A Phase I Trial of Obinutuzumab in Combination With Venetoclax in Previously Untreated Follicular Lymphoma Patients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 6
- 主要终点
- Dose limiting toxicities (DLT) during the first cycle
研究概览
简要总结
Follicular lymphoma (FL) is an indolent yet incurable lymphoma characterized by initial responses to standard therapies, invariably followed by shorter disease free intervals. Obinutuzumab, a novel type II, anti-CD20 monoclonal antibody has been approved in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia (CLL) and in combination with bendamustine followed by obinutuzumab alone for FL who did not respond to, or who progressed during or after treatment with rituximab or a rituximab-containing regimen, or in relapse after such treatment. Additionally, venetoclax, a small molecule Bcl-2 inhibitor, showed single agent activity in relapsed/refractory (R/R) CLL and other B-cell lymphomas, including R/R FL. Preclinical evidence suggests a synergism of the two drugs in vitro as well as in different lymphoma in vivo models. Based on single agent clinical activity and on the preclinical data of the combination of both drugs and aiming to develop a new chemotherapy-free combination regimen, this trial plans to evaluate the combination of obinutuzumab and venetoclax in previously untreated FL patients in need of systemic therapy. This phase I study will provide information on the safety and tolerability together with evidence of preliminary antitumor activity. Combination treatment consists of a 6 cycles of 28 days each. The combination therapy is followed by a 2 years maintenance with obinutuzumab. Dosing of obinutuzumab is as per Swissmedic approval in FL.Venetoclax will be administered in different dose levels according to the trial design.
详细描述
Follicular lymphoma is an indolent yet incurable lymphoma characterized by a relapsing-remitting course with initial responses to standard therapies, invariably followed by shorter disease free intervals. In recent years, significant treatment improvements have been achieved, mainly due to the introduction of the anti-CD20 monoclonal antibody rituximab in standard therapies. Unfortunately, most patients invariably relapse and require additional treatment. Therefore new therapies are needed in order to further improve treatment outcomes.
Recent advances in preclinical research and the improved knowledge of the molecular biology of lymphomas have permitted the development of a high number of new therapeutic compounds that inhibit components of altered signaling pathways that drive the genesis of lymphomas and their progression. Additionally, improvements in monoclonal antibody technology have permitted the development of new and active monoclonal antibodies that recognize different antigens on the surface of the lymphoma cells.
Obinutuzumab, a type II, anti-CD20 monoclonal antibody has been clinically tested both as single agent as well as in combination with chemotherapy or targeted agents, showing significant clinical activity in CLL and in FL patients that were refractory to rituximab.
Additionally venetoclax, a small molecule Bcl-2 inhibitor has recently advanced into clinical trials, showing a good safety profile and signs of single agent activity in CLL and other B-cell lymphomas, including patients with relapsed/refractory FL. There is interest to further investigate venetoclax in FL, given that the pathogenesis of this lymphoma relies on the chromosomal translocation t(14;18)(q32;q21), which is present in nearly all cases and results in constitutive overexpression of the BCL2 gene, allowing B cells to abrogate the default germinal center apoptotic program.
The combination of these two compounds is interesting given their single agent activity observed in FL. Preclinical studies have demonstrated a synergism both in vitro as well as in vivo models in different lymphomas and the two compounds are currently investigated in combination studies in CLL and with the chemotherapy CHOP regimen in non-Hodgkin lymphomas.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent according to ICH/GCP regulations before registration.
- •Histological diagnosis of FL CD20+; grade 1, 2, 3a; stage III+IV; stage II not suitable for radiotherapy; all FLIPI
- •In need of first systemic therapy
- •At least one two-dimensionally measurable nodal lesion with a longest diameter (LDi) ˃15 mm or a measurable extra nodal lesion with a LDi ˃ 10 mm in CT, PET/CT scan (preferable) or MRI, according to Cheson et al, 2014
- •Bone marrow biopsy within 6 months.
- •Age18-80 years
- •WHO performance status 0-2
- •Adequate bone marrow function
- •Adequate hepatic function
- •Adequate renal function
- •Women of childbearing potential have a negative serum (beta-human chorionic gonadotropin [β-hCG]) pregnancy test within 3 days before inclusion into the trial.
