2024-511768-97-01招募中2 期
A multicenter, open-label, randomized, phase II clinical trial comparing safety and durable overall response rate (DOR) at 56 days in patients with steroid resistant severe acute GvHD after allogeneic hematopoietic stem cell transplantation treated with decidua stromal cells (DSC) or best available treatment (BAT)
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 45
- 试验地点
- 4
- 主要终点
- Documenting AEs and SAEs and determining causality in relation to DSC. Causality of AEs and SAEs will be assessed by the Investigator.
研究概览
简要总结
To assess the safety and tolerability of DSC To assess Durable Overall Response Rate (DOR) at Day 56
研究设计
- 研究类型
- Interventional
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Study informed consent form signed by the patient her-/himself.
- •Male or female patients aged 18 or older at the time of informed consent
- •Have undergone HSCT from any donor source (unrelated, sibling, haploidentical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
- •Clinically diagnosed Grades II to IV acute GvHD as per standard criteria (Appendix 1) occurring after HSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
- •Confirmed diagnosis of steroid refractory aGvHD defined as patients administered high dose systemic corticosteroids (methylprednisolone ≥1 mg/kg/day (±20%) [or equivalent prednisone dose ≥1.25 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either: A. A Progression based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR B. Failure to achieve at a minimum partial response based on organ assessment after 5-7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR C. Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
- •Requirement for an increase in the corticosteroid dose to methylprednisolone ≥1 mg/kg/day (or equivalent prednisone dose ≥1.25 mg/kg/day) OR
- •Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days
排除标准
- •Has received systemic treatment for aGvHD apart from steroids. Standard aGvHD prophylaxis and treatment medications initiated before randomization including systemic corticosteroids, calcineurin inhibitors (CNI) (cyclosporine, tacrolimus or Mycofenolate Mofetil (MMF)), and topical corticosteroid therapy may be continued, per institutional guidelines.
- •Any corticosteroid therapy for indications other than aGvHD at doses > 1 mg/kg/day methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of Screening. Routine corticosteroids administered during conditioning or cell infusion is allowed.
- •History of progressive multifocal leuko-encephalopathy (PML).
- •Previous participation in a study of any investigational treatment agent within 30 days or within 5 half-lives of the study treatment, whichever is greater.
- •Any condition that would, in the Investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the patient; or interfere with interpretation of study data.
- •Known allergies, hypersensitivity, or intolerance to systemic immunosuppressive therapy
- •Known hypersensitivity to dimethyl sulfoxide (DMSO) or to porcine or bovine proteins
- •Known hypersensitivity to trace amounts of Gentamycin
- •Patients with coagulopathy (eg. hemofilia), history of past thrombo-embolic event (eg. deep venous thrombosis, lung embolism, cerebral thrombo-embolism) in the previous 3 months
- •Uncontrolled hypertension
- •History of severe chronic heart disease (documented ejection fraction ≤ 30% or NYHA > II), recent MI (6 months) or unstable angina, clinically significant (symptomatic) cardiac arrhythmias, lung disease (requiring home oxygen), pulmonary hypertension (RVSP > 50 on prior ECHO), or liver comorbidities (MELD score <10).
- •Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia, et al. 2015)
- •Pregnant or nursing (lactating) women OR Female patients ≥ 18 years of age and of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception as defined below, throughout the study and for up to 90 days after stopping treatment.
- •Sexually active men and male adolescents who do not agree to use condom during intercourse, if applicable and for up to 90 days after stopping treatment and/or wish to father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug via seminal fluid.
- •Presence of an active uncontrolled infection including significant bacterial, fungal, viral (CMV, EBV, HHV-6, HBV, or HCV) or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
- •Known human immunodeficiency virus infection (HIV).
- •Patients suffering on active tuberculosis or viral hepatitis
- •Significant respiratory disease including patients who are on mechanical ventilation or who have resting O2 saturation <90% by pulse-oximetry.
- •Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL (>176.8 μmol/L), renal dialysis requirement, or have estimated creatinine clearance <30 ml/min measured or calculated by Cockroft Gault equation (confirmed within 48h prior to study treatment start).
- •Presence of severely impaired liver function not due to liver GVHD defined by ALT / AST> 5 times the upper limit of the normal.
- •Malignancy (except the HSCT indication) that has required treatment in the previous two years (excluding non-melanoma skin malignancies treated by excision, or cryotherapy)
结局指标
主要结局
Documenting AEs and SAEs and determining causality in relation to DSC. Causality of AEs and SAEs will be assessed by the Investigator.
Documenting AEs and SAEs and determining causality in relation to DSC. Causality of AEs and SAEs will be assessed by the Investigator.
Durable Overall response rate (DOR) at Day 56 after randomization, defined as the proportion of patients in each arm demonstrating a complete response (CR) or partial response (PR) at day 28 and maintain a CR or PR at day 56 without requirement for additional systemic therapies for an earlier progression, mixed response or nonresponse.
Durable Overall response rate (DOR) at Day 56 after randomization, defined as the proportion of patients in each arm demonstrating a complete response (CR) or partial response (PR) at day 28 and maintain a CR or PR at day 56 without requirement for additional systemic therapies for an earlier progression, mixed response or nonresponse.
次要结局
- Proportion of patients in each arm who achieve a complete response (CR) or partial response (PR) at Day 28.
- Overall survival (OS), defined as the time from the date of randomization to the date of death due to any cause.
- Non-relapse mortality (NRM), defined as the time from date of randomization to death not preceded by hematologic disease relapse/progression.
- Proportion of patients in each treatment arm who develop infections or other transplant related complications.
- Safety and tolerability including myelosuppression, infections and bleeding will be assessed by monitoring the frequency, duration and severity of Adverse Events including occurrence of any secondary malignancies, infections, by performing physical exams and evaluating changes in vital signs from baseline, routine serum chemistry, hematology results and coagulation profile.
- For Norway: Event-free survival, defined as the time from the date of randomization to the date of hematologic disease relapse/ progression, graft failure or death due to any cause.>
- Exploratory endopint: Weekly cumulative steroid dose for each patient up to Day 56 and Day 84 or end of treatment will be calculated.
- Exploratory endpoing: Malignancy relapse/progression (MR), defined as the time from date of randomization to hematologic malignancy relapse or progression. Calculated for patients with underlying hematologic malignant disease.
- Exploratory endpoint: Chronic GvHD, defined as the diagnosis of any cGvHD including mild, moderate and severe according to NIH criteria. (see Appendix 3)
- Exploratory endpoint: Changes in immune reconstitution after aGvHD per randomization arm.
- Exploratory endpoint: Evaluation of patients´ self-experienced well-being (Quality of Life)(FACT-BMT version 4).
- Exploratory endpoint for Sweden and Denmark: Event-free survival, defined as the time from the date of randomization to the date of hematologic disease relapse/ progression, graft failure or death due to any cause.
研究者
Mats Remberger
Scientific
Uppsala University Hospital
研究点 (4)
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