A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by GA101 (obinutuzumab), Acalabrutinib (ACP-196) and ABT-199 (venetoclax) in Patients with Relapsed/refractory CLL (CLL2-BAAG Protocol)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 17
- 主要终点
- Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by 4-color flow cytometry
研究概览
简要总结
CLL2-BAAG is a prospective, open-label, multicenter phase-II trial to evaluate the efficacy and safety of a sequential regimen of debulking with bendamustine followed by induction and maintenance with GA101 (obinutuzumab), acalabrutinib (ACP-196) and venetoclax (ABT-199) in patients with relapsed/refractory CLL.
详细描述
In the CLL2-BAAG trial will be included a total of 46 patients with relapsed or refractory CLL in need of treatment.This trial will evaluate a debulking with two cycles bendamustine (only for patients with a higher tumor load), followed by an induction and a maintenance treatment with obinutuzumab, acalabrutinib and venetoclax in patients with re-lapsed/refractory CLL. The duration of maintenance treatment is depending on MRD levels. This trial combines one old (chemotherapy) and three novel, synergistic (antibody, BTK-inhibitor and Bcl-2 antagonist) principles of action in order to achieve deep and long lasting remissions with a short duration of treatment. Additionally, this trial has an extensive accompanying scientific program aiming at a better understanding of the kinetics of response and clonal evolution of CLL.
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
- •Relapsed/refractory CLL in need of treatment according to iwCLL (international workshop on CLL) criteria
- •In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treatment in the CLL2-BAAG trial:
- •chemotherapy ≥ 28 days
- •antibody treatment ≥ 14 days
- •kinase inhibitors, BCL2-antagonists or immuno-modulatory agents ≥ 3 days
- •corticosteroids may be applied until the start of the BAAG-regimen, these have to be reduced to an equivalent of ≤ 20mg prednisolone per day during treatment Please note: Patients with a progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, as well as patients with a known resistance mutation (e.g. BTK-/PLCg2) are excluded from study participation. However, patients who progressed after termination of treatment with venetoclax, ibrutinib, other BTK inhibitors and/or obinutuzumab or who stopped treatment due to in-tolerance to ibrutinib are eligible for participation.
- •Adequate renal function, as indicated by a creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection
- •Adequate hematologic function as indicated by a neutrophil count ≥ 1.0 x 109/L, a hemoglobin value ≥8.0 g/dL and a platelet count ≥ 25 x 109/L, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration), in this case, platelet count should be ≥ 10 × 109/L.
- •Adequate liver function as indicated by a total bilirubin ≤2x, AST/ALT ≤2.5x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
- •Negative serological testing for hepatitis B (HBsAg nega-tive and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every 4 weeks until one year after last dosage of GA101 (obinutuzumab)), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
- •Age ≥ 18 years
- •ECOG (Eastern Cooperative Oncology Group) performance status 0 - 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
- •Life expectancy ≥ 6 months
- •Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other proto-col requirements
排除标准
- •(Suspicion of) transformation of CLL (i.e. Richter's trans-formation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
- •Progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Bru-ton´s Tyrosine Kinase and Phospholipase C Gamma 2 (PLCg2)
- •Confirmed progressive multifocal leukoencephalopathy (PML)
- •Malignancies other than CLL currently requiring systemic therapies
- •Uncontrolled infection requiring systemic treatment
- •Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system1 or any other life-threatening illness, medical condition or organ system dysfunction that - in the investigator´s opinion - could compromise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastrointestinal tract)
- •Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathesis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hemorrhage ≤ 6 months.
- •Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists
- •Use of investigational agents ≤ 28 days prior to start of study treatment, however, kinase inhibitors, BCL2-antagonists and antibody treatment are allowed in accordance with inclusion criterion number 1 (see above).
- •Known hypersensitivity to obinutuzumab (GA101), venetoclax (ABT-199), acalabrutinib (ACP-196) or any of the excipients Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
- •Pregnant women and nursing mothers (a negative preg-nancy test is required for all women of childbearing potential within 7 days before start of treatment)
- •Fertile men or women of childbearing potential unless:
- •surgically sterile or ≥ 2 years after the onset of menopause, or
- •willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment.
- •Vaccination with a live vaccine ≤ 28 days prior to registration
- •Legal incapacity
- •Prisoners or subjects who are institutionalized by regula-tory or court order
- •Persons who are in dependence to the sponsor or an investigator
研究组 & 干预措施
BAAG
Debulking: 2 debulking cycles (q 28d) of bendamustine will be administered unless the patient has a contraindication or a debulking is not clinically indicated
Induction: 6 cycles (q 28d) of Obinutuzumab + Acalabrutinib + Venetoclax
Maintenance: max. 8 cycles (q 84d) of Obinutuzumab + Acalabrutinib + Venetoclax
Maintenance treatment will be continued until (whichever occurs first):
- 12 weeks (approx. 3 months) after confirmation of achievement of a CR/CRi and MRD negativity
- maintenance cycle 8
- progression of CLL or start of a subsequent therapy
- unacceptable toxicity
干预措施: Bendamustine (Drug)
BAAG
Debulking: 2 debulking cycles (q 28d) of bendamustine will be administered unless the patient has a contraindication or a debulking is not clinically indicated
Induction: 6 cycles (q 28d) of Obinutuzumab + Acalabrutinib + Venetoclax
Maintenance: max. 8 cycles (q 84d) of Obinutuzumab + Acalabrutinib + Venetoclax
Maintenance treatment will be continued until (whichever occurs first):
- 12 weeks (approx. 3 months) after confirmation of achievement of a CR/CRi and MRD negativity
- maintenance cycle 8
- progression of CLL or start of a subsequent therapy
- unacceptable toxicity
干预措施: Obinutuzumab (Biological)
BAAG
Debulking: 2 debulking cycles (q 28d) of bendamustine will be administered unless the patient has a contraindication or a debulking is not clinically indicated
Induction: 6 cycles (q 28d) of Obinutuzumab + Acalabrutinib + Venetoclax
Maintenance: max. 8 cycles (q 84d) of Obinutuzumab + Acalabrutinib + Venetoclax
Maintenance treatment will be continued until (whichever occurs first):
- 12 weeks (approx. 3 months) after confirmation of achievement of a CR/CRi and MRD negativity
- maintenance cycle 8
- progression of CLL or start of a subsequent therapy
- unacceptable toxicity
干预措施: Acalabrutinib (Biological)
BAAG
Debulking: 2 debulking cycles (q 28d) of bendamustine will be administered unless the patient has a contraindication or a debulking is not clinically indicated
Induction: 6 cycles (q 28d) of Obinutuzumab + Acalabrutinib + Venetoclax
Maintenance: max. 8 cycles (q 84d) of Obinutuzumab + Acalabrutinib + Venetoclax
Maintenance treatment will be continued until (whichever occurs first):
- 12 weeks (approx. 3 months) after confirmation of achievement of a CR/CRi and MRD negativity
- maintenance cycle 8
- progression of CLL or start of a subsequent therapy
- unacceptable toxicity
干预措施: Venetoclax (Biological)
结局指标
主要结局
Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by 4-color flow cytometry
时间窗: At final restaging (RE): 12 weeks after the start of the last induction cycle
MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed \[0.01%\], i.e. \< 10-4. The MRD negativity rate is defined as the proportion of patients having achieved MRD negativity based on the full analysis set (FAS).
次要结局
- MRD in PB measured by 4-color flow cytometry at different times: At screening, after debulking, 4-weekly during induction, at initial response assessment (after 6 induction cycles), at RE, every 12 weeks during maintenance and follow up.(From date of screening until the end of follow-up, up to 40 month.)
- Overall response rate (ORR)(At final restaging (RE): 12 weeks after the start of the last induction cycle)
- CR / CRi rate(At final restaging (RE): 12 weeks after the start of the last induction cycle)
- Safety: Adverse events (AE), serious adverse events (SAE) and adverse events of particular interest (AEPI)(up to 40 months after first dose of study drug)