A Trial Assessing the Effect of Pembrolizumab Combined With Radiotherapy in Patients With Relapsed, Refractory, Specified Stages of Cutaneous T-cell Lymphoma (CTCL) Mycosis Fungoides (MF)/Sezary Syndrome (SS) (PORT)
Primary Purpose
Cutaneous T Cell Lymphoma, Mycosis Fungoides/Sezary Syndrome
Status
Active
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Pembrolizumab
Radiotherapy
Sponsored by
About this trial
This is an interventional treatment trial for Cutaneous T Cell Lymphoma focused on measuring Relapsed, Refractory
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 18 years
- Diagnosis of Stage IB-IVB CTCL mycosis fungoides (MF)/Sézary Syndrome (SS)
- Have relapsed, are refractory or progressed after at least 1 systemic therapy
- Skin biopsy at the time of or within 6 months prior to study entry
- Patients must have a total mSWAT (modified Severity Weighted Assessment Tool) score of ≥10 OR have 2 or more measurable tumours of any size. Of this area: there should be at least 1 cutaneous lesion (MF) or a defined area of involved skin (erythrodermic MF or SS) which is an appropriate target for palliative radiotherapy. There should be an area of skin involved by measurable Mycosis Fungoides/SS that will not be irradiated (To assess the abscopal effect of radiotherapy)
- Have a minimum wash-out and adverse event (AE) recovery period from previous treatments (e.g. topical therapy, phototherapy, local radiotherapy, monoclonal antibody, systemic cytotoxic anticancer treatment or other novel agents) prior to the first dose of pembrolizumab
- Have ECOG performance status of 0 or 1
- Life expectancy of at least 6 months
- Demonstrate adequate organ function
- Female patients of childbearing potential must have a negative urine or serum pregnancy test at pre-registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Willing to comply with the contraception requirements
Written informed consent
•Exclusion Criteria:
- Received chemotherapy or targeted small molecule therapy within 4 weeks prior to study entry or has not recovered from adverse events due to agents administered >4 weeks earlier (except patients with ≤ grade 2 neuropathy)
- Is currently or has participated in an IMP or device study within 4 weeks prior to the first dose of pembrolizumab
- Received any other monoclonal antibody within 15 weeks prior to the first dose of pembrolizumab or has not recovered (≤ grade 1 or to baseline level) from adverse events due to agents administered >4 weeks earlier. The exception to this is alemtuzumab which should not have been administered in the previous 12 weeks
- Additional malignancy that is progressing or requires active treatment
- Patients with known central nervous system (CNS) involvement with lymphoma
- Hypersensitivity to pembrolizumab or its excipients
- Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Stable use of corticosteroids (at a dose no higher than 10mg prednisolone per day over the preceding 4 weeks) is allowed
- Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive therapy
- Current or prior use of immunosuppressive therapy within 7 days prior to start of treatment except the following: intranasal, inhaled, topical steroids or local steroid injections (eg. Intra-articular injection); systemic corticosteroids at physiologic doses (10mg/day or less of prednisolone or equivalent)
- Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 therapy
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia
- Has known history of, or any evidence of active, non-infectious pneumonitis
- History of other pulmonary disease such as interstitial lung disease, emphysema or chronic obstructive pulmonary disease
- Is pregnant or breastfeeding
- Has a known history of active TB
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial or interfere with the subject's participation for the full duration of the trial or to participate in the trial is not in the patient's best interest, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with the requirements of the trial
- Has a known history of HIV
- Has known active Hepatitis B or Hepatitis C
- Has received a live vaccine within 30 days prior to the planned start of study medication
- Patients who have previously received a solid organ transplant
- Patients who have previously received any allogeneic transplantation
Sites / Locations
- University Hospital Birmingham
- Velindre Cancer Centre
- University Hospital Coventry
- Beatson West of Scotland Cancer Centre
- Guy's & St Thomas'
- The Christie
- Freeman Hospital
- Nottingham City Hospital
- Churchill Hospital
- Southampton University Hospital
- Clatterbridge Cancer Centre
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Pembrolizumab with radiotherapy
Arm Description
All patients will receive single 200mg pembrolizumab IV infusions given 3-weekly until 2 years post study entry, termination of treatment, disease progression or unacceptable toxicity radiotherapy, 12Gy in 3 fractions
Outcomes
Primary Outcome Measures
Overall Response (Global Assessment)
Overall Response of the combination of pembrolizumab plus radiotherapy
Secondary Outcome Measures
Response
Response at the 5th infusion of pembrolizumab, typically 12 weeks after start of treatment
Change in Global Response
Change in Global Response from the 5th infusion to the 9th infusion, typically from week 12 to week 24
Safety and toxicity
Number & Percentage of patients who suffer grade 3 or 4 toxicity
Response Duration
Duration of tumour response
Progression Free Survival
Disease progression or death
Overall Survival
Death
Number of patients achieving abscopal effect
Full Information
NCT ID
NCT03385226
First Posted
December 12, 2017
Last Updated
May 9, 2023
Sponsor
University College, London
Collaborators
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT03385226
Brief Title
A Trial Assessing the Effect of Pembrolizumab Combined With Radiotherapy in Patients With Relapsed, Refractory, Specified Stages of Cutaneous T-cell Lymphoma (CTCL) Mycosis Fungoides (MF)/Sezary Syndrome (SS)
Acronym
PORT
Official Title
Phase II Trial of Pembrolizumab and Radiotherapy in Cutaneous T-cell Lymphoma
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 15, 2019 (Actual)
Primary Completion Date
May 2023 (Anticipated)
Study Completion Date
May 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University College, London
Collaborators
Merck Sharp & Dohme LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Trial Subjects (patients), will receive single infusions of pembrolizumab every 3 weeks until disease progression or unacceptable toxicity develops. They will receive radiotherapy at week 12.
