A Single-Center Phase IIa Study Evaluating the Safety and Tolerability of TGR-1202 and Ibrutinib in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Trial of the Lymphoma Precision Medicine Laboratory
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Participants With Adverse Events
研究概览
简要总结
This phase IIa trial studies the side effects and how well TGR-1202 and ibrutinib work in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement or does not respond to treatment. TGR-1202 and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of PI3K delta inhibitor TGR-1202 (TGR-1202) and ibrutinib in relapsed and refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL).
SECONDARY OBJECTIVES:
I. To determine the overall response rate (ORR) defined as the sum of complete responses (CR) and partial responses (PR).
II. To determine the event-free survival (EFS), time to response (TTR), and duration of response (DOR) in patients with rel/ref DLBCL.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed diffuse large B-cell lymphoma (DLBCL) or transformed DLBCL
- •Hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC) slides or a representative formalin-fixed, paraffin-embedded (FFPE) tissue block along with the pathology report from initial diagnosis, (as well as, an optional 8 unstained slides of 4 micron thickness to store for future IHC and DNA specified research use), should be sent to be reviewed, and the diagnosis confirmed by University of Nebraska Medical Center (UNMC) (retrospective diagnostic review: treatment may commence prior to the UNMC review); please NOTE: the diagnostic H&E slide and IHC slides will be returned after review; only the optional 8 unstained slides will be retained and stored for future unspecified research use
- •Patients with relapsed or refractory DLBCL that has relapsed post-transplant or that has been determined to be ineligible or unsuitable for transplant; patients must have to have received at least one prior systemic therapy
- •Patients must have measurable (>= 1.5 cm) or evaluable disease; baseline measurements and evaluations must be obtained within 6 weeks of registration to the study; abnormal PET scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging; measurable disease must have at least one objective measurable disease parameter; a clearly defined, bi-dimensionally measurable defect or mass measuring at least 1.5 cm in diameter on a CT scan will constitute measurable disease; proof of lymphoma in the liver is required by a confirmation biopsy; skin lesions can be used as measurable disease provided bi-dimensional measurements are possible
- •Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- •By automated or manual review, whichever is greatest
- •Platelets >= 100 x 10^9/L:
- •Unless due to bone marrow infiltration then eligible if platelets > 50 x 10^9/L)
- •Total bilirubin =< 1.5 x upper normal limit if documented hepatic involvement with lymphoma, or =< 5 x upper normal limit if history of Gilbert's disease
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) if no liver involvement or =< 5 x the ULN if documented liver involvement
- •Creatinine =< 2.0 mg/dL OR calculated creatinine clearance >= 50 mL/min (as calculated by the Cockcroft-Gault method)
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or expected survival duration of > 2 months
- •Ability to swallow and retain oral medication
- •Women must not be pregnant or breast-feeding
- •All female patients of child-bearing potential must have a negative serum pregnancy test within 2 weeks prior to treatment to rule out pregnancy
- •Pregnancy testing is not required for post-menopausal or surgically sterilized women
- •Male and female patients of reproductive potential must agree to follow accepted birth control measures throughout the study period and for 30 days after the last dose of either study drug for females and 3 months after the last dose of study drug for males
- •Patient must be able to adhere to the study visit schedule and other protocol requirements
- •Patient must be aware of the neoplastic nature of his/her disease and willingly sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study
- •No serious disease or condition that, in the opinion of the investigator, would compromise the patient's ability to participate in the study
排除标准
- •Currently receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, and surgery and/or tumor embolization) or any investigational drug within 7 days of cycle 1/day 1, 14 days of cycle 1/day 1 for limited palliative radiation, and/or five half-live of an oral therapy
- •Corticosteroid therapy started at least 7 days prior to initiation of treatment (prednisone =< 10 mg daily or equivalent) is allowed as clinically warranted); topical or inhaled corticosteroids are permitted
- •Major surgery or a wound that has not fully healed within 4 weeks of enrollment
- •History of stroke or intracranial hemorrhage within 6 months prior to enrollment
- •Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon)
- •Vaccinated with live, attenuated vaccines within 4 weeks of enrollment
- •Autologous hematologic stem cell transplant within 3 months of study entry
- •Allogeneic hematologic stem cell transplant within 12 months of study entry
- •Active graft versus-host disease and must not be on immunosuppression
- •Wide field radiotherapy within 28 days of cycle 1/day 1 or active side effects of such therapy
- •Active hepatitis B (hepatitis B virus [HBV]) or C (hepatitis C virus [HCV]) infection (negative serology required excluding those with are seropositive due to prior vaccination) and/or known history of human immunodeficiency virus (HIV)
- •Primary central nervous system involvement only
- •Require treatment with strong cytochrome P450 family 3 subfamily A (CYP3A) inhibitors
- •Known history of drug-induced liver injury, alcoholic liver disease, primary biliary cirrhosis, ongoing extra-hepatic obstruction caused by stones, cirrhosis of the liver or portal hypertension
- •Any life-threatening illness, severe and/or uncontrolled medical condition, or organ system dysfunction, laboratory abnormality, psychiatric illness or other condition which, in the Investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, put the study outcomes at undue risk or affect their participation in the study such as
- •Symptomatic, or history of documented congestive heart failure New York Heart Association (NYHA) functional classification III-IV (NYHA)
- •Corrected QT interval using Fridericia's formula (QTcF) > 470 msec (unless related to pacemaker) on echocardiogram (EKG) within 7 days of initiation of treatment
- •Angina not well-controlled by medication
- •Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting within 6 months prior to enrollment
- •Prior malignancies within the past 1 year with exception of adequately treated basal cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason grade 6 or less with stable prostate specific antigen (PSA) levels
- •Women who are pregnant or breastfeeding; women who agree to stop breastfeeding would be eligible
- •Known hypersensitivity to either study drug (TGR-1202 or ibrutinib)
研究组 & 干预措施
Group A (PI3K delta inhibitor TGR-1202, ibrutinib)
Patients receive PI3K delta inhibitor TGR-1202 PO QD on days 1-28 and ibrutinib PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Ibrutinib (Drug)
Group A (PI3K delta inhibitor TGR-1202, ibrutinib)
Patients receive PI3K delta inhibitor TGR-1202 PO QD on days 1-28 and ibrutinib PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Group A (PI3K delta inhibitor TGR-1202, ibrutinib)
Patients receive PI3K delta inhibitor TGR-1202 PO QD on days 1-28 and ibrutinib PO QD on days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: PI3K-delta Inhibitor TGR-1202 (Drug)
Group B (Ibrutinib, PI3K delta inhibitor TGR-1202)
Patients receive ibrutinib PO QD on days 1-28 and PI3K delta inhibitor TGR-1202 PO QD and days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Ibrutinib (Drug)
Group B (Ibrutinib, PI3K delta inhibitor TGR-1202)
Patients receive ibrutinib PO QD on days 1-28 and PI3K delta inhibitor TGR-1202 PO QD and days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Group B (Ibrutinib, PI3K delta inhibitor TGR-1202)
Patients receive ibrutinib PO QD on days 1-28 and PI3K delta inhibitor TGR-1202 PO QD and days 9-28 of course 1 and days 1-28 of subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: PI3K-delta Inhibitor TGR-1202 (Drug)
Group C (PI3K delta inhibitor TGR-1202, ibrutinib)
Patients then receive PI3K delta inhibitor TGR-1202 PO QD and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Ibrutinib (Drug)
Group C (PI3K delta inhibitor TGR-1202, ibrutinib)
Patients then receive PI3K delta inhibitor TGR-1202 PO QD and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Group C (PI3K delta inhibitor TGR-1202, ibrutinib)
Patients then receive PI3K delta inhibitor TGR-1202 PO QD and ibrutinib PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
干预措施: PI3K-delta Inhibitor TGR-1202 (Drug)
结局指标
主要结局
Participants With Adverse Events
时间窗: Up to 112 days (course 4)
Notable serious or recurrent adverse events (SAEs or AEs) of interest occurring across all cycles regardless of attribution assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
次要结局
- Estimated Progression-free Survival (PFS) at 6 Months(Time between study registration and documented progression or death if no progression was observed, assessed up to 4 years (6 Month estimate shown))
- Overall Response Rate (ORR)(Up to 4 years)