Clinical trial NCT03348956: Biomarkers in Chemotherapy-Induced Peripheral Neurotoxicity
Official title: Biomarkers in Chemotherapy-Induced Peripheral Neurotoxicity: Better Tools and Understanding
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: CIPN - Chemotherapy-Induced Peripheral Neuropathy
Lead sponsor: Dartmouth-Hitchcock Medical Center
Sponsor class: OTHER
Collaborators: name: Disarm Therapeutics
First posted: 2017-11-21
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: This pilot study will attempt to establish the feasibility of using tissue oxygen measurements and the protein, neurofilament light chain (NF-L), as potential biomarkers for chemotherapy-induced peripheral neuropathy (CIPN). Thirty (30) subjects scheduled to begin taxane-based chemotherapy for breast tumor will be assigned to receive an India ink injection under the skin of the foot. The ink will be used to make up to five (5) 45-minute "electron paramagnetic resonance" (EPR) oximetry readings prior to the start of chemotherapy. Subjects will undergo electrophysiologic assessments including nerve conduction studies, in addition to a neurological examination prior to the start of chemotherapy. Subjects will have the EPR oximetry readings, electrophysiologic tests, and neurological examination two more times: at the halfway point of their chemotherapy treatment -- or at the onset of CIPN symptoms -- and again after chemotherapy has been completed. Subjects will also have blood drawn prior to beginning taxane-based chemotherapy, prior to every scheduled chemotherapy treatment, and after completion of chemotherapy in order to test for neurofilament light chain (NF-L).

Detailed description: Therapy with chemotherapeutic drugs can make a huge impact on survival and quality of life in patients with cancer. Advances in medical monitoring and the effectiveness of these therapies have significantly improved outcomes so that a definitive cure or long-term survival is more likely. Cancer survivors are used to dealing with serious side effects of their therapy; however, some of the side effects from the chemotherapy drugs persist even after the medication course is completed. The impact of these sequelae on quality of survival is increasingly being appreciated and forming an important new direction of cancer care. One of the more severe side effects of chemotherapy is peripheral neurotoxicity resulting in neuropathy or neuronopathy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the least predictable and most prolonged sequelae with effects ranging from pain, numbness and tingling to diffuse weakness sometimes to the extent of paralysis. It results from damage or alteration in function of peripheral nerves usually, but not always, in a length-dependent manner. An indirect impact of CIPN includes difficulties with balance and susceptibility to falls. There are currently no therapies that have been proven to prevent CIPN. Similarly, there are few medications that are known to be effective in the reversing CIPN once it develops or effectively treating symptoms of CIPN. Currently, diagnosis is based mainly on clinical examination and electrophysiological testing to monitor CIPN; identification of candidate biomarkers through which disease onset can be identified at an earlier stage and which reflect presumed pathophysiologic mechanisms is of paramount importance.

There are different theories of CIPN pathogenesis. One of the leading hypotheses relates to mitochondrial dysfunction and oxidative stress affecting both the dorsal root ganglia neurons and supportive endothelial cells of the vasa nervorum. Here at Dartmouth, a specialized technique has been developed that allows the non-invasive assessment of tissue oxygen in and around peripheral nerve. This technique, called "electron paramagnetic resonance" (EPR) oximetry, allows for repeated measurements over time that can be correlated with other metrics of peripheral nerve function. Given its relevance to an important pathophysiologic mechanism of disease, EPR oximetry may provide an early marker of disease onset.

Neurofilament light chain (NF-L) is also emerging as a sensitive blood-based biomarker of axonal degeneration. NF-L is a component of the axonal cytoskeleton that leaks out of degenerating axons. NF-L has been reported to be elevated in plasma or serum in a wide range of neurodegenerative disorders, including CNS disorders such as multiple sclerosis and ALS as well as PNS disorders such as Charcot Marie Tooth and Guillain-Barre syndrome. To date, there are no published reports of elevated blood NF-L levels in patients with CIPN, although it has been reported to increase in rat model of vincristine-induced neuropathy.

In this proposal, the investigators will be testing the hypothesis that these could both be biomarkers of CIPN. It is hoped that the oximetry measurement and blood NF-L levels will (i) reflect the changes that occur on a cellular level and the damaged nerves, (ii) reflect the damage occurring to nerves more sensitively than existing techniques, and (iii) help to better understand the reason the nerves are being damaged. It is also hoped that these will be something that can be used in future clinical trials.

