Slide 1 Cutaneous Lymphoma Trials Update Eve Gallop-Evans Consultant Clinical Oncologist Velindre Cancer Centre, Cardiff on behalf of Julia Scarisbrick, Treasurer UKCLG UK CLINICAL TRIALS IN CUTANEOUS LYMPHOMA Consultant Dermatologist University Hospital Birmingham Senior Lecturer University of Birmingham
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Slide 1Cutaneous Lymphoma Trials Update
Eve Gallop-EvansConsultant Clinical OncologistVelindre Cancer Centre, Cardiffon behalf ofJulia Scarisbrick, Treasurer UKCLG
UK CLINICAL TRIALS IN CUTANEOUS LYMPHOMA
Consultant Dermatologist
University Hospital Birmingham
Senior LecturerUniversity of Birmingham
Slide 2Cutaneous Lymphoma Trials Update
Julia Scarisbrick
CTCL Trials
1. Alcanza Trial (Takeda) – phase 3 brentuximab vs MTX or bexarotene, in follow-up, Lancet 2018
2. Mavoric Trial (Kyowa) – phase 3 mogamulizumab vs vorinostat, in follow-up, abstract ASH 2017
3. PROCLIPI – Observational study in MF/SS, July 2015-ongoing
4. Innate Pharma - anti-KIR3DL2 monoclonal antibody, completed dose escalation - on hold for phase 2.
5. Resmain (4SC) - Double-blind, randomised, placebo-controlled, Phase II trial to evaluate resminostat as maintenance, Oct 2016-ongoing
6. NIHR BioResource for Translational Research into Rare Diseases (NIHRBR-RD) ethics, Rec Ref: 13/EE/0325, IRAS: Cambridge University.
7. Merck/UKCLG – PORT: Pembrolizumab + radiotherapy, Phase II Trial in set-up
Slide 3Cutaneous Lymphoma Trials Update
Julia Scarisbrick
EORTC Trials: National Coordinator J Scarisbrick
1. PARCT: atezolizumab (Anti-PDL1) for 2nd line systemic
treatment of stage IIB-IV MF/SS
2. PROMPT: photopheresis for erythrodermic MF and SS
3. REACH (Rash Etiology After CHlormethine gel): aetiology Of
Skin Drug Reactions With Chlormethine Gel In Early Stage MF
4. SPECTA: screening cancer patients for efficient clinical trial
access
Slide 4Cutaneous Lymphoma Trials Update
Julia Scarisbrick
Alcanza: brentuximab vedotin in CD30+ CTCL
Brentuximab vedotin (1.8 mg/kg iv) 3-wkly up to a total of 16 cycles (48 weeks)At least 1 prior systemic therapy for their diseaseRandomised 1:1 BV vs Physician’s choice (bex or MTX)
Slide 5Cutaneous Lymphoma Trials Update
Julia Scarisbrick
Mavoric: mogamulizumab vs vorinostat for refractory CTCL
Slide 6Cutaneous Lymphoma Trials Update
PROCLIPI Study for mycosis fungoides & Sezary syndromePROspective Cutaneous Lymphoma International Prognostic Index
Julia Scarisbrick, Pietro Quaglino, Maarten Vermeer, Youn KimOn Behalf of the EORTC Gp & CLIC
Slide 7Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PROCLIPI AIMS:
• Prognostic indices are useful to stratify patients for treatments and clinical studies where there is a range of survival according to stage
• To develop a prognostic index in cutaneous lymphoma by collecting data at diagnosis and measuring against survival
Slide 8Cutaneous Lymphoma Trials Update
Julia Scarisbrick
• To collect well-defined parameters at diagnosis, progression and annual follow up of MF/SS
Clinical
Pathological
Nodal
Haematological
Genotypic
Treatment
Biobank Material
• Prognostic variables will be tested against overall & progression free survival
• >1000 patients with early stage MF + 500 with advanced MF/SS, survival data for 10+ years
• 20% of patients in validation set
PROspective Cutaneous Lymphoma International Prognostic Index Study
0 20 40 60 80 100 120
Aristotle University of Thessalonik, in Papageorgiou General Hospital, GreeceAthens University Medical School, GreeceBeatson West of Scotland Cancer Centre
Bristol Royal Infirmary, Bristol, UKChristie Hospital, Manchester UK
CHU Hospital de Bordeaux, Bordeaux, FranceCity Of Hope National Medical Center, Duarte, California, US
• Centrally assessed expression of KIR3DL2 (cd158k) on tumors:• KIR3DL2-positivity on skin biopsies (and/or blood CD4+ T cells, if applicable), is required for
eligibility
• Treatment until progression
Slide 12Cutaneous Lymphoma Trials Update
IPH4102-101 dose escalationBest Response
in all patients
Global
N=25
Best Response in Sézary Syndrome patients
Global
n=20
Skin
n=20
Blood
n=20
Best Response (n)CRPR
SDPD
110
122
19
82
210
80
58
61
ORR 44 % 50 % 60 % 65 %
ORR4, n (%) 9 (36%) 8 (40%)
PFS (days) - median(min – max)
299 (9.8 months)(28 – 610+)
329 (10.8 months)(28 – 610+)
ORR: Overall Response Rate
ORR4: Rate of responses lasting ≥4 mo
PFS: Progression-Free Survival
DOR: Duration of Response
> Results for 25 patients (20 SS) treated with doses ranging from 0.0001 to 10 mg/kg
> All clinical responses are confirmed; 4 responses ongoing (DOR range 104 – 519 days)
> Median study follow-up time, 458 days (15 months)
• Best global ORR is 44% in the overall population
• Sezary patients
• 50% ORR, median duration 9.9 months, median PFS 10.8 months
• Pruritus is substantially improved in those with global response or stable disease
• Pharmacodynamic endpoints (monitoring of KIR3DL2-positive cells)
• prompt elimination of neoplastic cells in skin and in blood correlation with clinical response
Expansion cohorts (SS, tMF) opened July 2017 at the flat dose of 750 mg
Slide 14Cutaneous Lymphoma Trials Update
Julia Scarisbrick
RESMAIN
• Phase II double-blind, randomised, placebo-controlled trial
• Resminostat as maintenance treatment for patients with advanced stage MF/SS.
• Treatment until progression
• Placebo patients can crossover at progression
• First patient recruited January 2017
Slide 15Cutaneous Lymphoma Trials Update
Julia Scarisbrick
NIHR BIORESOURCE - RARE DISEASES (NIHRBR-RD)
Cutaneous Lymphoma adopted March 2018
Lead: J Scarisbrick
Aims:
To develop affordable DNA-based tests for the diagnosis
of rare diseases for which the gene is known
To discover genes causing rare diseases; only half of the
genes for rare diseases are currently known
CBCL
5 marginal zone lymphoma
5 follicular lymphoma
5 DLBCL
CTCL
20 patch MF
20 plaque MF
20 tumour MF
20 erythrodermic MF / Sezary
10 LCAL
NIHR Bioresource SitesNorth Bristol NHS Trust
Northern Lincolnshire & Goole NHS Trust
Northwick Pk and St Marks Hospitals Clinical Genetics
Centre
Oxford University NHS Trust
Papworth Hospital NHS FT
Plymouth Hospitals NHS Trust
Royal Brompton & Harefield NHS FT
Royal Devon & Exeter NHS FT
Royal Free London NHS FT
Royal Liverpool & Broadgreen University Hospitals NHS
Trust
Royal United Hospital Bath
Salford Royal NHS Foundation Trust
Salisbury NHS FT
Sandwell & West Birmingham Hospitals NHS Trust
Sheffield Children's Hospital NHS FT
Sheffield Teaching Hospitals NHS FT
St George's Healthcare NHS Trust
University College London Hospital
University Hospital Southampton NHS FT
University Hospitals Bristol NHS FT
University Hospitals of Leicester NHS Trust
University Hospitals of North Midlands
Warrington & Halton Hospitals NHS Foundation Trust
Participating Sites
Barts Health NHS Trust
Belfast City Hospital
Birmingham Children's Hospital
Birmingham Heart of England NHS FT
Birmingham University NHS FT
Birmingham Women's Hospital
Cambridge University Hospitals NHS FT
Cardiff & Vale University LHB
Central Manchester University Hospital NHS FT
Chelsea & Westminster Hospitals NHS Trust
East Kent Hospitals University NHS Trust
Epsom & St Helier University Hospitals NHS Trust
Frimley Park Hospital NHS FT
Great Ormond Street Hospital for Children NHS FT
Guy's & St Thomas' NHS FT
Hampshire Hospitals NHS FT (Basingstoke)
Hull and East Yorkshire Hospitals NHS FT
Imperial College Healthcare NHS Trust
Ipswich Hospitals NHS Trust
Kings College Hospital NHS FT
Lancashire Teaching Hospitals NHS Trust
Leeds University Hospital
Moorfields Eye Hospital NHS FT
Newcastle upon Tyne Hospitals NHS FT
NHS Grampian (Aberdeen)
NHS Greater Glasgow and Clyde
Further details at https://bioresource.nihr.ac.uk/If you are interested in receiving more information regarding site participation please contact [email protected]
Screening Patients for Effective Clinical Trial Access
SPECTA
SPECTA network
Slide 18Cutaneous Lymphoma Trials Update
Julia Scarisbrick
EORTC SPECTA platform
• To provide access to patients outside of therapeutic clinical trials for answering relevant questions, e.g. for cohort or cross-sectional studies
