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A Phase I Study of the Intrathecal Administration of Resiniferatoxin for Treating Severe Refractory Pain Associated With Advanced Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Pain/Cancer, Pain, Intractable

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Trial Information

A Phase I Study of the Intrathecal Administration of Resiniferatoxin for Treating Severe Refractory 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.


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


Up to 45 subjects will be accrued as described in Section 8.5. 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.


This will be a single-site, non-randomized, open-label, dose-escalation study using a
modified Fibonacci scheme. The starting dose of RTX will be 13 micro g. Doses will then be
increased in progressively smaller percentage increments. Dose escalation will occur in
sequential groups of 3 subjects until 1 escalation above the effective dose in 100% of
subjects (ED100), completion of the 166 mirco g dose level, or establishment of the maximum
tolerated dose (MTD), whichever occurs first. The total duration of study participation for
any subject will be up to 7 months.


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.

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

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

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

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:

(Bullet) Opioids (oral, IV, transcutaneous, rectal, intramuscular, subcutaneous,
inhaled, nasal, or sublingual routes of administration)

(Bullet) Adjuvant pain medications such as antidepressants, corticosteroids, local
anesthetics, and antiseizure medications

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

(Bullet) Complementary medicine approaches

(Bullet) Transcutaneous electric nerve stimulation

(Bullet) 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(s), including 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:

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

(Bullet) Medical oncologist or oncologic surgeon

(Bullet) A member of the PPCS

9. 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.

10. Platelet count greater than or equal to 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. 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.

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

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

14. 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

2. intrauterine device,

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

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

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


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

1. Moderate or severe pain, as determined by questioning at screening, involving
anatomical regions of the T5 dermatome or above.

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

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

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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I trial to demonstrate the safety of administering resiniferatoxin (RTX) directly into the human CNS (fluid bathing the spinal cord).

Outcome Time Frame:

6 months from treatment

Safety Issue:


Principal Investigator

John D Heiss, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Institute of Neurological Disorders and Stroke (NINDS)


United States: Federal Government

Study ID:




Start Date:

December 2008

Completion Date:

December 2014

Related Keywords:

  • Pain/Cancer
  • Pain, Intractable
  • Pain
  • Vanilloid
  • Capsaicin
  • Cancer Pain
  • Resiniferatoxin
  • Pain, Intractable



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892