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

• Sponsor: University College, London (Other)
• Overall Status: Completed
• CT.gov ID: NCT02545907
• Collaborator: (none)
• Enrollment: 10
• Locations: 14
• Arm: 1
• Actual Duration (Months): 25.2
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Amyloidosis	Drug: Carfilzomib; Drug: Thalidomide; Drug: Dexamethasone	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Sep 14, 2017
• Actual Primary Completion Date: Sep 26, 2019
• Actual Study Completion Date: Oct 21, 2019

Arms and Interventions

Arm

Intervention/Treatment

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.

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose-Limiting Toxicities as Assessed by Reported Data [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.

2. Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0. [Between informed consent provided and 30 days post last trial treatment administration, up to 7 months]

   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.

Secondary Outcome Measures

1. 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. [Within 3 months, at 3 months, within 6 months and at 6 months]

   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

2. Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment. [Within 3 months and 6 months]

   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.

3. Time to Amyloidotic Organ Response Based on Reported Data. [Within 6 months]

   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.

4. Number of Deaths at 6 Months Based on Reported Data. [6 months]

   The number of deaths at 6 months will be assessed and reported based on reported data.

5. Number of Patients Progression-free at 6 Months Based on Reported Data. [6 months]

   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. Maximum Response Determined by Paraprotein and Free Light Chain Assessment. [Within 6 months]

   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).

7. Time to Maximum Response Based on Reported Data. [Within 6 months]

   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.

8. Number of Patients Withdrawing From Treatment Based on Reported Data. [Within 6 months]

   The number of patients withdrawing from treatment will be assessed based on reported data.

9. Number of Patients Experiencing Dose Delays Based on Reported Data. [Within 6 months]

   The number of patients experiencing dose delays will be assessed based on reported data.

10. Compliance Profile of KTD Based on Reported Chemotherapy Compliance Data. [Within 6 months]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. Measurable clonal disease

2. Clonal relapse after previous chemotherapy or stem cell transplant OR refractory clonal disease to previous chemotherapy or stem cell transplant

3. Capable of providing written, informed consent and willing to follow study protocol

4. Life expectancy ≥ 6 months

5. ECOG performance status of <3

6. Platelet count ≥ 50x109/l)

7. Neutrophil count ≥ 1x109/l)

8. Haemoglobin ≥ 8g/dL

9. Bilirubin <2 times or Alkaline phosphatase <4 times upper limit of normal.

10. 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

1. Myocardial infarction in the preceeding 6 months or unstable angina or conduction abnormalities uncontrolled by medication or devices

2. Concurrent active malignancies, except surgically removed basal cell carcinoma of the skin or other in situ carcinomas

3. Pregnant, lactating or unwilling to use adequate contraception

4. Systemic infection unless specific anti-infective therapy is employed.

5. Known or suspected HIV infection

6. 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

7. Previous experimental agents or approved anti-tumour treatment within 3 months before the date of registration

8. Known allergies to the IMPs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Derriford Hospital	Plymouth	Devon	United Kingdom	PL6 8DH
2	Royal Bournemouth General Hospital	Bournemouth	Dorset	United Kingdom	BH7 7DW
3	Guy's Hospital	London	Greater London	United Kingdom	SE1 7EH
4	Manchester Royal Infirmary	Manchester	Greater Manchester	United Kingdom	M13 9WL
5	Southampton General Hospital	Southampton	Hampshire	United Kingdom	SO16 6YD
6	Leicester Royal Infirmary	Leicester	Leicestershire	United Kingdom	LE1 5WW
7	Norfolk and Norwich University Hospital	Norwich	Norfolk	United Kingdom	NR4 7UY
8	Royal Hallamshire Hospital	Sheffield	South Yorkshire	United Kingdom	S10 2JF
9	Freeman Hospital	Newcastle-upon-Tyne	Tyne And Wear	United Kingdom	NE7 7DN
10	Birmingham Queen Elizabeth Hospital	Birmingham	West Midlands	United Kingdom	B15 2TH
11	Birmingham Heartlands Hospital	Birmingham	West Midlands	United Kingdom	B9 5SS
12	St James' University Hospital	Leeds	West Yorkshire	United Kingdom	LS9 7TF
13	Bristol Haematology and Oncology Centre	Bristol		United Kingdom	BS2 8ED
14	The Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN

Sponsors and Collaborators

• University College, London

Investigators

• Principal Investigator: Ashutosh Wechalekar, Dr, University College London, National Amyloidosis Centre

Study Documents (Full-Text)

• Study Protocol - Jan 24, 2018
• Statistical Analysis Plan - May 1, 2019

More Information

Publications

None provided.

