Proof of Principle Study Evaluating Gonyautoxins NEURO SERUM, on Chemotherapy-induced Peripheral Neuropathy

Study Overview
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Brief Summary
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Proof-of-concept study to assess the effects of gonyautoxins (PSP NEURO SERUM) on safety and tactile sensitivity on patients with chemotherapy-induced peripheral neuropathy (CIPN). This is a multicenter, prospective proof-of-concept study in patients with solid tumors affected by CIPN. The study will be divided into two parts: Part 1 will assess the activity and tolerability of PSP NEURO SERUM and part 2 consists of a randomized cohort that will compare the activity of PSP NEURO SERUM vs placebo. Part 2 will depend on the results of part 1. If there are less than 8 responses in part 1, the study will be interrupted, and it will not be recommended to proceed with part 2. The detailed description of the study will be given only for part 1.

Detailed Description
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A multicenter, prospective proof-of-concept study in patients with solid tumors who developed chemotherapy-induced peripheral neuropathy (CIPN) in upper limbs, equal or greater than grade 2, according to NCI-CTCAE version 5.0. Patients must have been treated with cytotoxic agents known to cause CIPN in neoadjuvant, adjuvant or palliative setting. The primary objective is to assess the effects of gonyautoxins (PSP NEURO SERUM) on tactile sensitivity and safety on patients with CIPN. The study will be divided into two parts, 1 and 2 and the investigational treatment will have a maximum duration of 4 weeks (28 days). Part 1 is a two-stage (stage 1 and stage 2), two-cohort (C1 and C2), open-label study where 38 pts with G>2 CIPN secondary to taxanes (C1) and other anti-neoplastic drugs (C2) will receive PSP NEURO SERUM thrice a day for 28 days. Twelve patients will be evaluated in stage 1, expecting a 20% response (2/12) in each cohort to proceed to stage 2. Additional 7 patients will be recruited to stage, expecting 4/19 response in each cohort. If the number of responses is not met in a specific cohort, recruitment will be halted. The transition to the randomized part 2 will be determined by the efficacy in part 1 (stratified analysis of C1 and C2 or overall population). The primary objective of Part 1 is to evaluate response of the tactile sensation as assessed by the Semmes-Weinstein monofilament test and to evaluate safety and toxicity (type, frequency, grade and causality of adverse effects) of PSP NEURO SERUM according to NCI-CTCAE v5.0. The secondary objectives of Part 1 are to: Evaluate the improvement of overall neurological examination as assessed by the clinical version of Total Neuropathy Score (TNSc) Evaluate the improvement of manipulative dexterity and agility as assessed by the nine-hole pegboard test (NHPT). Evaluate the improvement in patient reported symptoms as assessed by the Patient Neuropathy Questionnaire (PNQ). Evaluate the improvement of quality of life by using the Portuguese version of the 30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC Quality of Life Questionnaire (QLQ-C30)) version. The study procedures include: Screening Assessments Pre-treatment / Baseline Assessments (D1) D7 (± 1 day) - Assessments during Treatment D14 (± 1 day) - Assessments during Treatment D21 (± 1 day) - Assessments during Treatment End of Treatment (D28 + 3 days) Safety Follow-up Visit (30 ± 7 days from the last dose) A patient will have responded to the CIPN in the study if there is a documented improvement of 30% (two sizes of evaluator) and / or normalization of the baseline pretreatment assessment as assessed by the Semmes-Weinstein monofilament test. A patient will have progressed CIPN in the study if there is a documented worsening in tactile sensation assessed by the Semmes-Weinstein monofilament test. Worse tactile sensation is defined as the change in one (1) size of the monofilament evaluator.

Official Title
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Proof of Principle Study Evaluating the Effects of Gonyautoxins, Paralytic Shellfish Poisoning (PSP) NEURO SERUM, on Objective and Subjective Symptoms of Chemotherapy-induced Peripheral Neuropathy (CINP)

Conditions
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Chemotherapy-induced Peripheral Neuropathy

Intervention / Treatment
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* Drug: PSP NEURO SERUM


