MRA Clinical Trials Day Myeloma UK Clinical Trial Network 21st June 2016 Myeloma UK Clinical Trial Network Overview Leeds Institute of Clinical Trials Research

MUK CTN – brief overview Established 2009 First 8 centres = proof of concept Expanded to 29 hospitals across the UK in 2014 Achievements: 1 trial published (MUK one) 3 trials completed recruitment (MUK three, four and six) 3 trials open to recruitment (MUK five, seven and eight) 2 trials to open this year (MUK nine and eleven) 2 trials in development (MUK twelve and fourteen) The Clinical Trial Network provides an opportunity to generate world class data with the potential to lead to significant improvements in patient outcomes

MUK CTN – network hospitals

MUK CTN – strategic objectives Improve patient outcomes by developing, prioritising and implementing a portfolio of strategic, clinically relevant and patient-centric clinical trials Improve the efficiency and speed with which new trials are set up and completed Produce results that are impactful and can be adopted and diffused as quickly as possible Ensure early access to experimental novel treatments by making the UK an internationally competitive clinical research environment Develop strong and mutually beneficial collaborations with all relevant stakeholders – especially the pharmaceutical industry

MUK CTN – Governance and Management Myeloma UK Board: strategy, accountability and governance of organisation Research Advisory Group (RAG): sub-group of Myeloma UK Board with overall responsibility for ensuring Myeloma UK research objectives are met Drug Discovery Sub-group: determines the specific studies to conduct within the CTN, in light of the current trial portfolio and the information gained through horizon-scanning CTN operational working group: portfolio management Trial specific TMGs: progress, problem solving for actively recruiting trials Patient and Public Involvement Panel: patient voice, ethics etc.

MUK CTN Portfolio Trial Concept Set up Closed Target Status MUK one 98 Recruiting Closed Target Status MUK one 98 Publication BJHaem 2015 MUK three 36 Final analysis and publication write up MUK four 68 MUK five 300 Open to recruitment 284 pts randomised. MUK six 54 MUK seven 250 Opened to recruitment – 14 patients MUK eight Open to recruitment – 16 patients MUK nine 95 Expected to open 2016 MUK eleven 29 MUK twelve 30 IIT Submitted MUK fourteen 42 Protocol development

MUK CTN – Trials (publications) MUK one - An open label multi-centre, randomised, parallel group, phase II study to evaluate the optimal starting dose of bendamustine (60 vs 100 mg/m2) in combination with thalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma Published Br J Haematol. 2015 Apr 20 This study demonstrates bendamustine at 60 mg/m2 twice per month with thalidomide and dexamethasone is deliverable for repeated cycles in heavily pre-treated myeloma patients and has substantial clinical activity

MUK CTN – Trials (closed to recruitment) MUK three - A Phase I/IIa, Dose-Escalation, Study of CHR-3996 in Combination with Tosedostat in Participants with Relapsed, Refractory Multiple Myeloma MUK four - A Phase II Trial of Combination Treatment with Vorinostat, Bortezomib and Dexamethasone in Participants with Relapsed Multiple Myeloma MUK six - A Phase I/IIa trial of VTD-panobinostat treatment and panobinostat maintenance in relapsed and relapsed/refractory multiple myeloma patients

MUK CTN – Trials (open to recruitment) MUK five - A phase II randomised trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs cyclophosphamide, velcade and dexamethasone (CVD) for first relapse multiple myeloma patients MUK seven – A randomised, phase II study comparing the triplet combination of pomalidomide, cyclophosphamide and dexamethasone to the standard combination pomalidomide and dexamethasone MUK eight - A randomised phase II trial of Cyclophosphamide and Dexamethasone in combination with Ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and bortezomib

MUK 5

MUK 5

MUK CTN – Trials (open to recruitment) MUK five - A phase II randomised trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs cyclophosphamide, velcade and dexamethasone (CVD) for first relapse multiple myeloma patients MUK seven – A randomised, phase II study comparing the triplet combination of pomalidomide, cyclophosphamide and dexamethasone to the standard combination pomalidomide and dexamethasone MUK eight - A randomised phase II trial of Cyclophosphamide and Dexamethasone in combination with Ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and bortezomib

