A Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis (CATALYST)
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|ClinicalTrials.gov Identifier: NCT02545907|
Recruitment Status : Unknown
Verified September 2015 by University College, London.
Recruitment status was: Not yet recruiting
First Posted : September 10, 2015
Last Update Posted : September 10, 2015
|Condition or disease||Intervention/treatment||Phase|
|Amyloidosis||Drug: Carfilzomib Drug: Thalidomide Drug: Dexamethasone||Phase 1 Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Study Start Date :||October 2015|
|Estimated Primary Completion Date :||October 2016|
|Estimated Study Completion Date :||April 2018|
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:
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.
Lyophilized carfilzomib for injection reconstituted with water to a final concentration of 2 mg/mL.
Other Name: Kyprolis
Other Name: Thalidomide Celgene
Other Name: Decadron
- Dose-Limiting Toxicities as assessed by reported data [ Time Frame: After 1 cycle of treatment; to be completed within 1 year. ]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.
- Number of participants experiencing Grade 3 or 4 toxicity as assessed by CTCAE v4.0. [ Time Frame: End of study; 30 months from opening. ]The proportion 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. The percentage of participants experiencing these toxicities will be reported.
- 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. [ Time Frame: End of study; 30 months from opening. ]Participant clonal response rate within 3 months, at 3 months, within 6 months and at 6 months will be assessed using measurement of the participant's paraprotein levels and free light chain levels. The proportion of participants who achieve at least a partial response will be reported.
- Amyloidotic organ response rate within 3 months and 6 months based on biochemical, electrocardiographical, and radiographical assessment. [ Time Frame: End of study; 30 months from opening. ]
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 proportion of patients who achieve organ response within 3 and 6 months of trial registration will be reported.
- Time to amyloidotic organ response based on reported data. [ Time Frame: End of study; 30 months from opening. ]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.
- Number of deaths at 6 months based on reported data. [ Time Frame: End of study; 30 months from opening. ]The number of deaths at 6 months will be assessed and reported based on reported data.
- Number of patients progression-free at 6 months based on reported data. [ Time Frame: End of study; 30 months from opening. ]The number of patients who are progression-free at 6 months will be assessed based on reported data.
- Maximum response determined by paraprotein and free light chain assessment. [ Time Frame: End of study; 30 months from opening. ]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).
- Time to maximum response based on reported data. [ Time Frame: End of study; 30 months from opening. ]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.
- Number of patients withdrawing from treatment based on reported data. [ Time Frame: End of study; 30 months from opening. ]The number of patients withdrawing from treatment will be assessed based on reported data.
- Number of patients experiencing dose delays based on reported data. [ Time Frame: End of study; 30 months from opening. ]The number of patients experiencing dose delays will be assessed based on reported data.
- Compliance profile of KTD based on reported chemotherapy compliance data. [ Time Frame: End of study; 30 months from opening. ]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 compliant and non-compliant.
- Relative dose intensity based on pharmacokinetic assessments. [ Time Frame: End of study; 30 months from opening. ]The Relative Dose intensity of KTD treatment will be assessed and calculated as the percentage ratio between the received and planned intensities, where dose intensity is the cumulative dose divided by the duration of treatment. This information will be expressed as a dose (e.g., 150mg/m^2).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02545907
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|Leicester Royal Infirmary|
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|Norfolk and Norwich University Hospital|
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|Royal Hallamshire Hospital|
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|Birmingham Queen Elizabeth Hospital|
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|Birmingham Heartlands Hospital|
|Birmingham, West Midlands, United Kingdom, B9 5SS|
|Contact: Guy Pratt, Dr 01214243698 Guy.Pratt@HeartofEngland.nhs.uk|
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|Principal Investigator: Guy Pratt, Dr|
|Sub-Investigator: Shankara Paneesha|
|St James' University Hospital|
|Leeds, West Yorkshire, United Kingdom, LS9 7TF|
|Bristol Haematology and Oncology Centre|
|Bristol, United Kingdom, BS2 8ED|
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|Principal Investigator: Jenny Bird, Dr|
|Sub-Investigator: James Griffin, Dr|
|The Beatson West of Scotland Cancer Centre|
|Glasgow, United Kingdom, G12 0YN|
|Contact: Grant McQuaker, Dr 01413017140 Grant.McQuaker@ggc.scot.nhs.uk|
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|Principal Investigator: Grant McQuaker, Dr|
|Sub-Investigator: Richard Soutar, Dr|
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|Principal Investigator:||Ashutosh Wechalekar, Dr||University College London, National Amyloidosis Centre|