| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously treated AL amyloidosis |
| Amylose AL traitée précédemment |
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| E.1.1.1 | Medical condition in easily understood language |
| Previously treated AL amyloidosis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002022 |
| E.1.2 | Term | Amyloidosis |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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)
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| E.2.2 | Secondary objectives of the trial |
- 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).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <1.5 x ULN, unless for subjects with Gilbert’s syndrome where the direct bilirubin should then be ≤2.0 x ULN.
8. Male participants must agree to use contraception during the intervention period and for at least 5 months after the last dose of Isatuximab treatment, 28 days after last dose of Pomalidomide treatment, and refrain from donating sperm during this period.
Female participants are eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a Female of childbearing potential (FCBP), OR a FCBP who must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days prior to and again within 24 hours prior to starting study medication and before each cycle of study treatment and must either commit to continue abstinence from heterosexual intercourse or apply a highly effective method of birth control during the intervention period and for at least 5 months after the last dose of Isatuximab treatment and 28 days after last dose of Pomalidomide treatment,
Female patients who are postmenopausal for at least 1 year before the screening visit, or are surgically sterile, or if they are of childbearing potential, agree to practice effective methods of contraception from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from intercourse (serum pregnancy test must be performed for all women of childbearing potential at the beginning of each cycle during the study. 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);
9. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
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| E.4 | Principal 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 observed during screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met
• Active HCV infection: positive HCV RNA and negative anti-HCV. Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion. Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible
22. Pregnant or breast-feeding females
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| E.5 End points |
| E.5.1 | 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)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6 months (after 6 cycles of treatment) |
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| E.5.2 | 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 .
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1, 2, 4, 6, 9 and 12 months |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will be ended 1 year after the last patient enters overall survival follow‐up. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 33 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 33 |
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