Evaluation of Isatuximab, Pomalidomide, and Dexamethasone Efficacy in AL Amyloidosis Patients Lacking VGPR Post-Therapy
- Trial ID
- 2024-513887-25-00
- Protocol
- IFM 2020-01
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **hematologic response** in patients with AL Amyloidosis who have not achieved a very good partial response (VGPR) or better after any previous therapy. The response is evaluated after 6 cycles of treatment with Isatuximab, Pomalidomide, and Dexamethasone (Isa-Pd), focusing on achieving VGPR or better, defined as a difference in free light chain (dFLC) of less than 40 mg/L, complete response (CR) including modified CR, low-dFLC response (dFLC < 10 mg/L), and involved free light chain (iFLC) < 10 mg/L. This is clinically relevant as achieving a VGPR or better is associated with improved patient outcomes and survival in AL Amyloidosis.
Secondary objectives include: - Assessing the overall hematologic response rate at various treatment cycles. - Evaluating preliminary efficacy measures such as hematologic progression-free survival (PFS), relapse-free survival (RFS), organ response rate (OrRR), overall survival (OS), and the time to and duration of hematologic and organ responses. - Determining the safety and tolerability of the Isa-Pd regimen. - Assessing the impact of genetic translocation t(11.14) on response. - Evaluating the correlation of strain improvement to NT-proBNP levels and albumin level to proteinuria/eGFR after treatment. - Assessing the quality of life using the EQ-5D-3L questionnaire.
Participants
The clinical trial involves a total of **16 participants** diagnosed with **AL Amyloidosis**. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on specific inclusion criteria, including a histologic diagnosis of AL amyloidosis and measurable hematologic disease. The trial does not involve a vulnerable population. Participants must have adequate bone marrow and organ function, as well as an ECOG status of 2 or less. Lifestyle considerations such as diet and physical activity are not specified. The selection process required participants to have received at least one line of treatment with an alkylating agent, PI, or anti-CD38, with the last administration occurring at least one year prior to the study's commencement. The trial excludes individuals who are pregnant or breastfeeding, and male participants must agree to use contraception during the study period. The sponsor has not provided additional information regarding lifestyle factors or other demographic details.
Plans and Procedures
The clinical trial is designed as a **phase 2**, open-label, multicenter, single-stage study to evaluate the efficacy of a combination therapy involving **isatuximab**, **pomalidomide**, and **dexamethasone** in patients with **AL amyloidosis** who have not achieved a very good partial response (VGPR) or better after previous therapy. The trial is expected to run from January 31, 2022, to March 31, 2026, with a maximum treatment period of 12 months for each participant. The study employs a non-randomized, open-label design, allowing for the direct observation of treatment effects without the use of a placebo or blinding.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, previous treatment history, and organ function. The primary objective is to assess hematologic response, specifically achieving VGPR or better, after six cycles of the combination therapy. Follow-up visits will occur at the completion of the 1st, 2nd, 4th, 6th, 9th, and 12th cycles to evaluate overall hematologic response, organ response, and other secondary endpoints such as progression-free survival and overall survival. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and any adverse events.
Participant involvement is expected to last up to 12 months, with conditions for early termination including significant adverse events, withdrawal of consent, or failure to adhere to study protocols. The study aims to provide comprehensive data on the efficacy and safety of the treatment regimen, contributing valuable insights into the management of AL amyloidosis. The trial's methodology ensures rigorous monitoring and evaluation of treatment effects, with a focus on achieving meaningful clinical outcomes for participants.
Treatment
The clinical trial involves the administration of several experimental medications. **Dexamethasone acetate** is provided in the form of **DECTANCYL 0.5 mg tablets**. This medication is administered orally with a maximum daily dose of 20 mg, and the treatment period can extend up to 12 months. The tablets are manufactured by Sanofi Winthrop Industrie and are classified under the ATC code H02AB02, indicating their role as a glucocorticoid.
**Pomalidomide** is administered in the form of **Imnovid hard capsules**, available in 1 mg, 2 mg, and 4 mg dosages. The capsules are taken orally, with a maximum daily dose of 4 mg. The treatment duration is also up to 12 months. These capsules are produced by Bristol-Myers Squibb Pharma EEIG and are categorized under the ATC code L04AX06, which denotes their use as an immunomodulatory agent.
**Dexamethasone** is also provided as **Neofordex 40 mg tablets**. These tablets are administered orally with a maximum daily dose of 20 mg, and the treatment can last up to 12 months. The manufacturer, Theravia, classifies this product under the same ATC code as Dectancyl, H02AB02, due to its glucocorticoid properties.
**Isatuximab** is administered as **SARCLISA 20 mg/mL concentrate for solution for infusion**. This medication is given intravenously with a maximum dose of 10 mg/kg. The treatment period is up to 12 months. Sanofi Winthrop Industrie manufactures this product, and it is classified under the ATC code L01FC02, indicating its role as a monoclonal antibody targeting CD38.
