Ignite Creation Date:
2024-06-16 @ 11:48 AM
Last Modification Date:
2024-10-26 @ 3:30 PM
Study NCT ID:
NCT06421571
Status:
RECRUITING
Last Update Posted:
2024-05-20
First Post:
2024-03-26
Brief Title:
The Mechanism of Action of Chlormethine CL Gel in the Treatment of MF-CTCL Adult Patients
Sponsor:
National and Kapodistrian University of Athens
Organization:
National and Kapodistrian University of Athens
Study Overview
Official Title:
A Greek Prospective Non-interventional Study Investigating the Effectiveness and the Mechanism of Action of Chlormethine CL Gel in the Treatment of MF-CTCL Adult Patients
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GR-CTCL_CL
Brief Summary:
Chlormethine is a topical alkylating agent whose role in MF-CTCL has been extensively studied over the last 40 years While its efficacy is well established many safety concerns have been raised due to high rates of delayed cutaneous hypersensitivity to aqueous solutions that limit the prolonged use of chlormethine in clinical practice It has been shown that complete response to topical chlormethine is associated with lower risk of disease progression Accordingly clinical data from the investigators clinic confirm that chlormethine gel is a safe and effective treatment which be used in early and advanced stages of cutaneous lymphomas Based investigators clinical and biological results the investigators like to further investigate the change in the percentage as well as the profile of malignant and inflammatory cells by CyTOF analysis and further investigate the pathways eg OX40 PDL1 involved in this process
Detailed Description:
1 RATIONALE Chlormethine is a topical alkylating agent whose role in MF-CTCL has been extensively studied over the last 40 years While its efficacy is well established many safety concerns have been raised due to high rates of delayed cutaneous hypersensitivity to aqueous solutions that limit the prolonged use of chlormethine in clinical practice It has been shown that complete response to topical chlormethine is associated with lower risk of disease progression Accordingly the clinical data confirm that chlormethine gel is a safe and effective treatment which be used in early and advanced stages of cutaneous lymphomas In a study of 23 patients with stage IA-IIB mycosis fungoides from investigators center an overall response of 6522 at 9 months of treatment with topical chlormethine was recorded Moreover in a recent multicenter greek study that included 58 patients with stage IA-IIB mycosis fungoides an overall response rate of 808 at 9 months of treatment was achieved In the same study better response in patients with patches in comparison to plaques or tumors was also depicted Unfortunately the occurrence of skin drug reactions was the leading cause of treatment discontinuation in studies evaluating chlormethine irrespective of drug formulation negatively affecting the achievement of a therapeutic response In investigators study severe dermatitis was one of the main causes of treatment discontinuation occuring in 155 of patients
Taper of application frequency as per SmPC and topical steroid use represent strategies allowing the management of dermatitis in order to maintain patients on CL gel treatment and prevent treatment discontinuation The presence or severity of dermatitis in the study population was not associated with ORR indicating that the development of dermatitis did not affect the likelihood of response It has previously been suggested that dermatitis may be a prognostic indicator for clinical response These data highlight the unmet need to explain the significance of dermatitis after topical chlomethine application and the immunological changes behind and how these affect the clinical response Additionally by standardizing a CyTOF technique in CTCL samples from skin biopsies of CTCL patients investigators established the methodology for identification and enumeration of different cells populations in situ and their interactions with tumor microenvironment Investigators preliminary data demonstrated that the evaluation of MF-CTCL patients immune profile revealed differences in cell proportion pinpointing the heterogeneity that characterizes different stages of MF
Based on investigators clinical and biological results investigators would like to further examine the change in the percentage as well as the profile of malignant and inflammatory cells by CyTOF analysis and further investigate the pathways eg OX40 PDL1 involved in this process
2 STUDY DESIGN 21 Study Description The proposed study is a non-interventional prospective data collection open-label single-arm study Data collection will be done prospectively The management of patients will be done in the classic framework of the management of adult patients with MF-CTCL in principal investigators university hospital
3 RESEARCH OBJECTIVES CLINICAL BIOLOGICAL AND PATIENT-REPORTED OUTCOMES - QUALITY OF LIFE 31 Clinical objectives
311 Effectiveness of CL gel treatment in routine medical practice in MF patients by
Evaluation of clinical response by mSWAT
