Peripheral Neuropathy
Conditions
Keywords
chemotherapy, peripheral neuropathy, paclitaxel, breast cancer
Brief summary
This study is being done because peripheral neuropathy, a condition that interrupts sensation in your limbs, is a common side effect of paclitaxel. There is some evidence that alpha lipoic acid (ALA), an antioxidant compound, protects neurons after exposure to paclitaxel. The purpose of this study is to assess the safety and tolerability of ALA and to find the best dose of ALA in patients that receive chemotherapy.
Interventions
DRUGAlpha lipoic acid
The baseline dose is 100 mg three times daily for four months. Dose escalation will occur until a maximum tolerated dose is found.
Sponsors
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Breast cancer. 2. Breast cancer must meet the following criteria: * Early stage breast cancer (stages I, IIA) must be estrogen receptor (ER) positive AND low tumor grade (histopathologic grade 1 or 2) * Locally advanced breast cancer (LABC) (stages IIB, IIIA, IIB as defined by the Union for International Cancer Control and American Joint Committee on Cancer) must be ER positive, HER2 positive or HER2 negative, AND satisfy the following requirements: high endocrine responsiveness (defined as greater than 50% of tumor cells staining for hormone receptors), Grade 1 or 2 histological grade, less than 4 nodes positive, absence of extensive peritumoral vascular invasion, AND pathological tumor size less than 5 cm. * Inflammatory breast cancer (IBC) (stage IIIC) * Metastatic breast cancer (stage IV) 3. Must be receiving single agent paclitaxel in their prescribed chemotherapy regimen. 4. Age \> 18 years. There is no upper age limit for participation in this study. 5. Required lab values: AST, ALT, creatinine 6. Women of childbearing potential and sexually active males must agree to use contraception while on study. 7. ECOG performance status 0,1,2 8. All patients must have given signed, informed consent.
Exclusion criteria
1. Breast cancer meeting the following criteria: * Breast cancer stage 0 * Early stage breast cancer (stages I, IIA) that is ER negative OR higher tumor grade (histopathologic grade greater than 2) * Stages I, II, and IIIA triple negative breast cancer (negative for estrogen receptors, progesterone receptors, and HER2) * LABC (stages IIB, IIIA, IIB) if they have low endocrine responsiveness (defined as less than 50% of tumor cells staining for hormone receptors), Grade 3 histological grade, 4 or more nodes positive, presence of extensive peritumoral vascular invasion, OR pathological tumor size greater than 5 cm * LABC (stages IIB, IIIA, IIB) that are ER negative 2. Evidence of pre-existing peripheral neuropathy as determined by baseline Michigan neuropathy screening instrument score \> 2. 3. Previous chemotherapy treatment of any kind. 4. AST and ALT \>2 times upper limit of normal; Creatinine \> 2.0 mg/dL. 5. Current use of medications or substances known to be associated with peripheral neuropathy. 6. Use of ALA or other anti-oxidant supplements during the prior three months. 7. Diabetes mellitus or use of medications known to lower blood sugar. 8. Participation in any other experimental trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Identification of the Optimal Dose of ALA Based on Acceptable Adverse Event(AE) Profile | 4 months | Based on acceptable adverse event (AE) profile and continual reassessment method dose escalation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Complete the Proposed Regimen of Daily ALA | 4 months | — |
| Cumulative Rate of Adverse Events | 4 months | — |
| Total Neuropathy Score (TNS) | 4 months | The Total Neuropathy score (TNS) is a validated score that combines signs, symptoms, and very limited nerve conduction studies (NCS). It was designed to assess peripheral nerve function and has been used as an endpoint in clinical trials of toxic neuropathy. The TNS is a composite scale with a range of values from 0 (normal) to 28 (severely affected). It includes data from 7 different categories. Patients are asked to assess the severity of sensory symptoms on a scale of 0 (no symptoms) to 4 (symptoms above knees or elbows, or functionally disabling). Next, 4 examination categories are assessed. These include pin sensation, vibration sensation, deep tendon reflexes, and strength. Signs are scored from 0 to 4 depending on severity. The nerve conduction portion of the scale consists of measurements of a motor (peroneal) and sensory (sural) nerve. Motor and sensory responses are graded on a scale of 0 to 4 depending on the severity of an abnormality. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alpha Lipoic Acid Oral administration three times daily (morning, mid-day, night)
Alpha lipoic acid: The baseline dose is 100 mg three times daily for four months. Dose escalation will occur until a maximum tolerated dose is found. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Cohort 2: Dose Level 2 (ALA 600mg Daily) | Adverse Event | 1 |
| Cohort 5: Dose Level 2 (ALA 600mg Daily) | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Alpha Lipoic Acid |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 56.7 years |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
Primary
Identification of the Optimal Dose of ALA Based on Acceptable Adverse Event(AE) Profile
Based on acceptable adverse event (AE) profile and continual reassessment method dose escalation.
Time frame: 4 months
Population: Although our dose finding analysis suggested a maximum tolerated dose of 500mg daily, it should be noted that we failed to fully complete the Continual Reassessment Method (CRM) dose finding portion of the study. As such, we can not make confident dose finding statements on the basis of this trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alpha Lipoic Acid | Identification of the Optimal Dose of ALA Based on Acceptable Adverse Event(AE) Profile | 500 mg |
Secondary
Cumulative Rate of Adverse Events
Time frame: 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alpha Lipoic Acid | Cumulative Rate of Adverse Events | 9 participants |
Secondary
Proportion of Patients Who Complete the Proposed Regimen of Daily ALA
Time frame: 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alpha Lipoic Acid | Proportion of Patients Who Complete the Proposed Regimen of Daily ALA | 7 participants |
Secondary
Total Neuropathy Score (TNS)
The Total Neuropathy score (TNS) is a validated score that combines signs, symptoms, and very limited nerve conduction studies (NCS). It was designed to assess peripheral nerve function and has been used as an endpoint in clinical trials of toxic neuropathy. The TNS is a composite scale with a range of values from 0 (normal) to 28 (severely affected). It includes data from 7 different categories. Patients are asked to assess the severity of sensory symptoms on a scale of 0 (no symptoms) to 4 (symptoms above knees or elbows, or functionally disabling). Next, 4 examination categories are assessed. These include pin sensation, vibration sensation, deep tendon reflexes, and strength. Signs are scored from 0 to 4 depending on severity. The nerve conduction portion of the scale consists of measurements of a motor (peroneal) and sensory (sural) nerve. Motor and sensory responses are graded on a scale of 0 to 4 depending on the severity of an abnormality.
Time frame: 4 months
Population: Failure to reach the MTD precluded our ability to perform any meaningful analysis of the TNS.