A randomised phase II trial of selinexor with cyclophosphamide and prednisolone in relapsed or refractory multiple myeloma (RRMM) patients

ISRCTN	ISRCTN15028850
DOI	https://doi.org/10.1186/ISRCTN15028850
EudraCT/CTIS number	2017-001736-19
Secondary identifying numbers	36466

Submission date: 05/03/2018
Registration date: 21/03/2018
Last edited: 28/10/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-selinexor-cyclophosphamide-and-prednisolone-for-myeloma-muk-twelve#undefined

Contact information

Mr Saqib Saghir
Scientific

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom

ORCID ID	0000-0002-9209-1290
Phone	+44 (0)113 343 1454
Email	S.Saghir@leeds.ac.uk

Study information

Study design	Randomised; Interventional; Design type: Treatment, Drug
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	No participant information sheet available
Scientific title	A randomised phase II trial of selinexor, cyclophosphamide and prednisone vs cyclophosphamide and prednisone in relapsed or refractory multiple myeloma (RRMM) patients
Study acronym	MUK Twelve
Study objectives	This study is designed to compare a new combination of Selinexor, cyclophosphamide and prednisone, with cyclophosphamide and prednisone alone followed by SCP at disease progression.
Ethics approval(s)	London – Hampstead Research Ethics Committee, 20/12/2017, ref: 17/LO/1847
Health condition(s) or problem(s) studied	Relapsed or refractory multiple myeloma
Intervention	The trial is designed as a randomised, controlled, open, parallel group, multicentre phase II trial to evaluate the clinical efficacy of selinexor in combination with cyclophosphamide and prednisolone. A calibration group will receive cyclophosphamide plus prednisolone alone, and will be used to evaluate the validity of the outcome in the experimental group. Participants will be randomised on a 3:1 basis to receive either selinexor + cyclophosphamide + prednisolone (SCP) or cyclophosphamide + prednisolone (CP). A maximum of 60 participants will be recruited (45 participants in the SCP arm, and 15 participants in the CP arm). Participants who experience disease progression on the CP arm may receive SCP, once progression has been confirmed by the CTRU and the participant has been deemed eligible to receive SCP. Patients randomised to SCP have no further trial treatment stipulated following SCP therapy. The analysis of the treatment switch phase of the trial is exploratory. SCP combination Selinexor oral 100mg once a week – days 1 , 8 , 15 & 22 Cyclophosphamide oral 50mg once daily, starting on day 1 Prednisolone oral 30mg every other day, starting on day 1 CP combination Cyclophosphamide oral 50mg once daily, starting on day 1 Prednisolone oral 30mg every other day, starting on day 1 Followed by SCP Combination Selinexor oral 100mg once a week – days 1, 8, 15 & 22 Cyclophosphamide oral 50mg (or dose given previously) once daily, starting on day 1 Prednisolone oral 30mg (or dose given previously) every other day, starting on day 1 The final analysis will take place after all patients have been followed up for at least 6 months or have progressed on the first phase of treatment (whichever is sooner). Further analyses relating to the treatment switch phase of the trial will take place after all patients have been followed up for at least 6 months or have progressed (whichever is sooner).
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Selinexor
Primary outcome measure	Progression free survival at 6 months
Secondary outcome measures	1. Safety and toxicity, via adverse reactions and adverse events from consent until 28 days post last dose of trial treatment 2. Progression-free survival at 6 months or until disease progression, monitored via blood results 3. Maximum response, monitored via blood results throughout the trial 4. Time to maximum response, monitored via blood results throughout the trial 5. Duration of response, monitored via blood results throughout the trial 6. Compliance to therapy, measured at all stages of the trial
Overall study start date	01/12/2016
Completion date	14/11/2023

