Immune Related-adverse Events in Patients Receiving Immune Checkpoint Inhibitors

• Conditions: Melanoma; Lung Cancer; Renal Cell Carcinoma; Cancer

• Registration Number: NCT04268368
• Lead Sponsor: Università Politecnica delle Marche

Brief Summary

The recent introduction of anti-PD-1 (nivolumab and pembrolizumab) and anti- PD-L1 (atezolizumab, durvalumab, avelumab) immune checkpoint inhibitors revolutionized oncological guidelines. Durable responses and prolongation of survival with these agents come at the price of the development of immune related adverse events (irAEs). Innovative tools are required in order to manage irAEs and to prevent their potential relapse, with the goal to improve the outcome of patients. In this regard, the Investigators aim to develop a multidisciplinary clinical pathway for cancer patients that are treated with immune checkpoint inhibitors.

Detailed Description

Recent evidences in immuno-oncology showed an important role of the immune system in tumor control. In fact, immune response, both innate and adaptive one, is the first defensive mechanism against cancer. However, several tumors, during their progression, develop an immune-tolerance characterized by the activation of immune inhibitory pathways including PD-1 and PD-L1.

The recent introduction of anti-PD-1 (nivolumab and pembrolizumab) and anti-PD-L1 (atezolizumab, durvalumab, avelumab) immune checkpoint inhibitors revolutionized oncological guidelines.

Currently, the aforementioned agents are approved for the treatment of advanced malignant melanoma; non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) and the number of treatment indications for immune checkpoint inhibitors is expanding. Durable responses and prolongation of survival with these agents come at the price of the development of immune-related adverse events (irAEs).

Immune-related adverse events are due to the loss of immune-tolerance towards structures of the self, with the induction of chronic inflammation with an autoimmune mechanism that can involve numerous organs and systems. The most frequent irAEs reported in clinical trials are represented by skin toxicity, gastrointestinal toxicity, endocrine toxicity, pulmonary toxicity, and others such as polymyalgia rheumatica, polyarthritis, myositis, nephritis, polyradiculoneuritis, encephalitis and myocarditis.

The irAEs reported in clinical trials with nivolumab amount to a maximum of 85% considering all grade of toxicities, while approximately 75% of patients treated with pembrolizumab presented irAEs. Grade 3/4 irAEs were reported in 10% of patients treated with anti-PD-1. With atezolizumab fewer patients had treatment-related grade 3 or 4 adverse events (15%).

In most cases, irAEs occur within some weeks after starting of immunotherapy; however these toxicities have been reported later and also years after treatment discontinuation. The development of irAEs is associated with significant morbidity and mortality in cancer patients treated with immune checkpoint inhibitors, and therefore they may significantly affect the quality of life, even in patients achieve the control of neoplastic disease.

The overseeing, early diagnosis and clinical management of immune checkpoint inhibitors' toxicities in the clinical setting are, currently, not standardized.

Innovative tools are required in order to manage irAEs and to prevent their potential relapse, with the goal to improve the outcome and quality of life of these patients.

In this regard, the Investigators also aim to evaluate a model of multidisciplinary clinical pathway for cancer patients that are treated with immune checkpoint inhibitors in order to improve their management and also ameliorate the quality of life of patients that develop irAEs.

Study Timeline

• Study Start: 2019-01-01
• Status Verified: 2020-02
• Study First Submitted: 2020-02-10
• Study First Submitted QC: 2020-02-10
• Study First Posted: 2020-02-13
• Last Update Submitted: 2020-02-13
• Last Update Posted: 2020-02-17
• Primary Completion: 2021-01-01
• Study Completion: 2022-01-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Adult patients above 18 years of age;

2. Cyto-histological diagnosis of one of the following cancers:

   1. advanced melanoma;
   2. metastatic or locally advanced non-small cell lung cancer;
   3. advanced renal cell carcinoma;
   4. metastatic or locally advanced urotelial carcinoma;
   5. squamous cell carcinoma of the head and neck;
   6. Hodgkin lymphoma;
   7. Merkel-cell carcinoma;

3. New prescription of one of the following PD-1/PD-L1 inhibitors:

   1. nivolumab
   2. pembrolizumab
   3. atezolizumab
   4. avelumab
   5. durvalumab alone or in combination therapy, following the indications of the Italian regulatory agency (AIFA).

Exclusion Criteria

1. Patients that refuse and/or are not able to sign the Informed Consent;
2. Parents/guardians or subjects who, in the opinion of the Investigator, may be noncompliant with study schedules or procedures;
3. No contraindications to the treatment with PD-1/PD-L1 antibodies, following the indications of the Italian regulatory agency (AIFA).

Subjects that do not meet all of the enrollment criteria may not be enrolled.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Incidence of irAEs	24 months	To determine the incidence and the characteristics of irAEs in a real-world setting
Risk factors for irAEs	24 months	To determine the risk factors for the development of irAEs
Impact of irAEs	24 months	To determine the impact of irAEs on patients' prognosis
Therapies of irAEs	24 months	To determine the effect of immunosuppressive therapies on tumor progression and patient's prognosis

Secondary Outcome Measures

Name	Time	Method
Clinical care pathway	24 months	To set up an integrated clinical care pathway for cancer patients that developed an irAE following immune checkpoint inhibitor administration
Quality of life	24 months	The quality of life will be measured by means of the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30). It is composed by five functional scales, three symptom scales, a global health status / QoL scale, and six single items. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.
Biomarkers	24 months	To evaluate potential biomarkers that may predict the development of irAEs and/or the response to treatment in biological samples from cancer patients treated with immune checkpoint inhibitors
Exploratory analyses	24 months	To get better insights on the biological basis of irAEs the response to treatment in biological samples from cancer patients treated with immune checkpoint inhibitors

Trial Locations

Locations (1)

Università Politecnica delle Marche; 🇮🇹 Ancona, AN, Italy