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

Amyloidosis; Systemic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03401372
• Other study ID #: PUMCH-AL2017
• Status: Completed
• Phase: N/A
• Start date: April 21, 2018
• Est. completion date: December 31, 2020

Study information

• Verified date: February 2021
• Source: Peking Union Medical College Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: December 31, 2020
• Est. primary completion date: December 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Amyloidosis
• Amyloidosis; Systemic

Intervention

Drug:
• Doxycycline
Oral doxycycline 100mg twice daily
• Bortezomib
1.3mg/m2 of bortezomib on days 1, 8, 15 and 22 of a 35-day cycle
• Cyclophosphamide
300mg/m2 cyclophosphamide on days 1, 8, 15 and 22 of a 35-day cycle
• Dexamethasone
40mg of dexamethasone on days 1, 8, 15 and 22 of a 35-day cycle

Locations

Country	Name	City	State
China	Peking Union Medical College Hospital	Beijing

Sponsors (9)

Lead Sponsor	Collaborator
Jian Li	Beijing Anzhen Hospital, Beijing Chao Yang Hospital, Nanfang Hospital of Southern Medical University, Peking University First Hospital, Shanghai Changzheng Hospital, Tongji Hospital Affiliated with Tongji Medical College of HUST, Union Hospital Affiliated with Tongji Medical College of HUST, West China Hospital Affiliated with Sichuan University

Country where clinical trial is conducted

China, 

References & Publications (7)

Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, Greipp PR, Witzig TE, Lust JA, Rajkumar SV, Fonseca R, Zeldenrust SR, McGregor CG, Jaffe AS. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for pri — View Citation

Feng J, Huang XF, Zhang CL, Shen KN, Zhang CL, Sun J, Tian Z, Cao XX, Zhang L, Zhou DB, Li J. [Analysis of clinical characteristics and outcome of patients with very high risk primary immunoglobulin light-chain amyloidosis]. Zhonghua Xue Ye Xue Za Zhi. 20 — View Citation

Kastritis E, Roussou M, Gavriatopoulou M, Migkou M, Kalapanida D, Pamboucas C, Kaldara E, Ntalianis A, Psimenou E, Toumanidis ST, Tasidou A, Terpos E, Dimopoulos MA. Long-term outcomes of primary systemic light chain (AL) amyloidosis in patients treated u — View Citation

Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 — View Citation

Shen KN, Li J. [Light Chain Amyloidosis: an Update for Treatment]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2015 Jun;23(3):910-4. doi: 10.7534/j.issn.1009-2137.2015.03.059. Chinese. — View Citation

Venner CP, Gillmore JD, Sachchithanantham S, Mahmood S, Lane T, Foard D, Rannigan L, Gibbs SD, Pinney JH, Whelan CJ, Lachmann HJ, Hawkins PN, Wechalekar AD. A matched comparison of cyclophosphamide, bortezomib and dexamethasone (CVD) versus risk-adapted c — View Citation

Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O'Hara C, Jasuja R, Trinkaus-Randall V, Liao R, Connors LH, Seldin DC. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis. Blood. 2011 Dec 15;118(25):6610-7. doi: 10.1182/blood-2011-04-351643. Epub 2011 Oct 12. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Adverse events	Adverse events are collected until 30 days after last dose of doxycycline.	up to 2 years