ADC-induced Neurotoxicity Treated With Duloxetine

Official title

A Single-arm Phase II Study of Duloxetine for the Treatment of Neurotoxicity Induced by Antibody-drug Conjugate

Overview

RATIONALE: Duloxetine may lessen peripheral neuropathy caused by chemotherapy. It is not yet known whether duloxetine is effective in treating peripheral neuropathy caused by antibody-drug conjugate. PURPOSE: This single arm phase II trial is studying duloxetine to see how well it works in treating peripheral neuropathy caused by antibody-drug conjugate in patients with cancer.

Detailed description

This study is a single arm phase II study. The study consisted of a screening period (subjects signed informed consent up to no more than 28 days before the first treatment of the study), a treatment period (treatment termination was defined as termination of treatment for any reason, such as imaging confirmation of disease progression, intolerance of toxicities despite dose adjustments, or early withdrawal for any reason), and a follow up period (consisting of an end-of-treatment visit, a safety visit, and a survival follow up).

Interventions

• Drug duloxetine
  Patients were treated with duloxetine at a recommended dose of 40mg/day, increasing to a maximum dose of 60mg/day after seven days of non-significant discomfort.

Primary outcome measures

• Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscale [Time frame: Day0 and Day36]

Secondary outcome measures (5)

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [Time frame: 16 months]
• Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscale [Time frame: 3 months]
• Numerical rating scale [Time frame: Day0 and Day36]
• European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [Time frame: Day0 and Day36]
• Neurotoxicity score assessed by CTCAE 5.0 scale [Time frame: Day0 and Day36]

Eligibility criteria

Inclusion criteria

• aged ≥ 18 years;
• patients with a diagnosis confirmed by histological and/or cytological examination combined with imaging or ultrasound assessment of various advanced cancers;
• consent to treatment;
• ECOG score: 0 to 2;
• have a recent treatment regimen that includes an ADC class of drug and experience a resulting grade 2 or higher peripheral neurotoxicity that has been discontinued, and grade 2 or higher peripheral neurotoxicity that has lasted for more than 28 days; and the tumour remains stable in the short term, and may be treated without the use of drugs that can cause peripheral neurotoxicity (ADCs, platinums, paclitaxels, etc.) for a period of two months.
• Have adequate organ function:

(1) blood routine: Absolute Neutrophil Count (ANC) 1.5×109/L, Platelet (PLT) ≥70×109/L, Hemoglobin (HGB) ≥80g/L; (2) Liver function: serum Total Bilirubin (TBIL) ≤1.5×Upper Limit of Normal Value (ULN); Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≥1.5×Upper Limit of Normal Value (ULN). Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤3×ULN; serum albumin ≥28 g/L; Alkaline Phosphatase (ALP) ≤5×ULN; after routine hepatoprotective treatment meeting the above criteria, and can be stabilised for at least 1 week after evaluation by the investigator can be enrolled; 3) Renal function: serum creatinine (Cr) ≤ 2 × ULN or creatinine clearance ≥ 30 mL/mi (applying the standard Cockcroft-Gault formula); 7. a predicted survival of ≥ 3 months; and tumour stability in the near future. 8. ability to comply with study visit schedules and other protocol requirements.

Exclusion criteria

• peripheral neurotoxicity of grade 2 or higher has occurred with platinum-containing paclitaxel chemotherapy prior to prior ADC class administration, and the toxicity has not significantly worsened before or after ADC administration;
• patients with severe diabetes mellitus and peripheral vascular disease;
• patients with a history of neuropathy due to any type of nerve compression (e.g., carpal tunnel or tarsal tunnel syndrome, radiculopathy, spinal stenosis, brachial plexopathy), severe depression, suicidal ideation, bipolar disorder, alcoholism, and severe eating disorders
• active or uncontrolled serious infections (≥ CTCAE grade 2 infections) requiring administration of systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infections.
• active hepatitis (aminotransferases do not meet the inclusion criteria, Hepatitis B reference: HBV DNA ≥2000 IU/ml or ≥104 copy number/ml; Hepatitis C reference: HCV RNA ≥2000 IU/ml or ≥104 copy number/ml; below the above criteria after nucleoside analogue antiviral therapy, can be enrolled); Chronic Hepatitis B viral carriers with HBV DNA \< 104 IU/ml, must receive concomitant antiviral therapy during the trial to be enrolled;
• renal failure requiring haemodialysis or peritoneal dialysis;
• those with a history of immunodeficiency, including being HIV-positive or suffering from other acquired or congenital immunodeficiency diseases, or with a history of organ transplantation
• those with severe nausea, headache, insomnia, fatigue, drowsiness, dry mouth, dizziness and constipation
• those with a history of active tuberculosis
• uncontrolled, still need repeated drainage appearing ascites, pericardial effusion, pleural effusion;
• research treatment related:
• patients who have undergone major organ transplantation
• those who have undergone major surgical treatment, incisional biopsy, or significant traumatic injury within 28 days prior to the start of study treatment; or those who have longstanding unhealed wounds or fractures
• those who have experienced a severe hypersensitivity reaction following the use of monoclonal antibodies; those with known hypersensitivity to active ingredients or excipients such as the study drug;
• those who are participating or have participated in other clinical studies within 4 weeks prior to the start of the study
• those with a history of severe allergy
• have a risk of bleeding, or coagulation disorders, or are receiving thrombolytic therapy
• have a history of psychotropic substance abuse that is not amenable to cessation or have a psychiatric disorder
• subjects with concomitant medical conditions that, in the judgement of the investigator, seriously jeopardise the safety of the subject or interfere with the completion of the study, or who are considered otherwise unsuitable for enrolment subjects who, in the judgement of the investigator, have concomitant medical conditions that, in the judgement of the investigator, seriously jeopardise the safety of the subject or interfere with the completion of the study, or who are considered otherwise unsuitable for enrolment. Past history of definite neurological and psychiatric disorders such as dementia, epilepsy, or seizure proneness
• in the judgement of the Investigator, a concomitant medical condition (e.g., severe diabetes mellitus, thyroid disease, psychiatric illness, etc.) which is a serious risk to the safety of the subject or which interferes with the subject\'s ability to complete the study, or the presence of a serious and/or unstable medical, psychiatric, or other condition (including abnormalities in laboratory tests) which interferes with the safety of the patient or with the patient\'s ability to provide informed consent, or any psychological, family, sociological, or psychological condition which interferes with the study protocol and the follow-up plan. Psychological, familial, sociological, or geographic conditions that affect the study protocol and follow-up plan that the investigator deems unsuitable for participation in this clinical trial for any reason

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Fudan University Cancer center — Shanghai

Identifiers

NCT: NCT06551051 · CIPN-ADC-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