A Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis (CATALYST)
Amyloidosis
About this trial
This is an interventional treatment trial for Amyloidosis focused on measuring Amyloidosis, AL Amyloidosis
Eligibility Criteria
Inclusion Criteria:
Patients with the following characteristics are eligible for this study:
- Aged 18 years or greater
Diagnosis of systemic AL amyloidosis with:
- exclusion of genetic mutations associated with hereditary amyloidosis and immunohistochemical exclusion of AA and TTR amyloidosis as appropriate.
- Amyloid related organ dysfunction or organ syndrome
- Measurable clonal disease
- Clonal relapse after previous chemotherapy or stem cell transplant OR refractory clonal disease to previous chemotherapy or stem cell transplant
- Capable of providing written, informed consent and willing to follow study protocol
- Life expectancy ≥ 6 months
- ECOG performance status of <3
- Platelet count ≥ 50x109/l)
- Neutrophil count ≥ 1x109/l)
- Haemoglobin ≥ 8g/dL
- Bilirubin <2 times or Alkaline phosphatase <4 times upper limit of normal.
- 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. Participants must comply with the Celgene pregnancy prevention programme for thalidomide
Exclusion Criteria:
Patients with the following characteristics are ineligible for this study:
- Overt symptomatic multiple myeloma
- Amyloidosis of unknown or non AL type
- Localised AL amyloidosis (in which amyloid deposits are limited to a typical single organ, for example the bladder or larynx, in association with a clonal proliferative disorder within that organ)
- Trivial or incidental AL amyloid deposits in the absence of a significant amyloid related organ syndrome (e.g., isolated carpal tunnel syndrome).
- Refractory to or progressive disease with an IMid and proteasome inhibitor combination
- Allogeneic stem cell transplantation
- Solid organ transplantation
- Severe peripheral or autonomic neuropathy causing significant functional impairment.
- eGFR <20ml/min
- Ejection fraction < 40% or NYHA class III or IV heart failure or uncontrolled hypertension
- Pulmonary Hypertension
- Advanced Mayo stage III disease as defined by hs-Troponin T>0.07 and NT-proBNP >700 pMol/L OR NT-proBNP >1000 pMol/L OR supine SBP <100 mm of Hg
- Myocardial infarction in the preceeding 6 months or unstable angina or conduction abnormalities uncontrolled by medication or devices
- Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas
- Pregnant, lactating or unwilling to use adequate contraception
- Systemic infection unless specific anti-infective therapy is employed.
- Known or suspected HIV infection
- Contraindication to any of the required concomitant drugs or supportive treatments. Any other clinically significant medical disease or condition or psychiatric illness that, in the Investigator's opinion, may interfere with protocol adherence or a participant's ability to give informed consent
- Previous experimental agents or approved anti-tumour treatment within 3 months before the date of registration
- Known allergies to the IMPs
Sites / Locations
- Derriford Hospital
- Royal Bournemouth General Hospital
- Guy's Hospital
- Manchester Royal Infirmary
- Southampton General Hospital
- Leicester Royal Infirmary
- Norfolk and Norwich University Hospital
- Royal Hallamshire Hospital
- Freeman Hospital
- Birmingham Queen Elizabeth Hospital
- Birmingham Heartlands Hospital
- St James' University Hospital
- Bristol Haematology and Oncology Centre
- The Beatson West of Scotland Cancer Centre
Arms of the Study
Arm 1
Experimental
KTD treatment
Participants in the escalation phase will receive carfilzomib (K), thalidomide (T), and dexamethasone (D) in combination. The dose of thalidomide will be 50mg/day. The dose of dexamethasone will be 20mg on Day 1, 8, and 15. Carfilzomib will be administered on Day 1, 8, and 15, but the level of carfilzomib delivered with depend on the cohort allocation. The dose of carfilzomib may be: Level -1 - 27mg/m2 Level 0 - 36mg/m2 Level 1 - 45mg/m2 Level 2 - 56mg/m2 Participants will receive up to six cycles of treatment. Following determination of the maximum tolerated dose and recommended dose, the trial will be opened to an expansion phase where participants will receive the RD of carfilzomib, along with thalidomide and dexamethasone, using the schedule outlined above.