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Daratumumab Therapy for Patients With Refractory or Relapsed AL Amyloidosis (AMYDARA)

Primary Purpose

Amyloidosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Daratumumab
Sponsored by
University Hospital, Limoges
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyloidosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients must be >18 years of age
  2. Histologic diagnosis of AL amyloidosis
  3. Genetic testing must be negative for transthyretin mutations
  4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
  5. Patients should have received at least one line with an alkylating agent and/or a proteasome inhibitor and dexamethasone and not be in VGPR or CR at the time of inclusion
  6. Measurable hematologic disease:
  7. Symptomatic organ involvement
  8. Wash-out period of at least 4 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies, whichever is longer,
  9. Adequate bone marrow function prior to 1st drug intake
  10. Adequate organ function defined as:
  11. Women with childbearing potential must be practicing one of the effective methods of birth control
  12. A man who has not had a vasectomy and who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control
  13. Only patients who are informed of the investigational nature of this study and sign and give written informed consent

Exclusion Criteria:

  1. Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of isolated vascular amyloid in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis
  2. Isolated soft tissue involvement
  3. Presence of non-AL amyloidosis
  4. Bone marrow plasma cells >30% on bone marrow aspirate at screening
  5. Cardiac mayo stage IIIb disease.
  6. Repetitive ventricular arrhythmias on 24h Holter ECG despite anti-arrhythmic treatment, except if a pacemaker has been implanted.
  7. Chronic atrial fibrillation
  8. Supine systolic blood pressure <100 mmHg
  9. Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen
  10. Clinically overt multiple myeloma with lytic bone lesions
  11. Patients with uncontrolled infection or active malignancy
  12. Any uncontrolled or severe cardiovascular or pulmonary disease
  13. Subjects with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy
  14. Subjects with known chronic obstructive pulmonary disease (COPD)
  15. Subject has known moderate or severe persistent asthma within the past 2 years
  16. Previous anti-CD38 therapy
  17. Hypersensitivity to Dexamethasone that would prohibit treatment with study therapy
  18. Known positive for HIV or active hepatitis B or C
  19. Refusal to consent or protected by legal regime

Sites / Locations

  • CHU d'Angers
  • CHU de Caen
  • CHU de Limoges
  • CHU de Lyon Sud
  • APHP - Necker
  • APHP - Saint Antoine
  • APHP - Saint Louis
  • CHU Poitiers
  • CHU de Rennes
  • Amyloidosis Research and Treatment Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Daratumumab

Arm Description

Patient will receive Daratumumab every week for the first 2 cycles then every 2 weeks from cycle 3 through cycle 6.

Outcomes

Primary Outcome Measures

Overall Response Rate
Overall Response Rate (CR+VGPR) at the completion of 6 cycles of Daratumumab using the new response criteria (J Clin Oncol, 2012. 30(36): p. 4541-9.

Secondary Outcome Measures

Number of participants with treatment-related adverse events as assessed by NCI-CTCAE V4.03.

Full Information

First Posted
June 22, 2016
Last Updated
July 8, 2021
Sponsor
University Hospital, Limoges
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1. Study Identification

Unique Protocol Identification Number
NCT02816476
Brief Title
Daratumumab Therapy for Patients With Refractory or Relapsed AL Amyloidosis
Acronym
AMYDARA
Official Title
A Multicentre Open Label Phase II Study of Daratumumab in AL Amyloidosis Patients Not in VGPR or Better
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
September 2016 (Actual)
Primary Completion Date
October 5, 2019 (Actual)
Study Completion Date
October 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Limoges

