An Open Label, Phase I/II Study of Venetoclax in Addition to Blinatumomab Immunotherapy in Adult Patients With Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 30
- 试验地点
- 17
- 主要终点
- Phase II/ part 2: rate of complete molecular remissions (Mol-CR)
研究概览
简要总结
This study is designed to determine the feasibility, safety, tolerability and maximum tolerated dose of Venetoclax in combination with Blinatumomab and to evaluate the response in patients treated with the combination of Venetoclax and Blinatumomab in in patients with hematological relapse or molecular relapse.
详细描述
Transfer of patients to alloHSCT after one cycle or after a subsequent cycle is considered as per protocol discontinuation and as premature treatment discontinuation.
There will be a safety follow-up visit at 30 days after end of the last infusion. There will be efficacy follow-up until 6 months after end of therapy. In patients scheduled for SCT the 30-day safety-visit may be performed at the latest time point possible before initiation of subsequent treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure
- •Age ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
- •Availability of patient-specific molecular MRD markers of immunoglobulin/T-cell receptor gene rearrangementsas assessed by PCR with a sensitivity of at least 10E-04
- •Diagnosis of Philadelphia negative, CD19-positive B-precursor acute lymphoblastic leukemia according to WHO classification:
- •Refractory BCP-ALL to primary induction therapy, including at least three cycles of standard chemotherapy
- •Untreated first relapse of BCP-ALL with first remission duration < 12 months or
- •Second or greater relapse of BCP-ALL or refractory relapse or
- •Relapse of BCP-ALL any time after allogeneic HSCT or
- •Positivity of MRD marker of immunoglobulin/T-cell receptor gene rearrangements of greater than 0.01% if in first or second remission of BCP-ALL
- •Negative pregnancy test < 7 days before first study drug in women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfil at least one of the following criteria:
- •Post-menopausal (i.e. 12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml
- •Post-operative after bilateral ovariectomy with or without hysterectomy
- •Continuous and correct application of a contraception method with a Pearl index of < 1% (e.g. implants, depots, oral contraceptives, intrauterine device) from initial study drug administration until at least 3 months after the last dose of study drug. A hormonal contraception method must always be combined with a barrier method (e.g. condom)
- •Sexual abstinence
- •Vasectomy of the sexual partner
- •Ability to understand and willingness to sign a written informed consent
- •Willingness to participate in the registry of the German Multicenter Study Group for Adult ALL (GMALL)
排除标准
- •Patients with diagnosis of Philadelphia positive BCP-ALL according to WHO classifiation
- •Patients with diagnosis of Burkitt´s Leukemia according to WHO classification
- •Patients with extramedullary relapse; non-bulky lymph node (< 7.5 cm diameter) involvement will be accepted
- •Patients with CNS involvement at relapse (as determined by CSF analysis)
- •Patients with suspected or histologically confirmed testicular involvement at relapse
- •Current autoimmune disease of any kind or history of autoimmune disease with potential CNS involvement
- •Patients with Philadelphia-positive BCP-ALL still receiving TKI
- •Prior or concomitant therapy with BH3 mimetics
- •Prior therapy with anti CD19 therapy, unless administered in MRD-positive setting (i.e. with bone marrow blasts ≤ 5%)
- •Treatment with any of the following within 7 days prior to the first dose of study drug: strong cytochrome P450 3A (CYP3A) inhibitors, moderate or strong CYP3A inducers
- •Intake of any of the following within 3 days prior to the first dose of study drug: grapefruit, grapefruit products, Seville oranges or star fruit
- •Presence of Graft-versus-Host Disease (GvHD) and/or on immunosuppressant medication within 2 weeks before start of protocol-specified therapy
- •Radiation, chemotherapy (with the exception of prephase therapy), or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to Cycle 1 Day 1 or radio-immunotherapy 4 weeks prior to Cycle 1 Day
- •Major surgery within 2 weeks of first dose of study drug
- •Patients who are pregnant or lactating
- •Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety
- •Unstable cardiovascular function:
- •Symptomatic ischemia, or
- •Uncontrolled clinically significant conduction abnormalities (1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or
- •Congestive heart failure (CHF) of NYHA Class ≥3, or
- •Myocardial infarction (MI) within 3 months
- •Evidence of clinically significant uncontrolled condition(s) including, but not limited to: Uncontrolled and/or active systemic infection (viral, bacterial or fungal), chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti- HBs antibody (anti-HBs) positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) or blood transfusions may participate.
- •Known human immunodeficiency virus (HIV) infection (HIV testing is not required)
- •Patients unable to swallow tablets, patients with malabsorption syndrome, or any other GI disease or GI dysfunction that could interfere with absorption of study treatment
- •Adequate hepatic function per local laboratory reference range as follows: Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0X ULN, Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
- •Severe renal dysfunction: estimated creatinine clearance of < 20 mL/min, measured in 24 hour urine or calculated using the formula of Cockroft and Gault
- •History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis. History of CNS leukemia that is controlled at relapse may be enrolled in this study.
- •History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:
- •Malignancy treated with curative intent and with no known active disease present for 2 years before enrollment and felt to be at low risk for recurrence by the treating physician including
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated cervical carcinoma in situ without evidence of disease
- •Adequately treated breast ductal carcinoma in situ without evidence of disease
- •Prostatic intraepithelial neoplasia without evidence of prostate cancer.