• Responsible Party: University College, London
• ClinicalTrials.gov Identifier: NCT02545907
• Other Study ID Numbers: 14/0786
• First Posted: Sep 10, 2015
• Last Update Posted: Apr 15, 2021
• Last Verified: Nov 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University College, London: Amyloidosis; AL Amyloidosis
• Additional relevant MeSH terms: Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Thalidomide; Dexamethasone

Study Results

Participant Flow

Arm/Group Title	Period 1- Dose Level 0 - 36mg/m^2	Period 2 - Dose Level 1 - 45mg/m^2	Period 3 - Dose Level 1 - 45mg/m^2
Arm/Group Description	3 evaluable participants were recruited to dose level 0.	3 evaluable participants were recruited to dose level 1, one of which experienced a dose limiting toxicity.	4 participants were recruited to dose level 1; three of which were evaluable for the maximum tolerated dose, one of which was deemed unevaluable due experiencing an SAE after the loading dose (20 mg/m^2) of carfilzomib and was replaced.
Period Title: Overall Study
STARTED	3	3	4
COMPLETED	3	3	4
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Dose Level 0 - 26/mg^2	Dose Level 1 - 45/mg^2	Total
Arm/Group Description	Participants received 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 36mg/m^2 administered on Day 1, 8, and 15,.	Participants received 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 36mg/m^2 administered on Day 1, 8, and 15,.	Total of all reporting groups
Overall Participants	3	7	10
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	1 33.3%	5 71.4%	6 60%
>=65 years	2 66.7%	2 28.6%	4 40%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	75.0	62.0	63.0
Sex: Female, Male (Count of Participants)
Female	1 33.3%	5 71.4%	6 60%
Male	2 66.7%	2 28.6%	4 40%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
United Kingdom	3 100%	7 100%	10 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose-Limiting Toxicities as Assessed by Reported Data
Description	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.
Time Frame	After 1 cycle of treatment; to be completed within 1 year.

Outcome Measure Data

Analysis Population Description

Evaluable set- patient who received at least one cycle of the study treatment. KTD Patients who do not receive one complete cycle due to experiencing a DLT will be included in the analysis; patients who do not receive at least one complete cycle for reasons other than toxicity, without experiencing a DLT, and who miss a dose of Carfilzomib, more than 14 doses Thalidomide or 2 doses of Dexamethasone in the first cycle, will be replaced.

Arm/Group Title	Dose Level 0	Dose Level 1
Arm/Group Description	Participants who were allocated to receive dose level 0 and received at least one cycle of the study treatment. KTD Patients who do not receive one complete cycle due to experiencing a DLT will be included in the analysis; patients who do not receive at least one complete cycle for reasons other than toxicity, without experiencing a DLT, and who miss a dose of Carfilzomib, more than 14 doses Thalidomide or 2 doses of Dexamethasone in the first cycle, will be replaced.	Participants who were allocated to receive dose level 1 and received at least one cycle of the study treatment. KTD Patients who do not receive one complete cycle due to experiencing a DLT will be included in the analysis; patients who do not receive at least one complete cycle for reasons other than toxicity, without experiencing a DLT, and who miss a dose of Carfilzomib, more than 14 doses Thalidomide or 2 doses of Dexamethasone in the first cycle, will be replaced.
Measure Participants	3	6
Count of Participants [Participants]	0 0%	1 14.3%

2. Primary Outcome

Title	Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0.
Description	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.
Time Frame	Between informed consent provided and 30 days post last trial treatment administration, up to 7 months

Outcome Measure Data

Analysis Population Description

All patients that receive at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Count of Participants [Participants]	2 66.7%	3 42.9%

