Single Agent JNJ-56022473 in MDS and AML Patients Failing Hypomethylating Agent Based Therapy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- GWT-TUD GmbH
- 入组人数
- 25
- 试验地点
- 10
- 主要终点
- Overall hematological response rate
研究概览
简要总结
The outcome of HMA-refractory patients with MDS or AML is dismal with a median survival of 5 months after failure, representing a significant unmet medical need due to the very limited treatment options. In this context, a specific targeting of the leukemic stem cell (LSC) seems a promising option to selectively combat the leukemic progenitor cells. In fact, CD123 is overexpressed in AML and MDS progenitors making it an attractive target for immunotherapy-based approaches. JNJ-56022473 is a promising compound that has been engineered with regard to this strategy and the current phase II trial has the aim to evaluate the overall hematological response rate at 3 months in HMA refractory/relapsed AML and MDS patients.
详细描述
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies of the pluripotent hematopoietic stem cells characterized by clonal hematopoiesis and progressive bone marrow failure. Clinically, patients suffer from fatigue and are at high risk of infections or bleeding. Also, MDS patients are endangered by progression to secondary acute myeloid leukemia (AML), a disorder of early hematopoietic progenitor cells characterised by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues.
Up to now, allogeneic transplantation is considered the only curative option for both MDS and AML patients. However, as MDS and AML mainly manifest in the 7th and 8th decade of life, only a limited number of patients tolerating bone marrow transplantation and are therefore eligible for this procedure. In fact, comorbid conditions are common among the elderly such as heart disease, renal insufficiency and vascular disease thus influencing the ability to withstand exhausting transplantation procedures.
Hence in recent years, novel therapeutic strategies have been developed and hypomethylating agents (HMAs) azacitidine and decitabine have emerged as new therapeutic options. In 2009, azacitidine was the first HMA in use having received approval for treatment of MDS and AML patients with 20-30% blasts. In 2012, also the sister compound decitabine got approval for treatment of AML patients ≥ 65 years of age and in 2015, azacitidine's approval was extended to AML patients ≥ 65 years of age that are considered unfit for allogeneic transplantation with > 30% blasts.
However, despite the efficacy and reported activity, only 50% of patients respond to the treatment with HMAs and the majority of them do relapse. Also the outcome of HMA- refractory patients is dismal with a median survival of 5 months after failure and hence MDS and AML patients with HMA failure represent a significant unmet medical need due to the poor prognosis and very limited treatment options.
In this context, a specific targeting of the leukemic stem cell (LSC) seems a promising option to selectively combat the leukemic cells. In fact, CD123 (also known as interleukin-3-Rα) is expressed in different hematological malignancies, among others in MDS and AML. Interestingly, CD123 is expressed by the majority of AML blasts and it is also overexpressed by CD34+ CD38- LSCs compared with normal hematopoietic stem cells and other normal tissues. These features make CD123 an attractive target for anti-leukemia therapy. Recent data suggests that treatment with HMA can induce expression of CD123 on AML tumors opening up the potential that HMA failure patients may have even higher expression levels of CD123.
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
- •≥18 years of age
- •Diagnosis of AML or MDS
- •At least ≥ 5% BM blasts at the time of screening (done by central morphology)
- •At least one cytopenia (ANC < 1800/μL or platelet count < 100,000/μL or hemoglobin < 10 g/dL)
- •Failure to achieve complete or partial response or hematological improvement after at least six (azacitidine) or four (decitabine) 4-week treatment cycles administered during the past two years OR
- •Relapse after initial complete or partial response or hematological improvement observed after at least six (azacitidine) or four (decitabine) 4-week treatment cycles administered during the past two years OR
- •Intolerance to treatment with HMA (hypomethylating agents) defined by drug-related ≥ Grade 3 liver or renal toxicity leading to treatment discontinuation during the past two years
- •Failed to respond to, relapsed following, not eligible, or opted not to participate in bone marrow transplantation
- •Off all other treatments for AML/MDS for at least four weeks; Filgrastim (G-CSF) and erythropoietin are allowed before and during the study as clinically indicated
- •No medical need for or patient opted not to receive induction chemotherapy
- •ECOG performance status of 0-2
- •Willing to adhere to the prohibitions and restrictions specified in the protocol
- •Signed informed consent
排除标准
- •Previous treatment with a CD123 agent or T- or NK cell redirecting therapy
- •Patients having received intensive chemotherapy to treat HMA failure
- •Diagnosis of acute promyelocytic leukemia (APL)
- •WBC > 15 GPT/L
- •Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
- •Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
- •Active infection not adequately responding to appropriate therapy
- •Total bilirubin > 1.5 mg/dL not related to hemolysis or Gilbert's disease
- •ALT/AST > 2.5 x upper limit of normal
- •Serum creatinine > 2.0 mg/dL
- •Patients who are unwilling to follow highly effective contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives, contraceptive injections, intrauterine device, , contraceptive patch, surgical sterilization or true sexual abstinence) before entry, at least at screening, throughout the study and within 3 months after last study drug administration
- •Female patients with reproductive potential who do not have a negative urine β-HCG pregnancy test at screening and prior to the first study drug administration at visit 1 (day 0) of JNJ-56022473 treatment period.
- •Female patients who are lactating
研究组 & 干预措施
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: JNJ-56022473 (Drug)
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: Bone marrow analyses and CBC with differential (Procedure)
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: Flow cytometry analyses (Other)
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: Central biobanking (Other)
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: Histopathology analysis (Procedure)
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: Cytogenetic analysis (Genetic)
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: Serum chemistry (Procedure)
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: Automated CBC (Procedure)
Treatment Arm
JNJ-56022473 will be given intravenously to all subjects at a dose of 9 mg/kg once every 14 days for an initial treatment period of 3 months (6 infusions). Responders will then receive up to 20 additional infusions whereas for non-responders the initial treatment will be followed by a up to 9 months observation period without further JNJ-56022473 treatment. Thus, the individual study duration for a subject will be approx. 1 year. A follow up visit will be performed after 3 months after last study drug administration for all patients to track pregnancy status according to IB.
干预措施: Pregnancy Test (Procedure)
结局指标
主要结局
Overall hematological response rate
时间窗: 3 months
Overall hematological response rate at 3 months (either CR, PR, marrow-CR, HI, SD)
次要结局
- Toxicity(3 or 12 months)
- Overall survival(1 year)
- Progression-free-survival(1 year)
- Time to treatment failure(3 or 12 months)
- Duration of response (best overall response)(3 or 12 months)
- Overall hematological response rate at 12 months(1 year)
- Quality of life EORTC-QLQ30(9 or 15 months)