BCD With or Without Doxycycline in Mayo Stage II-III Light Chain Amyloidosis Patients

Study Overview
=================
Brief Summary
-----------------
Survival of intermediate and high-risk primary light chain amyloidosis (pAL) remains poor due to high mortality within 3-6 months of diagnosis. Rapidly effective regimens such as bortezomib, cyclophosphamide and dexamethasone (BCD) still failed to overcome the poor prognosis in very advanced pAL amyloidosis patients. Recently, doxycycline was demonstrated to induce disruption of fibril formation and reduce the number of intact fibrils in transgenic mouse model of pAL amyloidosis. Furthermore, case-control study suggested that adjuvant oral doxycycline could improve response and survival in cardiac pAL amyloidosis, which necessities further confirmation through a randomized trial. Therefore, we designed a multi-center randomized open-label controlled study to investigate the efficacy and safety of co-administration of oral doxycycline with BCD regimen in treatment-naïve patients with Mayo stage II-III pAL amyloidosis. The primary outcome progression-free survival, and secondary endpoints including overall survival, hematologic response, organ response and toxicity of doxycycline will be evaluated.

Official Title
-----------------
Comparison of Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy With or Without Doxycycline in Newly Diagnosed Mayo Stage II-III Light Chain Amyloidosis Patients: A Multi-center Randomized Controlled Trial

Conditions
-----------------
Amyloidosis; Systemic

Intervention / Treatment
-----------------
* Drug: Doxycycline
* Drug: Bortezomib
* Drug: Cyclophosphamide
* Drug: Dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ≥18 years old adults. Biopsy proved treatment-naïve pAL amyloidosis. Mayo 2004 stage II-III. dFLC > 50mg/L. Patient must provide informed consent. Exclusion Criteria: Co-morbidity of uncontrolled infection. Co-morbidity of grade 2 or 3 atrioventricular block. Co-morbidity of sustained or recurrent nonsustained ventricular tachycardia. Co-morbidity of other active malignancy. Co-diagnosis of multiple myeloma or waldenstrom macroglobulinemia. Grade 2 or higher neuropathy according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Allergic history of doxycycline. 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 < 60mL/min.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxycycline/BCD chemotherapy<br>Doxycycline combined with bortezomib-cyclophosphamide-dexamethasone chemotherapy | Drug: Doxycycline<br>* Oral doxycycline 100mg twice daily<br>Drug: Bortezomib<br>* 1.3mg/m2 of bortezomib on days 1, 8, 15 and 22 of a 35-day cycle<br>Drug: Cyclophosphamide<br>* 300mg/m2 cyclophosphamide on days 1, 8, 15 and 22 of a 35-day cycle<br>Drug: Dexamethasone<br>* 40mg of dexamethasone on days 1, 8, 15 and 22 of a 35-day cycle<br>|
| Active Comparator: BCD chemotherapy<br>Bortezomib-cyclophosphamide-dexamethasone chemotherapy | Drug: Bortezomib<br>* 1.3mg/m2 of bortezomib on days 1, 8, 15 and 22 of a 35-day cycle<br>Drug: Cyclophosphamide<br>* 300mg/m2 cyclophosphamide on days 1, 8, 15 and 22 of a 35-day cycle<br>Drug: Dexamethasone<br>* 40mg of dexamethasone on days 1, 8, 15 and 22 of a 35-day cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | The patients are assessed after each cycle of chemotherapy following treatment initiation until progression, relapse, death or study closure at 24-month follow-up. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The patients are assessed after each cycle of chemotherapy following treatment initiation until progression, relapse, death or study closure at 24-month follow-up. If the primary endpoint has reached, patients will also be followed up every 3 months thereafter until death or study closure. | 2 years | 
| Hematologic response | The patients are assessed after each cycle of chemotherapy following treatment initiation until progression, relapse, death or study closure at 24-month follow-up. If the primary endpoint has reached, patients will also be followed up every 3 months thereafter until death or study closure. | 2 years | 
| Organ response | The patients are assessed after each cycle of chemotherapy following treatment initiation until progression, relapse, death or study closure at 24-month follow-up. If the primary endpoint has reached, patients will also be followed up every 3 months thereafter until death or study closure. | 2 years | 
| Adverse events | Adverse events are collected until 30 days after last dose of doxycycline. | up to 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Primary light chain amyloidosis, Doxycycline, Bortezomib, Prognosis, Progression-free survival, Overall survival, Organ response