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

2. 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

3. MUK CTN – network hospitals

4. 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

5. 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.

6. 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

7. 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 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

8. 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

9. 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

10. MUK 5

11. MUK 5

12. 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

13. MUK 7

14. 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

15. 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

16. MUK 8

17. 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.

18. 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

19. 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.

20. 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

21. 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

22. 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 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.

23. Questions?