Eligibility criteria: Inclusion Criteria:

* Scheduled to receive chemotherapy with taxane compounds for the treatment of breast cancer.
* No prior taxane or platinum chemotherapy prior to enrollment.
* Life expectancy greater than or equal to 12 months.
* Able to provide independent informed consent for the study.
* Able to undergo EPR oximetry
* Age 18 years or older

Exclusion Criteria:

* Central nervous system or other impairments that interfere with clinical and electrophysiological assessment.
* Unable to provide independent informed consent.
* Pacemaker or other metallic objects that would be contraindicated for MRI.
* A requirement for supplemental oxygen at baseline, or known, severe chronic obstructive pulmonary disease .
* Previous exposure to neurotoxic chemotherapeutic agents.

Primary outcomes:
measure: Relative Change in % pO2
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
Secondary outcomes:
measure: Neurologic Examination_ Strength_ Toe Fan
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Strength_ Toe Flex
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Strength_ Inv
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Strength_ Ev
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Strength_ ADF
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Vibration Sense_Toe
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Vibration Sense_MM
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Vibration Sense_Knee
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Vibration Sense_DIP2
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Vibration Sense_DIP5
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Deep Tendon Reflexes _ Biceps
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Deep Tendon Reflexes _ Triceps
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Deep Tendon Reflexes _ BR
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Deep Tendon Reflexes _ Patella
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Neurologic Examination_ Deep Tendon Reflexes _ Achilles
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Nerve Conduction Metrics (Amplitude)_DORSAL SURAL
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Change in Nerve Conduction Metrics (Amplitude)_MED PLANTAR
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Change in Nerve Conduction Metrics (Amplitude)_SURAL
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean of the Difference in Nerve Conduction Amplitudes Between Pre-Mid and Pre-Post exposure_Dorsal Sural
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Change in Nerve Conduction/Mixed Nerve Amplitudes _Medial Plantar
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Change in Nerve Conduction/Mixed Nerve Amplitudes _Sural
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Change in Nerve Conduction_Motor_ (Amplitude)_Peron-EDB
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Change in Nerve Conduction_Motor_ (Amplitude)_Peron-TA
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Change in Nerve Conduction_Motor_ (Amplitude)_Tibial-AH
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Nerve Conduction Metrics as Measured by Mean Change (Velocity) for Peroneal CMAP AMP, EDB
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Nerve Conduction Metrics as Measured by Mean Change (Velocity) for Peroneal CMAP, AT
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Nerve Conduction Metrics as Measured by Mean Change (Velocity) for Tibial CMAP, AH
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Nerve Conduction Metrics as Measured by Mean Change (Velocity) for Dorsal Sural CV
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Nerve Conduction Metrics as Measured by Mean Change (Velocity) for Med Plantar CV
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Nerve Conduction Metrics as Measured by Mean Change (Velocity) for Sural CV
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Nerve Conduction Metrics as Measured by Mean Change (Velocity) for Peroneal CV, Distal
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of Neuro-Quality of Life - Positive Affect and Well-Being Scale
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of Neuro-Quality of Life - Satisfaction With Social Roles and Activities Scale
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of Neuro-Quality of Life - Lower Extremity Function (Mobility) Scale
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of Neuro-Quality of Life - Upper Extremity Function (Fine Motor, Activities of Daily Living) Scale
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of The Neuropathy Total Symptom Score-6 Questionnaire
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of Toronto Clinical Neuropathy Scoring System
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of National Cancer Institute - Common Toxicity Criteria
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of Total Neuropathy Scores
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of Survey of Autonomic Symptoms, Column B
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of McGill Pain Visual Analog Scale
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Scores of Short Form McGill Pain Questionnaire
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Mean Score of Survey of Autonomic Symptoms, Column A
timeFrame: Pre-chemotherapy (Baseline), Mid-chemotherapy (approximately 6 - 8 weeks from Baseline), Post-chemotherapy (approximately 2 - 3 weeks after the participant completed chemotherapy or approximately 14 - 18 weeks from Baseline)
measure: Serum NF-L Levels
timeFrame: 1 year
Other outcomes:
Locations:
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center in Lebanon, NH
state: New Hampshire
Study officials:
affiliation: Dartmouth-Hitchcock Medical Center
name: Victoria H Lawson, M.D.
role: PRINCIPAL_INVESTIGATOR
References: