AL amyloidosis MedDRA version: 20.0 Level: HLGT Classification code 10035227 Term: Plasma cell neoplasms System Organ Class: 10005329 - Blood and lymphatic system disorders
Conditions
Interventions
Product Name: HuMax-CD38
Product Code: NA
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Daratumumab
CAS Number: 945721-28-8
Current Sponsor code: NA
Concentration uni
Sponsors
CHU DE LIMOGES
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients must be =18 years of age 2. Histologic diagnosis of AL amyloidosis 3. Patients without a clear evidence of ¿ or ¿ light chains positivity of amyloid deposits by immunohistochemistry who present: 1) with peripheral neuropathy as the dominant organ involvement should have a genetic testing negative for transthyretin mutations associated with hereditary amyloidosis, 2) who present with cardiac involvement as the dominant organ involvement should have a (99m)Tc-HMDP-scintigraphy to rule out TTR amyloidosis. 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 ¿/¿ 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 1 drug intake (C1D1), without transfusion or growth factor support within 5 days prior to 1 drug intake, defined as: Absolute neutrophils = 1000/mm Platelets = 50000/mm Hemoglobin = 8.5g/dl 10. Adequate organ function defined as: 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* must be practicing one of the following methods of birth control : subcutaneous hormonal implant, levonorgestrel releasing intra-uterine system, medroxyprogesterone acetate depot, tubal sterilization, ovulation inhibitory progesterone only pills, or sexual intercourse with a vasectomized male partner (vasectomy must be confirmed by 2 negative semen analyses). Or women will commit to absolute and continuous abstinence confirmed to her physician on a monthly basis*. Contraception will start at the beginning of therapy including dose interruptions, and for 3 months after discontinuation of Daratumumab 12. A woman with childbearing potential must have negative serum or urine pregnancy tests at screening and within 48H 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. 13. A woman of childbearing potential must remain on a highly effective method of birth control. Contraception must start prior initiating treatment with Daratumumab, during therapy, during dose interruptions and 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/film/cream/suppository, and all men
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 - Overall Hematologic Response Rate (CR+VGPR+PR) at the completion of 1 and 3 the cycles. - The Overall Hematologic Response Rate including PR at the completion of 6 cycles - the duration of hematologic response - the rate of organ response and organ improvement, according to standard criteria - the time to hematologic and organ response - the hematologic disease progression free survival (PFS) and 1-year PFS - the overall survival (OS) and 1-year OS ¿ Assess QoL using EORTC QLQ30, EQ5D-3L and Amyloidosis Symptoms Scale;Primary end point(s): Thee Overall Response Rate (CR+VGPR) in patients with AL Amyloidosis not in CR or VGPR after any previous therapy, using the new response criteria.;Timepoint(s) of evaluation of this end point: After 6 cycles | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Type, frequency, severity, relationship of adverse events to study treatment and changes in vital signs, physical exams, incidence of Treatment Emergent Adverses E vents ( TEAE), Serious Adverses Events (SAE), drug discontinuation for toxicity, dose modification/delay and laboratory abnormalities will be assessed using NCI-CTCAE V4.03 2. In all patients according to their disease history 2.1. the overall hematologic response rate (CR + VGPR + PR) at the completion of 1 and 3 cycles 2.2. the Overall Hematologic Response Rate including PR at the completion of 6 cycles 2.3. the time to hematologic disease progression 2.4. the rate of organ response and organ improvement, according to standard criteria 2.5. the time to hematologic and organ response 2.6. the hematologic disease progression free survival (PFS) and 1-year PFS 2.7. 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. 3. QoL using EORTC QLQ30, EQ5D-3L, Amyloidosis Symptoms Scale;Timepoint(s) of evaluation of this end point: Safety is evaluated at the start of each cycle Responses at the completion of 1 and 3 cycles The Overall Hematologic Response Rate including PR at the completion of 6 cycles | — |
Countries
France, Italy
Contacts
Public ContactCentro per lo studio e la cura dell
Fondazione IRCCS Policlinico San Matteo
Outcome results
None listed