AL Amyloidosis MedDRA version: 19.0 Level: HLGT Classification code 10035227 Term: Plasma cell neoplasms System Organ Class: 10005329 - Blood and lymphatic system disorders
Conditions
Interventions
Product Name: HuMax-CD38
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DARATUMUMAB
CAS Number: 945721-28-8
Concentration unit: mg/ml milligram(s)/millilitre
Concent
Sponsors
CHU de Limoges
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Histologic diagnosis of AL amyloidosis 2.Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis or immunohistochemistry of amyloid deposits must provide clear evidence of kappa or lambda light chains in those who present with peripheral neuropathy or heart as the dominant organ involvement. 3.Patients must be >=18 years of age 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 (patients who did not reach VGPR or patients who reached VGPR or better but have an hematological relapse can be included). 6.Measurable hematologic disease: difference between involved and uninvolved FLC > 50 mg/L with an abnormal kappa/lambda ratio (with Freelite® test kits, The Binding Site) 7.Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system) 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 (C1D1), without transfusion or growth factor support within 5 days prior to 1st drug intake, 10.Adequate organ function defined as: - Serum creatinine clearance (Cockcroft-Gault formula) >= 30 ml/min - Serum SGOT/AST or SGPT/ALT < 3.0 X Upper Limit Of The Normal Range (ULN) - Serum total bilirubin < 2.0 mg/dL, unless the patient has Gilbert’s syndrome where the direct bilirubin should then be < 2.0 mg/dL 11.Women who are partners of men and with childbearing potential*(defined below) must be practicing a methods of birth control 12.A woman with childbearing potential must have 2 negative serum or urine pregnancy tests at Screening, first within 14 days prior to dosing and the second within 48 hours prior to dosing, and remain on a highly effective method of birth control. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception, Highly effective methods : Intrauterine device (IUD), Hormonal (birth control pills, injections, implants), Tubal ligation, Partner’s vasectomy Additional effective methods : Male condom, Diaphragm, Cervical Cap Serum (urine in the case where serum is not possible in a timely manner) pregnancy test to be performed for all women of childbearing potential regularly during the therapy. In addition, a pregnancy test may be done at any time during the study at the discretion of the investigator if a subject misses a period or has unusual menstrual bleeding 13.A woman of childbearing potential must remain on a highly effective method of birth control. Contraception must begin 4 weeks before initiating treatment with Daratumumab, during therapy, during dose interruptions and continuing for 3 months following discontinuation of Daratumumab. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy 14.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 e.g., condom with spermicidal foam/gel/
Exclusion criteria
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. (i.e. cardio mayo stage III with NT-proBNP >= 8500 ng/L 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 with the exception of -adequately treated basal cell or squamous cell skin cancer, -in situ cervical cancer -low grade (Gleason 3+3 or less) prostate cancer or in situ breast carcinoma if surgically treated -adequately treated Stage I cancer from which the patient is currently in complete remission, -or any other cancer from which the patient has been disease-free for 3 years. 12. Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator including: - NYHA functional classification IV congestive heart failure - LVEF (Left Ventricular Ejection Fraction) <45% - Uncontrolled angina, hypertension or arrhythmia - Myocardial infarction in the past 6 months 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/underlying medical conditions that, in the investigator’s opinion would make the administration of the study drug hazardous (ie: uncontrolled diabetes or uncontrolled coronary artery disease) 15.Subjects with known chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for patients suspected of having COPD and subjects must be excluded if FEV1 <50% of predicted normal 16.Subject has known moderate or severe persistent asthma within the past 2 years (see APPENDIX 8), or currently has uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study) 17.Previous anti-CD38 therapy 18.Hypersensitivity to Dexamethasone that would prohibit treatment with study therapy 19.Known positive for HIV or active hepatitis B or C 20.Refusal to consent or protected by legal regime
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To Assess Overall Hematologic Response Rate (CR + VGPR) at the completion of 6 cycles of Daratumumab in patients with AL Amyloidosis not in CR or VGPR after any previous therapy;Secondary Objective: •To determine safety and tolerability of Daratumumab (type, frequency, severity, and relationship of adverse events to study treatment). •To Assess in all patients according to their disease history oOverall Hematologic Response Rate (CR+VGPR+PR) at the completion of 1 and 3 the cycles (PR: 50% drop from dFLC at inclusion). oThe Overall Hematologic Response Rate including PR at the completion of 6 cycles othe duration of hematologic response othe rate of organ response and organ improvement, according to standard criteria othe time to hematologic and organ response othe hematologic disease progression free survival (PFS) and 1-year PFS othe overall survival (OS) and 1-year OS •Assess QoL using EORTC QLQ30, EQ5D-3L and Amyloidosis Symptoms Scale ;Primary end point(s): The primary endpoint is the Overall Response Rate (CR+VGPR) at the completion of 6 cycles of Daratumumab in patients with AL Amyloidosis not in CR or VGPR after any previous therapy, using the new response criteria . The data used for the primary statistical analysis will be central laboratories data. Key parameters will be M-protein, serum free light chain values and ratio, and DIRA when applicable.;Timepoint(s) of evaluation of this end point: At the completion of 6 cycles | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The safety and tolerability by type, frequency, severity, relationship of adverse events to study treatment and changes in vital signs, physical exams. Incidence of Treatment Emergent Adverses Events (TEAE), Serious Adverses Events (SAE) and laboratory abnormalities will be assed using NCI CCTAE V4.03 • In all patients according to their disease history o the overall hematologic response rate (CR + VGPR + PR) at the completion of 1 and 3 cycles o the Overall Hematologic Response Rate including PR at the completion of 6 cycles o the duration of hematologic response o the time to hematologic disease progression o the rate of organ response and organ improvement, according to standard criteria o the time to hematologic and organ response o the hematologic disease progression free survival (PFS) and 1-year PFS o the overall survival (OS) and 1-year OS The data used for the primary statistical analysis will be central laboratories data. Key parameters will be M-protein, serum free light chain dosage and ratio, and DIRA when applicable. • QoL using EORTC QLQ30, EQ5D-3L, Amyloidosis Symptoms Scale ;Timepoint(s) of evaluation of this end point: Safety is evaluated at the strt of each cycle Responses at the completion of 1 and 3 cycles The Overall Hematologic Response Rate including PR at the completion of 6 cyclesPlease enter information in English and add any other language that is applicable | — |
Countries
France
Contacts
Public ContactClinical Trial Coordinator
CHU de Limoges
Outcome results
None listed