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Resiniferatoxin to Treat Severe Pain Associated With Advanced Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT00804154
Recruitment Status : Recruiting
First Posted : December 8, 2008
Last Update Posted : September 2, 2019
National Institute of Neurological Disorders and Stroke (NINDS)
Sorrento Therapeutics, Inc.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Dental and Craniofacial Research (NIDCR) )

Tracking Information
First Submitted Date  ICMJE December 5, 2008
First Posted Date  ICMJE December 8, 2008
Last Update Posted Date September 2, 2019
Actual Study Start Date  ICMJE August 14, 2009
Estimated Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 21, 2019)
Safety and efficacy of RTX administered intrathecally in subjects with severe refractory pain associated with advanced cancer along with ED100, MTD, or the maximum dose administered, whichever is achieved first during dose escalation @... [ Time Frame: Day 7, Day 15, Day 68, Day 188 ]
Dose escalation decisions are based on both effectiveness (as assessed by mean worst pain on the NRS) and DLT. The dose escalation population will include all subjects who are dosed, complete the NRS, and have the DLT assessments from baseline through Day 15. Subjects who are not evaluable for dose escalation will be replaced.
Original Primary Outcome Measures  ICMJE
 (submitted: December 5, 2008)
Phase I trial to demonstrate the safety of administering resiniferatoxin (RTX) directly into the human CNS (fluid bathing the spinal cord).
Change History Complete list of historical versions of study NCT00804154 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2019)
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. [ Time Frame: Day 7, Day 15, Day 68, Day 188 ]
The secondary outcome variables will be summarized over time by dose cohort as appropriate for the outcome measure. Absolute and percentage change in the NRS and VAS pain scores between the pre- and post-RTX dosing assessments (baseline period and study Days 8 through 14, respectively) will also be summarized.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 5, 2008)
Confirm that injection of RTX in CNS has pain-relieving properties (analgesia) resulting in lower pain scores, improvements in quality of life, and possibly opoid sparing properites in patients with refractory pain.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Resiniferatoxin to Treat Severe Pain Associated With Advanced Cancer
Official Title  ICMJE A Phase I Study of the Intrathecal Administration of Resiniferatoxin for Treating Severe Refractory Pain Associated With Advanced Cancer
Brief Summary

This study will examine the safety of giving the experimental drug, resiniferatoxin (RTX), to treat severe pain in patients with advanced cancer. RTX is a chemical extracted from a cactus-like plant. It is similar to capsaicin, the active ingredient in hot pepper. RTX has relieved pain and reduced the need for pain medication in several animal experiments. It works by destroying nerves that transmit pain information.

People at least 18 years of age with severe pain from advanced cancer at or below the level of the chest that cannot be controlled with standard treatments may be eligible for this study. Participants undergo the following procedures:

Pretreatment Visit

Before beginning treatment with RTX, patients give a medical history and undergo a physical examination that includes:

  • Electrocardiogram (EKG)
  • Blood draw
  • Urinalysis
  • Neurological examinations
  • Peak expiratory flow rate (PEFR)
  • Eye examination
  • MRI
  • Urology assessment
  • Pregnancy test, when appropriate
  • Questionnaires to collect information on health, personality, mood, pain levels and symptoms.

    2-Day Hospitalization

Patients are hospitalized for 2 days for RTX injection and monitoring, as follows:

  • RTX injection: RTX is injected in the operating room under general anesthesia. It is given through a catheter placed in the patient s spine. The catheter is also used to obtain samples of cerebrospinal fluid (CSF) the clear fluid that bathes the spinal cord. The fluid is examined to assess drug effects and side effects, chemical changes in the content of the CSF associated with RTX, and how RTX is handled by the body.
  • Post-injection monitoring, including:
  • Surveys about symptoms such as pain or weakness
  • Neurological examinations
  • Blood and CSF sampling
  • EKG
  • AEs

Outpatient followup

  • Vitals
  • Blood draw, Urinalysis, neurological and sensory testing, EKG on days 7, 14 and 30 after the injection
  • MRI scans of the head and back, Urology assessment and PEFR on day 15 after the injection
  • Eye examination
  • Follow-up phone calls monthly for 6 months
Detailed Description

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. 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 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.


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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Intractable Pain
  • Palliative Care
Intervention  ICMJE Drug: Intrathecal Resiniferatoxin
phase I, single-site, non-randomized, open-label, dose- escalation study to determine the safety and efficacy of IT RTX in subjects with severe refractory pain due to advanced malignancy
Study Arms  ICMJE Experimental: Single Arm
advanced cancer patients with pain
Intervention: Drug: Intrathecal Resiniferatoxin
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 29, 2017)
Original Enrollment  ICMJE
 (submitted: December 5, 2008)
Estimated Study Completion Date  ICMJE August 31, 2020
Estimated Primary Completion Date August 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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


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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 45 Years to 200 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: John D Heiss, M.D. Not Listed
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00804154
Other Study ID Numbers  ICMJE 090039
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Dental and Craniofacial Research (NIDCR) )
Study Sponsor  ICMJE National Institute of Dental and Craniofacial Research (NIDCR)
Collaborators  ICMJE
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Sorrento Therapeutics, Inc.
Investigators  ICMJE
Principal Investigator: John D Heiss, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date August 20, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP