Gender Difference in sidE eFfects of ImmuNotherapy: a Possible Clue to Optimize cancEr tReatment (G-DEFINER)

The study aim is to investigate the differences between sex and gender in the immune-related adverse events (irAEs) development associated with immune checkpoint inhibitors (ICI) treatment. The study will be a multicenter prospective observational study focusing on biological differences between females and males, possibly affecting discrepant irAEs incidence.

Study Overview

• Status: Completed
• Conditions: Melanoma; Urogenital Neoplasms; Breast Cancer; Head and Neck Cancer; Lung Cancer
• Intervention / Treatment: Drug: Immunotherapy

Detailed Description

The study aim is to investigate the differences between sex and gender in the immune-related adverse events (irAEs) development associated with immune checkpoint inhibitors (ICI) treatment.

In common feeling, sex and gender represent the same concept, that is the traditional division of individuals into females (F) and males (M) defined by differential organization of chromosomes, reproductive organs, and sex steroid levels. However, if going beyond these aspects, which characterize "sex", it can be observed how the differences between people are also characterized by behaviors and relationships that are the product of the culture and sociality typical of human beings. This is what is called "gender", i.e. the process of social and cultural construction that determines the behaviors that give life to the status of an individual. Gender is therefore learned and not innate. Sex and gender do not constitute two opposing but interdependent dimensions: the process of determining gender identity is triggered on biological characters. The relationship between sex and gender varies according to geographical areas, historical periods and cultures.

Sex influences the adaptive immunity, and may influence irAEs types, frequency and severity. Together with genetic and biological differences, the roots of irAEs inequalities between F and M could be linked to psycho-social and behavioral determinants. IrAEs usually develop within the first few weeks to 6 months after treatment initiation; however, they can also present after cessation of ICI therapy. Most studies indicate that prolonged treatment does not result in an increased cumulative incidence of irAEs. Accumulating evidences support the existence of sex-driven differences in immune responses as potential factors contributing to disease outcome and response to therapy. Increasing use of ICI is associated with immune-related adverse events caused by non-specific activation of the immune system.

The investigators will conduct a multicenter prospective observational study investigating sex differences in irAEs in relation to clinical factors and genetic, immunological and hormonal profiles. By focusing on biological F/M differences possibly affecting discrepant irAEs incidence, sex inequality will be explicitly addressed and complemented by the exploration of association between gender dimension and irAEs development. Exploring the irAEs occurrence in a "real world" (outside RCT) context will be more easily translated in a ready-to-use personalized approach to irAEs timely diagnosis and treatment.

• Study Type: Observational
• Enrollment (Actual): 247

Contacts and Locations

• Study Contact: Name: Rosalba Miceli, PhD; Phone Number: +39 02 23903198; Email: rosalba.miceli@istitutotumori.mi.it

Study Locations

• Italy
  • Milano, Italy, 20133
    • Fondazione Irccs Istituto Nazionale Dei Tumori

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

To allow for balanced sex groups, we will include patients according to the following stratification : ICI: 100 F/100 M; ICI+ CT/RT: 100 F/100 M. Due to the current ICI use in clinical practice we are expecting to mainly populate the ICI strata during the first recruitment period. As the recruitment progresses, the sample will be enriched of ICI+CT and ICI+RT treated patients, since combinations are expanding for many cancers such for instance melanoma, lung and head and neck

Description

Inclusion Criteria:

• Signed informed consent.
• Histologically confirmed diagnosis of one of the following cancers: melanoma, lung, head and neck, urogenital, breast cancer. In addition, other solid tumors characterized by the presence of microsatellite instability (MSI-high), treated with immunocheckpoint inhibitors (ICI) irrespective of treatment schedule. It is possible to include patients treated with Immunotherapy in a compassionate use setting.
• Any disease stage.
• Patients eligible for immune checkpoint inhibitors (ICI)-containing regimens: ICI single agent; Combination of ICIs; ICI-chemotherapy combination; ICI-radiotherapy combination.
• Any treatment setting (neoadjuvant, adjuvant, advanced disease, maintenance).
• Patient age ≥18 years
• ECOG Performance Status of 0-2.
• Adequate bone marrow, liver and renal function.
• Life expectancy of at least 12 weeks.

Exclusion Criteria:

• Patients not eligible for ICI-containing regimens.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Overall series; Patients treated with immunocheckpoint inhibitors (ICI) irrespective of treatment schedule. No limitations to previous lines of treatment. ICI therapy may be either as single agent or in combination. Concomitant chemotherapy (CT) and radiotherapy (RT) is allowed.	Drug: Immunotherapy; Patients treated as per clinical prescription with immunocheckpoint inhibitors (ICI) irrespective of treatment schedule, either as single agent or in combination with chemotherapy and/or radiotherapy; Other Names: Radiotherapy; Chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune-related severe (G≥ 2) adverse events (irAEs)	The incidence of first severe (G≥ 2) irAEs of any type will be estimated in females and males	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune-related adverse events (irAEs)	The incidence of irAEs of any type and any grade will be estimated in females and males	1 year

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Collaborators: Karolinska University Hospital; Oslo University Hospital; St Vincent's University Hospital, Ireland

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2020
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: June 11, 2020
• First Submitted That Met QC Criteria: June 15, 2020
• First Posted (Actual): June 17, 2020

Study Record Updates

• Last Update Posted (Actual): March 24, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Urogenital Neoplasms
• Other Study ID Numbers: INT156-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No