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 60; UK Sample Size: 60
Total final enrolment	66
Key inclusion criteria	1. Able to give informed consent and willing to follow all trial protocol assessments 2. Aged 18 years or over 3. Participants with confirmed myeloma based on International Myeloma Working Group (IMWG) criteria 4. Measurable disease with at least one of the following: 4.1. Paraprotein ≥5g/L 4.2. Serum free light chains ≥100mg/L with abnormal ratio for light chain only myeloma 4.3. Bence Jones protein ≥200mg/24h 5. Participants with relapsed or relapsed refractory myeloma who have received ≥ 2 prior anti-myeloma treatments including a proteasome inhibitor and lenalidomide, and now require further treatment 6. Patients for which cyclophosphamide and prednisolone alone would be a suitable treatment 7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 8. Female participants of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception, see section 11) and have a negative urine pregnancy test at screening. Male participants must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female participants, effective methods of contraception must be used throughout the trial and for at least 12 months following the last dose of trial treatment 9. Required laboratory values are required at registration and within 14 days prior to randomisation: 9.1. Platelet count ≥50x109/L. Platelet count of 30-50 is acceptable if bone marrow aspirate or trephine shows tumour replacement of >50%. Platelet support is permitted within 14 days prior to randomisation, although platelet transfusions to help participants meet eligibility criteria are not allowed within 72 hours prior to the blood sample to confirm protocol eligibility 9.2. Absolute neutrophil count ≥1.0 x 109/L. Growth factor support is not permitted within 14 days prior to randomisation 9.3. Haemoglobin ≥ 80 g/L. Blood support is permitted 9.4. Alanine transaminase (ALT) and / or aspartate transaminase (AST) ≤3 x upper limit of normal 9.5. Creatinine clearance ≥ 20 ml/min (using Cockcroft Gault formula) 9.6. Bilirubin ≤1.5 x upper limit of normal. Suspected Gilberts syndrome patients must have a total bilirubin ≤3 x upper limit of normal
Key exclusion criteria	Current exclusion criteria as of 23/06/2022: 1. The following participants will be excluded: 1.1. Those with non-measurable disease 1.2. Those with a solitary bone or solitary extramedullary plasmacytoma 1.3. Plasma cell leukaemia 2. Participants with a history of malignancy (other than myeloma) within 5 years before the date of registration (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that, in the opinion of the investigator, with concurrence with the Chief Investigator, is considered cured with minimal risk of recurrence within 5 years) 3. Participants with a known or underlying uncontrolled concurrent illness that, in the investigator’s opinion, would make the administration of the study drug hazardous or circumstances that could limit compliance with the study, including, but not limited to the following: 3.1. Acute or chronic graft versus host disease 3.2. Uncontrolled hypertension 3.3. Symptomatic congestive heart failure 3.4. Unstable angina pectoris 3.5. Myocardial infarction within past 6 months 3.6. Uncontrolled cardiac arrhythmia (CTCAE grade >2) 3.7. Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B or C) hepatitis 3.8. Psychiatric or social conditions that may interfere with participant compliance 3.9. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral 3.10. Ocular herpes simplex 3.11. Any other condition (including laboratory abnormalities) that in the opinion of the Investigator places the participant at unacceptable risk for adverse outcome if he/she were to participate in the study 4. Participants who have previously received Selinexor or any other selective inhibitor of Nuclear Export (SINE) compound 5. Previous anti-tumour therapies including investigational medicinal products at any dose within 28 days before the start of protocol treatment. (NB: Prednisone up to a dose of 175 mg per week may be given between screening and the beginning of treatment if medically required but should be stopped before trial treatment starts. Other steroids are not permitted. Bisphosphonates for bone disease are also permitted) 6. Participants with a history of a refractory nausea, diarrhoea, vomiting, malabsorption, gastrointestinal surgery or other procedures or conditions that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s) 7. Female participants who are lactating or have a positive pregnancy test at screening 8. Known allergy or intolerance to any of the study medications, their analogues, or excipients in the various formulations of any agent that would prevent participant receiving these as directed in the protocol. 9. Major surgery within 14 days prior to randomisation 10. Radiotherapy within 7 days prior to randomisation for palliative pain control or therapeutic radiotherapy within 14 days prior to randomisation 11. Myeloma involving the Central Nervous System Previous exclusion criteria: 1. The following participants will be excluded: 1.1. Those with non-measurable disease 1.2. Those with a solitary bone or solitary extramedullary plasmacytoma 1.3. Plasma cell leukaemia 2. Participants with a history of malignancy (other than myeloma) within 5 years before the date of randomisation (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that, in the opinion of the investigator, with concurrence with the Chief Investigator, is considered cured with minimal risk of recurrence within 5 years) 3. Participants with a known or underlying uncontrolled concurrent illness that, in the investigator’s opinion, would make the administration of the study drug hazardous or circumstances that could limit compliance with the study, including, but not limited to the following: 3.1. Acute or chronic graft versus host disease 3.2. Uncontrolled hypertension 3.3. Symptomatic congestive heart failure 3.4. Unstable angina pectoris 3.5. Myocardial infarction within past 6 months 3.6. Uncontrolled cardiac arrhythmia 3.7. Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B or C) hepatitis 3.8. Psychiatric or social conditions that may interfere with participant compliance 3.9. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral 3.10. Any other condition (including laboratory abnormalities) that in the opinion of the Investigator places the participant at unacceptable risk for adverse outcome if he/she were to participate in the study 4. Participants who have previously received Selinexor 5. Previous anti-tumour therapies including investigational medicinal products at any dose within 28 days before the start of protocol treatment. (NB: Prednisone up to a dose of 175 mg per week may be given between screening and the beginning of treatment if medically required but should be stopped before trial treatment starts. Bisphosphonates for bone disease are also permitted) 6. Participants with a history of a refractory nausea, diarrhoea, vomiting, malabsorption, gastrointestinal surgery or other procedures or conditions that might, in the opinion of the Investigator, interfere with the absorption or swallowing of the study drug(s) 7. Female participants who are lactating or have a positive pregnancy test at screening 8. Known allergy or intolerance to any of the study medications, their analogues, or excipients in the various formulations of any agent 9. Major surgery within 14 days prior to randomisation 10. Radiotherapy within 7 days prior to randomisation for palliative pain control or therapeutic radiotherapy within 14 days prior to randomisation 11. Chemotherapy or immunotherapy or any other anticancer therapy within 2 weeks prior to Cycle 1 Day 1 or radio-immunotherapy 4 weeks prior to Cycle 1 Day 1 (except steroids in the doses outlined above) 12. Myeloma involving the Central Nervous System
Date of first enrolment	20/06/2018
Date of final enrolment	30/05/2021

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

The Royal Marsden

Downs Road
Sutton
SM2 5PT
United Kingdom

St Bart’s Hospital

West Smithfield
London
EC1A 7BE
United Kingdom

Hammersmith Hospital - Imperial

Imperial College Healthcare NHS Trust
Du Cane Road
London
W12 0HS
United Kingdom

Royal Stoke University Hospital

Cancer Clinical Trials
Cancer Centre
Newcastle Road
Stoke-on-Trent
ST4 6QG
United Kingdom

Royal Hallamshire Hospital

Glossop Road
Sheffield
S10 2JF
United Kingdom

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

Worthing Hospital - University Hospitals Sussex

Lyndhurst Road
Worthing
BN11 2DH
United Kingdom

St Richards Hospital - University Hospitals Sussex

Spitalfield Lane
Chichester
PO19 6SE
United Kingdom

Birmingham Heartlands Hospital

Bordesley Green East
Birmingham
B9 5SS
United Kingdom

Guys & St Thomas Hospital

Guy's Hospital
Great Maze Pond
London
SE1 9RT
United Kingdom

Royal Bournemouth Hospital

Clinical Trial Office
Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Clatterbridge Cancer Centre

Clatterbridge Road
Wirral
CH63 4JY
United Kingdom

Norfolk and Norwich University Hospital

Colney Lane
Norwich
NR4 7UY
United Kingdom

Nottingham City Hospital

Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Sponsor information

University of Leeds
University/education

Research and Innovation Support
University of Leeds
Leeds
LS2 9JT
England
United Kingdom

"ROR"	https://ror.org/024mrxd33

Funders

Funder type

Charity

Myeloma UK; Grant Codes: HM17/95228
Government organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): Myeloma United Kingdom
Location: United Kingdom

Results and Publications

Intention to publish date	14/11/2024
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request, Data sharing statement to be made available at a later date
Publication and dissemination plan	The protocol will be published. Planned publication of the results in a high-impact peer-reviewed journal, 12 months after the trial ends
IPD sharing plan	De-identified individual participant data datasets generated and/or analysed during the current study will be available upon request from the Clinical Trials Research Unit, University of Leeds (contact CTRU-DataAccess@leeds.ac.uk in the first instance). Data will be made available at the end of the trial, i.e. usually when all primary and secondary endpoints have been met and all key analyses are complete. Data will remain available from then on for as long as CTRU retains the data. CTRU makes data available by a 'controlled access' approach. Data will only be released for legitimate secondary research purposes, where the Chief Investigator, Sponsor and CTRU agree that the proposed use has scientific value and will be carried out to a high standard (in terms of scientific rigour and information governance and security), and that there are resources available to satisfy the request. Data will only be released in line with participants' consent, all applicable laws relating to data protection and confidentiality, and any contractual obligations to which the CTRU is subject. No individual participant data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention, usually stipulating that data recipients must delete their copy of the released data at the end of the planned project. The CTRU encourages a collaborative approach to data sharing, and believe it is best practice for researchers who generated datasets to be involved in subsequent uses of those datasets. Recipients of trial data for secondary research will also receive data dictionaries, copies of key trial documents and any other information required to understand and reuse the released datasets. The conditions of release for aggregate data may differ from those applying to individual participant data. Requests for aggregate data should also be sent to the above email address to discuss and agree suitable requirements for release.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article		26/10/2022	27/10/2022	Yes	No
HRA research summary			28/06/2023	No	No
Basic results	version 1.0		28/10/2024	No	No

Additional files

ISRCTN15028850 MUK12_ISRCTN report_v1.0.pdf

Editorial Notes

NHW 28/10/2024: The basic results have been uploaded as an additional file.
23/01/2024: The intention to publish date was changed from 30/11/2023 to 14/11/2024.
11/01/2024: The total final enrolment was added.
13/12/2023: The overall study end date was changed from 30/11/2022 to 14/11/2023.
27/10/2022: Publication reference added.
19/07/2022: The participant level data sharing plan was added.
28/06/2021: The following changes have been made:
1. The participant exclusion criteria have been changed.
2. The recruitment start date has been changed from 01/04/2018 to 20/06/2018.
3. The intention to publish date has been changed from 01/04/2022 to 30/11/2023.
28/06/2021: The following changes have been made:
1. The recruitment end date has been changed from 31/10/2020 to 30/05/2021.
2. The overall trial end date has been changed from 01/04/2021 to 30/11/2022.
3. The scientific contact has been updated.
4. The trial participating centers "Royal Stoke University Hospital", "Royal Hallamshire Hospital", "Southampton General Hospital", "Worthing Hospital - University Hospitals Sussex", "St Richards Hospital - University Hospitals Sussex", "Birmingham Heartlands Hospital", "Guys & St Thomas Hospital", "Royal Bournemouth Hospital", "Clatterbridge Cancer Centre", "Norfolk and Norwich University Hospital", and "Nottingham City Hospital" have been added.
5. The trial participating center "Leicester Royal Infirmary" has been removed.
09/07/2020: The trial contact details have been made publicly visible.
15/04/2020: The scientific contact has been updated.
17/01/2020: Cancer Research UK lay summary link added to plain English summary field.
13/08/2019: Internal review.
27/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Haematological Oncology; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue" to "Relapsed or refractory multiple myeloma" following a request from the NIHR.