Trial Outcomes & Findings for A Dose Escalation Study of Carfilzomib Taken With Thalidomide and Dexamethasone in Relapsed AL Amyloidosis (NCT NCT02545907)

Last Updated: 2021-04-15

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

10 participants

Primary outcome timeframe

After 1 cycle of treatment; to be completed within 1 year.

Results posted on

2021-04-15

Participant Flow

Participant milestones

Participant milestones
Measure	Period 1- Dose Level 0 - 36mg/m^2 3 evaluable participants were recruited to dose level 0.	Period 2 - Dose Level 1 - 45mg/m^2 3 evaluable participants were recruited to dose level 1, one of which experienced a dose limiting toxicity.	Period 3 - Dose Level 1 - 45mg/m^2 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.
Overall Study STARTED	3	3	4
Overall Study COMPLETED	3	3	4
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dose Level 0 - 26/mg^2 n=3 Participants 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,.	Dose Level 1 - 45/mg^2 n=7 Participants 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 n=10 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=3 Participants	0 Participants n=7 Participants	0 Participants n=10 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=3 Participants	5 Participants n=7 Participants	6 Participants n=10 Participants
Age, Categorical >=65 years	2 Participants n=3 Participants	2 Participants n=7 Participants	4 Participants n=10 Participants
Age, Continuous	75.0 years n=3 Participants	62.0 years n=7 Participants	63.0 years n=10 Participants
Sex: Female, Male Female	1 Participants n=3 Participants	5 Participants n=7 Participants	6 Participants n=10 Participants
Sex: Female, Male Male	2 Participants n=3 Participants	2 Participants n=7 Participants	4 Participants n=10 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment United Kingdom	3 Participants n=3 Participants	7 Participants n=7 Participants	10 Participants n=10 Participants

PRIMARY outcome

Timeframe: After 1 cycle of treatment; to be completed within 1 year.

Population: 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.

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=6 Participants 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.
Number of Participants With Dose-Limiting Toxicities as Assessed by Reported Data	0 Participants	1 Participants

PRIMARY outcome

Timeframe: Between informed consent provided and 30 days post last trial treatment administration, up to 7 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Number of Participants Experiencing Grade 3 or 4 Toxicity as Assessed by CTCAE v4.0.	2 Participants	3 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
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 cycles	1 Participants	5 Participants
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. At the end of cycle 3	1 Participants	5 Participants
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 6 cycles	2 Participants	5 Participants
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. At the end of cycle 6	2 Participants	5 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment. Response within 3 months	0 Participants	0 Participants
Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment. Response within 6 months	0 Participants	0 Participants
Amyloidotic Organ Response Rate Within 3 Months and 6 Months Based on Biochemical, Electrocardiographical, and Radiographical Assessment. No response	3 Participants	7 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Time to Amyloidotic Organ Response Based on Reported Data.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 6 months

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

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Number of Deaths at 6 Months Based on Reported Data.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Number of Patients Progression-free at 6 Months Based on Reported Data.	3 Participants	7 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Maximum Response Determined by Paraprotein and Free Light Chain Assessment. No response	1 Participants	0 Participants
Maximum Response Determined by Paraprotein and Free Light Chain Assessment. Partial response	0 Participants	1 Participants
Maximum Response Determined by Paraprotein and Free Light Chain Assessment. Very good partial response	2 Participants	1 Participants
Maximum Response Determined by Paraprotein and Free Light Chain Assessment. Complete response	0 Participants	3 Participants
Maximum Response Determined by Paraprotein and Free Light Chain Assessment. Not evaluable	0 Participants	2 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Dose Level 0 n=10 Participants 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.	Dose Level 1 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.
Time to Maximum Response Based on Reported Data.	5.3 months Seven out of 10 participants achieved a maximum response. Two participants who experienced DLTs were not evaluable for response and one participant who discontinued after two cycles of treatment did not achieve a response. Corresponding 95% confidence intervals is not calculable due to the low number of events.	—

SECONDARY outcome

Timeframe: Within 6 months

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

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Number of Patients Withdrawing From Treatment Based on Reported Data.	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Within 6 months

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

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Number of Patients Experiencing Dose Delays Based on Reported Data.	2 Participants	1 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Dose Level 0 n=3 Participants 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.	Dose Level 1 n=7 Participants 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.
Compliance Profile of KTD Based on Reported Chemotherapy Compliance Data.	1 Participants	5 Participants

Adverse Events

Dose Level 0 - Safety Population

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Dose Level 1 - Safety Population

Serious events: 2 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Dose Level 0 - Safety Population n=3 participants at risk 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.	Dose Level 1 - Safety Population n=7 participants at risk 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.
Renal and urinary disorders Abdominal pain	33.3% 1/3 • Number of events 1 • 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. Definitions are the same as those in clinicialtrials.gov	0.00% 0/7 • 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. Definitions are the same as those in clinicialtrials.gov
Investigations Acute kidney injury on CKD	0.00% 0/3 • 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. Definitions are the same as those in clinicialtrials.gov	14.3% 1/7 • Number of events 1 • 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. Definitions are the same as those in clinicialtrials.gov
Immune system disorders Fever	0.00% 0/3 • 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. Definitions are the same as those in clinicialtrials.gov	14.3% 1/7 • Number of events 1 • 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. Definitions are the same as those in clinicialtrials.gov

Other adverse events

Additional Information

Alexandra Pitchford

Leeds Institute of Clinical Trials Research

Phone: 0113 343 9077

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place