3. Secondary Outcome

Title	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.
Description	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
Time Frame	Within 3 months, at 3 months, within 6 months and at 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Within 3 cycles	1 33.3%	5 71.4%
At the end of cycle 3	1 33.3%	5 71.4%
Within 6 cycles	2 66.7%	5 71.4%
At the end of cycle 6	2 66.7%	5 71.4%

4. Secondary Outcome

Title	Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment.
Description	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.
Time Frame	Within 3 months and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Response within 3 months	0 0%	0 0%
Response within 6 months	0 0%	0 0%
No response	3 100%	7 100%

5. Secondary Outcome

Title	Time to Amyloidotic Organ Response Based on Reported Data.
Description	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.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Count of Participants [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Number of Deaths at 6 Months Based on Reported Data.
Description	The number of deaths at 6 months will be assessed and reported based on reported data.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Count of Participants [Participants]	0 0%	0 0%

7. Secondary Outcome

Title	Number of Patients Progression-free at 6 Months Based on Reported Data.
Description	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
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Count of Participants [Participants]	3 100%	7 100%

8. Secondary Outcome

Title	Maximum Response Determined by Paraprotein and Free Light Chain Assessment.
Description	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 Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
No response	1 33.3%	0 0%
Partial response	0 0%	1 14.3%
Very good partial response	2 66.7%	1 14.3%
Complete response	0 0%	3 42.9%
Not evaluable	0 0%	2 28.6%

9. Secondary Outcome

Title	Time to Maximum Response Based on Reported Data.
Description	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.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Safety Population
Arm/Group Description	All patients that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set..
Measure Participants	10
Median (95% Confidence Interval) [months]	5.3

10. Secondary Outcome

Title	Number of Patients Withdrawing From Treatment Based on Reported Data.
Description	The number of patients withdrawing from treatment will be assessed based on reported data.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Count of Participants [Participants]	0 0%	0 0%

11. Secondary Outcome

Title	Number of Patients Experiencing Dose Delays Based on Reported Data.
Description	The number of patients experiencing dose delays will be assessed based on reported data.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Count of Participants [Participants]	2 66.7%	1 14.3%

12. Secondary Outcome

Title	Compliance Profile of KTD Based on Reported Chemotherapy Compliance Data.
Description	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.
Time Frame	Within 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 0- Safety Population	Dose Level 1- Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.	All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
Measure Participants	3	7
Count of Participants [Participants]	1 33.3%	5 71.4%

