PEA for the Relief of Chemotherapy-Induced Peripheral Neuropathy

Study Overview
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Brief Summary
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This phase II trial tests whether PEA works to relieve the symptoms of chemotherapy-induced peripheral neuropathy in patients with cancer. Chemotherapy-induced peripheral neuropathy refers to a nerve problem that causes pain, numbness, tingling, or muscle weakness in different parts of the body, and is caused by chemotherapy. PEA may be useful against bothersome nerve symptoms.

Detailed Description
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PRIMARY OBJECTIVE: I. To look for evidence of the efficacy of PEA (N-palmitoylethanolamide) at two different doses relative to placebo responses, as a treatment for chemotherapy-induced neuropathy (CIPN). SECONDARY OBJECTIVES: I. To assess the safety of PEA at the two study doses. II. To evaluate changes in patient-reported quality of life from baseline to the end of 8 weeks. EXPLORATORY OBJECTIVES: I. To explore whether PEA appears to affect cognition in the study patients. II. To explore the weekly trajectory of CIPN from baseline to 8 weeks. III. To explore the weekly trajectory of pain using the single-item numerical rating scale from baseline to 8 weeks. IV. To explore the weekly patient global impression of change in each treatment arm from baseline to 8 weeks. V. To explore the weekly chemotherapy induced peripheral neuropathy in each treatment arm from baseline to 8 weeks. VI. To explore the PEA effects on CIPN20 between two PEA dosage arms. VII. To explore the number of recurrent cancer events by study arm. VIII. To explore the overall survival by study arm. OUTLINE: Patients are randomized to 1 of 4 arms. ARM I: Patients receive PEA orally (PO) once daily (QD) for 8 weeks as long as there is not any unacceptable toxicity. ARM II: Patients receive PEA PO twice daily (BID) for 8 weeks as long as there is not any unacceptable toxicity. ARM III: Patients receive placebo PO QD for 8 weeks. ARM IV: Patients receive placebo PO BID for 8 weeks. After completion of study intervention, patients are followed up at 6 and 12 months.

Official Title
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Treatment of Established Chemotherapy-Induced Neuropathy With N-Palmitoylethanolamide, a Cannabimimetic Nutraceutical: A Randomized Double-Blind Phase II Pilot Trial

Conditions
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Chemotherapy-Induced Peripheral Neuropathy, Hematopoietic and Lymphoid Cell Neoplasm, Malignant Solid Neoplasm

Intervention / Treatment
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* Drug: Palmidrol
* Drug: Placebo Administration
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, 2 NOTE: Patients with a history of metastatic cancer or an ECOG performance status of 2 must have laboratory (lab) work completed =< 28 days prior to registration Pain, numbness, tingling or other symptoms of CIPN of >= 3 months (90 days) duration for which the patient is seeking an intervention Neurotoxic chemotherapy must have been completed >= 3 months (90 days) prior to registration and there must be no further planned neurotoxic -chemotherapy for > 2 months after registration Note: The study is limited to those with taxane- and/or platinum-based neuropathy Patient must note tingling, numbness or pain symptoms of at least a four out of ten =< 7 days prior to registration. Note: On a 0-10 scale where zero was 'no problem' and ten being 'as bad a problem that could be imagined': how much of a problem has numbness, tingling, and/or pain in your fingers and/or toes been in the past week? Patient must be able to speak, read and comprehend English For women of childbearing potential only, a negative urine or serum pregnancy test done =< 14 days prior to registration is required A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) NOTE: If the urine test cannot be confirmed as negative, a serum pregnancy test will be required Life expectancy >= 6 months Platelet count > 100,000/mm^3 NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration Absolute neutrophil count (ANC) >= 1,000/mm^3 NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration Hemoglobin > 11 g/dL NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration Serum transaminase (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) =< 1.2 x upper limit of normal (ULN) NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have these labs completed =< 28 days prior to registration Alkaline phosphatase =< 1.2 x ULN NOTE: Patients with a history of metastatic breast cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration Serum creatinine =< 1.2 x ULN NOTE: Patients with a history of metastatic cancer or an ECOG performance status of 2 must have this lab completed =< 28 days prior to registration Able to swallow oral medication Provide written informed consent =< 28 days prior to registration Exclusion Criteria: Currently receiving neurotoxic chemotherapy for a second cancer or recurrence of the primary cancer Impaired decision-making capacity (such as with a diagnosis of dementia or memory loss) Evidence of residual cancer, per routine clinical practice-based parameters Comorbid conditions: Previous diagnosis of diabetic or another non chemotherapy induced peripheral neuropathy Previous history of peripheral neuropathy prior to receiving neurotoxic chemotherapy Neuropathy from human immunodeficiency virus (HIV) infection. Note: Patients with HIV infections are eligible as long as they do not have a neuropathy from their viral illness Concurrent use of a cannabis product (tetrahydrocannabinol [THC] and/or cannabidiol [CBD]). Patients should have discontinued these products >= 4 weeks prior to registration Current or previous use of PEA Currently receiving or planning to start any of the following agents: opioids, duloxetine, gabapentin or pregabalin. Patients are eligible if they discontinue these medications >= 1 week prior to registration Any of the following because the study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown: Pregnant persons Nursing persons Persons of childbearing potential who are unwilling to employ adequate contraception

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: BID placebo<br>Patients receive placebo PO BID for 8 weeks. | Drug: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Higher-dose PEA<br>Patients receive PEA PO BID for 8 weeks as long as there is not any unacceptable toxicity. | Drug: Palmidrol<br>* Given PEA PO<br>* Other names: PEA;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Lower-dose PEA<br>Patients receive PEA PO QD for 8 weeks as long as there is not any unacceptable toxicity. | Drug: Palmidrol<br>* Given PEA PO<br>* Other names: PEA;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Placebo Comparator: QD placebo<br>Patients receive placebo PO QD for 8 weeks. | Drug: Placebo Administration<br>* Given PO<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN20) score | Will be scored and summarized at each time point for each patient. The change from baseline to 8 weeks will then be calculated for each patient. The mean (standard deviation [SD]) and median (range) of the change will be calculated for each PEA arm and the combined placebo arm. The difference in change scores between each PEA arm and the combined placebo will be estimated along with a 95% confidence interval. For the primary analysis, the CIPN20 analysis dataset will include all eligible patients who are randomized, initiated treatment, and completed the baseline questionnaire. For patients who go off protocol treatment before 8 weeks, the score at their final observation will be used to calculate the change. For patients who do not have any post baseline data, they will be considered to have no change from baseline. | Baseline up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Adverse events by patient will be summarized by frequencies and severity using Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. The proportion of patients who experience at least one grade 3+ adverse event (regardless of attribution) will be reported. The overall adverse event rates for grade 3 or higher adverse events will be compared across the three arms (the two PEA arms and combined placebo) using a Chi-squared or Fisher's Exact tests as appropriate. | Up to 8 weeks | 
| Difference in change of quality of life | Will be assessed by Question 3, patient-reported outcomes-quality of life (PRO-QOL). The mean and standard deviation of the change will be reported for each PEA arm and the combined placebo arm. Additional analysis using data collected from the Symptom Experience Diary may be performed. For patients who go off protocol treatment before 8 weeks, the question 3 response at their final observation will be used to calculate the change. For patients who do not have any post baseline data, they will be considered to have no change from baseline. | Baseline up to 8 weeks |