Daratumumab Combined With Bortezomib and Dexamethasone in Mayo 04 Stage III Light Chain Amyloidosis

Study Overview
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Brief Summary
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Patients with light chain (AL) amyloidosis who have advanced cardiac damage are at risk of premature mortality. There is ongoing unmet need for effective therapies to rapidly induce deep hematologic response and decrease the early death rate. Lately, trials of daratumumab in newly-diagnosed and relapsed/refractory AL amyloidosis have shown dramatic response rates. However, the benefits of upfront daratumumab in stage III AL patients, especially stage IIIb patients, have not yet been demonstrated definitely in prospective studies. Therefore, we designed a phase II, single arm clinical trial to investigate the efficacy and safety of co-administration of daratumumab with bortezomib and dexamethasone (BD) regimen in treatment-naïve patients with Mayo 04 stage III AL amyloidosis. We planned to enroll 40 patients, who would receive daratumumab and BD treatment for a total duration of 12 months. The primary endpoint is complete response and very good partial response at 3 months after treatment initiation. Secondary endpoints include overall survival, organ response and adverse events.

Official Title
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Efficacy of Daratumumab Combined With Bortezomib and Dexamethasone in Patients With Mayo 04 Stage III Light Chain Amyloidosis: a Prospective Phase II Clinical Trial

Conditions
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Amyloidosis; Systemic

Intervention / Treatment
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* Drug: Daratumumab
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years old adults. Biopsy proved treatment-naïve AL amyloidosis. Mayo 2004 stage III. dFLC > 50mg/L. Patient must provide informed consent. Exclusion Criteria: Co-morbidity of uncontrolled infection. Co-morbidity of other active malignancy. Co-diagnosis of multiple myeloma or waldenstrom macroglobulinemia. Co-morbidity of grade 2 or 3 atrioventricular block. Co-morbidity of sustained or recurrent nonsustained ventricular tachycardia. Seropositive for human immunodeficiency virus. Seropositive for hepatitis B (positive test for HBsAg). Participants with resolved infection (ie, HBsAg negative but positive for anti-HBc and/or anti-HBs) must be screened of HBV-DNA. Those who are PCR positive will be excluded. Seropositive for hepatitis C (except in the setting of a sustained virologic response). Grade 2 or higher neuropathy according to National Cancer Institute Common Terminology Criteria for Adverse Events. Neutrophil <1×10E9/L，hemoglobin < 7g/dL，or platelet < 75×10E9/L. Severely compromised hepatic or renal function: ALT or AST > 2.5 × ULN, total bilirubin > 1.5mg/dL，or eGFR < 40mL/min (those with renal dysfunction due to renal involvement or renal hypoperfusion from cardiac amyloidosis could be included)

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: Dara-BD<br>Daratumumab combined with bortezomib and dexamethasone | Drug: Daratumumab<br>* 16mg/kg, QW Cycles 1-2 (28 days/cycle), Q2W Cycles 3-6, and Q4W thereafter for up to 1 year<br>Drug: Bortezomib<br>* 1.3mg/m2 of subcutaneous bortezomib on days 1, 8, 15 and 22 of a 28-day cycle for 6 cycles<br>Drug: Dexamethasone<br>* 20mg of dexamethasone on days 1, 8, 15 and 22 of a 28-day cycle for 6 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic very good partial response or better at 3 months after treatment initiation | Very good partial response or better is defined as complete response or very good partial response. Complete response: normalization of free light chain levels and ratio with negative serum and urine immunofixation electrophoresis. Very good partial response: difference between involved and uninvolved free light chains (dFLC) less than 40 mg/L | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 2 years | 
| major organ deterioration progression-free survival |  | 2 years | 
| Time to next treatment |  | 2 years | 
| Mortality within 1 month from treatment initiation |  | 1 month | 
| Mortality within 3 months from treatment initiation |  | 3 months | 
| Mortality within 6 months from treatment initiation |  | 6 months | 
| Hematologic very good partial response or better at 1 month after treatment initiation |  | 1 month | 
| Hematologic very good partial response or better at 6 months after treatment initiation |  | 6 months | 
| Hematologic very good partial response or better at 12 months after treatment initiation |  | 12 months | 
| Stringent dFLC response | dFLC declined to less than 10 mg/L | 1 year | 
| Time to hematologic response |  | 1 year | 
| Organ response at 3 months after treatment initiation |  | 3 months | 
| Organ response at 6 months after treatment initiation |  | 6 months | 
| Organ response at 12 months after treatment initiation |  | 12 months | 
| Time to cardiac response |  | 1 year | 
| Time to liver response |  | 1 year | 
| Time to renal response |  | 1 year | 
| Adverse events | Adverse events are collected until 30 days after last dose of treatment | treatment initiation to 30 days after last dose of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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light chain amyloidosis, daratumumab, bortezomib, hematologic response, prognosis