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

Cancer-induced bone pain (CIBP) is a common clinical problem.1 While primary osteosarcoma is
relatively uncommon, bone metastases frequently cause cancer-related pain with metastatic
spread to bone in 60-84% of cases. 2 Resiniferatoxin (RTX) is an ultrapotent agonist analog
of capsaicin that targets a receptor expressed on specific dorsal root sensory ganglia (DRG)
neurons and is expected to reduce pain within the targeted zone. The overall program goal is
to develop a new treatment for intractable chronic pain below the mid-thoracic level
resulting from CIBP that has not been controlled with conservative treatments.

Primary Objectives

To determine the maximum tolerated dose (MTD) of RTX when injected near one or more DRGs, and
to characterize its safety/toxicity profile and identify any dose-limiting toxicity (DLT).

Study Population

Up to 30 adult subjects are estimated to be necessary for enrollment to have up to 16
subjects who will receive RTX and provide study-related assessment results through the 30-day
time point.

Design

The study is a single center, open-label Phase 1b dose escalation safety and efficacy trial
for adult subjects with intractable pain due to CIBP below the mid-thoracic level who meet
all other eligibility criteria.

Subjects who have undergone the informed consent (IC) process and signed the approved IC form
for the study will be assigned a Screen # (S1, S2, etc.). Those subjects who meet all
inclusion and exclusion criteria will undergo various study procedures and then be scheduled
for the unilateral periganglionic (PG) DRG injection(s) (a maximum of 3 contiguous levels)
under fluoroscopic guidance to treat the targeted DRGs demonstrated to be responsible for the
chronic CIBP.

Subjects who are screen failures and those who prematurely terminate participation will be
replaced until 16 subjects have received the injection(s) and completed study-related
assessments through the day 30 (D30) time point.

Outcome Measures

The primary outcome is to achieve a dose-response relationship for safety, although data for
pain reduction will be obtained as a secondary outcome measure. All subjects will receive
RTX. There is no placebo group because of the invasive nature of the injection and the dose
escalation performed in the study.

This dose escalation safety study is based upon 4 progressive dose levels (0.8
microg/ganglion; 1.6 microg/ganglion; 3.2 microg/ganglion, and 6.4 microg/ganglion.

The adaptive dose selection design is employed to establish the primary outcome, the MTD for
RTX. MTD will be defined as 1 dose level below that at which DLT is observed in more than
one-third of the subjects.

The efficacy outcome variable will be evaluated by establishing dose-response curves, with
dose plotted on the x-axis and changes in efficacy endpoints (between before and D30, D60,
D90 and D180 after treatment) plotted on the y-axis. If, at the end of the study, all dose
levels of RTX have equal pain-relieving efficacy, the Data Safety Monitoring Committee (DSMC)
may determine it is appropriate to include a dose lower than 0.8 mcg and/or a control group.
On the other hand, if the dose-response curves show that higher doses could result in greater
pain-relieving efficacy, the protocol may be amended to include higher doses of RTX.

- INCLUSION CRITERIA:

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. Must have moderate to severe pain that is not relieved by standard treatments.

4. The chronic pain must result in an average score of at least 5 on the Brief Pain
Inventory (BPI) Pain Interference (BPI-PI) Items. The score across the 7 BPI-PI
items is averaged: the number (0 to 10) that describes how, during the past week,
the subject s pain has interfered with the following: general activity, mood,
walking ability, normal work (whether work outside the home or housework),
relations with other people, sleep, and enjoyment of life.

5. The subject must have undergone 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, prior to
study drug treatment. Evidence of pain relief by bipuvicaine validates that a
ganglia is involved in transmitting the pain signal from the site of cancer to
the central nervous system.

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. If able to become pregnant or to father a child, agree to use a reliable/accepted
method of birth control (i.e. hormonal contraception (birth control pills,
injected hormones, vaginal ring), intrauterine device, barrier methods with
spermicide (diaphragm with spermicide, condom with spermicide) or surgical
sterilization (hysterectomy, tubal ligation, or vasectomy) for the duration of
the study. Subjects must be willing and capable of understanding and cooperating
with the birth control requirements of the study.

9. Medical clearance from referring physician.

10. Must be willing and able to participate in all study procedures.

11. Must be capable of understanding and cooperating with the requirements of the
study.

12. Subjects must be able to understand and complete study-related forms and
adequately communicate in English.

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.

EXCLUSION CRITERIA:

1. Subjects must not be undergoing or have plans to undergo any active treatment for
their cancer during the study until after the day 30 assessment timepoint, after the
RTX injection.

2. Subjects must not have had prior surgical procedures, such as posterior spinal fusions
in the area of the injection site that could impair the ability to perform the
periganglionic injection.

3. 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 > 1.5 times upper limit normal range (ULNR)

PTT > 35 seconds

4. Platelet count less than 50,000 Subjects must not have a total neutrophil count (TNC)
< 1500. 1500. The US Clinical Practice Guideline for lumbar puncture is a platelet
count of 50,000, which is higher risk for hemorrhage than periganglionic injection.

4.5.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).

5. Subjects must not be febrile or have other evidence of an infection within 7 days of
the planned periganglionic injection.

6. Subjects must not have an allergy or hypersensitivity to chili peppers, capsaicin or
radiographic contrast agents.

7. Female subjects must not be pregnant or breastfeeding

8. 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.

9. 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 while participating in this study.

10. 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.