Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02545907
Other study ID # 14/0786
Secondary ID
Status Completed
Phase Phase 1/Phase 2
First received
Last updated
Start date September 14, 2017
Est. completion date October 21, 2019

Study information

Verified date November 2020
Source University College, London
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This study evaluates the safety and efficacy of carfilzomib used in combination with thalidomide and dexamethasone in patients with relapsed AL amyloidosis. The trial begins with a dose escalation phase, in which the maximum tolerated and recommended dose will be determined. The trial will then open into an expansion phase in which the combination efficacy is assessed.


Description:

Amyloidosis is a disorder of protein folding in which normally soluble proteins are deposited as abnormal, insoluble fibrils that progressively disrupt tissue structure and impair function. The treatment of systemic AL amyloidosis has evolved to a risk adapted approach based on the end organ damage, particularly cardiac involvement, and the functional status of the patient. Intensive therapies like high dose melphalan followed by an autologous stem cell transplant are considered for patients with limited organ involvement, younger age and excellent functional status. The majority of patients with AL amyloidosis, however, will not be candidates for ASCT and are generally treated with combination chemotherapy. This therapy may include bortezomib, a proteasome inhibitor which is particularly effective in AL amyloidosis but which may have a severe side-effect profile. Carfilzomib is specific for the chymotrypsin-like active site of the 20S proteasome, is structurally and mechanistically distinct from bortezomib, and has demonstrated less reactivity against non-proteasomal proteases when compared to bortezomib. It also appears to be better tolerated. However, information regarding the use of carfilzomib in the treatment of AL amyloidosis is limited. In the dose escalation phase of this study, a minimum of 6 (3 at dose level 0 and 3 at dose level -1)and a maximum of 18 (6 at dose level 0, 1, and 2) patients will recruited in a 3+3 design with cohorts of between 3 and 6 patients, in order to determine maximum tolerated dose and recommended dose. At the recommended dose level identified, a further 20 (minimum) patients will be recruited to further assess safety and toxicities at the RD.


Recruitment information / eligibility

Status Completed
Enrollment 10
Est. completion date October 21, 2019
Est. primary completion date September 26, 2019
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Patients with the following characteristics are eligible for this study: 1. Aged 18 years or greater 2. 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 3. Measurable clonal disease 4. Clonal relapse after previous chemotherapy or stem cell transplant OR refractory clonal disease to previous chemotherapy or stem cell transplant 5. Capable of providing written, informed consent and willing to follow study protocol 6. Life expectancy = 6 months 7. ECOG performance status of <3 8. Platelet count = 50x109/l) 9. Neutrophil count = 1x109/l) 10. Haemoglobin = 8g/dL 11. Bilirubin <2 times or Alkaline phosphatase <4 times upper limit of normal. 12. 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: 1. Overt symptomatic multiple myeloma 2. Amyloidosis of unknown or non AL type 3. 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) 4. Trivial or incidental AL amyloid deposits in the absence of a significant amyloid related organ syndrome (e.g., isolated carpal tunnel syndrome). 5. Refractory to or progressive disease with an IMid and proteasome inhibitor combination 6. Allogeneic stem cell transplantation 7. Solid organ transplantation 8. Severe peripheral or autonomic neuropathy causing significant functional impairment. 9. eGFR <20ml/min 10. Ejection fraction < 40% or NYHA class III or IV heart failure or uncontrolled hypertension 11. Pulmonary Hypertension 12. 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 13. Myocardial infarction in the preceeding 6 months or unstable angina or conduction abnormalities uncontrolled by medication or devices 14. Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas 15. Pregnant, lactating or unwilling to use adequate contraception 16. Systemic infection unless specific anti-infective therapy is employed. 17. Known or suspected HIV infection 18. 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 19. Previous experimental agents or approved anti-tumour treatment within 3 months before the date of registration 20. Known allergies to the IMPs

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Carfilzomib
Lyophilized carfilzomib for injection reconstituted with water to a final concentration of 2 mg/mL.
Thalidomide
50mg capsule.
Dexamethasone
2mg tablet.