排除标准
- •FL stage I
- •Transformation to high-grade DLBCL prior to therapy
- •FL grade 3 b
- •Indolent lymphoma other than FL
- •Known primary central nervous system (CNS) lymphoma
- •Known CNS or leptomeningeal involvement
- •Previous systemic FL therapies
- •History of other malignancy that could affect compliance with the protocol or interpretation of results
- •Concurrent treatment with other experimental drugs or other anticancer therapy in a clinical trial within 30 days prior to registration.
- •Live-virus vaccines treatment within 28 days prior to registration
- •Patients regularly taking corticosteroids during the last 30 days, unless administered at a dose equivalent to prednisone ≤ 15 mg/day for indications other than lymphoma or lymphoma-related symptoms
- •Women who are breastfeeding
- •Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia), uncontrolled hypertension (sustained systolic blood pressure > 150 mm Hg and/or diastolic > 100 mm Hg despite antihypertensive therapy)
- •History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration
- •Known history of
- •human immunodeficiency virus (HIV)
- •active/chronic Hepatitis C
- •active/chronic Hepatitis B Virus infection (HBsAg+ and/or HBcAb+)
- •or any active systemic infection requiring intravenous (iv) antimicrobial treatment.
- •Patients with a history of recurring or chronic infections may be included in the study but caution should be exercised and an infectious disease expert should be consulted before enrollment in the trial.
- •Requires anticoagulation with vitamin K antagonists (e.g. phenprocoumon, warfarin)
- •Coagulation parameters
- •INR ˃1.5x ULN
- •PT or PTT/aPTT ˃1.5x ULN
- •Requires treatment with strong CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin) and strong CYP3A inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) 7 days prior to registration
- •Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information (if applicable) or most recent IB (if approved product information not available)
- •Known hypersensitivity to trial drugs or to any component of the trial drugs
- •History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products
- •Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
- •Psychiatric disorder precluding understanding information of trial-related topics, giving informed consent
研究组 & 干预措施
Part A - dose escalation and part B - dose expansion
Part A: dose escalation:
Combination therapy N= 4-18 pts Cycle 1-6 (1 cycle = 28 days) Obinutuzumab: 1000 mg, i.v. infusion; d1, 8, 15 C1 and d1 C2-6 Venetoclax: p.o. once daily according to dose level (DL)
Part B - dose expansion:
Combination therapy N= up to 25 pts Cycle 1-6 (1 cycle = 28 days) Obinutuzumab: 1000 mg, i.v. infusion d1, 8, 15 C1 and d1 C2-6 Venetoclax: p.o. once daily according to MTD
Part A and part B are followed (in case of no PD) by an obinutuzumab maintenance therapy for 2 years
干预措施: Obinutuzumab (Drug)
Part A - dose escalation and part B - dose expansion
Part A: dose escalation:
Combination therapy N= 4-18 pts Cycle 1-6 (1 cycle = 28 days) Obinutuzumab: 1000 mg, i.v. infusion; d1, 8, 15 C1 and d1 C2-6 Venetoclax: p.o. once daily according to dose level (DL)
Part B - dose expansion:
Combination therapy N= up to 25 pts Cycle 1-6 (1 cycle = 28 days) Obinutuzumab: 1000 mg, i.v. infusion d1, 8, 15 C1 and d1 C2-6 Venetoclax: p.o. once daily according to MTD
Part A and part B are followed (in case of no PD) by an obinutuzumab maintenance therapy for 2 years
干预措施: Venetoclax (Drug)
结局指标
主要结局
Dose limiting toxicities (DLT) during the first cycle
时间窗: Day 28 of the first cycle
The primary endpoint is the frequency of DLTs which are relevant for the determination of the maximum tolerated dose (MTD) in the dose escalation phase of the trial.
次要结局
- Complete response (CR)(at 6 months and 30 months)
- Overall response (OR) based on best response observed during combination therapy.(at 6 months, based on best response observed during combination therapy, at 30 months and based on best response observed during whole therapy (combination and maintenance))
- Adverse events (AEs)(at 6 months (combination therapy) and at 2 years (maintenance therapy))
- Duration of response(at 2.5 years)
- Laboratory safety variables(at 6 months (combination therapy) and at 2 years (maintenance therapy))
- Progression free survival (PFS)(at 12 months, at 30 months)