- •Current autoimmune disease or history of autoimmune disease with potential CNS involvement
- •Live vaccination within 2 weeks before the start of study treatment
- •Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation
- •Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing.
- •Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study(s). Thirty days is calculated from day 1 of protocol-specified therapy
- •Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject's and Investigator's knowledge.
- •History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
- •Woman of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they fulfil at least one of the following criteria:
- •Post-menopausal (i.e. 12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml
- •Post-operative after bilateral ovariectomy with or without hysterectomy
- •Continuous and correct application of a contraception method with a Pearl index of < 1% (e.g. implants, depots, oral contraceptives, intrauterine device) from initial study drug administration until at least 3 months after the last dose of study drug. A hormonal contraception method must always be combined with a barrier method (e.g. condom)
- •Sexual abstinence
- •Vasectomy of the sexual partner
- •Male who has a female partner of childbearing potential, and is not willing to use 2 highly effective forms of contraception while receiving protocol-specified therapy and for at least an additional 3 months after the last dose of protocol-specified therapy
研究组 & 干预措施
hematological relapse
Diagnosis of Ph-negative, CD19-positive B-precursor acute lymphoblastic leukemia according to WHO classification:
- Refractory BCP-ALL to primary induction therapy, including at least three cycles of standard chemotherapy
- Untreated first relapse of BCP-ALL with first remission duration < 12 months or
- Second or greater relapse of BCP-ALL or refractory relapse or
- Relapse of BCP-ALL any time after allogeneic HSCT
干预措施: Blinatumomab (Drug)
hematological relapse
Diagnosis of Ph-negative, CD19-positive B-precursor acute lymphoblastic leukemia according to WHO classification:
- Refractory BCP-ALL to primary induction therapy, including at least three cycles of standard chemotherapy
- Untreated first relapse of BCP-ALL with first remission duration < 12 months or
- Second or greater relapse of BCP-ALL or refractory relapse or
- Relapse of BCP-ALL any time after allogeneic HSCT
干预措施: Venetoclax (Drug)
molecular relapse
Diagnosis of Ph-negative, CD19-positive B-precursor acute lymphoblastic leukemia according to WHO classification:
-Positivity of MRD marker of immunoglobulin/T-cell receptor gene rearrangements of greater than 0.01% if in first or second remission of BCP-ALL
干预措施: Blinatumomab (Drug)
molecular relapse
Diagnosis of Ph-negative, CD19-positive B-precursor acute lymphoblastic leukemia according to WHO classification:
-Positivity of MRD marker of immunoglobulin/T-cell receptor gene rearrangements of greater than 0.01% if in first or second remission of BCP-ALL
干预措施: Venetoclax (Drug)
结局指标
主要结局
Phase II/ part 2: rate of complete molecular remissions (Mol-CR)
时间窗: after one cycle of treatment (up to 43 days)
The primary efficacy measure of the part II expansion part will be the rate of complete molecular remissions (Mol-CR) after one cycle of Blinatumomab and Venetoclax. - Mol-CR is defined as MRD negativity with a sensitivity of at least 10E-04 Disease status will be assessed by bone marrow and peripheral blood analysis at the end of Cycle 1. Bone marrow aspiration is required at any time on study in case peripheral blood analysis is suspicious for progression of disease.
Phase I/ part 1: Maximum tolerated dose (MTD)
时间窗: through study part I completion, anticipated after 1 year
The primary endpoint of the part I dose escalation part will be maximum tolerated dose (MTD). The combination of Venetoclax and Blinatumomab will be evaluated for tolerability in a 3+3 design. In a 3+3 design, three patients will form a cohort. Each cohort will receive a higher cumulative dose of Venetoclax in pre-defined dose escalation steps (see table below). If one patient experiences dose limiting toxicity (DLT), the cohort will be expanded to six patients. If two or more of these 6 patients experience a DLT, the next lower Venetoclax dose will be defined as maximum tolerated dose (MTD). If 0/3 or \<2/6 patients in a cohort experience a DLT, the next dose escalation cohort will be opened. In case of ≥ 2 DLTs at the dose level 1, dose level -1 will be used as a fallback option. The DLT evaluation period is defined as the first 49 days after initiation of Venetoclax in cycle 1 (i.e. C1D-7 to C1D42)
次要结局
- Rate of allogeneic stem cell transplantation(until End of Follow-Up (up to 6 months after EOT))
- Rate of composite complete remissions (cCR)(until End of Follow-Up (up to 6 months after EOT))
- Event-free survival (EFS)(at 1 year and 2 years after EOT)
- Duration of MRD response(until End of Follow-Up (up to 6 months after EOT))
- Measurement of Quality of Life(until End of Follow-Up (up to 6 months after EOT))
- Relapse localisations(until End of Follow-Up (up to 6 months after EOT))
- Overall response rate (ORR)(after one cycle of treatment (up to 43 days))
- Remission duration(at 1 year and 2 years after EOT)
- Overall survival (OS)(at 1 year and 2 years after EOT)
- CR rates in comparson to Blinatumomab monotherapy(after one cycle of treatment (up to 43 days))
研究者
Nicola Goekbuget
Principal Investigator
Goethe University