MUK 7

Clonal evolution of disease MUK 7 Pomalidomide biomarker discovery program C4D14 C1D14 Protein biomarkers (Imid binding proteins and effector proteins) Gene expression biomarkers (e.g. IKZF effector gene networks) Genetic profiling (risk markers/ biologic markers) Clonal evolution of disease

MUK CTN – Trials (open to recruitment) MUK five - A phase II randomised trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs cyclophosphamide, velcade and dexamethasone (CVD) for first relapse multiple myeloma patients MUK seven – A randomised, phase II study comparing the triplet combination of pomalidomide, cyclophosphamide and dexamethasone to the standard combination pomalidomide and dexamethasone MUK eight - A randomised phase II trial of Cyclophosphamide and Dexamethasone in combination with Ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and bortezomib

MUK 8

MUK CTN – Trials (in set up) MUK 9 – single arm phase II trial to determine whether a combination of four novel agents (VRd + Daratumumab) in combination with low-dose cyclophosphamide is sufficiently active in a high risk population of myeloma patients, to take forward into a phase III trial compared to standard treatment (OPTIMUM). High risk defined as one of the following: >1 adverse* lesion GEP – high risk score** Plasma Cell Leukaemia (PCL)*** *Adverse lesions include t(4:14) translocation and t(14;16) / t(14;20), gain 1q, del 17p, del 1p. ** As per EMC92 GEP model *** PCL is defined as the presence of more than 2x109/L peripheral blood plasma cells or a plasmacytosis accounting for > 20% of the differential white cell count.

Consolidation Part 1 (VRDd) Consolidation Part 2 (VRD) MUK 9 Induction (CVRDd) (Cyclophosphamide, Bortezomib, Lenalidomide, Daratumumab, dexamethasone) 21 day cycles until maximal response Velcade-HD-MEL+ASCT (Cyclophosphamide, GCSF, Melphalan, Bortezomib) Weekly Bortezomib to consolidation Consolidation Part 1 (VRDd) (Bortezomib, Lenalidomide, Daratumumab and dexamethasone) 6 Cycles of 28 days Consolidation Part 2 (VRD) (Bortezomib, Lenalidomide, Daratumumab) 12 Cycles of 28 days Maintenance (RD) (Lenalidomide and Daratumumab) 28 day cycles until first disease progression

MUK CTN – Trials (in set up) MUK 11 - A Phase I Study to Assess the Safety and Tolerability of Reovirus REOLYSIN® (pelareorep) in Combination with Lenalidomide or Pomalidomide (VIRel) Patients receiving either lenalidomide or pomalidomide, now with serologically progressive disease Participants will be treated with 28-day cycles of REOLYSIN® plus lenalidomide / pomalidomide (at the allocated doses) until further disease progression or treatment-limiting toxicity is demonstrated.

MUK CTN – Trials (in set up) MUK 12 – Phase I trial to determine the safe dose of cyclophosphamide administered in combination with Selinexor and dexamethasone (SCD) to take forward to a randomised phase II trial in relapsed refractory myeloma

MUK CTN – Trials (in set up) MUK14 - A Phase I/ II study investigating the combination of Pembrolizumab (Keytruda) with Cyclophosphamide and Lenalidomide (Revlimid) for patients with relapsed multiple myeloma Relapsed or relapsed and refractory MM following 2 or more prior lines of therapy Prior lenalidomide is permitted as long as: At least a PR was achieved (unless was only used as maintenance) Was not refractory to lenalidomide, defined as no disease progression whilst receiving lenalidomide or disease progression was < 60 days of last dose Was not intolerant of lenalidomide or discontinued due to ≥ grade 3 adverse event

MUK CTN – Trials (in set up) Key-CR will be given in 28 day cycles. Within this cyclophosphamide will be given on days 1, 8 & 15. Lenalidomide will be given on days 1-21. Pembrolizumab will be given every 21 days regardless of when cyclophosphamide and lenalidomide will be given. This will require doses to be given days 1 & 21 in cycle 1, day 15 in cycle 2 and day 8 in cycle 3. This schedule will then be repeated over the following cycles of treatment.

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