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age ≥18 years. Histological diagnosis of cancer (hematologic or solid tumors). Treatment with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Peripheral sensory neuropathy grade 2 or higher on upper limbs as per NCI-CTCAE v5.0. Diagnosis of peripheral sensory neuropathy during treatment with chemotherapy or at least 2 weeks after the last infusion. Patients who completed treatment with chemotherapy over 2 weeks, but have chronic symptoms related to peripheral sensory neuropathy and no exclusion criteria can be included. Patients on neuropathic pain modulators will be allowed if on stable dose, if there were no dose changes in dosages in the last 2 weeks or if the use is for another reason. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2, Documented willingness to use an effective means of contraception while participating in the study. Skin of the hands and cuticles should be intact. Exclusion Criteria: Prior treatment with gonyautoxins or any small molecule neurotoxins. Female participants who are pregnant (positive urine pregnancy test), who have an infant they are breastfeeding, or intend to become pregnant within 3 months. History of sensory peripheral neuropathy attributed to any cause other than chemotherapy. Currently receiving chemotherapy or having had received chemotherapy in the past 2 weeks. Patients on systemic treatment that peripheral neuropathy is a commonly known side effect or received treatment in the last 2 weeks. Patients receiving systemic treatment, such as hormonal therapy or other agents where peripheral neuropathy is not a common side effect will be allowed. Patients with grade 2 CIPN with perceived improvement of symptoms. Changes in neuropathic pain modulators will not be allowed. Any other therapies for chemotherapy-induced peripheral neuropathy must be discontinued at least 2 weeks before the first dose of study drug. Hypersensitivity reaction to PSP Neuro serum. Patients with a known or suspected shellfish allergy. Patients receiving steroids or having received steroids in the past 2 weeks except for maximum of 10mg of prednisone or equivalent. No dermatologic lesions on hands and cuticles that might increase systemic exposure of the investigational medicinal product (IMP). Distal muscle weakness and/or atrophy. History of alcoholism or regular (> 3 months) weekly alcohol intake of 168 g (21 units) for men and 112g (14units) for women. 1 unit = 10ml = 8g of pure alcohol. Clinically significant abnormalities of glucose metabolism as defined by any of the following: Diagnosis of diabetes mellitus type I or II (irrespective of management) with preexisting symptoms related to peripheral neuropathy. Asymptomatic diabetic patients with well controlled glucose levels are allowed. Glycosylated hemoglobin (HbA1C) ≥8.0% at screening. Fasting serum glucose ≥ 160 mg/dL at screening. Fasting is defined as no caloric intake for at least 8 hours. Vitamin B12 deficiency defined as < 250 ng/mL. Phosphate levels above upper limit of normal (ULN). ECG: corrected QT interval (QTc) (Fridericia Formula) ≥ 450ms. Positive Tinel and/or Phalen test. Participation in another clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry / randomization. Surgery, radiotherapy, or other anti-cancer therapy that in the investigators' opinion might interfere/ worsen symptoms or the evaluation of peripheral neuropathy within 2 weeks prior to trial entry /randomization. Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patients at high risk from treatment complications. Unresolved clinically significant toxicity from prior therapy except for alopecia. Inability to comply with study and follow-up procedures.

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: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: The first part of the study will consist of a two-stage (stage 1 and stage 2), two-cohort (C1 and C2), open-label study where 38 pts with G>2 CIPN secondary to taxanes (C1) and other anti-neoplastic drugs (C2) will receive PSP NEURO SERUM thrice a day for 28 days. Twelve patients will be evaluated in stage 1, expecting a 20% response (2/12) in each cohort to proceed to stage 2. Additional 7 patients will be recruited to stage, expecting 4/19 response in each cohort. If the number of responses is not met in a specific cohort, recruitment will be halted. The transition to the randomized part 2 will be determined by the efficacy in part 1 (stratified analysis of C1 and C2 or overall population).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: PSP NEURO SERUM<br>The first part, will consist of a single arm in which all patients will receive PSP NEURO SERUM in their hands three times a day for 28 days. Each application will consist of 1 g of PSP NEURO SERUM. | Drug: PSP NEURO SERUM<br>* PSP NEURO SERUM is a topical product that contains a concentration of Paralytic Shellfish Toxins of 10 micrograms/mL of equivalent of Gonyautoxin 2/3. Each patient will apply 1 g of PSP NEURO SERUM in their hands.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the change in response caused by PSP NEURO SERUM on the tactile sensation from baseline to day 28. | The response will be assessed using the Semmes-Weinstein monofilament test. | Screening and day 28 | 
| Evaluate the appearance of Adverse Events according to NCI-CTCAE v5.0 (National Cancer Institute - Commun Toxicity Criteria For Adverse Events). | Evaluate safety and toxicity (type, frequency, grade and causality of adverse effects) of PSP NEURO SERUM according to NCI-CTCAE v5.0. | Through the 28 days of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the change in the overall neurological examination using the Total Neuropathy Score (TNSc), from baseline to day 28. | Evaluate the improvement of overall neurological examination as assessed by the clinical version of the Total Neuropathy Score (TNSc). The examination includes sensory symptoms, motors symptoms, autonomic symptoms, pin sensation, vibration sensibility, strength and tendon reflexes. The scores for each measurement goes from 0 to 4, being 0 a normal result and 4 an abnormal one. | Screening and day 28. | 
| Evaluate the change of manipulative dexterity and agility from baseline to day 28. | Evaluate the improvement of manipulative dexterity and agility as assessed through the NHPT (Nine-hole Pegboard Test - test of nine pins and holes). | Screening and day 28. | 
| Evaluate the change in patient reported symptoms from baseline to day 28. | Evaluate the improvement in patient reported symptoms as assessed by the Patient Neuropathy Questionnaire (PNQ). | Screening and day 28. | 
| Evaluate the change in the quality of life from baseline to day 28. | Evaluate the improvement of quality of life by using the Portuguese version of the 30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) version. | Screening and day 28. |