Locations

Country Name City State
United Kingdom Birmingham Heartlands Hospital Birmingham West Midlands
United Kingdom Birmingham Queen Elizabeth Hospital Birmingham West Midlands
United Kingdom Royal Bournemouth General Hospital Bournemouth Dorset
United Kingdom Bristol Haematology and Oncology Centre Bristol
United Kingdom The Beatson West of Scotland Cancer Centre Glasgow
United Kingdom St James' University Hospital Leeds West Yorkshire
United Kingdom Leicester Royal Infirmary Leicester Leicestershire
United Kingdom Guy's Hospital London Greater London
United Kingdom Manchester Royal Infirmary Manchester Greater Manchester
United Kingdom Freeman Hospital Newcastle-upon-Tyne Tyne And Wear
United Kingdom Norfolk and Norwich University Hospital Norwich Norfolk
United Kingdom Derriford Hospital Plymouth Devon
United Kingdom Royal Hallamshire Hospital Sheffield South Yorkshire
United Kingdom Southampton General Hospital Southampton Hampshire

Sponsors (1)

Lead Sponsor Collaborator
University College, London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Number of Participants With Dose-Limiting Toxicities as Assessed by Reported Data Dose-Limiting Toxicities (Dose escalation phase), between the time of receiving the first registered dose of carfilzomib in cycle 1 and day 1 cycle 2, in order to establish the Maximum Tolerated Dose (MTD) of carfilzomib in combination with thalidomide and dexamethasone, will be assessed based on reported data. The number of reported dose limiting toxicities will be reported. After 1 cycle of treatment; to be completed within 1 year.
Primary Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0. The percentage of patients treated who experience any grade 3 or 4 toxicity as assessed by CTCAE v4.0 throughout all treatment cycles will be assessed based on reported data. Between informed consent provided and 30 days post last trial treatment administration, up to 7 months
Secondary Clonal Response Rate Within 3 Months, at 3 Months, Within 6 Months and at 6 Months as Determined by Paraprotein and Free Light Chain Assessment. Participant clonal response rate within 3 months, at 3 months, within 6 months and at 6 months will be assessed. The percentage of participants who achieve at least a partial response will be reported.
Clonal response is defined as:
CR: Negative immunofixation of serum and urine (serum alone in anuric patients) AND normal FLC concentration and kappa/lambda FLC ratio (FLC ratio alone in renal failure) AND =5% plasma cells in bone marrow without clonality by immunohistochemistry or immunofluorescencea
VGPR: >90% reduction in serum paraprotein or abnormal component of FLC or dFLC over the starting value or dFLC <40mg/L
PR: =50% decrease in aberrant FLC concentration or dFLC (or =50% decrease in dFLC if renal failure) or serum paraprotein but not fulfilling criteria for CR or VGPR
MR: >25% but <50% decrease in aberrant FLC or dFLC or paraprotein
NR: Not meeting FLC criteria for CR, PR or MR
Within 3 months, at 3 months, within 6 months and at 6 months
Secondary Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment. Amyloidotic organ response rate is assessed using the following criteria:
Heart - Interventricular septal thickness decreased by 2 mm or 10% improvement in ejection fraction or a 30% and 35 pMol/L reduction in NT-ProBNP (only applicable if there is no change or <25% improvement in renal function) or significant improvement in lateral wall TDI S wave and E/E' ratio
Kidney - 50% decrease (at least 0.5 g/day) in 24-hr urinary protein loss (urine protein must be>0.5 g/day pretreatment) without fall in creatinine clearance of =25% from baseline
Liver - 50% decrease in abnormal alkaline phosphatase value or a decrease in liver size radiographically by at least 2 cm
Nerve - Improvement in electromyogram nerve conduction velocity
Soft tissue - Definite clinical and/or radiographic improvement with associated functional improvement in affected tissue.
The percentage of patients who achieve organ response within 3 and 6 months of trial registration will be reported.
Within 3 months and 6 months
Secondary Time to Amyloidotic Organ Response Based on Reported Data. The time to amyloidotic organ response (as outlined above) will be assessed based on reported data. The number of months this takes will be reported. Within 6 months
Secondary Number of Deaths at 6 Months Based on Reported Data. The number of deaths at 6 months will be assessed and reported based on reported data. 6 months
Secondary Number of Patients Progression-free at 6 Months Based on Reported Data. The number of patients who are progression-free at 6 months will be assessed based on reported data. Patients who are progression-free will have not had an haematological relapse or organ progression.
Haematological relapse is defined as:
From CR: Increase in the aberrant serum free light chain concentration to outside the normal range and by a factor of =2 from that at the time of CR or re-appearance of the original paraprotein
