Previously treated AL amyloidosis MedDRA version: 20.0 Level: PT Classification code 10002022 Term: Amyloidosis System Organ Class: 10021428 - Immune system disorders
Conditions
Interventions
Trade Name: SARCLISA
Product Name: Isatuximab
Product Code: SAR650984
Pharmaceutical Form: Concentrate for solution for infusion
Trade Name: IMNOVID 4 mg
Product Name: IMNOVID
Pharmaceutical Form: Ca
Sponsors
Intergroupe Francophone du Myélome
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologic diagnosis of AL amyloidosis; 2. Patients should have received at least one line with an alkylating agent and/or a PI and Dexamethasone and not be in VGPR or CR at the time of inclusion (patients who did not reach VGPR or patients in VGPR or better but with a hematological relapse can be included); 3. Measurable hematologic disease: difference between involved and uninvolved FLC > 50 mg/L with an abnormal k/l ratio; 4. Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system) (See Appendix 1); 5. 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. 6. Adequate bone marrow function prior to 1st drug intake (C1D1), without transfusion or growth factor support within 5 days prior to 1st drug intake, defined as: - Absolute neutrophils count = 1000/mm3, - Platelets = 75000/mm3 , - Hemoglobin = 8.0 g/dL, 7. Adequate organ function defined as: - Serum ASAT or ALAT = 3.0 X Upper Limit of the normal range (ULN), - Serum total bilirubin level =65 years) yes F.1.3.1 Number of subjects for this age range 23
Exclusion criteria
Exclusion criteria: 1. Presence of non-AL amyloidosis 2. AL amyloidosis with isolated soft tissue involvement 3. Bone marrow plasma cells >30% and clinically symptomatic multiple myeloma with lytic bone lesions 4. NT-proBNP > 8500 ng/L and hs-troponin I >100 ng/L or hs-troponin T > 50 ng/L (cardiac stage IIIb patients) 5. Repetitive ventricular arrhythmias on 24h Holter ECG despite anti-arrhythmic treatment sustained ventricular tachycardia, aborted ventricular fibrillation, atrioventricular nodal or sinoatrial nodal dysfunction with no pacemaker 6. Chronic atrial fibrillation with uncontrolled heart rate 7. Significant cardiac dysfunction; myocardial infarction within 12 months; unstable poorly controlled angina pectoris 8. Uncorrected valvular disease unrelated to AL amyloid cardiomyopathy 9. QT interval as corrected by Fridericia’s formula >550 msec without pacemaker, 10. Undergoing dialysis 11. ECOG status >2 12. Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) from any prior therapy >G1 (NCI-CTCAE v5.0) 13. Supine systolic blood pressure <90 mm Hg, or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of <80 mmHg despite medical management (I.e. midodrine, fludrocortisones) in the absence of volume depletion 14. Previous anti-CD38 or pomalidomide therapy (if refractory to pomalidomide) 15. Hypersensitivity to IMiD® defined as any hypersensitivity reaction leading to stop IMiD® within the 2 first cycles or toxicity, which does meet intolerance definition 16. Hypersensitivity or history of intolerance to steroids, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, polysorbate 80, poloxamer 188, sucrose or any of the other components of study treatment that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents 17. History of malignancy (other than AL amyloidosis) within 3 years before the date of inclusion (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years ) 18. Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose the patient to excessive risk or may interfere with compliance or interpretation of the study results 19. Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics 20. Received any investigational drug within 14 days or 5 half-lives of the investigational drug prior to initiation of study intervention, whichever is longer. In case of very aggressive disease delay could be shortened after agreement between sponsor and investigator, in absence of residual toxicities from previous therapy 21. Known positive for HIV or active hepatitis A, B or C: • Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA: Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period. Patients with negative HBsAg and positive HBV DNA ob
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to assess hematologic response (VGPR or better, dFLC< 40 mg/l) including modified CR* and dFLC<10 mg/l and iFLC<10 mg/l) achieved after 6 cycles of isatuximab, pomalidomide and dexamethasone (Isa Pd). *: If iFLC <ULN and serum and urine immunofixation are negative, then neither a normal uFLC level nor a normal FLC ratio are required for complete response (CR) ;Secondary Objective: - Overall Hematologic Response Rate (VGPR, CR, modified CR*, Low-dFLC response at the completion of the 1st, 2nd, 4th, 6th, 9th and 12th cycles - To evaluate the following efficacy measures following treatment with Isa-Pd: -Haematologic Progression-free survival (PFS) and 1-year PFS -Relapse-free survival (RFS) -Organ response rate (OrRR) at 1 year -Overall survival (OS) and 1-year OS -Time to and duration of hematologic and organ responses -To determine safety and tolerability of Isatuximab plus Pomalidomide and Dexamethasone. - To assess the impact of t(11.14) determined by FISH at inclusion on response. - To assess correlation of Strain improvement to NT-proBNP after 6 cycles of IsaPd or end of therapy and at 1 year from start of therapy or 12 cycles of IsaPd - To assess albumin level to proteinuria/ eGFR after 6 cycles of IsaPd or end of therapy and at 1 year from start of therapy or 12 cycles of IsaPd - To assess Quality of Life (EQ-5D-5L questionnaire). ;Primary end point(s): The primary endpoint is the VGPR or better including modified CR* assessed using consensus response criteria (Appendix 2) at the end of 6 cycles of IsaPd. *: If iFLC <ULN and serum and urine immunofixation are negative, then neither a normal uFLC level nor a normal FLC ratio are required for complete response (CR) ;Timepoint(s) of evaluation of this end point: 6 months (after 6 cycles of treatment) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary End points : In all patient according to their disease history: • Hematologic response assessed using consensus criteria (Appendix 2), modified to consider modified CR * and Low-dFLC response (dFLC < 10 mg/l) at the end of the 1st, 2nd, 6th, 9th and 12th cycles • Relapse Free Survival in responding population measured from the date of best response • Haematologic Progression Free Survival measured from the date of inclusion • Organ response rate (OrRR) (Appendix 3) at 1 year • Overall Survival measured from the date of inclusion • Time to and duration of hematologic and organ responses • Type, frequency, severity (NCI-CTCAE v4.03V 5.0), drug discontinuation for toxicity or intolerance, dose modification/delay and relationship of adverse events to study treatment. • t(11.14) assessed by fish/NGS at inclusion • Strain Left ventricular stain assessed by TTE after 6 cycles of IsaPd or end of therapy and at 1 year from startthe end of therapy or 12 cycles of IsaPd • Albumin level and proteinuria assessed by electrophoresis eGFR estimated by CKD epi after 6 cycles of IsaPd or and at the end of therapy and at 1 year from start of therapy or 12 cycles of IsaPd • Health-related QoL and potential for improvement over the course of the study assessed by the ED-5D-53L patient-reported outcome questionnaire *: If iFLC <ULN and serum and urine immunofixation are negative, then neither a normal uFLC level nor a normal FLC ratio are required for complete response (CR) Exploratory Endpoints : • Study of the immunoglobulin repertoire of heavy and light chains in bone marrow RNA and to compare MRD done by NGS with RNA or DNA sequencing . ;Timepoint(s) of evaluation of this end point: 1, 2, 4, 6, 9 and 12 months | — |
Countries
Australia, France
Contacts
Public ContactLéa Tabone
Intergroupe Francophone du Myélome
Outcome results
None listed