UK CLINICAL TRIALS IN CUTANEOUS LYMPHOMA€¦ · Stanford Univeristy, USA Torbay Hospital, Torbay,...

Cutaneous 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


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


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


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)


Julia Scarisbrick

Mavoric: mogamulizumab vs vorinostat for refractory CTCL


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


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


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


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


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


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)


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


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


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]

https://bioresource.nihr.ac.uk/


Screening Patients for Effective Clinical Trial Access

SPECTA

SPECTA network


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.


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)


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


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


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


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


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)


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: [email protected] 0207 679 9867| Fax: 0207 679 9861


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)


Julia Scarisbrick

PARCT

SC

RE

EN

ING

29 ELIGIBLE

PATIENTS

RE

GIS

TR

AT

ION

ATEZOLIZUMAB

1200 mg IV Q3 WEEKS


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


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)


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)


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)


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.


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.


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.


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)


Julia Scarisbrick

REACH (Rash Etiology After CHlormethine gel)


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


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


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

UK CLINICAL TRIALS IN CUTANEOUS LYMPHOMA€¦ · Stanford Univeristy, USA Torbay Hospital, Torbay,...

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Transcript of UK CLINICAL TRIALS IN CUTANEOUS LYMPHOMA€¦ · Stanford Univeristy, USA Torbay Hospital, Torbay,...