest and not adequately
relieved by other pain control therapies.

DESIGN:

This is a single site, non-randomized, open-label, dose-escalation study using a modified
Fibonacci scheme. The starting dose of RTX was 13 micrograms given as a 2 mL injection via an
intra-spinal catheter over approximately 30 seconds followed by a 1 mL flush. Six subjects
were dosed at this level and 3 were dosed at the 26 g dose level at the same volume of
injectate, flush and injection time. Pursuant to the study design, RTX doses were to be
increased in progressively smaller percentage increments with each dose escalation to occur
in sequential groups of 3 subjects until 1 escalation above the effective dose in 100% of
subjects (ED100), completion of the 100 g dose level, or establishment of the maximum
tolerated dose (MTD), whichever occurs first. The total duration of study participation for
any subject will received a dose of 26 micrograms.

The amended RTX injection technique reduced the injection volume and increased the injection
time to reduce spread of RTX to above the T6 (sixth thoracic) vertebral level. The present
rechnique is a 1 mL injection over 60 seconds (0.25 mL/15 seconds) given via infusion pump,
followed by flushing of the IT catheter with the minimum volume of sterile, preservative-free
saline necessary to clear the internal volume of the catheter used for the injection. Three
patients were treated at the new starting dose of 13 micrograms with the new injection
technique. The next 3-patient cohort at this dose.

OUTCOME MEASURES:

The primary study outcome is the ED100, the MTD, or the maximum dose administered, whichever
is achieved first during dose escalation. The primary pain variable for determining the ED100
is the daily worst pain score averaged over a 7-day period during the 3 weeks before RTX
dosing and during Days 8 through 14 after dosing. The numerical rating scale (NRS),
administered verbally during a daily telephone interview, will be the primary pain assessment
instrument. For a given subject, the treatment will be considered effective if the subject
experiences a greater than or equal to 50% reduction in the mean daily worst pain score
assessed by NRS (evaluated at Study Day 15). We may also consider RTX treatment to be
successful if there is greater than or equal to 50% reduction in opiate intake, measured by
morphine milligram equivalents (MME) per day, even if pain levels are unchanged after RTX
treatment.

Secondary outcome measures will be other surveys of pain, including an assessment of worst
daily pain by the visual analog scale, and assessments of function and quality of life.

Safety assessments will include hematology; serum clinical chemistry tests; cerebrospinal
fluid examinations; physical, neurological, and eye examinations; reporting of adverse
events; electrocardiograms; and findings of magnetic resonance imaging of the spine and
brain.

- INCLUSION CRITERIA:

Patient inclusion criteria are based on inadequate control of pain despite best efforts
including appropriate use of medication(s). Thus, criteria include the following:

1. Age 18 years or older.

2. Clinical and histological diagnosis of cancer with disease that has not adequately
responded to standard therapies. A pathology report documenting malignancy is
required.

3. Subject not currently seeking or receiving potentially curative therapies for cancer
(e.g., chemotherapy or immunotherapy). Curative cancer therapy may be sought after the
Day 15 clinic visit, and palliative anti-tumor therapy is allowed as long as the
subject was established on that therapy prior to enrollment (see exclusion criterion
7).

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

- Opioids (all routes of administration including neuraxial infustion)

- Adjuvant pain medications such as antidepressants, corticosteroids, local
anesthetics, and antiseizure medications

- Procedures such as catheter or implantable pump placement for delivery of
analgesic medication or neurolytic interventions (including intercostal, superior
hypogastric, or celiac plexus blocks)

- Complementary medicine approaches

- Transcutaneous electric nerve stimulation

- Radiation therapy

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

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

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

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

10. Ability to stop any anticoagulant (e.g., Coumadin) and antiplatelet therapies (e.g.,
aspirin) before and during intrathecal catheter placement according to accepted
medical guidelines.

11. Ability and willingness to undergo a complete eye examination.

12. Ability to read, speak, and understand English, and willingness to complete the study
tools and forms.

13. For women of childbearing potential and men with partners of childbearing potential,
the ability and willingness to use an effective method of contraception during the
study. Effective methods of birth control include:

1. hormonal contraception (birth control pills, injected hormones, or vaginal ring),

2. intrauterine device,

3. barrier methods (condom or diaphragm) combined with spermicide, or

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

14. Availability of a responsible adult to live with the subject through the Day 15 visit.

15. Ability 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. 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 in
intensity.

3. Anatomic abnormality or pathology of the spinal cord and/or intrathecal space on
magnetic resonance imaging (MRI) that could increase the risk of adverse effects of
intrathecal catheter placement or interfere with CSF flow.

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

5. Presence of an intrathecal shunt device (e.g., ventriculo-peritoneal and
ventriculo-atrial shunts).

6. Anticipating initiation of palliative anti-tumor therapy or significant changes to
current 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 study
participation or greatly increase safety risk to the subject, as judged by a study
investigator.

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

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

13. Have abnormal electrolyte levels (i.e. low potassium) that connot be corrected.