The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedules and administration routes as specified for each medication. The study aims to evaluate the efficacy of the combination of Isatuximab, Pomalidomide, and Dexamethasone in patients with AL amyloidosis who have not achieved a very good partial response (VGPR) or better after previous therapy.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the hematologic response in patients with AL **amyloidosis**. The primary endpoint is achieving a Very Good Partial Response (VGPR) or better, defined as a difference in free light chain (dFLC) of less than 40 mg/L, assessed using consensus response criteria at the end of six cycles of treatment with Isatuximab, Pomalidomide, and Dexamethasone (Isa-Pd). Secondary endpoints include the overall hematologic response rate, which encompasses VGPR, Complete Response (CR), modified CR, low-dFLC response (dFLC < 10 mg/L), and involved free light chain (iFLC) < 10 mg/L, assessed at the completion of the 1st, 2nd, 4th, 6th, 9th, and 12th cycles.
Additional secondary endpoints include relapse-free survival measured from the date of best response, progression-free survival from the date of inclusion, and organ response rate at one year according to current consensus criteria. Overall survival will be measured from the date of inclusion. The time to and duration of hematologic and organ responses will also be evaluated. Safety assessments will include the type, frequency, and severity of adverse events, drug discontinuation due to toxicity or intolerance, dose modification or delay, and the relationship of adverse events to the study treatment, using the NCI-CTCAE v5.0 criteria.
Other assessments include left ventricular strain via transthoracic echocardiography after six cycles of Isa-Pd and at one year from the start of therapy or after 12 cycles. Albumin levels and proteinuria will be assessed by electrophoresis, and estimated glomerular filtration rate (eGFR) will be calculated using the CKD-EPI formula after six cycles and at one year or after 12 cycles. Health-related quality of life and potential improvements over the course of the study will be assessed using the EQ-5D-3L patient-reported outcome questionnaire.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18
- Histologic diagnosis of AL amyloidosis;
- Patients should have received at least one line with an alkylating agent and/or a PI, and/or with an anti-CD38 which the last administration ≥ 1 year before the C1D1 and dexamethasone and not be in VGPR (or better) at the time of inclusion (patients who did not reach VGPR before, or patients in VGPR or better before but with a hematological relapse at the time of inclusion can be included);
- Measurable hematologic disease: difference between involved and uninvolved FLC > 50 mg/L with an abnormal k/l ratio;
- Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system)
- 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.
- 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,
- Adequate organ function defined as: - Serum ASAT and 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.
- ECOG status ≤ 2
- Male participants must agree to use contraception during the intervention period and for at least 5 months after the last dose of IsaPd 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 complete abstinence from heterosexual intercourse or apply two reliable methods of birth control (One highly effective method and one additional effective method) used at the same time, beginning 4 weeks before initiation of treatment, during the intervention period and for at least 5 months after IsaPd treatment, Serum pregnancy test must be performed for all women of childbearing potential within 24 hours prior to the start of the treatment, weekly for the first 28 days of treatment and then, every 28 days while on treatment, during dose interruption, then at study discontinuation and at day 28 after end of treatment. 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.
- 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.
Exclusion Criteria
- Presence of non-AL amyloidosis
- Undergoing dialysis
- Ongoing toxicity (excluding alopecia and those listed in eligibility criteria) from any prior therapy > G1 (NCI-CTCAE v5.0)
- Supine systolic blood pressure < 90 mmHg, 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
- Previous anti-CD38 therapy < 1 year before the C1D1 or Pomalidomide therapy (if refractory to Pomalidomide and/or anti-CD38 therapy)
- Hypersensitivity to IMiD® or anti-CD38 defined as any hypersensitivity reaction leading to stop IMiD® or anti-CD38 within the 2 first cycles or toxicity, which does meet intolerance definition
- Hypersensitivity or history of intolerance to steroids, mannitol, 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
- AL amyloidosis with isolated soft tissue involvement
- Bone marrow plasma cells >30% or symptomatic multiple myeloma
- NT-proBNP > 8500 ng/L and hs-troponin I > 100 ng/L or hs-troponin T > 50 ng/L (cardiac stage IIIb patients)
- 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
- Chronic atrial fibrillation with uncontrolled heart rate
- Significant cardiac dysfunction; myocardial infarction within 12 months; unstable poorly controlled angina pectoris
- Uncorrected valvular disease unrelated to AL amyloid cardiomyopathy
- QT interval as corrected by Fridericia’s formula > 550 msec without pacemaker,
- 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)
- 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
- Active systemic infection and severe infections requiring treatment with a parenteral administration of antibiotics
- 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 (i.e acute leukemia) delay could be shortened after agreement between sponsor and investigator, in absence of residual toxicities from previous therapy
- Known positive for HIV or active hepatitis A, B or C: • Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA Of note: Patient can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but HBsAg and HBV DNA are negative. o 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. Of note: 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
- Pregnant or breast-feeding females
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 31 Jan 2022 | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SARCLISA 20mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 10 | 12 | PRD8132767 |
Imnovid 2 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 4 | 12 | PRD9260805 |
Imnovid 1 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 4 | 12 | PRD9260804 |
SARCLISA 20mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 10 | 12 | PRD8132765 |
DECTANCYL 0,5 mg, comprimé | Other | COMPRIMÉ | ORAL | 20 | 12 | PRD425675 |
Imnovid 4 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 4 | 12 | PRD9260808 |
Neofordex 40 mg tablets | Other | TABLETS | ORAL | 20 | 12 | PRD3861554 |