Biomarkers in Chemotherapy-Induced Peripheral Neurotoxicity

NCT ID: NCT03348956

Last Updated: 2024-06-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-01
• Study Completion Date: 2022-02-14

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.

Conditions

CIPN - Chemotherapy-Induced Peripheral Neuropathy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

EPR Oximetry

All subjects in the study will receive the paramagnetic India ink injection to the foot. At three time points (pre-exposure, during-exposure or CIPN incidence, and post exposure), subjects will have three EPR oximetry readings, a neurological examination, and electrophysiologic testing.

Group Type: EXPERIMENTAL

EPR Oximetry

Intervention Type: DIAGNOSTIC_TEST

Subjects will have up to five EPR oximetry readings at each study visit. Subjects will place the foot with the paramagnetic ink injection between the two magnets of the EPR device. Continuous scans will be acquired for 10 minutes while the subject breathes room air, 10 minutes while the subject breathes enriched 100% oxygen, and 10 minutes while breathing room air again.

Interventions

EPR Oximetry

Subjects will have up to five EPR oximetry readings at each study visit. Subjects will place the foot with the paramagnetic ink injection between the two magnets of the EPR device. Continuous scans will be acquired for 10 minutes while the subject breathes room air, 10 minutes while the subject breathes enriched 100% oxygen, and 10 minutes while breathing room air again.

Intervention Type: DIAGNOSTIC_TEST

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Disarm Therapeutics

INDUSTRY

Sponsor Role: collaborator

Dartmouth-Hitchcock Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Victoria H. Lawson

Assistant Professor of Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Victoria H Lawson, M.D.

Role: PRINCIPAL_INVESTIGATOR

Dartmouth-Hitchcock Medical Center

Locations

Dartmouth-Hitchcock Medical Center in Lebanon, NH

Lebanon, New Hampshire, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

D17062

Identifier Type: -

Identifier Source: org_study_id