Detailed Description
Trial Subjects (patients) who are deemed eligible for the trial will be administered a single infusion of pembrolizumab (200mg) every 3 weeks. At week 12, patients will be planned to start radiotherapy at a dose of 12 Gray (Gy) in 3 fractions which will be given concomitantly with pembrolizumab. Patients who progress on pembrolizumab before week 12 will start radiotherapy as soon as possible after progression. Following completion of radiotherapy, patients will continue receiving pembrolizumab at 3 weekly intervals for a maximum of 2 years until disease progression or unacceptable toxicity develops. Patients on pembrolizumab will be seen every 3 weeks until 2 years after study entry, while Patients who progressed/ stopped pembrolizumab will be seen annually for survival/disease status only. Patients completing 2 years of treatment will then be followed up annually for survival and disease status until the end of trial is declared (2 years after the last patient is registered).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cutaneous T Cell Lymphoma, Mycosis Fungoides/Sezary Syndrome
Keywords
Relapsed, Refractory
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
46 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Pembrolizumab with radiotherapy
Arm Type
Experimental
Arm Description
All patients will receive
single 200mg pembrolizumab IV infusions given 3-weekly until 2 years post study entry, termination of treatment, disease progression or unacceptable toxicity
radiotherapy, 12Gy in 3 fractions
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
Chemical Abstract Service (CAS) number - 1374853-91-4
Intervention Description
Pembrolizumab is a humanised monoclonal antibody which targets the programmed cell death 1 (PD-1) receptor. It blocks a protective mechanism on cancer cells, and allows the immune system to destroy those cancer cells.
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy
Intervention Description
12Gy in 3 fractions
Primary Outcome Measure Information:
Title
Overall Response (Global Assessment)
Description
Overall Response of the combination of pembrolizumab plus radiotherapy
Time Frame
24 weeks after commencement of pembrolizumab
Secondary Outcome Measure Information:
Title
Response
Description
Response at the 5th infusion of pembrolizumab, typically 12 weeks after start of treatment
Time Frame
12 weeks after start of pembrolizumab
Title
Change in Global Response
Description
Change in Global Response from the 5th infusion to the 9th infusion, typically from week 12 to week 24
Time Frame
24 weeks after start of pembrolizumab
Title
Safety and toxicity
Description
Number & Percentage of patients who suffer grade 3 or 4 toxicity
Time Frame
5 months after last dose of pembrolizumab (anticipated 2 years and 5 months after last patient being registered)
Title
Response Duration
Description
Duration of tumour response
Time Frame
Time from date of first confirmed response to the first date of diagnosis of progressive disease or death from any cause (anticipated by 2 years and 5 months after the last patient being registered)
Title
Progression Free Survival
Description
Disease progression or death
Time Frame
Time from date of registration to the date of first progression or death from any cause ((anticipated by 2 years and 5 months after the last patient being registered)
Title
Overall Survival
Description
Death
Time Frame
Time from date of registration to the date of death from any cause ((anticipated by 2 years and 5 months after the last patient being registered)
Title
Number of patients achieving abscopal effect
Time Frame
Through study completion, 2 years post last patient being registered
Other Pre-specified Outcome Measures:
Title
Assessment of changes in the immune status
Description
Peripheral blood mononuclear cell phenotyping
Time Frame
24 weeks after start of pembrolizumab
Title
Analysis of plasma High Mobility Group Box 1 (HMGB-1) isoform levels
Description
Peripheral blood mononuclear cell phenotyping
Time Frame
24 weeks after start of pembrolizumab
Title
Functional analysis of isolated cell populations
Description
Peripheral blood mononuclear cell phenotyping
Time Frame
24 weeks after start of pembrolizumab
Title
Assessment of diversity and clonality of T cell clones
Description
DNA extraction for T cell receptor sequencing
Time Frame
24 weeks after start of pembrolizumab
Title
Evaluation of immune signatures for responders and non-responders
Description
Peripheral blood mononuclear cell phenotyping
Time Frame
24 weeks after start of pembrolizumab
Title
Epitope screening for tumour infiltrating lymphocyte specific neo-antigens
Description
Peripheral blood mononuclear cell phenotyping
Time Frame
24 weeks after start of pembrolizumab
Title
Immunohistochemical analysis of expression of immunological checkpoints
Description
Assessment of PD-L1 expression
Time Frame
At baseline
Title
Investigation of the baseline tumour immune microenvironment
Description
Immune cell infiltration
Time Frame
At baseline
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age ≥ 18 years
Diagnosis of Stage IB-IVB CTCL mycosis fungoides (MF)/Sézary Syndrome (SS)
Have relapsed, are refractory or progressed after at least 1 systemic therapy
Skin biopsy at the time of or within 6 months prior to study entry
