Post on 04-Jul-2020
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
Gloustershire Hospitals NHS Trust, Gloustershire, UKHELIOS Klinikum Hildesheim GmbH
Helsinki University Central Hospital, FinlandHospital 12 de Octubre, Madrid, Spain
Hospital Clinico, University of BarcelonaHospital del Mar. Barcelona, Barcelona, Spain
Hospital Italiano De Buenos Aires, Argentina, South AmericaHospital St Louis, Paris, France
Hospital Universatari de Bellvitge, Barcelona, SpainJohannes Wesling Medical Centre, Minden, Germany
Kiel University Hospital, Kiel, GermanyLeiden University Medical Centre, The Netherlands
Newcastle Upon Tyne NHS Trust, Newcastle, UKOxford Radcliffe Hospital, Oxford UK
Peter Maccallum Cancer Centre, Melbourne, AustraliaPoole Hospital, Dorset, UK
Rabin Medical Center, IsraelRoyal Devon & Exeter Hospital, Exeter, UK
Royal Liverpool Hospital, Liverpool, UKSemmelweis University, Budapest, Hungary
St Thomas’ Hospital, London, UKStadtisches Klinikum Karlsruhe, Karlsruhe, Germany
Stanford Univeristy, USATorbay Hospital, Torbay, UK
Università di Bologna, ItalyUniversity Hospital Louvain, Belgium
University Hospital Southampton, Southampton, UKUniversity Hospital Wuerzburg, Germany
University Hospital Zurich, SwitzerlandUniversity Hospitals Birmingham, UK
University of Florence, ItalyUniversity of Milano, Italy
University Of Pittsburgh School Of Medicine, Pennsylvania, USAUniversity Of Sao Paulo Medical School, Brazil, South America
University of Turin (Torino), ItalyUniversity of Vienna Medical School, Austria
University St Poelten & Karl Landsteiner Institute of Dermatology, St Poelten, Austria
Grand Total
IIB-IVB
IA- IIA
PROCLIPI: 879 patients recruited; 680 early, 199 late stage, 44 sites, from 18 countries, 4 continents
Slide 10Cutaneous Lymphoma Trials Update
Julia Scarisbrick
Must pass central review to be included in prognostic modelling Early Stage review is clinical, histopathological & immunohistochemical
Central Review of 407 samples
313 (77%) passed
94 (23%) failed
−58 cases non-diagnostic
−17 cases advanced MF
−Real-Time Central Review; 19 additional passed
• Pass rate 82% - 332 patients
−275 patients (83%) classical MF
−57 patients (17%) folliculotropic MF Rein Willemze
Werner Kempf
Lorenzo Cerroni
Central Review Team
Slide 11Cutaneous Lymphoma Trials Update
First-in-Human Phase I study of IPH4102
• First anti-KIR3DL2 monoclonal antibody
• Two-part study:• Dose-escalation (accelerated 3+3 design) – up to 10 dose-levels; all CTCL subtypes (GSTT)
• Cohort expansion – for SS and tMF
• Patient profile:• Relapsed/refractory (≥ 2 previous lines of systemic therapy) CTCL
• MF/SS patients: stage ≥ IB
• 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)
Slide 13Cutaneous Lymphoma Trials Update
IPH4102-101 dose escalation
• Well-tolerated in heavily pretreated advanced CTCL (median 4 prior lines)
• 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 julia.scarisbrick@uhb.nhs.uk
Slide 17Cutaneous Lymphoma Trials Update
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
19
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
20
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)
21
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
Hassan Bass 619 Oxford University Hospitals NHS Trust - Churchill Hospital
Brazil Lucy 625 Guy's and St Thomas' NHS - Guy s and St Thomas' NHS - Guy's Hospital
Evans Mererid 626 Velindre NHS Trust - Velindre Cancer Centre
Scarisbrick Julia
(National co-Ordinator) 629 University Hospitals Birmingham NHS Foundation Trust (UHB) - UHB-Queen Elisabeth Medical Centre
Shah Tahir 629 University Hospitals Birmingham NHS Foundation Trust (UHB) - UHB-Queen Elisabeth Medical Centre
Benghiat Helen 629 University Hospitals Birmingham NHS Foundation Trust (UHB) - UHB-Queen Elisabeth Medical Centre
Hatcher Helen 632 Cambridge University Hospital NHS - Addenbrookes Hospital
Peoples Sharon 641 NHS Lothian - Western General Hospital
Edgar Angela 644 Royal Hospital For Sick Children
White Jeffery David 6982 NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital
Weickert Martin 7099 University Hospitals Coventry and Warwickshire NHS Trust - University Hospital
Slide 23Cutaneous Lymphoma Trials Update
TRIALS IN SET UP FOR CTCL
• PORT – Pembrolizumab & RT July 2018
• PARCT – PD-L1 atezolizumab June 2018
• PROMPT – ECP monotherapy Sept 2018
• REACH – Ledaga skin reaction Nov 2018
Slide 24Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PORT: Phase I/II Study of pembrolizumab, (anti PD-1) with radiotherapy in CTCLCI: Professor Tim Illidge, Manchester
Primary endpoint:
• Response to pembrolizumab, in combination with RT, using mSWAT
Secondary endpoints:
• Safety profile of pembrolizumab in combination with RT (abscopaleffect)
• Disease free survival (expanded cohort)
• Overall survival (expanded cohort)
Slide 25Cutaneous Lymphoma Trials Update
PI name Site name
Dr Wendy Osborne Freeman Hospital
Dr Stephen Morris Guys & St Thomas’
Dr Julia Scarisbrick University Hospital Birmingham, QE
Dr Arvind Arumainathan Royal Liverpool University Hospital
Prof Tim Illidge The Christie
Dr Eve Gallop-Evans Velindre Cancer Centre
Dr Graham Collins Oxford University Hospitals
Dr Andrew Bates Southampton General Hospitals
PORT Sites to be activated
Contact: Toyin Adedayo, Trial Coordinator CRUK and UCL-CTC email: o.adedayo@ucl.ac.uk 0207 679 9867| Fax: 0207 679 9861
Slide 26Cutaneous Lymphoma Trials Update
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
Slide 29Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PARCT
• Primary endpoint:
Overall response rate (ORR), complete response (CR) or partial response (PR)
• Secondary endpoints:
−Progression free survival
−Overall survival
−Time to response
−Duration of response
−Time to next systemic treatment
−Safety and tolerability
−Identification of biomarkers (PD-1, PD-L1 expression)
Slide 30Cutaneous Lymphoma Trials Update
Julia Scarisbrick
PARCT: Correlative Translational ResearchJulia Scarisbrick, Paul Moss (University Hospital Birmingham, UK)
• 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)
37
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
• EORTC Meeting 27-29th September 2019, Athens
• 4th World Congress Cutaneous Lymphoma, 13-16th
February 2020, Barcelona