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.