Adverse Events

Time Frame	All adverse events that occur between informed consent and 30 days post last trial treatment administration must be recorded in the patient notes and the trial CRFs, up to 7 months.
Adverse Event Reporting Description	Definitions are the same as those in clinicialtrials.gov
Arm/Group Title	Dose Level 0 - Safety Population		Dose Level 1 - Safety Population
Arm/Group Description	All patients allocated to dose level 0 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.		All patients allocated to dose level 1 that received at least one dose of Carfilzomib and with no protocol deviations with relevant impact on safety will be included in the safety analysis set.
All Cause Mortality
	Dose Level 0 - Safety Population		Dose Level 1 - Safety Population
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/7 (0%)
Serious Adverse Events
	Dose Level 0 - Safety Population		Dose Level 1 - Safety Population
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		2/7 (28.6%)
Immune system disorders
Fever	0/3 (0%)	0	1/7 (14.3%)	1
Investigations
Acute kidney injury on CKD	0/3 (0%)	0	1/7 (14.3%)	1
Renal and urinary disorders
Abdominal pain	1/3 (33.3%)	1	0/7 (0%)	0
Other (Not Including Serious) Adverse Events
	Dose Level 0 - Safety Population		Dose Level 1 - Safety Population
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)	1	2/7 (28.6%)	2
Cardiac disorders
Heart failure	1/3 (33.3%)	1	1/7 (14.3%)	1
Sinus tachycardia	0/3 (0%)	0	1/7 (14.3%)	1
Eye disorders
Blurred Vision	0/3 (0%)	0	1/7 (14.3%)	1
Gastrointestinal disorders
Abdominal Pain	1/3 (33.3%)	1	0/7 (0%)	0
Bloating	0/3 (0%)	0	1/7 (14.3%)	1
Constipation	0/3 (0%)	0	2/7 (28.6%)	2
Diarrhea	1/3 (33.3%)	1	2/7 (28.6%)	2
Mucositis oral	0/3 (0%)	0	1/7 (14.3%)	1
Nausea	1/3 (33.3%)	1	2/7 (28.6%)	2
General disorders
Edema face	0/3 (0%)	0	1/7 (14.3%)	1
Edema limbs	2/3 (66.7%)	2	5/7 (71.4%)	5
Edema trunk	0/3 (0%)	0	1/7 (14.3%)	1
Fatigue	1/3 (33.3%)	1	1/7 (14.3%)	1
Gait disturbance	1/3 (33.3%)	1	0/7 (0%)	0
Fever	0/3 (0%)	0	1/7 (14.3%)	1
Infections and infestations
Bladder Infection	1/3 (33.3%)	1	0/7 (0%)	0
Infections and infestations - Other, specify	1/3 (33.3%)	2	1/7 (14.3%)	1
Upper respiratory infection	1/3 (33.3%)	1	1/7 (14.3%)	1
Urinary Tract Infection	1/3 (33.3%)	1	0/7 (0%)	0
Vaginal infection	0/3 (0%)	0	1/7 (14.3%)	1
Injury, poisoning and procedural complications
Vascular access complication	0/3 (0%)	0	1/7 (14.3%)	1
Investigations
Alkaline phosphatase increased	0/3 (0%)	0	1/7 (14.3%)	1
Alanine aminotransferase increased	0/3 (0%)	0	1/7 (14.3%)	1
Blood Bilirubin Increased	0/3 (0%)	0	1/7 (14.3%)	1
Creatinine increased	1/3 (33.3%)	1	1/7 (14.3%)	1
Ggt Increased	0/3 (0%)	0	1/7 (14.3%)	1
Urine output decreased	0/3 (0%)	0	1/7 (14.3%)	1
Metabolism and nutrition disorders
Anorexia	0/3 (0%)	0	1/7 (14.3%)	1
Hypocalcemia	0/3 (0%)	0	2/7 (28.6%)	2
Hypophosphatemia	0/3 (0%)	0	1/7 (14.3%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	0/3 (0%)	0	3/7 (42.9%)	4
Nervous system disorders
Dizziness	1/3 (33.3%)	1	2/7 (28.6%)	2
Headache	0/3 (0%)	0	2/7 (28.6%)	2
Lethargy	0/3 (0%)	0	1/7 (14.3%)	3
Nervous system disorders - Other, specify	0/3 (0%)	0	2/7 (28.6%)	2
Peripheral sensory neuropathy	1/3 (33.3%)	2	1/7 (14.3%)	1
Psychiatric disorders
Agitation	1/3 (33.3%)	1	0/7 (0%)	0
Insomnia	0/3 (0%)	0	1/7 (14.3%)	1
Psychiatric disorders - Other, specify	1/3 (33.3%)	1	0/7 (0%)	0
Restlessness	0/3 (0%)	0	1/7 (14.3%)	1
Renal and urinary disorders
Acute kidney injury	0/3 (0%)	0	2/7 (28.6%)	2
Renal and urinary disorders - Other, specify	1/3 (33.3%)	1	1/7 (14.3%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/3 (33.3%)	1	0/7 (0%)	0
Dyspnea	1/3 (33.3%)	2	2/7 (28.6%)	2
Skin and subcutaneous tissue disorders
Alopecia	0/3 (0%)	0	1/7 (14.3%)	1
Pruritus	1/3 (33.3%)	1	0/7 (0%)	0
Rash maculo-papular	1/3 (33.3%)	1	1/7 (14.3%)	2
Skin and subcutaneous tissue disorders - Other, specify	0/3 (0%)	0	1/7 (14.3%)	1
Social circumstances
Social circumstances - Other, specify	0/3 (0%)	0	1/7 (14.3%)	1
Vascular disorders
Hypertension	2/3 (66.7%)	2	0/7 (0%)	0
Hypotension	0/3 (0%)	0	1/7 (14.3%)	1

Limitations/Caveats

The trial closed to recruitment following the dose escalation stage without opening the expansion phase due to slow recruitment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.