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase II, single-arm, multicentre study of Daratumumab (16mg/kg IV route) in adult patients with Light-Chain (AL) Amyloidosis who are not in VGPR or better after previous treatment. A sample size of 40 patients who meet all eligibility criteria will be enrolled to receive study treatment. Patients will receive treatment until either disease progression or toxicity has occurred with a maximum planned of six 28-day cycles. Daratumumab will be administrated every week for the first 2 cycles then. every 2 weeks from cycle 3 through cycle 6. Patients will also receive best supportive care (BSC) to mitigate Daratumumab side-effects, and to address underlying Amyloidosis, including blood product transfusions, antimicrobials, and (as appropriate) growth factors including granulocyte colony-stimulating factors for neutropenia, erythropoietin for anaemia, and/or transfusions for thrombocytopenia
Detailed Description
Systemic AL amyloidosis is a rare disease caused by the deposition of misfolded monoclonal immunoglobulin free light chains (FLC) in various tissues and organs. It is usually associated with a clonal plasma cell dyscrasia with a low tumour burden. Treatment of AL amyloidosis relies mainly on chemotherapy aimed at suppressing the underlying plasma cell clone secreting monoclonal FLC. The organ responses and the survival are greatly influenced by the degree of hematological response evaluated by the decrease in serum FLC that has been the principal endpoint in recent trials in AL amyloidosis. The goal of treatment is to reach at least a very good partial response (VGPR) defined as a difference between the involved FLC and the normal <40 mg/l. Over the last 2 years, Daratumumab, a novel, high-affinity, therapeutic, human monoclonal antibodies (mAb) that specifically recognizes the CD38 epitope has emerged as a breakthrough targeted therapy for patients with myeloma. Taking into account that, in 90% of AL patients, the monoclonal cells producing amyloidogenic FLC are Cluster of Differentiation 38 (CD38) expressing plasma cells Daratumumab should be a promising treatment in AL amyloidosis. The study will consist of 4 steps: A 21 day screening period This period start with screening visit which may occurs up to 21 days before the first study drug administration. After signature of the informed consent form, procedures will be performed to ensure patient meet all inclusion/exclusion criteria and document health status to receive study treatment. These assessments will include quality of life questionnaires A treatment period Patient eligible to enter the study will receive 6 cycles of 28 days of intra venous Daratumumab. During cycles 1 and 2, Daratumumab will be administered weekly at days 1, 8, 15, and 22 then from cycles 3 to 6, Daratumumab will be administered every two weeks at days 1 and 15. Patient will have assessments at the ignition of a new cycle to document haematological and organs response and intra cycle to watch for toxicities. An end of study visit (when PD or unacceptable adverse events occurs, or planned end of study visit). Study procedures will be performed at 28 days (± 15) after the last dose of study medication for all patients, including early termination patients. Followup period After treatment discontinuation, followup will be made to the patient every 3 months for at least 1 year to inquire about the patient's hematological and organ status, general health, and information on any new medical events. DOSING REGIMEN Daratumumab. Six 28-day cycles, 16 mg/kg administered by IV route, During cycle 1 and 2, Daratumumab will be administered weekly at days 1, 8, 15, and 22 For cycles 3 to 6, Daratumumab will be administered every other week at days 1 and 15

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyloidosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Daratumumab
Arm Type
Experimental
Arm Description
Patient will receive Daratumumab every week for the first 2 cycles then every 2 weeks from cycle 3 through cycle 6.
Intervention Type
Drug
Intervention Name(s)
Daratumumab
Primary Outcome Measure Information:
Title
Overall Response Rate
Description
Overall Response Rate (CR+VGPR) at the completion of 6 cycles of Daratumumab using the new response criteria (J Clin Oncol, 2012. 30(36): p. 4541-9.
Time Frame
After 6 cycles treatment (6 months).
Secondary Outcome Measure Information:
Title
Number of participants with treatment-related adverse events as assessed by NCI-CTCAE V4.03.
Time Frame
Every month during 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must be >18 years of age Histologic diagnosis of AL amyloidosis Genetic testing must be negative for transthyretin mutations Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 Patients should have received at least one line with an alkylating agent and/or a proteasome inhibitor and dexamethasone and not be in VGPR or CR at the time of inclusion Measurable hematologic disease: Symptomatic organ involvement Wash-out period of at least 4 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies, whichever is longer, Adequate bone marrow function prior to 1st drug intake Adequate organ function defined as: Women with childbearing potential must be practicing one of the effective methods of birth control A man who has not had a vasectomy and who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control Only patients who are informed of the investigational nature of this study and sign and give written informed consent Exclusion Criteria: Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of isolated vascular amyloid in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis Isolated soft tissue involvement Presence of non-AL amyloidosis Bone marrow plasma cells >30% on bone marrow aspirate at screening Cardiac mayo stage IIIb disease. Repetitive ventricular arrhythmias on 24h Holter ECG despite anti-arrhythmic treatment, except if a pacemaker has been implanted. Chronic atrial fibrillation Supine systolic blood pressure <100 mmHg Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen. Or, subject is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of any component of the treatment regimen Clinically overt multiple myeloma with lytic bone lesions Patients with uncontrolled infection or active malignancy Any uncontrolled or severe cardiovascular or pulmonary disease Subjects with psychiatric illnesses or social situations that would preclude them understanding the informed consent, study compliance or the ability to tolerate study procedures and/or study therapy Subjects with known chronic obstructive pulmonary disease (COPD) Subject has known moderate or severe persistent asthma within the past 2 years Previous anti-CD38 therapy Hypersensitivity to Dexamethasone that would prohibit treatment with study therapy Known positive for HIV or active hepatitis B or C Refusal to consent or protected by legal regime
Facility Information:
Facility Name
CHU d'Angers
City
Angers
Country
France
Facility Name
CHU de Caen
City
Caen
ZIP/Postal Code
14000
Country
France
Facility Name
CHU de Limoges
City
Limoges
ZIP/Postal Code
87042
Country
France
Facility Name
CHU de Lyon Sud
City
Lyon
Country
France
Facility Name
APHP - Necker
City
Paris
Country
France
Facility Name
APHP - Saint Antoine
City
Paris
Country
France
Facility Name
APHP - Saint Louis
City
Paris
Country
France
Facility Name
CHU Poitiers
City
Poitiers
Country
France
Facility Name
CHU de Rennes
City
Rennes
Country
France
Facility Name
Amyloidosis Research and Treatment Center
City
Pavia
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
No

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Daratumumab Therapy for Patients With Refractory or Relapsed AL Amyloidosis

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