A Study of Daratumumab Monotherapy in Previously Untreated Patients With Stage 3B Light Chain (AL) Amyloidosis

NCT04131309 | Completed Phase 2 DMC

• 2 other identifiers: EMN22/54767414AMY20052018-004333-33
• Study Type: interventional
• Target: 40
• Locations: 4 countries
• Sites: 5

Brief Summary

This is an open-label, multicenter, Phase 2 study in subjects with newly diagnosed stage 3B light chain (AL) amyloidosis.

Conditions

Light Chain (AL) Amyloidosis, Stage 3B

Outcome Measures

Primary Outcomes (1)

• overall survival

  To evaluate the overall survival rate at 6 months following treatment with daratumumab in frontline AL patients with stage 3B disease.

  6 months

Secondary Outcomes (7)

• overall Response Rate (ORR)

  at 3 and 6 months

• Major Organ Deterioration Progression-Free Survival (MOD-PFS).

  every 28 days from start of study treatment (cycle 1 Day1) to death or major organ deterioration 2 years with an average of 6 month

• Progression Free Survival

  from registration to the date of disease progression or death with a maximum of 2 years

• organ response rate (OrRR)

  from registration to the date of disease progression or death with a maximum of 2 years

• Time to hematologic response

  2 years

Study Arms (1)

Daratumumab

EXPERIMENTAL

Daratumumab monotherapy 16 mg/kg intravenous infusion (iv) or 1800 mg subcutaneous injection (sc) weekly for Cycles 1-2, every 2 weeks for Cycles 3-6 and every 4 weeks thereafter. Subjects who do not achieve either a hematologic VGPR or better, OR a hematologic PR with a major organ response by Cycle 4 Day 1 may receive, in addition to daratumumab, bortezomib (for a maximum of 6 cycles) and low dose dexamethasone.

Drug: Daratumumab; Drug: Bortezomib Injection; Drug: Dexamethasone oral tablet

Interventions

Daratumumab DRUG

As of Protocol Amendment 1, all new subjects are dosed with daratumumab subcutaneous injection (SC) co-formulated with recombinant human hyaluronidase rHuPH20. Subjects who already began treatment with daratumumab intravenous (IV) infusion (i.e., prior to Am 1) switch to SC on the next administration date according to the protocol schedule. Subjects receive daratumumab IV at a dose of 16 mg/kg and daratumumab SC at a fixed dose of 1800 mg for the first 8 weeks (Cycles 1 and 2) of treatment and then every 2 weeks for 4 cycles (Cycles 3 to 6) and then every 4 weeks until progression of disease (according to MOD-PFS), unacceptable toxicity or subsequent therapy, for a maximum of 2 years in total. All treatment cycles are 4 weeks (28 days) in length.

Daratumumab

Bortezomib Injection DRUG

Subjects who do not achieve either a hematologic VGPR or better, OR a hematologic PR with a major organ response by Cycle 4 Day 1 may receive at Investigator's discretion, in addition to daratumumab, bortezomib at a dose of 1.3 mg/m2 weekly for a maximum of 6 cycles as a subcutaneous injection

Also known as: velcade

Daratumumab

Dexamethasone oral tablet DRUG

Subjects who do not achieve either a hematologic VGPR or better, OR a hematologic PR with a major organ response by Cycle 4 Day 1 may receive at Investigator's discretion, in addition to daratumumab low dose dexamethasone at a maximum total dose of 20 mg weekly.

Daratumumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men or women 18 years of age or older.
• Diagnosis of amyloidosis, AL type, based on:
• Histopathological diagnosis of amyloidosis based on detection by immunohistochemistry and polarizing light microscopy of green bi-refringent material in Congo Red stained tissue specimens (excluding bone marrow) or characteristic electron microscopy appearance
• Considerations for specific populations where other types of amyloidosis may be encountered:
• For male subjects over 70 years of age who have cardiac involvement only, and subjects of African descent (black subjects), mass spectrometry, immunoelectron microscopy, or other immunohistochemistry-based typing of AL amyloid in a tissue biopsy or a negative bone scintigraphy with Tc99m-PYP or -DPD is recommended to rule out other types of amyloidosis such as age related amyloidosis and/or hereditary amyloidosis (ATTR mutation) AND
• Measurable disease of amyloid light chain amyloidosis as defined by at least ONE of the following:
• serum monoclonal protein ≥0.5 g/dL by protein electrophoresis (routine serum protein electrophoresis and immunofixation performed at local lab),
• serum free light chain (FLC) ≥2.0 mg/dL (20 mg/L) with an abnormal kappa:lambda ratio or the difference between involved and uninvolved free light chains (dFLC) ≥2mg/dL (20 mg/L). Serum free light chains (FLCs) will be measured using the Freelite assay at a central laboratory
• Note: Measurable disease by Urine Bence-Jones Proteinuria is not sufficient for study enrolment.
• AND
• Cardiac involvement by AL amyloidosis according to consensus guidelines
• Mayo Stage 3B disease, defined as both A. increased cardiac troponin (hsTnT \> 54 pg/ml) AND B. increased NT-proBNP ≥ 8500 pg/ml

You may not qualify if:

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, 2 or 3
• Subject must have pre-treatment clinical laboratory values meeting the following criteria during the Screening Phase:
• Absolute neutrophil count ≥1.0 × 109/L;
• Hemoglobin level ≥8.0 g/dL (≥5 mmol/L)
• Platelet count ≥75 × 109/L; platelet transfusions are NOT acceptable
• Alanine aminotransferase level (ALT) ≤2.5 x the upper limit of normal (ULN);
• Aspartate aminotransferase (AST) ≤2.5 x ULN
• Total bilirubin level ≤1.5 × ULN, except for subjects with history of Gilbert Syndrome, in which case direct bilirubin ≤ 2 × ULN
• Estimated Glomerular Filtration Rate (eGFR) ≥20 mL/min; Please note that the eGFR is measured using the CKD-EPI equation
• Women of childbearing potential must commit to either abstain continuously from heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the subject) or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal \[birth control pills, injections, hormonal patches, vaginal rings or implants\] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing and continue for 1 year after discontinuation of cyclophosphamide or 3 months after discontinuation of daratumumab, whichever is longer. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
• During the study and for 3 months after receiving the last dose of daratumumab, female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
• A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g. either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository during and up to 3 months after discontinuation of daratumumab. All men must not donate sperm during the study and for 3 months after discontinuation of daratumumab.
• Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to Cycle 1 Day 1. For requirements during the Treatment Phase, please see the Time and Events Schedule.
• Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of the procedures required for the study and are willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
• Any potential subject who meets any of the following criteria will be excluded from participating in the study:

Sponsors & Collaborators

• Stichting European Myeloma Network: lead
• Janssen Pharmaceutica: collaborator

Study Sites (5)

Hopitaux Universitaires Henri-Mondor

Créteil, France

Location

Hopital De Rangueil CHU

Toulouse, France

Location

National and Kapodistrian University of Athens, School of Medicine

Athens, Greece

Location

University Hospital San Matteo

Pavia, Italy

Location

UMCU

Utrecht, Netherlands

Location

Related Links

• website of the European Myeloma Network

MeSH Terms

Conditions

Amyloidosis

Interventions

daratumumab; Bortezomib; Dexamethasone

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2019
• First Posted: October 18, 2019
• Study Start: September 23, 2019
• Primary Completion: January 27, 2025
• Study Completion: January 27, 2025
• Last Updated: April 16, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1); GR (1); NL (1); FR (2)