• To provide a common infrastructure for EORTC translational research projects, targeting high quality and operational efficiency
Primary objective
• To establish a quality assured platform for collecting clinicopathologically annotated biological material from patients with primary rare tumors to support biospecimen-based translational research and biomarker discovery.
Slide 19Cutaneous Lymphoma Trials Update
Julia Scarisbrick
SPECTA WORKFLOW
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Clinical data qualityEORTC VISTA RDC/eCRF and clinical database
Controlled and documented tissue managementCentralized tissue handling, storage, and biological material extraction in audited biobanks
ReproducibilityTissue available for repeat testing
Clinical focus in the selection of laboratory tests
Central Review Board (Panel of Experts)
Slide 20Cutaneous Lymphoma Trials Update
Julia Scarisbrick
SPECTA data collection
• Date of diagnosis, histology, grade, and stage
• Age, sex, weight, height
• WHO performance status
• Local tumour biomarkers
• Medical history, disease and treatment history & outcomes
• Disease status, survival status
• New malignancy
• Enrolment date in clinical trials or reason why not
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Slide 21Cutaneous Lymphoma Trials Update
Julia Scarisbrick
SPECTA Biobank
• Central quality control of tissue samples (quality check)
• DNA and RNA extraction and quality control for molecular testing
• Long-term storage of biological material
• Central pathology review if indicated
• Central biological material assessment (e.g. MSI for colorectal cancer)
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Slide 22Cutaneous Lymphoma Trials Update
Julia Scarisbrick
SPECTA Sites
Name Inst Institution
Stark Daniel 601 Leeds Teaching Hospitals NHS Trust - St. James's University Hospital
Lewis Joanne 605 Newcastle Hospitals NHS Trust - Freeman Hospital, Northern Centre For Cancer Care
Rankin Kenneth 605 Newcastle Hospitals NHS Trust - Freeman Hospital, Northern Centre For Cancer Care
McCabe Martin 610 The Christie NHS Foundation Trust
van der Graaf Winette 613 Royal Marsden Hospital - Chelsea, London
EORTC – CLTF Study 1652: PARCTPhase II trial of atezolizumab (anti-PD-L1) for stage IIB-IV MF/SS relapsed/refractory after previous systemic treatment
Rudolf Stadler (University Hospital Johannes Wesling Klinikum, Minden, Germany)
Julia Scarisbrick (University Hospital Birmingham, UK)
Slide 27Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PARCT
SC
RE
EN
ING
29 ELIGIBLE
PATIENTS
RE
GIS
TR
AT
ION
ATEZOLIZUMAB
1200 mg IV Q3 WEEKS
Slide 28Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PARCT eligibility criteria
• MF/SS stage IIB to IVB
• PD-L1 testing mandatory
• Inadequate response or secondary treatment failure to at least 1 prior systemic therapy for CTCL (including IFNα or bexarotene), wash out period 4 weeks
• WHO performance status 0-1
• No prior therapy with anti-PD1, anti-PD-L1, anti-PD-L2
• No additional malignancy that requires active treatment
• Effect of PD-L1 blockade with atezolizumab on PD-1/PD-L1 expression in tumour lymphocytes versus non-tumour infiltrating lymphocytes (TIL) in the skin and correlation with response
• 2 Projects:
−PD-1 and PD-L1 expression in tumour microenvironment: correlation with response rate and progression free survival (predictive biomarker-Project 1)
−Change in T cell, tumour and CD4 and CD8 TIL populations during treatment (prognostic biomarker-Project 1)
−Does treatment with atezolizumab increases the activation of TIL (Project 2)
Slide 31Cutaneous Lymphoma Trials Update
EORTC – CLTF Study 1636: PROMPTA Prospective, Multicenter, Single-Arm Cohort Study of Photopheresis in the Treatment of Erythrodermic MF and SS
Robert Knobler (Medical University of Vienna, Austria)
Franz Trautinger (University Hospital of St. Poelten, Austria)
Slide 32Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PROMPT: Treatment according to guidelines
• One cycle (two consecutive days) 2 weekly for 3 months, then monthly.
