AmyloidosisPhase 1/2CATALYSTNCT02545907
A Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis
A Phase 1/2 study testing Carfilzomib, Thalidomide and Dexamethasone in people with Amyloidosis, run by University College, London at 14 sites in United Kingdom.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Amyloidosis
- What is being tested?
- Carfilzomib, Thalidomide and Dexamethasone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 14 sitesUnited Kingdom
- Study dates
- 14 Sep 2017to 21 Oct 2019
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
United Kingdom14 sites
Birmingham Queen Elizabeth Hospital
Birmingham, West Midlands, B15 2TH
Birmingham Heartlands Hospital
Birmingham, West Midlands, B9 5SS
Royal Bournemouth General Hospital
Bournemouth, Dorset, BH7 7DW
Bristol Haematology and Oncology Centre
Bristol, BS2 8ED
The Beatson West of Scotland Cancer Centre
Glasgow, G12 0YN
St James' University Hospital
Leeds, West Yorkshire, LS9 7TF
Leicester Royal Infirmary
Leicester, Leicestershire, LE1 5WW
Guy's Hospital
London, Greater London, SE1 7EH
Manchester Royal Infirmary
Manchester, Greater Manchester, M13 9WL
Freeman Hospital
Newcastle upon Tyne, Tyne and Wear, NE7 7DN
Norfolk and Norwich University Hospital
Norwich, Norfolk, NR4 7UY
Derriford Hospital
Plymouth, Devon, PL6 8DH
Royal Hallamshire Hospital
Sheffield, South Yorkshire, S10 2JF
Southampton General Hospital
Southampton, Hampshire, SO16 6YD
About this study
Official title: A Single Arm Open Labeled Multicentre Phase 1b Dose Escalation Study of Carfilzomib Taken in Combination With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis
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.
Read the detailed 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.
- Conditions
- Amyloidosis
- Being tested
- Carfilzomib, Thalidomide, Dexamethasone
- Keywords
- Amyloidosis, AL Amyloidosis
- Medical subject headings
- Amyloidosis, Immunoglobulin Light-chain Amyloidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CarfilzomibDrug
Also called Kyprolis
Lyophilized carfilzomib for injection reconstituted with water to a final concentration of 2 mg/mL.
ThalidomideDrug
Also called Thalidomide Celgene
50mg capsule.
DexamethasoneDrug
Also called Decadron
2mg tablet.
| Study group | Role | What they receive |
|---|---|---|
| KTD treatment | Experimental | 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. Receives: Drug: Carfilzomib; Drug: Thalidomide; Drug: Dexamethasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: After 1 cycle of treatment; to be completed within 1 year.
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.
Measured: Between informed consent provided and 30 days post last trial treatment administration, up to 7 months
Secondary outcomes (10)
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
Measured: Within 3 months, at 3 months, within 6 months and at 6 months
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.
Measured: Within 3 months and 6 months
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.
Measured: Within 6 months
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.
Measured: 6 months
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
Measured: 6 months
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).
Measured: Within 6 months
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.
Measured: Within 6 months
Number of Patients Withdrawing From Treatment Based on Reported Data.
The number of patients withdrawing from treatment will be assessed based on reported data.
Measured: Within 6 months
Number of Patients Experiencing Dose Delays Based on Reported Data.
The number of patients experiencing dose delays will be assessed based on reported data.
Measured: Within 6 months
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.
Measured: Within 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Sep 2015 (estimated)
- Study start14 Sep 2017
- Primary completion26 Sep 2019
- Study completion21 Oct 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for AmyloidosisStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ashutosh Wechalekar, Dr, Principal investigator, University College London, National Amyloidosis Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02545907
- Sponsor's protocol ID
- 14/0786
- Acronym
- CATALYST
- Status last verified
- Nov 2020
- First submitted
- 27 Aug 2015
- Last updated
- 15 Apr 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No