International CIPN Assessment and Validation Study

International Chemotherapy Induced Peripheral Neurotoxicity (CIPN) Assessment and Validation Study

This is an observational study of chemotherapy-induced peripheral neurotoxicity (CIPN) patients to be investigated prospectively in order to assess responsiveness of a set of outcome measures in an international multi-center study.

The study will be performed at all participating centers and will consist of the following assessments:

Core study (assessments at baseline and at the end of treatment)

• Standard oncology assessment per local site
• NCI-CTC (national cancer institute common toxicity criteria) v.5 sensory and motor
• PRO-CTCAE (patient reported outcome-cancer common tocixity adverse event)
• PI-NRS (pain intensity numeric rating scale)
• NPS-CIN (Neuropathic Pain Scale for chemotherapy-induced neuropathy)
• EORTC CIPN20© (The European Organisation of Research and Treatment of. Cancer Quality of Life Questionnaire-CIPN twenty-item scale)
• FACT-GOG NTX v.4© (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity)
• TNSn© (total neuropathy score, nurse version)
• PGIC (patient global impression of change)
• OXA-NQ (oxaliplatin neurotoxicity questionnaire)

Extended study (at all available sites - any combination of assessment methods is allowed, minimum at baseline and at the end of treatment)

• EORTC CIPN15
• CIPN-R-ODS (CIPN Rash overall disability scale)
• TNSc© at the same time points as for questionnaire
• OXA-NQ (also at mid-treatment)
• nerve conduction study of the radial (motor and sensory), ulnar (motor and sensory), sural, dorsal sural and common peroneal nerves (*)
• QST (*) [quantitative sensory testing]
• Serum for biomarkers search (*)
• DN4

Rationale: Within a multi-center international collaboration among experienced neurologists, oncologists, nurses and symptom scientists, the principal aim of this study is to evaluate responsiveness of a set of outcome measures for CIPN evaluation in order to define the gold standard for its assessment.

The assessment of CIPN will be performed at different levels of investigation. The Core study will allow the evaluation of subjects with common devices, so that an assessment can be performed at any medical site (expected time for questionnaires completion 15 minutes).

The Extended study will add any combination of the listed assessment methods/biological sample collection, in order to ascertain whether this approach can provide a more careful and clinically-relevant estimate of the peripheral nervous system damage. Comparison between healthcare evaluation and subjects' report of CIPN severity using established questionnaires will be performed in both Core and Extended studies.

Aims: The primary aim for this study is to test responsiveness of the different assessment methods used in the core study, in a multi-center, multi-regional International setting, comparing changes from baseline to end of treatment. Secondary aims are:

• to evaluate responsiveness (changes from base line to end of treatment) also of the other outcome measures used in the Extended Study;
• to evaluate mid-treatment data predictiveness of end of treatment neurological status for each outcome measure;
• to evaluate recovery rate/modification of the neurological status for the follow up evaluations (3/6/12/24 months after treatment), stratifying data for different drugs.

Study Design: 1000 patients who are candidates for neurotoxic chemotherapy for any cancer with non-investigational drugs (including immune checkpoint inhibitors and "targeted" drugs) will be enrolled from participating centers. A trained investigator in each participating center will perform the selected healthcare-assessed scales and supervise the patient-completed measures as presented in Table 1. Subjects will be examined at least at baseline and end of treatment (Core Study) and at additional intermediate and follow-up timepoints (Extended study), according to their treatment plan.

Study Treatments: There are no study-specified treatments, as subjects will receive only their standard of care chemotherapy. The investigators will not influence decisions regarding treatment duration nor supply medication for this study. However, all treatment regimens will be registered.

Participating Centers minimum requirements: Participating Centers should:

1. accept the study protocol and have their participation approved by a local Ethics Committee/Institutional Review Board
2. have access through an internet connection to the secure server located at the main site
3. guarantee the proper assessment of the selected patients at least at the Core study level
4. have the potential to recruit at least 30 patients/year
5. have the capacity to upload the data collected from each patient within 1 week

Inclusion Criteria

Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the study:

1. Subjects must be candidates for neurotoxic chemotherapy at doses expected to be potentially neurotoxic (a list of neurotoxic drugs is provided in Appendix 1).
2. Male and female subjects who are 18 years of age or older.
3. Subjects freely provide informed consent by signing and dating an informed consent form prior to study entry.
4. Subjects must be willing to complete all study-related activities and follow-up visits required by the protocol.
5. Subjects must have a Karnofsky performance score greater than or equal to 70. Exclusion Criteria

Subjects presenting with any of the following will not be included in the study:

1. Poor prognosis, with high probability to be unable to complete the planned chemotherapy treatment.
2. Concomitant neurologic conditions (e.g., brain tumor, spinal or brain metastases) that would interfere or complicate the assessments.
3. Severe depression that in the opinion of the Investigator would complicate the assessments.
4. Chronic treatment with antiepileptic drugs, antidepressants and major analgesics, unless stable dosing and conditions have been reached for 3 months prior to entry.
5. Preventive interventions (e.g., antioxidants, cryotherapy, distal pressure).
6. Subjects who are currently receiving another medication other than antineoplastic chemotherapy drugs that has known potential to produce neurologic peripheral nerve toxicity (e.g. metronidazole, isoniazid, amiodarone, antiretroviral medications).
7. Subjects with any other condition, which, in the investigator's judgment, might decrease the chance of obtaining satisfactory data to achieve the objectives of the study.
8. Previous neurotoxic chemotherapy.