Patients must have a total mSWAT (modified Severity Weighted Assessment Tool) score of ≥10 OR have 2 or more measurable tumours of any size. Of this area: there should be at least 1 cutaneous lesion (MF) or a defined area of involved skin (erythrodermic MF or SS) which is an appropriate target for palliative radiotherapy. There should be an area of skin involved by measurable Mycosis Fungoides/SS that will not be irradiated (To assess the abscopal effect of radiotherapy)
Have a minimum wash-out and adverse event (AE) recovery period from previous treatments (e.g. topical therapy, phototherapy, local radiotherapy, monoclonal antibody, systemic cytotoxic anticancer treatment or other novel agents) prior to the first dose of pembrolizumab
Have ECOG performance status of 0 or 1
Life expectancy of at least 6 months
Demonstrate adequate organ function
Female patients of childbearing potential must have a negative urine or serum pregnancy test at pre-registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Willing to comply with the contraception requirements
Written informed consent
•Exclusion Criteria:
Received chemotherapy or targeted small molecule therapy within 4 weeks prior to study entry or has not recovered from adverse events due to agents administered >4 weeks earlier (except patients with ≤ grade 2 neuropathy)
Is currently or has participated in an IMP or device study within 4 weeks prior to the first dose of pembrolizumab
Received any other monoclonal antibody within 15 weeks prior to the first dose of pembrolizumab or has not recovered (≤ grade 1 or to baseline level) from adverse events due to agents administered >4 weeks earlier. The exception to this is alemtuzumab which should not have been administered in the previous 12 weeks
Additional malignancy that is progressing or requires active treatment
Patients with known central nervous system (CNS) involvement with lymphoma
Hypersensitivity to pembrolizumab or its excipients
Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (such as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Stable use of corticosteroids (at a dose no higher than 10mg prednisolone per day over the preceding 4 weeks) is allowed
Diagnosis of prior immunodeficiency or organ-transplant requiring immunosuppressive therapy
Current or prior use of immunosuppressive therapy within 7 days prior to start of treatment except the following: intranasal, inhaled, topical steroids or local steroid injections (eg. Intra-articular injection); systemic corticosteroids at physiologic doses (10mg/day or less of prednisolone or equivalent)
Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2 therapy
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia
Has known history of, or any evidence of active, non-infectious pneumonitis
History of other pulmonary disease such as interstitial lung disease, emphysema or chronic obstructive pulmonary disease
Is pregnant or breastfeeding
Has a known history of active TB
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial or interfere with the subject's participation for the full duration of the trial or to participate in the trial is not in the patient's best interest, in the opinion of the treating investigator
Has known psychiatric or substance abuse disorders that would interfere with the requirements of the trial
Has a known history of HIV
Has known active Hepatitis B or Hepatitis C
Has received a live vaccine within 30 days prior to the planned start of study medication
Patients who have previously received a solid organ transplant
Patients who have previously received any allogeneic transplantation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tim Illidge
Organizational Affiliation
University of Manchester
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Birmingham
City
Birmingham
Country
United Kingdom
Facility Name
Velindre Cancer Centre
City
Cardiff
Country
United Kingdom
Facility Name
University Hospital Coventry
City
Coventry
Country
United Kingdom
Facility Name
Beatson West of Scotland Cancer Centre
City
Glasgow
Country
United Kingdom
Facility Name
Guy's & St Thomas'
City
London
Country
United Kingdom
Facility Name
The Christie
City
Manchester
Country
United Kingdom
Facility Name
Freeman Hospital
City
Newcastle
Country
United Kingdom
Facility Name
Nottingham City Hospital
City
Nottingham
Country
United Kingdom
Facility Name
Churchill Hospital
City
Oxford
Country
United Kingdom
Facility Name
Southampton University Hospital
City
Southampton
Country
United Kingdom
Facility Name
Clatterbridge Cancer Centre
City
Wirral
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33072126
Citation
Narducci MG, Tosi A, Frezzolini A, Scala E, Passarelli F, Bonmassar L, Monopoli A, Accetturi MP, Cantonetti M, Antonini Cappellini GC, De Galitiis F, Rosato A, Picozza M, Russo G, D'Atri S. Reduction of T Lymphoma Cells and Immunological Invigoration in a Patient Concurrently Affected by Melanoma and Sezary Syndrome Treated With Nivolumab. Front Immunol. 2020 Sep 25;11:579894. doi: 10.3389/fimmu.2020.579894. eCollection 2020.
Results Reference
derived
Learn more about this trial
A Trial Assessing the Effect of Pembrolizumab Combined With Radiotherapy in Patients With Relapsed, Refractory, Specified Stages of Cutaneous T-cell Lymphoma (CTCL) Mycosis Fungoides (MF)/Sezary Syndrome (SS)
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