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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Amyloidosis; Systemic
• Intervention / Treatment: Drug: Daratumumab; Drug: Bortezomib; Drug: Dexamethasone

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100730
    • Peking Union Medical College Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital
• Collaborators: Xian-Janssen Pharmaceutical Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 24, 2021
• Primary Completion (ANTICIPATED): June 1, 2023
• Study Completion (ANTICIPATED): March 1, 2024

Study Registration Dates

• First Submitted: July 14, 2020
• First Submitted That Met QC Criteria: July 14, 2020
• First Posted (ACTUAL): July 17, 2020

Study Record Updates

• Last Update Posted (ACTUAL): May 10, 2022
• Last Update Submitted That Met QC Criteria: May 9, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: prognosis; bortezomib; daratumumab; light chain amyloidosis; hematologic response
• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Amyloidosis; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Daratumumab; Bortezomib
• Other Study ID Numbers: PUMCH-AL2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No