Duration of response defined as the interval from the time measurement criteria for CR and PR are first met until the first date that progressive disease is documented time to next treatment TNTT defined as the time from the time the next treatment is recorded
Correlation between dermatitis occurrence and clinical response
quality of life of the patients
Chlormethine gel tube consumption
safety and tolerability of the treatment with CL gel frequency of skin side effects 32 Biological objectives For this part of the study the percentage change of malignant and inflammatory cells profile of inflammatory new and existing and malignant cells in all MF patients treated with chlormethine gel with or without dermatitis cytokines and signaling pathways at a single cell level will be also measured
321 Assessments Dermatitis occurrence before any topical steroids application Clinical response at least score 50 improvement from baseline At months 6 and 12
Evaluation of the impact of chlormethine gel treatment on malignant and inflammatory cells
Evaluation of the impact of chlormethine gel treatment exhibits on the profile of Th1Th2 cytokines ELISA
Evaluation of the impact that CL gel treatment exerts on the JAKSTAT NF-κB AKT MAP signaling pathways Western Blotting 33 Patient-Reported Outcomes - quality of life SKINDEX-29 Quality of Life QoL change from Baseline in the European Organization for Research and Treatment of Cancer EORTC Disease-Related Symptom Scales of the SKINDEX-29 at every visit
34 Study Population MF patients treated with CL gel as monotherapy Study design is presented in figure below
This study will include 40 patients treated with CL gel as monotherapy
Patients will discontinue study treatment permanently if the following condition is met
Patients are still unable to tolerate CL gel treatment at reduced frequency with co-administration of corticosteroids
All patients will be assessed every month for the first three months and every 3 months thereafter at months 6 9 12 as per current clinical practice
In case of dermatitis the patient is encouraged to continue treatment with reduced frequency at every other day or every third day Steroids will be used only if the reduced schedule is not sufficient A temporary treatment interruption might occur for a period of 2 weeks and then treatment can be restarted
35 Research objectives detailed Clinical biological and patient quality of life 351 Clinical objective
Effectiveness of CL gel treatment in routine medical practice in MF patients Overall Response Rate ORR defined as the proportion of patients who achieved a CR or PR at least score 50 improvement from baseline in all patients determined by mSWAT within 12 months of the start of CL gel treatment
Duration of response RD time to next treatment TNTT in the framework of the trial
safety and tolerability of the drug Frequency of skin side effects with a focus on dermatitis the time to occurrence and duration of dermatitis as well as the percentage of patients with dermatitis remaining on treatment at the end of the study
Correlation between dermatitis occurrence and clinical response ORR in patients experiencing or not dermatitis during treatment by chlormethine gel
quality of life of the patients using Skindex-29 tool receiving CL gel for at baseline and at the end of treatment
Chlormethine gel tube consumption estimated from medical prescription and patients statement 36 Biological objectives
For this part of the study the percentage change of malignant and inflammatory cells profile of inflammatory new and existing and malignant cells in all MF patients treated with chlormethine gel with or without dermatitis cytokines and signaling pathways at a single cell level will be also measured at
Baseline
o Dermatitis occurrence before any topical steroids application
Clinical response at least score 50 improvement from baseline
At months 6 and 12
Evaluation of the impact of chlormethine gel treatment on malignant and inflammatory cells using mass cytometry CyTOF
Evaluation of the impact of chlormethine gel treatment exhibits on the profile of Th1 Th2 cytokines ELISA
Evaluation of the impact that CL gel treatment exerts on the JAKSTAT NF-κB AKT MAP signalling pathways western blot analysis
Skin histology description immunohistochemistry and PCR are used in clinical routine practice to assess malignant T cells and clonality
The exploratory study will use both blood samples and skin biopsies taken as per routine management of the patients tests for the study of CL gel mechanism of action 1
the pathophysiology of dermatitis after CL gel application 2
We will correlate the above with the clinical effectiveness of CL gel treatment 3 as well as dermatitis occurrence and clinical response in MF patients 4
More specifically
the profile of malignant cells and inflammatory by characterizing the immune cells deriving from single cell suspensions from biopsies andor PBMCs by mass cytometry
The signaling pathways involved such as JAKSTAT NF-κB AKT MAP kinases by identifying the phosphorylation status of implicated proteins by Western blot analyses
37 Patient-Reported Outcomes - quality of life SKINDEX-29 Definition Quality of Life QoL change from Baseline in the European Organization for Research and Treatment of Cancer EORTC Disease-Related Symptom Scales of the SKINDEX-29 at every visit
The Skindex-29 is a skin disease-specific questionnaire that comprehensively assesses the effects of skin diseases on patients quality of life It was specifically developed to detect changes throughout time as well as differences among patients with different skin diseases The questionnaire covers areas considered crucial in an instrument designed to evaluate quality of life such as degree of symptoms psychosocial functioning and emotional status The 29-item version is a refinement of a previous 61-item version It was originally written in English and has already been translated and validated in other languages The Skindex-29 inquiries about how often Never Rarely Sometimes Often All the time during the previous four weeks the patient experienced the effect described in each item Seven items address the Symptoms domain ten items the Emotional domain and twelve items the Functioning domain All responses are transformed to a linear scale of 100 varying from 0 no effect to 100 effect experienced all the time Skindex scores are reported as three scale scores corresponding to the three domains a scale score is the average of a patients responses to items in a given domain
Five distinct categories for the Symptoms scale and four for the Emotions and Functioning scales have been categorized as summarized in the table below
Emotional Symptoms Functioning Very little 6 4 4 Mild 6-249 4-109 4-109 Moderate 25-499 11-259 11-329 Severe 50 26-499 33 Extreme 50
Taper of application frequency as per SmPC and topical steroid use represent strategies allowing the management of dermatitis in order to maintain patients on CL gel treatment and prevent treatment discontinuation The presence or severity of dermatitis in the study population was not associated with ORR indicating that the development of dermatitis did not affect the likelihood of response It has previously been suggested that dermatitis may be a prognostic indicator for clinical response These data highlight the unmet need to explain the significance of dermatitis after topical chlomethine application and the immunological changes behind and how these affect the clinical response Additionally by standardizing a CyTOF technique in CTCL samples from skin biopsies of CTCL patients investigators established the methodology for identification and enumeration of different cells populations in situ and their interactions with tumor microenvironment Investigators preliminary data demonstrated that the evaluation of MF-CTCL patients immune profile revealed differences in cell proportion pinpointing the heterogeneity that characterizes different stages of MF
Based on investigators clinical and biological results investigators would like to further examine the change in the percentage as well as the profile of malignant and inflammatory cells by CyTOF analysis and further investigate the pathways eg OX40 PDL1 involved in this process
2 STUDY DESIGN 21 Study Description The proposed study is a non-interventional prospective data collection open-label single-arm study Data collection will be done prospectively The management of patients will be done in the classic framework of the management of adult patients with MF-CTCL in principal investigators university hospital
3 RESEARCH OBJECTIVES CLINICAL BIOLOGICAL AND PATIENT-REPORTED OUTCOMES - QUALITY OF LIFE 31 Clinical objectives
311 Effectiveness of CL gel treatment in routine medical practice in MF patients by
Evaluation of clinical response by mSWAT
Duration of response defined as the interval from the time measurement criteria for CR and PR are first met until the first date that progressive disease is documented time to next treatment TNTT defined as the time from the time the next treatment is recorded
Correlation between dermatitis occurrence and clinical response
quality of life of the patients
Chlormethine gel tube consumption
safety and tolerability of the treatment with CL gel frequency of skin side effects 32 Biological objectives For this part of the study the percentage change of malignant and inflammatory cells profile of inflammatory new and existing and malignant cells in all MF patients treated with chlormethine gel with or without dermatitis cytokines and signaling pathways at a single cell level will be also measured
321 Assessments Dermatitis occurrence before any topical steroids application Clinical response at least score 50 improvement from baseline At months 6 and 12
Evaluation of the impact of chlormethine gel treatment on malignant and inflammatory cells
Evaluation of the impact of chlormethine gel treatment exhibits on the profile of Th1Th2 cytokines ELISA
Evaluation of the impact that CL gel treatment exerts on the JAKSTAT NF-κB AKT MAP signaling pathways Western Blotting 33 Patient-Reported Outcomes - quality of life SKINDEX-29 Quality of Life QoL change from Baseline in the European Organization for Research and Treatment of Cancer EORTC Disease-Related Symptom Scales of the SKINDEX-29 at every visit
34 Study Population MF patients treated with CL gel as monotherapy Study design is presented in figure below
This study will include 40 patients treated with CL gel as monotherapy
Patients will discontinue study treatment permanently if the following condition is met
Patients are still unable to tolerate CL gel treatment at reduced frequency with co-administration of corticosteroids
All patients will be assessed every month for the first three months and every 3 months thereafter at months 6 9 12 as per current clinical practice
In case of dermatitis the patient is encouraged to continue treatment with reduced frequency at every other day or every third day Steroids will be used only if the reduced schedule is not sufficient A temporary treatment interruption might occur for a period of 2 weeks and then treatment can be restarted
35 Research objectives detailed Clinical biological and patient quality of life 351 Clinical objective
Effectiveness of CL gel treatment in routine medical practice in MF patients Overall Response Rate ORR defined as the proportion of patients who achieved a CR or PR at least score 50 improvement from baseline in all patients determined by mSWAT within 12 months of the start of CL gel treatment
Duration of response RD time to next treatment TNTT in the framework of the trial
safety and tolerability of the drug Frequency of skin side effects with a focus on dermatitis the time to occurrence and duration of dermatitis as well as the percentage of patients with dermatitis remaining on treatment at the end of the study
Correlation between dermatitis occurrence and clinical response ORR in patients experiencing or not dermatitis during treatment by chlormethine gel
quality of life of the patients using Skindex-29 tool receiving CL gel for at baseline and at the end of treatment
Chlormethine gel tube consumption estimated from medical prescription and patients statement 36 Biological objectives
For this part of the study the percentage change of malignant and inflammatory cells profile of inflammatory new and existing and malignant cells in all MF patients treated with chlormethine gel with or without dermatitis cytokines and signaling pathways at a single cell level will be also measured at
Baseline
o Dermatitis occurrence before any topical steroids application
Clinical response at least score 50 improvement from baseline
At months 6 and 12
Evaluation of the impact of chlormethine gel treatment on malignant and inflammatory cells using mass cytometry CyTOF
Evaluation of the impact of chlormethine gel treatment exhibits on the profile of Th1 Th2 cytokines ELISA
Evaluation of the impact that CL gel treatment exerts on the JAKSTAT NF-κB AKT MAP signalling pathways western blot analysis
Skin histology description immunohistochemistry and PCR are used in clinical routine practice to assess malignant T cells and clonality
The exploratory study will use both blood samples and skin biopsies taken as per routine management of the patients tests for the study of CL gel mechanism of action 1
the pathophysiology of dermatitis after CL gel application 2
We will correlate the above with the clinical effectiveness of CL gel treatment 3 as well as dermatitis occurrence and clinical response in MF patients 4
More specifically
the profile of malignant cells and inflammatory by characterizing the immune cells deriving from single cell suspensions from biopsies andor PBMCs by mass cytometry
The signaling pathways involved such as JAKSTAT NF-κB AKT MAP kinases by identifying the phosphorylation status of implicated proteins by Western blot analyses
37 Patient-Reported Outcomes - quality of life SKINDEX-29 Definition Quality of Life QoL change from Baseline in the European Organization for Research and Treatment of Cancer EORTC Disease-Related Symptom Scales of the SKINDEX-29 at every visit
The Skindex-29 is a skin disease-specific questionnaire that comprehensively assesses the effects of skin diseases on patients quality of life It was specifically developed to detect changes throughout time as well as differences among patients with different skin diseases The questionnaire covers areas considered crucial in an instrument designed to evaluate quality of life such as degree of symptoms psychosocial functioning and emotional status The 29-item version is a refinement of a previous 61-item version It was originally written in English and has already been translated and validated in other languages The Skindex-29 inquiries about how often Never Rarely Sometimes Often All the time during the previous four weeks the patient experienced the effect described in each item Seven items address the Symptoms domain ten items the Emotional domain and twelve items the Functioning domain All responses are transformed to a linear scale of 100 varying from 0 no effect to 100 effect experienced all the time Skindex scores are reported as three scale scores corresponding to the three domains a scale score is the average of a patients responses to items in a given domain
Five distinct categories for the Symptoms scale and four for the Emotions and Functioning scales have been categorized as summarized in the table below
Emotional Symptoms Functioning Very little 6 4 4 Mild 6-249 4-109 4-109 Moderate 25-499 11-259 11-329 Severe 50 26-499 33 Extreme 50
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None