• Response assessment at 6 months, then taper to one treatment every 5–8 weeks as maintenance therapy if required.
• Treatment can be stopped upon CR.
• Combination therapy can be added after 3 months for SD/PD
• Skin care and topical steroids can be continued if established before study entry.
• Antihistamine can be used for itch.
• PD will be part of primary endpoint. However, treatment can be continued beyond progression at the discretion of the investigator.
Slide 33Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PROMPT
• Primary objective: to evaluate applicability of photopheresisused in line with consensus guidelines in patients with MF/SS.
• Secondary objectives: quality-of-life, safety, response rates, progression-free survival, number of treatments required to obtain remission, and frequency, type of, and time to initiation of add-on therapies.
Slide 34Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PROMPT: Correlative Translational Research
• Lead: Maarten Vermeer, LUMC, Netherlands
• Overall aim is to investigate effect of ECP on:
−number of tumour cells and reactive cells
−cytokine milieu in peripheral blood
−cytotoxic function of NK cells and CD8+ cells.
Slide 35Cutaneous Lymphoma Trials Update
EORTC – CLTF Study 1754: REACH (Rash Etiology After CHlormethine gel)
STUDY TO DETERMINE THE AETIOLOGY OF SKIN DRUG REACTIONS WITH CHLORMETHINE GEL IN EARLY STAGE MYCOSIS FUNGOIDES
Julia Scarisbrick (University Hospital Birmingham)
Emmanuella Guenova (University Hospital Zurich)
Slide 36Cutaneous Lymphoma Trials Update
Julia Scarisbrick
REACH (Rash Etiology After CHlormethine gel)
Slide 37Cutaneous Lymphoma Trials Update
Julia Scarisbrick
REACH (Rash Etiology After CHlormethine gel)
• Primary endpoint: to determine aetiology of skin drug reactions to CL gel in early stage patients.
−Skin biopsies of new skin drug reaction and patch testing to discriminate between irritant and allergic contact dermatitis
• Co-primary endpoints:
−response rate in patients without skin drug reaction (Group A).
−response rate in patients with skin drug reactions and subsequent reduced CL gel application frequency (Group B
−response rate in patients with skin drug reactions with subsequent reduced CL gel application and administration of topical corticosteroids (Group C)
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Slide 38Cutaneous Lymphoma Trials Update
Julia Scarisbrick
REACH (Rash Etiology After CHlormethine gel)Correlative Translational Research – Emmanuella Guenova, Zurich
• Skin biopsies of skin drug reaction from an area unaffected and one area affected by MF-CTCL. Additional biopsies at complete response and end of treatment.
• Histopathology assessment for disease and skin drug reaction.
• T-cell receptor (TCR) clonality assessment and comparison in skin drug reactions to CL gel from both the treated non-affected area and from a selected affected area, compared with pre-treatment if possible.
• Immunohistochemistry, RNA sequencing, tissue CyTOFF mass cytometry on the same biopsy specimens to gain additional insights into mode of action of CL gel and mechanism of development of skin drug reactions.
• Blood samples are collected from all patients at baseline, at time of skin drug reaction, at complete response and at end of treatment
Slide 39Cutaneous Lymphoma Trials Update
Julia Scarisbrick
Diary Dates
• EORTC Meeting 27-29th September 2018, St Gallen
• EGAM 14th-15th March 2019, Brussels
• 24th World Congress Dermatology, 10-15th June 2019, Milan