Optimising Renal Outcome in Myeloma Renal Failure

Multiple Myeloma Clinical Trial

— OPTIMAL  

Official title:

A Study of Thalidomide, Bendamustine and Dexamethasone (BTD) Versus Bortezomib, Bendamustine and Dexamethasone (BBD) in Patients With Renal Failure Defined as a GFR Below 30 Mls/Min

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02424851
• Other study ID #: 26866138-MMY2070
• Secondary ID: 2012-003947-31
• Status: Completed
• Phase: Phase 2
• Start date: November 2014
• Est. completion date: April 20, 2020

Study information

• Verified date: January 2022
• Source: Oxford University Hospitals NHS Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the effectiveness of bortezomib versus thalidomide in reducing free light chains in the blood of myeloma patients. In addition participants will receive bendamustine (chemotherapy) and dexamethasone (steroids), which increase the effectiveness of both bortezomib and thalidomide. The trial will also study whether an earlier reduction of free light chains increases the chances of the kidneys recovering.

Description:

Renal impairment is a life threatening condition of myeloma. 20-25% of patients will present at diagnosis with renal dysfunction. Outcome is poor due to high early mortality, with 28% of newly diagnosed myeloma patients in myeloma trials with renal failure not surviving beyond 100 days, compared with 10% overall. This study aims to establish: 1. Whether proteosomal inhibition (bortezomib) or immunomodulatory (thalidomide) based therapy achieves threshold reduction of serum free light chains (sFLCs) in a significant majority of patients. 2. Whether sFLC response to the first 2 cycles (early responder) predicts haematological and renal response to the next 2 cycles of therapy. 3. An early time point for assessment of sFLC reduction as a biomarker for response. Participants will be stratified by age and chronic kidney disease (CKD) stage to receive either bortezomib, bendamustine and dexamethasone (BBD) or thalidomide, bendamustine and dexamethasone (BTD).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: April 20, 2020
• Est. primary completion date: April 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the trial.
• Patients attending NHS (National Health Service) Haemato-oncology centres.
• Patients with newly diagnosed symptomatic myeloma.
• Glomerular Filtration Rate (GFR) <30 mls/min.
• Chronic kidney disease (CKD) staging is based on estimated or measured GFR. CKD stage 4 (15-29 ml/min) and CKD stage 5 (<15 ml/min) are eligible to enter the study. It is expected centres will consider use of fluid resuscitation and pulsed dose of steroid therapy in this group of patients to salvage renal function prior to trial screening.
• 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 (e.g. hypertension, diabetes) which may cause renal damage, there must have been a further decline (=15 mls/min GFR) between previous steady state and the study screening.
• Female participants of childbearing potential and male patients whose partner is a woman of childbearing potential 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.
• Women of childbearing potential 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.
• 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.
• In the Investigator's opinion, is able and willing to comply with all trial requirements.
• Willing to allow his or her General Practitioner and consultant, if appropriate, to be notified of participation in the trial.

Exclusion Criteria:

• Female participant 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.
• Known allergy to investigational drugs.
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants 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.
• Any of the following laboratory abnormalities:
• Absolute neutrophil count (ANC) < 1.0 x10^9/L
• Platelet count <75 x 10^9/L
• Serum SGOT/AST or SGPT/ALT (serum glutamic oxaloacetic transaminase/aspartate aminotransferase or serum glutamic pyruvic transaminase/alanine aminotransferase) >3 x upper limit of normal.
• Use of any standard/experimental anti-myeloma drug therapy excluding dexamethasone 14 days prior to trial entry.
• CKD stages < 4.
• Intention to use a physical method of serum free light chain removal such as plasma exchange or high cut off dialysis.
• Grade 2 neuropathy or more (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.0) will preclude use of thalidomide and bortezomib.
• Participants who have participated in another research trial involving an investigational product in the past 12 weeks.
• Contraindicated to receive either one of the study drugs, thalidomide, bortezomib, bendamustine based on the respective summary of product characteristics.

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Kidney Diseases
• Multiple Myeloma
• Neoplasms, Plasma Cell
• Renal Insufficiency
• Renal Insufficiency, Chronic

Intervention

Drug:
• Bortezomib
1.3 mg/m2 subcutaneously* days 1, 4, 8 and 11 of each cycle. Number of cycles: Four 21 day cycles (participants not suitable for ASCT (autologous stem cell transplant) will continue up to 6 cycles on the treatment regimen to which they were randomised). *intravenous infusion available in case of patient intolerance to subcutaneous bortezomib
• Thalidomide
100 mg daily orally, preferably at night, days 1-21 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised)
• Bendamustine
60 mg/m2 i.v. days 1 and 8 of each cycle. Four 21 day cycles (participants not suitable for ASCT will continue up to 6 cycles on the treatment regimen to which they were randomised)
• Dexamethasone
40mg orally days 1-2, 4-5, 8-9 and 11-12 of each cycle

Locations

Country	Name	City	State
United Kingdom	Basingstoke & North Hampshire Hospital	Basingstoke
United Kingdom	Heartlands Hospitals	Birmingham
United Kingdom	Kent & Canterbury Hospital	Canterbury
United Kingdom	St Helier Hospital	Epsom
United Kingdom	Royal Liverpool Hospital	Liverpool
United Kingdom	Kings College Hospital	London
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Queen Alexandra Hospital	Portsmouth
United Kingdom	Great Western Hospital	Swindon

Sponsors (5)

Lead Sponsor	Collaborator
Oxford University Hospitals NHS Trust	Bloodwise, Janssen-Cilag Ltd., University of Birmingham, University of Warwick

Country where clinical trial is conducted

United Kingdom, 

References & Publications (26)

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Pönisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig W, Niederwieser D; East German Study Group of Hematology and Oncology (OSHO). Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone--a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO). J Cancer Res Clin Oncol. 2006 Apr;132(4):205-12. Epub 2006 Jan 10. — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With >50% Reduction From Baseline in Serum Free Light Chain		End of week 6 (after receiving two cycles of therapy)
Primary	Number of Participants With Different Renal Responses to Treatment		End of week 12 (after receiving 4 cycles of therapy)
Secondary	Haematological and Non-haematological Toxicity in Both Treatment Arms		End of weeks 3, 6, 9, 12 (after receiving 4 cycles of therapy), 30 days after final treatment and 12 months after randomisation
Secondary	Overall Survival		1 month post end of treatment and 1 year post randomisation
Secondary	Renal Response After Two Cycles of Trial Treatment		End of 2nd treatment cycle, week 6
Secondary	Quality of Life Measured by the EQ-5D-3L Questionnaire at Baseline and 1 Month Follow up	The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is scored on a scale of 1 to 3: 1 (no problems), 2 (some problems), and 3 (extreme problems). Higher score equates to a worse outcome.; As stated in the official EQ-5D user guide, patient responses to the 5 questions were converted into a single index value as per Dolan P (1997). Modeling valuations for EuroQol health states. Med Care 35(11):1095-108. These index values, with country specific value sets, facilitate the calculation of quality-adjusted life years (QALYs) that are used to inform economic evaluations of health care interventions. In the UK, the values range from -0.594 to +1.	Baseline and 1 month follow up

External Links

•   Cancer Research UK - Myeloma Statistics