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)

• ClinicalTrials.gov Identifier: NCT03385226
• Recruitment Status: Recruiting
• First Posted: December 28, 2017
• Last Update Posted: November 1, 2022
• Sponsor: University College, London
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): University College, London

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.

Condition or disease	Intervention/treatment	Phase
Cutaneous T Cell Lymphoma; Mycosis Fungoides/Sezary Syndrome	Drug: Pembrolizumab; Radiation: Radiotherapy	Phase 2

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Pembrolizumab and Radiotherapy in Cutaneous T-cell Lymphoma
• Actual Study Start Date: January 15, 2019
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: January 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab with radiotherapy; 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	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.; Other Name: Chemical Abstract Service (CAS) number - 1374853-91-4; Radiation: Radiotherapy; 12Gy in 3 fractions

Outcome Measures

Primary Outcome Measures :

1. Overall Response (Global Assessment) [ Time Frame: 24 weeks after commencement of pembrolizumab ]
   Overall Response of the combination of pembrolizumab plus radiotherapy

Secondary Outcome Measures :

1. Response [ Time Frame: 12 weeks after start of pembrolizumab ]
   Response at the 5th infusion of pembrolizumab, typically 12 weeks after start of treatment
2. Change in Global Response [ Time Frame: 24 weeks after start of pembrolizumab ]
   Change in Global Response from the 5th infusion to the 9th infusion, typically from week 12 to week 24
3. Safety and toxicity [ Time Frame: 5 months after last dose of pembrolizumab (anticipated 2 years and 5 months after last patient being registered) ]
   Number & Percentage of patients who suffer grade 3 or 4 toxicity
4. Response Duration [ 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) ]
   Duration of tumour response
5. Progression Free Survival [ 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) ]
   Disease progression or death
6. Overall Survival [ 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) ]
   Death
7. Number of patients achieving abscopal effect [ Time Frame: Through study completion, 2 years post last patient being registered ]

Other Outcome Measures:

1. Assessment of changes in the immune status [ Time Frame: 24 weeks after start of pembrolizumab ]
   Peripheral blood mononuclear cell phenotyping
2. Analysis of plasma High Mobility Group Box 1 (HMGB-1) isoform levels [ Time Frame: 24 weeks after start of pembrolizumab ]
   Peripheral blood mononuclear cell phenotyping
3. Functional analysis of isolated cell populations [ Time Frame: 24 weeks after start of pembrolizumab ]
   Peripheral blood mononuclear cell phenotyping
4. Assessment of diversity and clonality of T cell clones [ Time Frame: 24 weeks after start of pembrolizumab ]
   DNA extraction for T cell receptor sequencing
5. Evaluation of immune signatures for responders and non-responders [ Time Frame: 24 weeks after start of pembrolizumab ]
   Peripheral blood mononuclear cell phenotyping
6. Epitope screening for tumour infiltrating lymphocyte specific neo-antigens [ Time Frame: 24 weeks after start of pembrolizumab ]
   Peripheral blood mononuclear cell phenotyping
7. Immunohistochemical analysis of expression of immunological checkpoints [ Time Frame: At baseline ]
   Assessment of PD-L1 expression
8. Investigation of the baseline tumour immune microenvironment [ Time Frame: At baseline ]
   Immune cell infiltration

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: PORT Trial Coordinator; +44-2076799860; ctc.port@ucl.ac.uk

Contact: Jon Teague; +44-2076799891; j.teague@ucl.ac.uk

Locations

United Kingdom

Guys & St Thomas's NHS Foundation Trust; Recruiting

London, United Kingdom

Contact: PORT Trial Coordinator

Principal Investigator: Stephen Morris

The Christie NHS Foundation Trust; Recruiting

Manchester, United Kingdom

Contact: PORT Trial Coordinator

Sub-Investigator: Richard Cowan

Sponsors and Collaborators

University College, London

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Tim Illidge; University of Manchester

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University College, London
• ClinicalTrials.gov Identifier: NCT03385226
• Other Study ID Numbers: UCL/17/0053
• First Posted: December 28, 2017
• Last Update Posted: November 1, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by University College, London:

Relapsed; Refractory

Additional relevant MeSH terms:

Mycoses; Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Mycosis Fungoides; Sezary Syndrome; Lymphoma, T-Cell, Cutaneous; Syndrome; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease; Pathologic Processes; Lymphoma, Non-Hodgkin; Bacterial Infections and Mycoses; Infections; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents