OPTIMAL: OPTimising renal outcome in Myeloma renal failure

ISRCTN	ISRCTN32505664
DOI	https://doi.org/10.1186/ISRCTN32505664
EudraCT/CTIS number	2012-003947-31
ClinicalTrials.gov number	NCT02424851
Secondary identifying numbers	26866138-MMY2070

Submission date: 19/06/2014
Registration date: 19/06/2014
Last edited: 12/12/2022

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

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-bortezomib-and-thalidomide-in-people-with-myeloma-whose-kidneys-are-not-working-well-optimal

Contact information

Dr Karthik Ramasamy
Scientific

Late Phase Haematology Research Team
Cancer & Haematology Centre
Churchill Hospital Old Road
Headington
Oxford
OX3 7LE
United Kingdom

Email	OPTIMAL.trial@nhs.net

Study information

Study design	Randomised; Interventional; Design type: Process of Care
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
Scientific title	A study of Thalidomide, Bendamustine, and Dexamethasone (BTD) vs Bortezomib, Bendamustine, and Dexamethasone (BBD) in patients with renal failure defined as a GFR below 30 ml/min
Study acronym	OPTIMAL
Study objectives	Renal impairment is a life-threatening complication of myeloma. Up to 20-25% of patients will present at myeloma diagnosis with renal dysfunction. In this Phase II study, 120 newly diagnosed myeloma patients with eGFR less than 30 ml/min from approximately 20 centres will be randomised to receive either Thalidomide or Bortezomib; all patients will receive bendamustine and dexamethasone in three weekly cycles. All patients will receive a minimum of four cycles. Aims: 1. Establish whether proteasomal inhibition (bortezomib) or IMiD (thalidomide) based therapy achieves threshold reduction of sFLC in a significant majority of patients 2. Establish whether sFLC response to the first two cycles (early responder) predicts haematological and renal response to the next two cycles of therapy 3. Establish an early time point for assessment of sFLC reduction as a biomarker for response
Ethics approval(s)	Northeast Newcastle and North Tyneside2 (NNT2) Committee, 03/03/2014, ref:13-NE-0361;
Health condition(s) or problem(s) studied	Topic: Cancer; Subtopic: Haematological Oncology; Disease: Myeloma
Intervention	BTD vs BBD, Thalidomide + Bendamustine + Dexamethasone (BTD) vs Bortezomib + Bendamustine + Dexamethasone (BBD); Follow Up Length: 12 month(s); Study Entry: Single Randomisation only Added 16/02/2017: Potential eligible participants are screened and baseline assessments undertaken including: medical history; treatment history; concomitant medications; bone imaging; local laboratory evaluations. Eligible patients are randomised to one of two treatment groups, stratified by age and Chronic Kidney Disease (CKD) stage. Group 1: Bortezomib, Bendamustine and Dexamethasone (BBD) Participants receive Bortezomib 1.3 mg/m2 subcutaneous on days 1, 4, 8 and 11. They receive Bendamustine 60 mg/m2 intravenous infusion on days 1 and 8. They also take Dexamethasone 40 mg daily orally on days 1-2,4-5,8-9,11-12. Group 2: Thalidomide, Bendamustine and Dexamethasone (BTD) Participants take Thalidomide 100 mg daily p.o. preferably at night for 21 days. They receive Bendamustine 60 mg/m2 intravenous infusion on days 1 and 8. They also take Dexamethasone 40 mg daily orally on days 1-2,4-5,8-9,11-12. Participants are randomised to receive up to 4 cycles of either Bortezomib (Arm A) or Thalidomide (Arm B) (21 days in each cycle). All participants receive Bendamustine and Dexamethasone as combination therapy. Participants not considered suitable for autologous stem cell transplant (ASCT) may be given a further two cycles of their allocated treatment (up to 6 cycles in total). During treatment assessments are undertaken including: physical examination; concomitant medications, local laboratory evaluations and adverse event reporting. All participants who have received at least 2 cycles of their allocated treatment are followed up at 1 month post end of treatment (approximately 30 days after last dose) and 12 months post randomisation. These assessments include physical examination, disease status, treatment efficacy, overall survival and local laboratory evaluations. Participants are asked to complete a validated (EQ-5D- 3L) Quality of Life questionnaire at screening (baseline), on day 1 of each treatment cycle and at 1 month and 12 month follow-up. Central laboratory samples are collected at screening (baseline), during treatment and at 1 month follow up and sent to both Oxford and Birmingham.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Thalidomide + Bendamustine + Dexamethasone (BTD), Bortezomib + Bendamustine + Dexamethasone (BBD)
Primary outcome measure	Response defined as >50% reduction (from baseline) in sFLC week 6 (end of cycle 2) Added 16/02/2017: 1. Serum free light chain response is measured as the proportion of participants with response defined as >50% reduction (from baseline) in sFLC week 6 (end of cycle 2). 2. Myeloma response is measured by the renal response (Modified IMWG Uniform Criteria Of Response and Progression) at the end of 4 cycles of therapy
Secondary outcome measures	Renal response at end of four cycles of therapy. Added 16/02/2017: 1. Overall response and correlation with monoclonal protein the urine is measured by the sFLC response at week 1, 2, 3, 4, 5, 6, 9 and 12 2. Haematological and non-hameatological toxicity in both arms is preasured by haematological responses adverse Events (NCI CTCAE v4.0) criteria 3. Survival at 1 month post end of treatment and 12 months post randomisation 4. change in renal function between the two treatment regimens is assessed by the renal response (defined by the IMWG renal response criteria) at the end of cycle 2 and cycle 4 5. Treatment effects on other patient reported outcomes is measured by the EQ-5D-3L Quality of life questionnaire at baseline, start of each treatment cycle and at 1 and 12 months post follow-up
Overall study start date	06/06/2014
Completion date	01/06/2020

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Both
Target number of participants	Planned Sample Size: 120; UK Sample Size: 120
Total final enrolment	31
Key inclusion criteria	1. Patients attending NHS haemato-oncology centres 2. Patients with newly diagnosed symptomatic myeloma and renal failure 3. Patients willing and able to give written informed consent 4. Chronic kidney disease stage 4 or 5 5. GFR <30 ml/min 6. A number of patients with newly diagnosed myeloma and renal failure will have a pre-existing medical condition (hypertension, diabetes etc) causing renal damage. Where there is a medical condition (eg. hypertension, diabetes) which may cause renal damage, there must have been a further decline (=15 ml/min) between previous steady state and the study screening 7. Women of childbearing potential (WCBP) and male participants whose partner is a WCBP must be prepared to use contraception in accordance with (and consent) to the Celgene-approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention Programme 8. WCBP must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene-approved process for thalidomide and lenalidomide Risk Management and Pregnancy Prevention 9. Free of prior malignancies for = 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, localised prostate cancer or carcinoma 'in situ' of the cervix or breast 10. In the Investigator's opinion, is able and willing to comply with all trial requirements 11. Willing to allow his or her GP and consultant, if appropriate, to be notified of participation in the trial
Key exclusion criteria	1. Female patient who is pregnant, lactating or planning pregnancy during the course of the trial or the female partner of a male participant planning a pregnancy during the course of the trial 2. Age <18 years 3. Known allergy to investigational drugs 4. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial 5. Any of the following laboratory abnormalities: 5.1. Absolute neutrophil count (ANC) <1.0 x 10(9)/L 5.2. Platelet count <75 x 10(9)/L 5.3. Serum SGOT/AST or SGPT/ALT >3 x upper limit of normal 6. Use of any standard/experimental anti-myeloma drug therapy 14 days prior to trial entry 7. CKD <4 8. Intention to use a physical method of serum free light chain removal such as plasma exchange or high cut-off dialysis 9. Grade 2 neuropathy (NCICTCAE v 4.0) or more will preclude use of thalidomide and bortezomib 10. Participants who have participated in another research trial involving an investigational product in the past 12 weeks.
Date of first enrolment	21/03/2015
Date of final enrolment	31/03/2019

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

Churchill Hospital, Oxford (lead site)

Oxford University Hospitals NHS Foundation Trust
Old Road
Oxford
OX3 7LE
United Kingdom

St Helier Hospital

Epsom and St Helier University Hospitals NHS Trust
Wrythe Lane
Sutton
Carshalton
SM5 1AA
United Kingdom

Queen Alexandria Hospital

Portsmouth Hospitals NHS Trust
Southwick Hill Road
Portsmouth
PO6 3LY
United Kingdom

Basingstoke and North Hampshire Hospital

Hampshire Hospitals NHS Foundation Trust
Aldermaston Road
Basingstoke
RG24 9NA
United Kingdom

Kent and Canterbury Hospital

East Kent Hospitals University NHS Foundation Trust
Ethelbert Road
Canterbury
Kent
Canterbury
CT1 3NG
United Kingdom

Royal Liverpool Hospital

Royal Liverpool Hospital and Broadgreen University Hospitals NHS Trust
Prescot Street
Liverpool
L7 8XP
United Kingdom

Sponsor information

Oxford University Hospitals NHS Foundation Trust
Hospital/treatment centre

Headley Way
Headington
Oxford
OX3 9DU
England
United Kingdom

Website	http://www.ouh.nhs.uk/
"ROR"	https://ror.org/03h2bh287

Funders

Funder type

Charity

Bloodwise
Private sector organisation / Other non-profit organizations

Location: United Kingdom

Janssen Cilag International NV

No information available

Results and Publications

Intention to publish date	01/12/2020
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Other
Publication and dissemination plan	Final study report and publication planned 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.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results	EU Clinical Trials Register results	23/05/2021	20/05/2022	No	No
Basic results	ClinicalTrials.gov results	27/01/2022	23/05/2022	No	No
Protocol file	version 12.0	01/08/2017	07/07/2022	No	No
Protocol article	results	29/11/2022	12/12/2022	Yes	No

Additional files

ISRCTN32505664_Protocol_V12.0_01Aug2017.pdf

Editorial Notes

12/12/2022: Publication reference added.
07/07/2022: The following changes have been made:
1. The recruitment start date has been changed from 06/06/2014 to 21/03/2015.
2. A protocol file has been uploaded.
23/05/2022: ClinicalTrials.gov results added.
20/05/2022: EU Clinical Trials Register results added.
29/04/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/10/2017 to 31/03/2019.
2. The overall trial end date was changed from 30/10/2018 to 01/06/2020.
3. The intention to publish date was changed from 30/10/2019 to 01/12/2020.
4. The total final enrolment number was added.
25/04/2019: No publications found. Verifying results with principal investigator.
22/02/2017: Basingstoke and North Hampshire Hospital, Kent and Canterbury Hospital and Royal Liverpool Hospital have been added as trial participating centres.
16/02/2017: Overall trial end date was changed from 28/02/2016 to 30/10/2018. Recruitment end date changed from 28/02/2016 to 30/10/2017. Churchill Hospital, St Helier Hospital and Queen Alexandria Hospital as trial participating centres have been added. Changed contact from Elizabeth Ward to Karthik Ramasamy. Please note that NAPP Pharmaceuticals is no longer funding the study and Bloodwise charity (formerly LLR) has funded from the start of this study.