A Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Single Arm Open Labeled Multicentre Phase 1b Dose Escalation Study of Carfilzomib Taken in Combination With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis

Conditions
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Amyloidosis

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Thalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KTD treatment<br>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. | Drug: Carfilzomib<br>* Lyophilized carfilzomib for injection reconstituted with water to a final concentration of 2 mg/mL.<br>* Other names: Kyprolis;Drug: Thalidomide<br>* 50mg capsule.<br>* Other names: Thalidomide Celgene;Drug: Dexamethasone<br>* 2mg tablet.<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyloidosis, AL Amyloidosis