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

Chemotherapy-induced Peripheral Neuropathy

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.

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 up to 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. If needed, 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: 1. Evaluate the improvement of overall neurological examination as assessed by the clinical version of Total Neuropathy Score (TNSc) 2. Evaluate the improvement of manipulative dexterity and agility as assessed by the nine-hole pegboard test (NHPT). 3. Evaluate the improvement in patient reported symptoms as assessed by the Patient Neuropathy Questionnaire (PNQ). 4. 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. 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. Part 2 of the study consists of two randomized groups of 26 patients each, one control group, and one experimental group, resulting in a total of 52 patients. The composition of the study population will follow an adaptive approach, considering which cohorts benefited the most from the effects of PSP NEURO SERUM in Part 1. Due to the greater benefit observed in cohort 1, we will proceed in Part 2 with only the population of patients who developed peripheral neuropathy secondary to taxanes. The 52 patients will be allocated in a 1:1 ratio to either Arm A (control, n=26) or Arm B (experimental, n=26) with the objective of estimating and comparing the responses of tactile sensitivity using the Semmes-Weinstein monofilament test in hands caused by NPIQ. Patients in Arm A will receive a placebo (topical formulation composed of the same excipients without the active ingredient) three times a day for 28 days, and patients in Arm B will receive PSP NEURO SERUM (topical formulation) three times a day for 28 days. This study will follow a two-stage randomized analysis approach with the expectation that the control group will have up to 20% response rate compared to 50% in the experimental group. An independent committee will assess and monitor the data collection results, allowing or disallowing the continuation of the analysis. The first stage will occur when both groups reach 50% of patients with complete validation, where a partial evaluation of necessary criteria will take place to proceed with data collection until reaching the required sample size for the final analysis (second stage). In Part 2, patients with symptoms in their feet will be offered the possibility of using PSP NEURO SERUM/placebo on their lower limbs. The evaluation of symptoms will be assessed by extrapolation based on data collected by the EORTC QLQ CIPN20 Neuropathy Questionnaire. The primary objective of Part 2 is to Evaluate tactile sensitivity response through the monofilament test of Semmes-Weinstein. The secondary objectives of Part 2 are to: 1. Evaluate the improvement of overall neurological examination as assessed by the clinical version of Total Neuropathy Score (TNSc) 2. Evaluate the improvement of manipulative dexterity and agility as assessed by the nine-hole pegboard test (NHPT). 3. Evaluate the improvement in patient reported symptoms as assessed by the Patient Neuropathy Questionnaire (PNQ).EORTC CIPN20 4. Assess safety and toxicity as per NCI-CTCAE v5.0 (National Cancer Institute - Common Toxicity Criteria For Adverse Events). Adverse events will be collected weekly and at the visit of safet/monitoring; 5. 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: 1. Screening Assessments (Part 1 and 2) 2. Pre-treatment / Baseline Assessments (D1) (Part 1 and 2) 3. D7 (± 1 day) - Assessments during Treatment (Part 1) 4. D14 (± 1 day) - Assessments during Treatment (Part 1 and 2) 5. D21 (± 1 day) - Assessments during Treatment (Part 1) 6. End of Treatment (D28 + 3 days) (Part 1 and 2) 7. Safety Follow-up Visit (30 ± 7 days from the last dose) (Part 1 and 2)

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