From PR or VGPR: Increase in the aberrant free light chain concentration by a factor of =2 from that at the time of PR (=50% change in ratio away from normal in patients with renal failure) or doubling of the serum paraprotein level (if starting >5g/L) or doubling and increase of serum paraprotein to >5g/L (if starting <5g/L)
Organ progression is defined, by organ, as:
Heart: Interventricular septal thickness increased by >2 mm compared with baseline or 20% decline in ejection fraction
Kidney: 50% increase (at least 1 g/day) in 24-hr urinary
6 months
Secondary Maximum Response Determined by Paraprotein and Free Light Chain Assessment. The maximum response to therapy will be determined by assessing the best reported response for each participant. Maximum response will be determined based on free light chain and paraprotein assessments by the National Amyloidosis Centre. The data will be reported using the response rates observed (complete, very good partial, partial, no response). Within 6 months
Secondary Time to Maximum Response Based on Reported Data. The time to maximum response to treatment will be assessed by determining the time required for each participant to achieve maximum response (defined above), and will be presented on Kaplan-Meier curves. The number of months taken to achieve this maximum response will be reported. Time to maximum response was analysed overall only, and not by arm due the small sample size. Within 6 months
Secondary Number of Patients Withdrawing From Treatment Based on Reported Data. The number of patients withdrawing from treatment will be assessed based on reported data. Within 6 months
Secondary Number of Patients Experiencing Dose Delays Based on Reported Data. The number of patients experiencing dose delays will be assessed based on reported data. Within 6 months
Secondary Compliance Profile of KTD Based on Reported Chemotherapy Compliance Data. The compliant profile of participants to KTD will be assessed by determining the number of missed doses from recorded data. Participants will be regarded as compliant if participants have missed no more than 14 days of thalidomide, 2 days of dexamethasone, and 1 dose of carfilzomib per cycle. Compliance will be reported in terms of the number of participants who were compliant. Within 6 months
See also
  Status Clinical Trial Phase
Recruiting NCT04893889 - Substudy (NCT04456582): Noninvasive Assessment of Myocardial Stiffness by 2D-SWE Ultrasound Technique (Two-dimensional Shear Wave Elastography) in Patients With Amyloidosis and Fabry Disease. N/A
Withdrawn NCT04943302 - Isatuximab and Bendamustine in Systemic Light Chain Amyloidosis Phase 2
Active, not recruiting NCT02909036 - Study of Captisol Enabled Melphalan and Pharmacokinetics for Patients With Multiple Myeloma or Light Chain Amyloidosis That Are Receiving an Autologous Transplant. Phase 1
Completed NCT02816476 - Daratumumab Therapy for Patients With Refractory or Relapsed AL Amyloidosis Phase 2
Completed NCT01083316 - Bortezomib and Dexamethasone Followed by High-Dose Melphalan and Stem Cell Transplantation for Primary (AL) Amyloidosis Phase 2
Completed NCT01527032 - Risk-adapted Therapy for Primary Systemic (AL) Amyloidosis Phase 2
Recruiting NCT05263817 - A Clinical Study of CD19/BCMA CAR-T Cells in the Treatment of Refractory POEMS Syndrome, Amyloidosis, Autoimmune Hemolytic Anemia, and Vasculitis Early Phase 1
Active, not recruiting NCT03201965 - A Study to Evaluate the Efficacy and Safety of Daratumumab in Combination With Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Compared to CyBorD Alone in Newly Diagnosed Systemic Amyloid Light-chain (AL) Amyloidosis Phase 3
Withdrawn NCT02589860 - Analysis of Oral Mucositis in Patient's Undergoing Melphalan Conditioning and Autologous Stem Cell Transplant
Recruiting NCT05635266 - Tissue Repository Providing Annotated Biospecimens for Approved Investigator-directed Biomedical Research Initiatives
Completed NCT02574676 - Quality of Life (QOL) Registry for Patients With AL Amyloidosis
Active, not recruiting NCT02260466 - Prevalence and Post-surgical Outcomes of CARdiac Wild-type TransthyrEtin amyloidoSIs in Elderly Patients With Aortic steNosis Referred for Valvular Replacement. N/A
Withdrawn NCT02462213 - Prospective Identification of Cardiac Amyloidosis by Cardiac Magnetic Resonance Imaging N/A
Recruiting NCT05577819 - Prevalence and Prediction of ATTR in Ambulatory Patients With HFpEF N/A
Completed NCT01406314 - SAP Depleter Dose Assessment Study in Patients Phase 1
Not yet recruiting NCT04985734 - Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM) in Patients With Idiopathic Peripheral Neuropathy N/A
Active, not recruiting NCT03584022 - Clinical Trial to Assess the Safety of a Novel Scaffold Biomaterial N/A
Active, not recruiting NCT05235269 - A Study to Evaluate Organ Level Uptake Repeatability of 124I AT-01 in Subjects With Systemic Amyloidosis Phase 2
Active, not recruiting NCT05199337 - Phase 1/2 Study of ZN-d5 for the Treatment of Relapsed or Refractory Light Chain (AL) Amyloidosis Phase 1/Phase 2
Completed NCT02716103 - Assessment of Minimal Residual Disease (MRD) After Antineoplastic Treatment in Patients With AL Amyloidosis