Condition category
Cancer
Date applied
24/04/2017
Date assigned
08/05/2017
Last edited
16/10/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Public

Primary contact

Ms Rachael Kearns

ORCID ID

Contact details

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom
+44 113 343 30555
medmuk09@leeds.ac.uk

Additional identifiers

EudraCT number

2016-002670-12

ClinicalTrials.gov number

Protocol/serial number

33205

Study information

Scientific title

MUK nine b: OPTIMUM. A phase II study evaluating multiple novel agentsoptimised combination of biological therapy in newly diagnosed high risk multiple myeloma and plasma cell leukaemia

Acronym

OPTIMUM

Study hypothesis

The aim of this study is to look at whether a combination of four novel agents bortezomib (Velcade), lenalidomide (Revlamid) dexamethasone & Daratumumab (darzalex) with cyclophosphamide is active in a high risk patients, to take forward into a phase III trial compared to standard treatment.

Ethics approval

London- South East Research Ethics Committee, 25/01/2017, ref: 17/LO/0023

Study design

Non-randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Cancer, Primary sub-specialty: Haematological Oncology; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissu

Intervention

All participants undergo the following treatment:

Induction (6 cycles):
Cyclophosphamide 500mg, days 1, 8 Bortezomib 1.3mg/m2, days 1, 4, 8, 11 Lenalidomide 25mg, days 1-14 Daratumumab 16mg/kg, days 1, 8, 15 (cycles 1& 2), day 1 only from cycle 3 Dexamethasone 20-40mg, days 1, 4, 8, 11

ASCT stem cell harvest:
with Bortezomib 1.3mg/m2, (12 hours post melphalan) Bortezomib 1.3mg/m2, day +5, +14, weekly

Consolidation part 1 (6 cycles):
Bortezomib 1.3mg/m2 days 1, 8, 15, 22 Lenalidomide 25mg days 1-21 Daratumumab 16mg/kg day 1 Dexamethasone 20-40mg days 1, 8, 15, 22

Consolidation part 2 (12 cycles):
Bortezomib 1.3mg/m2 days 1, 8, 15 Lenalidomide 25mg days 1-21 Daratumumab 16mg/kg day 1

Maintenance (until disease progression):
Lenalidomide 10mg days 1-21 Daratumumab 16mg/kg day 1

Participants will be required to attend a follow up visit at 3 months post the end of treatment to allow any adverse reactions up to 90 days post the last dose of trial treatment to be documented.

Intervention type

Drug

Phase

Phase II

Drug names

1. Bortezomib (Velcade)
2. Lenalidomide (Revlamid)
3. Dexamethasone
4. Daratumumab (darzalex)

Primary outcome measures

Whether a combination of four novel agents bortezomib, lenalidomide, Daratumumab & dexamethasone in combination with low-dose cyclophosphamide is sufficiently active in a high risk population of myeloma patients, to take forward into a phase, as determined during analysis at the end of the recruitment.

Secondary outcome measures

1. The safety and toxicity profile will be determined by capturing AEs, ARs, SAEs and SUSARs from registrations to 90 days post treatment discontinuation
2. Clinical activity will be measured by collecting bone marrow samples and measuring response from registration until the end of the trial.
3. Treatment compliance is assessed by reviewing the patient’s data at the end of each cycle during the treatment period
4. Overall treatment benefit and a clinician’s assessment of treatment benefit is measured on how both the patient and clinicians feel that the patient is doing on treatment. This is captured at the end of induction therapy and 100 days post-ASCT
5. Quality of life will be captured on QOL questionnaires at the end of induction, 100 days post-transplant, at day 1 of consolidation 1 and 2 and at day 1 of maintenance

Overall trial start date

01/10/2014

Overall trial end date

31/12/2021

Reason abandoned

Eligibility

Participant inclusion criteria

1. Confirmation of High Risk status from ICR following bone marrow and blood sample processed through the MUKnine a screening protocol
2. Previously untreated participants, although participants may have received up to 2 cycles of CTD, CVD, CRD or VTD pre-trial induction chemotherapy while awaiting the results of the laboratory analysis from the MUK nine a Screening Protocol. (In addition, non-systemic therapy such as therapeutic plasma exchange, dexamethasone up to a maximum of 160mg or radiotherapy sufficient to alleviate or control pain or local invasion is permitted)
3. Measurable disease with at least one of the following or willing to undergo further bone marrows for assessment:
3.1. Paraprotein ≥ 5g/L or ≥ 0.5 g/L for IgD subtypes
3.2. Serum free kappa or lambda light chains ≥ 100 mg/L with abnormal ratio (for light chain only myeloma).
3.3. Urinary Bence Jones protein ≥ 200 mg/L
4. Non measurable participants providing they accept a 3 monthly bone marrow during induction and a 6 monthly bone marrow assessment during consolidation and maintenance
5. Aged 18 years or over
6. Fit for intensive chemotherapy and autologous stem cell transplant (at clinician's discretion)
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2
8. The Celgene Pregnancy Prevention Plan must be followed and participants must agree to comply with this:
8.1. Females of childbearing potential (FCBP) must agree to utilise two reliable forms of contraception simultaneously or practice complete abstinence for at least for 28 days prior to starting trial treatment, during the trial and for at least 28 days after trial treatment discontinuation, and even in case of dose interruption, and must agree to regular pregnancy testing during this timeframe
8.2. Males must agree to use a latex condom during any sexual contact with FCBP during the trial, including during dose interruptions and for 28 days following discontinuation from this trial even if he has undergone a successful vasectomy o Males must also agree to refrain from donating semen or sperm while on trial treatment including during any dose interruptions and for at least 6 months after discontinuation from this trial
o All participants must agree to refrain from donating blood while on trial drug including during dose interruptions and for 28 days after discontinuation from this trial
9. Calculated creatinine clearance ≥ 30mL/min (using Cockcroft-Gault formula)
10. ALT and/or AST ≤ 2.5 times upper limit of normal (ULN)
11. Bilirubin ≤ 2.0 x ULN, except in participants with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2.0 times ULN
12. Platelet count ≥ 75 x 109/L. (≥ 50 x 109/L if myeloma involvement in the bone marrow is >50%). Platelet support is permitted.
13. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L. Growth factor support is permitted
14. Haemoglobin ≥ 80 g/L. (Participants may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines.
15. Corrected serum calcium ≤ 3.5 mmol/L

Inclusion Criteria for ASCT
1. Minimum stem cell harvest of 2 x 106 CD34+ cells/kg body weight
2. Received a minimum of 4, unless CR has been achieved with a lesser number, or a maximum of 6 Induction (CVRDd) cycles
3. Achieved a response of SD or better

Inclusion Criteria for Consolidation Part 1 (VRDd)
1. Undergone autologous transplant with HDM-V conditioning (Participants must have received a minimum of 100 mg/m2 Melphalan in order to proceed with consolidation)
2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted
3. Platelet count ≥ 75 x 109/L. Platelet support is permitted

Inclusion Criteria for Consolidation Part 2 (VRD)
1. Received 6 cycles of Consolidation Part 1 (VRDd) or 1 cycle of VRd pre-harvest plus 5 cycles of Consolidation Part 1 (VRDd)
2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted
3. Platelet count ≥ 75 x 109/L. Platelet support is permitted

Inclusion Criteria for Maintenance (RD)
1. Received 12 cycles of Consolidation Part 2 (VRD)
2. Neutrophils ≥ 1.0 x 109/L. Growth factor support is permitted
3. Platelet count ≥ 75 x 109/L. Platelet support is permitted

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 95; UK Sample Size: 95

Participant exclusion criteria

1. Participants that have progressive disease
2. Solitary bone/solitary extramedullary plasmacytoma
3.Primary diagnosis of amyloidosis, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma or Waldenstrom’s Disease

Medical history and Concurrent disease:
1. Prior or concurrent invasive malignancies except the following:
1.1. Adequately treated basal cell or squamous cell skin cancer
1.2. Incidental finding of low grade (Gleason 3+3 or less) prostate cancer
1.3. Any cancer from which the subject has been disease free for at least 3 years
2. Known/underlying medical conditions that, in the investigator’s opinion, would make the administration of the study drug hazardous (e.g uncontrolled diabetes or uncontrolled coronary artery disease)
3. Any clinically significant cardiac disease, including:
3.1. Myocardial infarction within 1 year before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV
3.2. Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4 Grade > = 2) or clinically significant ECG (Electrocardiogram) abnormalities
3.3. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) > 470 msec
4. Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second < 60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (intermittent asthma is allowed). Participants with known or suspected COPD or asthma must have a FEV1 test during screening
5. Known to be seropositive for history of human immunodeficiency virus (HIV) or known to have active hepatitis B or hepatitis C
6. Any known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products
7. Clinically significant allergies or intolerance to cyclophosphamide, lenalidomide, velcade, daratumumab or dexamethasone
8. Previous treatment with daratumumab or any other anti-CD38 therapies
9. Participants with contraindication to thromboprophylaxis
10. Grade 2 or greater peripheral neuropathy (per NCI-CTCAEv4.0)
11. Participants with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
12. Any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study
13. Known or suspected of not being able to comply with the study protocol (e.g. because of alcoholism, drug dependency, or psychological disorder). Participant has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g. compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
14. Participant is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this trial, 4 months after the last dose of trial treatment. Or, participant is a man who plans to father a child while taking part in this trial, within 4 months after the last dose of trial treatment
15. Major surgery within 2 weeks before treatment protocol registration or has not fully recovered from surgery, or has surgery planned during the time the participant is expected to participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery
16. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before treatment protocol registration or is currently enrolled in an interventional investigational study

Recruitment start date

30/05/2017

Recruitment end date

30/11/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

The Royal Marsden NHS Foundation Trust
Fulham road
London
SW3 6JJ
United Kingdom

Trial participating centre

University Hospitals of Leicester NHS Trust
Gwendolen House Gwendolen Road
Leicester
LE5 4QF
United Kingdom

Trial participating centre

Southampton University Hospitals NHS Trust
Mailpoint 18 s Southampton General Hospital Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Barts and the London NHS Trust
Trust offices Whitechapel The Royal London Hospital
London
E1 1BB
United Kingdom

Trial participating centre

Leeds Teaching Hospitals NHS Trust
St. James's University Hospital Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

King's College Hospital NHS Foundation Trust
Denmark Hill
London
SE5 9RS
United Kingdom

Trial participating centre

Guy's and St Thomas' NHS Foundation Trust
Trust Offices Guy's hospital Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

University Hospitals Bristol NHS Foundation Trust
Marlborough Street
Bristol
BS1 3NU
United Kingdom

Trial participating centre

University Hospital Birmingham NHS Foundation Trust
Trust HQ PO box 9551 Queen Elizabeth Medical Centre Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Heart of England NHS Foundation Trust Birmingham
Heartlands Hospital Bordesley Green East
Birmingham
B9 5ST
United Kingdom

Trial participating centre

Nottingham University Hospitals NHS Trust
Trust Headquarters QMC Campus Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

Central Manchester University Hospitals NHS Foundation Trust
Trust Headquarters, Cobbett House Manchester Royal Infirmary Oxford Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

Belfast City Hospital
Department of Haematology Lisburn Road
Belfast
BT9 7AB
United Kingdom

Trial participating centre

NHS Tayside
Department of Haematology Ninewells Hospital
Dundee
DD2 1UB
United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre
Department of Haematology 1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Trial participating centre

Cambridge University Hospitals NHS Foundation Trust
Addenbrookes Hospital Hills road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Oxford Radcliffe Hospitals NHS Trust
John Radcliffe Hospital Headley way Headington
Oxford
OX3 9DU
United Kingdom

Sponsor information

Organisation

University of Leeds

Sponsor details

Leeds Sponsor Quality Assurance Office
34 Hyde Terrace
Leeds
LS9 6LN
United Kingdom
+44 113 392 6473
daniel.skinner@nhs.net

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

Myeloma UK

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal

IPD Sharing plan:
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Intention to publish date

01/12/2014

Participant level data

Other

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

16/10/2017: Internal review. 11/08/2017: Internal review. 06/06/2017: Internal review.