NCT05024045已完成1 期
A Phase 1 Study of Oral LOXO-338, a Selective BCL-2 Inhibitor, in Patients With Advanced Hematologic Malignancies
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 27
- 试验地点
- 23
- 主要终点
- Part 1 - To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of oral LOXO-338
研究概览
简要总结
The purpose of this study is to find out whether the study drug, LOXO-338, is safe and effective in patients with advanced blood cancer. Patients must have already received standard therapy. The study may last up to approximately 3 years.
详细描述
This study will be conducted in 2 parts. Part 1 will evaluate LOXO-338 as monotherapy. If safety and initial evidence of efficacy of LOXO-338 monotherapy are confirmed, part 2 will evaluate the combination of LOXO-338 with the highly selective, noncovalent Bruton's tyrosine kinase (BTK) inhibitor, pirtobrutinib (LOXO-305).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •B-cell malignancy.
- •Patients must have received prior therapy.
- •Patients must have an objective indication for therapy.
- •Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-
- •Anticipated life expectancy of greater than or equal to (≥) 12 weeks.
- •Adequate bone marrow function.
- •Adequate hepatic function.
- •Creatinine clearance of ≥ 60 milliliters (mL)/minute.
- •Ability to swallow tablets.
- •Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
- •Prior treatment-related adverse events (AEs) must have recovered to grade less than or equal to (≤) 1 or pretreatment baseline, with the exception of alopecia.
- •Men with partners of childbearing potential or women of childbearing potential (WOCBP) must agree to use highly effective birth control.
- •WOCBP must not be pregnant.
- •Additional Inclusion Criteria for Patients with AL Amyloidosis
- •In Part 1 Dose Expansion, patients with AL amyloidosis are eligible based on prior detection of primary systemic light-chain amyloidosis.
- •Must have measurable disease of AL amyloidosis.
- •Prior local fluorescence in-situ hybridization (FISH) testing results for t(11;14) are required to be submitted prior to enrollment.
排除标准
- •Prior to identification of an appropriate RP2D (Dose Expansion) of LOXO-338, a history of known, active or suspected:
- •Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocyticleukemia, or Hodgkin lymphoma
- •Transformed low grade lymphoma
- •Burkitt or Burkitt-like lymphoma
- •Diffuse large B-cell lymphoma
- •AL amyloidosis
- •Multiple myeloma
- •Lymphoblastic lymphoma or leukemia
- •Posttransplant lymphoproliferative disorder
- •Known or suspected history of central nervous system (CNS) involvement.
- •History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T cell (CAR-T) therapy within the past 60 days and with any of the following:
- •Active graft versus host disease (GVHD)
- •Cytopenias from incomplete blood cell count recovery post-transplant or CAR-T therapy
- •Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity Grade > 1 from CAR-T therapy
- •Ongoing immunosuppressive therapy
- •Known human immunodeficiency virus (HIV) positive, regardless of cluster of differentiation 4 (CD4) count. Unknown or negative status eligible.
- •Inability to take necessary uric acid lowering agents (i.e., allopurinol, rasburicase, orfebuxostat).
- •Concurrent anticancer therapy.
- •Concurrent treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers that can include antifungals.
- •Use of ≥ 20 milligrams (mg) prednisone once a day (QD) or equivalent dose of steroid per day, within 7 days of start of study treatment. Patients may not be on any dose of prednisone intended for antineoplastic use.
- •Vaccination with a live vaccine within 28 days prior to start of study therapy.
- •Major surgery within four weeks of planned start of study therapy Prolongation of the QT interval corrected by Fridericia's Formula for heart rate (QTcF) greater than (>) 470 milliseconds (msec).
- •Clinically significant cardiovascular disease.
- •Female patient who is pregnant or lactating.
- •Active second malignancy which may preclude assessment of DLT.
- •Clinically significant active malabsorption syndrome including surgical resection of small intestine or other condition likely to affect gastrointestinal (GI) absorption of the orally administered study drugs.
- •Active hepatitis B or C infection.
- •Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) or other clinically significant active disease process.
- •Active uncontrolled auto-immune cytopenia.
- •Additional Exclusion Criteria for Patients with AL Amyloidosis (Part 1 Dose-Expansion)
- •Previous or current diagnosis of symptomatic MM.
- •Heart failure that, in the opinion of the Investigator, is on the basis of ischemic heart disease.
- •Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatic hypotension in the absence of volume depletion.
- •N-terminal pro hormone natriuretic peptide (NT-proBNP) > 8500 ng/L (or BNP > 700 ng/L if NT-proBNP is not available by local or central testing).
- •Additional exclusion criteria for patients enrolled to part 2: LOXO-338 and pirtobrutinib combination
- •Prior progression or intolerance to pirtobrutinib.
- •Patients requiring therapeutic anticoagulation with warfarin.
- •Known hypersensitivity to any component or excipient of pirtobrutinib.
- •In patients with history of myocardial infarction or congestive heart failure, documented left ventricular ejection fraction (LVEF) by any method of ≤ 45 percent (%) in the 12 months prior to planned start of study treatment.
- •History of uncontrolled or symptomatic arrhythmias including grade ≥ 3 arrhythmia on a prior BTK inhibitor.
- •History of major bleeding on a prior BTK inhibitor.
- •Current treatment with strong permeability glycoprotein (P-gp) inhibitors.
研究组 & 干预措施
LOXO-338 + Pirtobrutinib (Combination)
Experimental
LOXO-338 administered orally in combination with pirtobrutinib
干预措施: Pirtobrutinib (Drug)
LOXO-338 + Pirtobrutinib (Combination)
Experimental
LOXO-338 administered orally in combination with pirtobrutinib
干预措施: LOXO-338 (Drug)
LOXO-338 (Monotherapy)
Experimental
LOXO-338 administered orally.
干预措施: LOXO-338 (Drug)
结局指标
主要结局
Part 1 - To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of oral LOXO-338
时间窗: Cycle 1 (28 Days)
Measured by the number of patients with dose-limiting toxicities (DLTs)
Part 1 - To determine the effect of LOXO-338 on response rates
时间窗: Estimated up to 2 years
Measured by the appropriate disease specified response criteria as appropriate to tumor type
Part 2 - To determine the safety and tolerability of LOXO-338 when given in combination with pirtobrutinib
时间窗: Cycle 2 (28 Days)
Measured by the number of patients with dose-limiting toxicities (DLTs)
次要结局
- