MUK5

Trial overview

A phase II randomised trial of carfilzomib, cyclophosphamide and dexamethasone (CCD) vs cyclophosphamide, velcade and dexamethasone (CVD) for first relapse and primary refractory multiple myeloma

Inclusion criteria

Participants must meet all of the following inclusion criteria to be eligible to register in this trial. Eligibility waivers will not be permitted under any circumstances.

Disease-related:

* Diagnosed with symptomatic MM (according to IMWG 2003 criteria) and requiring therapy for first relapse or primary refractory disease (according to appendix 2). (Participants previously immunofixation negative who are now immunofixation positive need to demonstrate a greater than 5g/l absolute increase in paraprotein to be eligible for inclusion).

* Participants with measurable disease as defined by one or more of the following criteria (assessed within 21 days prior to randomisation):

- Serum paraprotein ≥ 5 g/L (For IgA participants whose disease can only be reliably measured by serum quantitative immunoglobulin (IgA): ≥ 7.5 g/L)

- Urine Bence Jones Protein: ≥ 200 mg/24 h

- Serum LC assay: Involved FLC level ≥100 mg/L, provided serum FLC ratio is abnormal

Demographic:

* Age ≥ 18 years

* Life expectancy ≥ 6 months

* Eastern Cooperative Oncology Group (ECOG) performance status 0–2

 Laboratory:

* Adequate hepatic function, with ALT or AST <3 times the upper limit of normal and serum direct bilirubin ≤ 17 μmol/L (1mg/100 ml) within 14 days prior to randomisation

* Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomisation. Growth factor support is not permitted. ANC ≥ 0.8 × 109/L is allowed for participants with racial neutropenia.

* Haemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomisation (participants may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)

* Platelet count ≥ 75 × 109/L (≥ 50 × 109/L if myeloma involvement in the bone marrow is > 50%) within 14 days prior to randomisation. Platelet support is not permitted

* Creatinine clearance (CrCl) ≥ 20 mL/minute or plasma creatinine ≤ 120 μmol/L within 14 days prior to randomisation, either measured or calculated using a standard formula (eg, Cockcroft-Gault)

 Ethical/Other:

* Written informed consent

* Female participants of child-bearing potential must have a negative pregnancy test prior to treatment and agree to use dual methods of contraception for the duration of the study and for 30 days following completion of study. Male participants must also agree to use a barrier method of contraception for the duration of the study and for 30 days following completion of study if sexually active with a female of child-bearing potential.

 

Exclusion criteria

 Disease-related

* Non-secretory multiple myeloma

* Extramedullary plasmacytoma (without evidence of myeloma)

* Received therapy for their first relapsed or primary refractory disease other than local radiotherapy, therapeutic plasma exchange, or dexamethasone up to a maximum of 200mg. (Radiotherapy sufficient to alleviate or control pain or local invasion is permitted).

* Previous bortezomib therapy is permitted, providing participant was not refractory (achieved at least a PR, and no disease progression within 6 months of last dose of bortezomib)

* Previous carfilzomib therapy

 * Pregnant or lactating females

* Major surgery within 21 days prior to randomisation

* Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomisation

* Known human immunodeficiency virus infection (testing is not required for the trial)

* Active hepatitis B or C infection

* Unstable angina or myocardial infarction within 6 months prior to randomisation, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless participant has a pacemaker, history of torsade de pointe, QTc prolongation (> 450 msec), LVEF < 40

* Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomisation

* Previous or concurrent malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localised transitional cell carcinoma of the bladder or benign tumours of the adrenal or pancreas

* Significant neuropathy (Grades 3–4, or Grade 2 with pain) within 14 days prior to randomisation

* Participants with haemorrhagic cystitis

* Participants undergoing active treatment for infiltrative lung disease

* Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and anti-platelet options, antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment

* Contraindication to a programme of oral or IV hydration

* Participants with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomisation

* Any other clinically significant medical disease or condition that, in the Investigator’s opinion, may interfere with protocol adherence or a participant’s ability to give informed consent

 

Contact details

Research Nurse

Lindsay Taylor

Tel 01132068577

Email lindsay.taylor5@nhs.net



Other trials currently active for Multiple Myeloma

Myeloma XI

Myeloma XI is intended to be a unifying trial addressing issues in patients of all ages and providing a strategy within which to introduce new treatments as they become available.

There are two distinct treatment pathways.

Intensive pathway: for younger/fitter patients where intensive HDT with stem cell support is considered appropriate.  Comparing a thalidomide-containing regimen with a lenalidomide-containing regimen, as induction treatment prior to HDT.

Non-intensive pathway: for older/less fit patients where standard-dose chemotherapy is considered appropriate. To compare an attenuated thalidomide-containing regimen with an attenuated lenalidomide-containing regimen.

 

LenaRIC

LenaRIC -  Phase II study of the adjunctive use of Lenalidomide in patients undergoing reduced intensity conditioning allogenic transplantation for multiple myeloma.

MUK8

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


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