NCT03401372

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
140

participants targeted

Target at P50-P75 for not_applicable

Timeline
Completed

Started Apr 2018

Typical duration for not_applicable

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

January 9, 2018

Completed
8 days until next milestone

First Posted

Study publicly available on registry

January 17, 2018

Completed
3 months until next milestone

Study Start

First participant enrolled

April 21, 2018

Completed
2.7 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 31, 2020

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 31, 2020

Completed
Last Updated

February 23, 2021

Status Verified

February 1, 2021

Enrollment Period

2.7 years

First QC Date

January 9, 2018

Last Update Submit

February 19, 2021

Conditions

Amyloidosis; Systemic

Keywords

Primary light chain amyloidosisDoxycyclineBortezomibPrognosisProgression-free survivalOverall survivalOrgan response

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (4)

  • Overall survival

    2 years

  • Hematologic response

    2 years

  • Organ response

    2 years

  • Adverse events

    up to 2 years

Study Arms (2)

Doxycycline/BCD chemotherapy

EXPERIMENTAL

Doxycycline combined with bortezomib-cyclophosphamide-dexamethasone chemotherapy

Drug: DoxycyclineDrug: BortezomibDrug: CyclophosphamideDrug: Dexamethasone

BCD chemotherapy

ACTIVE COMPARATOR

Bortezomib-cyclophosphamide-dexamethasone chemotherapy

Drug: BortezomibDrug: CyclophosphamideDrug: Dexamethasone

Interventions

DoxycyclineDRUG

Oral doxycycline 100mg twice daily

Doxycycline/BCD chemotherapy
BortezomibDRUG

1.3mg/m2 of bortezomib on days 1, 8, 15 and 22 of a 35-day cycle

BCD chemotherapyDoxycycline/BCD chemotherapy
CyclophosphamideDRUG

300mg/m2 cyclophosphamide on days 1, 8, 15 and 22 of a 35-day cycle

BCD chemotherapyDoxycycline/BCD chemotherapy
DexamethasoneDRUG

40mg of dexamethasone on days 1, 8, 15 and 22 of a 35-day cycle

BCD chemotherapyDoxycycline/BCD chemotherapy

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • ≥18 years old adults.
  • Biopsy proved treatment-naïve pAL amyloidosis.
  • Mayo 2004 stage II-III.
  • dFLC \> 50mg/L.
  • Patient must provide informed consent.

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Peking Union Medical College Hospital

Beijing, 100730, China

Location

Related Publications (8)

  • 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.

    PMID: 21998211BACKGROUND

  • 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.

    PMID: 26117060RESULT

  • 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. 2017 Feb 14;38(2):107-111. doi: 10.3760/cma.j.issn.0253-2727.2017.02.005. Chinese.

    PMID: 28279033RESULT

  • 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 primary systemic amyloidosis. J Clin Oncol. 2004 Sep 15;22(18):3751-7. doi: 10.1200/JCO.2004.03.029.

    PMID: 15365071RESULT

  • 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 May 10;119(19):4391-4. doi: 10.1182/blood-2011-11-390930. Epub 2012 Feb 13.

    PMID: 22331188RESULT

  • 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 cyclophosphamide, thalidomide and dexamethasone (CTD) in AL amyloidosis. Leukemia. 2014 Dec;28(12):2304-10. doi: 10.1038/leu.2014.218. Epub 2014 Jul 16.

    PMID: 25027514RESULT

  • 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 upfront with bortezomib or lenalidomide and the importance of risk adapted strategies. Am J Hematol. 2015 Apr;90(4):E60-5. doi: 10.1002/ajh.23936. Epub 2015 Mar 9.

    PMID: 25580702RESULT

  • Shen KN, Fu WJ, Wu Y, Dong YJ, Huang ZX, Wei YQ, Li CR, Sun CY, Chen Y, Miao HL, Zhang YL, Cao XX, Zhou DB, Li J. Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial. Circulation. 2022 Jan 4;145(1):8-17. doi: 10.1161/CIRCULATIONAHA.121.055953. Epub 2021 Sep 10.

    PMID: 34503349DERIVED

MeSH Terms

Conditions

Immunoglobulin Light-chain Amyloidosis

Interventions

DoxycyclineBortezomibCyclophosphamideDexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma CellNeoplasms by Histologic TypeNeoplasmsAmyloidosisProteostasis DeficienciesMetabolic DiseasesNutritional and Metabolic DiseasesLymphoproliferative DisordersImmunoproliferative DisordersImmune System DiseasesParaproteinemias

Intervention Hierarchy (Ancestors)

TetracyclinesNaphthacenesPolycyclic Aromatic HydrocarbonsHydrocarbons, AromaticHydrocarbons, CyclicHydrocarbonsOrganic ChemicalsPolycyclic CompoundsBoronic AcidsAcids, NoncarboxylicAcidsInorganic ChemicalsBoron CompoundsPyrazinesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsPhosphoramide MustardsNitrogen Mustard CompoundsMustard CompoundsHydrocarbons, HalogenatedPhosphoramidesOrganophosphorus CompoundsPregnadienetriolsPregnadienesPregnanesSteroidsFused-Ring CompoundsSteroids, Fluorinated

Study Officials

  • Jian Li, MD

    Peking Union Medical College Hospital

    STUDY DIRECTOR

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
Professor

Study Record Dates

First Submitted

January 9, 2018

First Posted

January 17, 2018

Study Start

April 21, 2018

Primary Completion

December 31, 2020

Study Completion

December 31, 2020

Last Updated

February 23, 2021

Record last verified: 2021-02

Locations

CN(1)