Daratumumab for the Treatment of Patients With AL Amyloidosis

Study Overview
=================
Brief Summary
-----------------
Participants with AL Amyloidosis will receive the drug daratumumab by IV infusion once weekly for two months, then every 2 weeks for four months, then once each month. Study treatment may continue until disease progression, unacceptable toxicity, or decision to withdraw from the trial. Disease evaluations will be performed every three months until disease progression.

Detailed Description
-----------------
This Phase I/II study is intended to evaluate the safety and tolerability of infusion of daratumumab in AL amyloidosis, specifically with respect to infusion reactions. In addition, the investigators would like to assess organ response with respect to cardiac biomarkers and proteinuria, as well as hematologic response and time to next treatment. Participants with AL Amyloidosis will receive the drug daratumumab by IV infusion once weekly for two months, then every 2 weeks for four months, then once each month. Study treatment may continue until disease progression, unacceptable toxicity, or decision to withdraw from the trial. Disease evaluations will be performed every three months until disease progression.

Official Title
-----------------
A Phase I-II Trial of Daratumumab for the Treatment of Patients With AL Amyloidosis

Conditions
-----------------
AL Amyloidosis

Intervention / Treatment
-----------------
* Drug: daratumumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological diagnosis of primary systemic (AL) amyloidosis: At least one tissue demonstrating positive Congo Red staining with characteristic apple green birefringence AND Evidence of a clonal plasma cell dyscrasia: i. Monoclonal protein in the serum and/or urine by immunofixation electrophoresis AND/OR ii. Abnormal serum free light chain assay AND/OR iii. Clonal plasma cell population in the bone marrow demonstrated by immunohistochemistry, flow cytometry or in situ hybridization AND c. Evidence of organ involvement other than carpal tunnel syndrome. Confirmation of tissue diagnosis at all sites of organ dysfunction is encouraged, but not required. Must have relapsed after or been refractory to at least one prior treatment regimen of proven efficacy in the treatment of AL amyloidosis Must be > 18 years of age. Must have a performance status of 0-2 by Eastern Cooperative Oncology Group (ECOG) criteria Must have adequate hepatic function as evidenced by serum bilirubin values < 2.0 mg/dL; alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < 3x upper limit of normal (ULN). Must have an absolute neutrophil count ≥1000/mm3, hemoglobin ≥7.5 g/dL, and platelet count ≥50×109/L Exclusion Criteria: • Renal Insufficiency (CrCL <20mL/min), calculated by Cockcroft-Gault Equation Creatinine Clearance = Sex * ((140 - Age) / (SerumCreat)) * (Weight / 72) Equation parameters such as sex have two or more discrete values that may be used in the calculation. The numbers in the parentheses, e.g. (1), represent the values that will be used. The default unit of measure for weight is kilograms. Please verify that the correct unit of measure has been selected. Mayo clinic cardiac biomarker stage IIIb Evidence of significant cardiovascular conditions as specified below: B-type Natriuretic Peptide; N-terminal pro b-type Natriuretic Peptide (NT-ProBNP) > 8500 ng/L (Mayo Stage IIIb patients are excluded) New York Heart Association (NYHA) classification IIIB or IV heart failure Unstable Angina, Arrhythmia, prolonged corrected QT (QTc) interval, symptomatic orthostatic hypotension, or supine systolic blood pressure < 90 mm Hg. left ventricular ejection fraction (LVEF) <40% Overt multiple myeloma (>30% bone marrow plasmacytosis, extensive (>2) lytic lesions, or hypercalcemia). Plan for autologous stem cell transplant in the six months prior to study drug (stem cell collection is permitted during the first six months of study treatment) Any form of secondary or familial (ATTR) amyloidosis The presence or history of another malignancy is not allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, any other cancer from which the patient has been disease-free for 5 years. Known to be Human Immunodeficiency Virus (HIV) positivity. Pregnant or nursing women. Women and men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume at one second (FEV1) <50% of predicted normal. Note that forced expiratory volume at one second FEV1 testing is required for patients suspected of having COPD. Known moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daratumumab<br>Daratumumab, 16mg/kg body weight in 1000 mL for the first dose, followed by 500mL for subsequent doses, once weekly for two months, then every 2 weeks for four months, then once each month. | Drug: daratumumab<br>* Daratumumab by IV infusion once weekly for two months, then every 2 weeks for four months, then once each month until progression or inability to tolerate.<br>* Other names: Darzalex;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Number of Patients Who Respond to Treatment | Number of participants with response and ability to tolerate study treatment in each of these categories: Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD). All participants were able to tolerate study treatment. Per protocol, overall response designations are a combination of hematologic response. A CR is defined as negative serum and urine immunofixation electrophoresis with normal serum free light chain ratio; a VGPR is reduction in the dFLC* to <40 mg/L, a PR is dFLC reduction by >50%; SD is not meeting criteria for CR, VGPR, PR, or PD; and PD is an increase in FLC of 50% to >100 mg/L. * dFLC is difference in involved and uninvolved serum Free Light-Chain levels. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Next Treatment | Number of months from study drug initiation to starting another treatment | Up to 3 years | 
| Assess Hematologic Response Based on Blood and Urine Testing Using Standard Criteria | Number of patients with hematologic complete response (CR), very good partial response (VGPR), or partial response (PR). Per protocol, a hematologic CR is defined as negative serum and urine immunofixation electrophoresis with normal serum free light chain ratio; a VGPR is reduction in the dFLC* to <40 mg/L; and a PR is dFLC reduction by >50%. * dFLC is difference in involved and uninvolved serum free light-chain levels | 3 months | 
| Assess Organ Responses Based on Standard Criteria Included in Protocol | Number of patients with organ response based on standard criteria included in protocol. Cardiac response is defined as: NT-proBNP response (>30% and >300 ng/L decrease in patients with a baseline NT-proBNP >650 ng/L; and/or NYHA class response (> two-class decrease if baseline NYHA class 3 or 4) Renal response is defined as: Decrease in proteinuria by > 30% or below 0.5 g/24 h without renal progression. Serum creatinine and creatinine clearance must not worsen by 25% over baseline | 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Daratumumab