A Phase 2, Open Label, Multicenter, Single-stage Study to Evaluate the Efficacy of Isatuximab Plus Pomalidomide and Dexamethasone (IPd), in Patients With AL Amyloidosis Not in VGPR or Better After Any Previous Therapy
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 46
- 试验地点
- 15
- 主要终点
- Hematologic Response
研究概览
简要总结
This phase 2 study ain to evaluate the efficacy of Isatuximab plus Pomalidomide and Dexamethasone (IPd), in patients with AL amyloidosis not in VGPR or better after any previous therapy. It will enrolled 46 patients (34 in France and 12 in Australia) through 15 sites (11 in France and 4 in Australia).
详细描述
Systemic AL amyloidosis is a rare disease caused by the deposition of misfolded monoclonal immunoglobulin free light chains (FLC) in various tissues and organs. It is usually associated with a clonal plasma cell dyscrasia with a low tumor burden. Treatment of AL amyloidosis relies mainly on chemotherapy aimed at suppressing the underlying plasma cell clone secreting monoclonal FLC.
The organ responses and the survival are greatly influenced by the degree of hematological response evaluated by the decrease in serum FLC that has been the principal endpoint in recent trials in AL amyloidosis. The goal of treatment is to reach at least a very good partial response (VGPR) defined as a difference between the involved FLC and the normal one below 40 mg/L.
Over the last 5 years, monoclonal antibodies (mAb) as daratumumab and Isatuximab (anti CD38 mAb) has emerged as a breakthrough targeted therapies for patients with multiple myeloma (MM).
CD38, is a type II transmembrane glycoprotein that functions both as a signal-transducing receptor and a multifunctional ectoenzyme. The expression of CD38 is increased in MM and AL amyloidosis plasma cells.
Daratumumab (DARA) is an IgG 1k human mAb that received initial approval as monotherapy in patients with heavily pretreated RRMM and who were refractory to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiD®). DARA has since been approved in combination with Lenalidomide/Dexamethasone1,2 and Bortezomib/Dexamethasone3,4 for the treatment of frontline and relapsed/refractory (RR) MM patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologic diagnosis of AL amyloidosis;
- •Patients should have received at least one line with an alkylating agent and/or a PI, 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) (See Appendix 1);
- •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 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.
- •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 abstinence from heterosexual intercourse or apply a highly effective method of birth control 4 weeks before initiation of treatment, during the intervention period and for at least 5 months after IsaPd 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);
- •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.
排除标准
- •Presence of non-AL amyloidosis
- •AL amyloidosis with isolated soft tissue involvement
- •Bone marrow plasma cells >30% and clinically symptomatic multiple myeloma with lytic bone lesions
- •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,
- •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 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
- •Previous anti-CD38 therapy or Pomalidomide therapy (if refractory to Pomalidomide)
- •Hypersensitivity to IMiD® defined as any hypersensitivity reaction leading to stop IMiD® 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
- •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
- •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
- •Pregnant or breast-feeding females
研究组 & 干预措施
Single-stage
Patient eligible to enter the study will receive 9 to 12 cycles (according to response) of intravenous Isatuximab (10 mg/kg) and oral Pomalidomide 4 mg from day 1 to day 21 and Dexamethasone 10-20 mg weekly on days 1, 8, 15 and 22.
Each cycle will be of 28 days duration. During cycle 1, Isatuximab will be administered weekly on days 1, 8, 15, and 22 then days 1 and 15 in subsequent cycles from cycle 2 to 9 or 12.
For each individual patient, the treatment period will be 12 months, unless CR at the completion of 9 cycles, disease progression or unacceptable toxicity occurs. The duration of follow-up for overall survival will be 1 year after the last patient enters overall survival follow-up.
干预措施: Isatuximab (Drug)
结局指标
主要结局
Hematologic Response
时间窗: At the end of Cycle 6 (each cycle is 28 days)
To assess hematologic response (VGPR or better i.e. dFLC \< 40 mg/L, CR including modified CR\*, low-dFLC response (dFLC \< 10 mg/L), iFLC \< 10 mg/l) achieved after 6 cycles of 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).
次要结局
- Overall Hematologic Response Rate(At the completion of the 1st, 2nd, 4th, 6th, 9th and 12th cycles (each cycle is 28 days))
- Efficacy Measurement: Progression-free survival (PFS)(During the intervention and at 1 year)
- Efficacy Measurement: relapse-free survival (RFS)(During the intervention)
- Efficacy Measurement: Organ response rate (OrRR)(1 year)
- Time to and the duration of haematologic and organ responses(During the intervention)
- Safety analysis(Until 30 days post last dose of protocol treatment)
- Cytogenetic: incidence of genetic translocation t(11;14) and impact on hematologic and organ response(Though study completion, an average of 33 months)
- Cardiac function(After 6 cycles of IsaPd and at 1 year from start of therapy or 12 cycles of IsaPd (each cycle is 28 days).)
- Renal function(After 6 cycles of IsaPd and at 1 year from start of therapy or 12 cycles of IsaPd (each cycle is 28 days))
- Quality of Life : European Quality of Life 5 dimensions (EQ-5D-3L)(up to 15 months)
- Efficacy Measurement: Overall Survival (OS)(Though study completion, an average of 33 months)