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)

Cutaneous T Cell Lymphoma Clinical Trial

— PORT  

Official title:

Phase II Trial of Pembrolizumab and Radiotherapy in Cutaneous T-cell Lymphoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03385226
• Other study ID #: UCL/17/0053
• Secondary ID: 2017-000433-30
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 15, 2019
• Est. completion date: September 2024

Study information

• Verified date: December 2023
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 46
• Est. completion date: September 2024
• Est. primary completion date: September 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cutaneous T Cell Lymphoma
• Lymphoma
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Cutaneous
• Lymphoma, T-Cell, Peripheral
• Mycoses
• Mycosis Fungoides
• Mycosis Fungoides/Sezary Syndrome
• Sezary Syndrome
• Syndrome

Intervention

Drug:
• Pembrolizumab
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.

Radiation:
• Radiotherapy
12Gy in 3 fractions

Locations

Country	Name	City	State
United Kingdom	University Hospital Birmingham	Birmingham
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	University Hospital Coventry	Coventry
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Guy's & St Thomas'	London
United Kingdom	The Christie	Manchester
United Kingdom	Freeman Hospital	Newcastle
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Southampton University Hospital	Southampton
United Kingdom	Clatterbridge Cancer Centre	Wirral

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Assessment of changes in the immune status	Peripheral blood mononuclear cell phenotyping	24 weeks after start of pembrolizumab
Other	Analysis of plasma High Mobility Group Box 1 (HMGB-1) isoform levels	Peripheral blood mononuclear cell phenotyping	24 weeks after start of pembrolizumab
Other	Functional analysis of isolated cell populations	Peripheral blood mononuclear cell phenotyping	24 weeks after start of pembrolizumab
Other	Assessment of diversity and clonality of T cell clones	DNA extraction for T cell receptor sequencing	24 weeks after start of pembrolizumab
Other	Evaluation of immune signatures for responders and non-responders	Peripheral blood mononuclear cell phenotyping	24 weeks after start of pembrolizumab
Other	Epitope screening for tumour infiltrating lymphocyte specific neo-antigens	Peripheral blood mononuclear cell phenotyping	24 weeks after start of pembrolizumab
Other	Immunohistochemical analysis of expression of immunological checkpoints	Assessment of PD-L1 expression	At baseline
Other	Investigation of the baseline tumour immune microenvironment	Immune cell infiltration	At baseline
Primary	Overall Response (Global Assessment)	Overall Response of the combination of pembrolizumab plus radiotherapy	24 weeks after commencement of pembrolizumab
Secondary	Response	Response at the 5th infusion of pembrolizumab, typically 12 weeks after start of treatment	12 weeks after start of pembrolizumab
Secondary	Change in Global Response	Change in Global Response from the 5th infusion to the 9th infusion, typically from week 12 to week 24	24 weeks after start of pembrolizumab
Secondary	Safety and toxicity	Number & Percentage of patients who suffer grade 3 or 4 toxicity	5 months after last dose of pembrolizumab (anticipated 2 years and 5 months after last patient being registered)
Secondary	Response Duration	Duration of tumour response	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)
Secondary	Progression Free Survival	Disease progression or death	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)
Secondary	Overall Survival	Death	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)
Secondary	Number of patients achieving abscopal effect		Through study completion, 2 years post last patient being registered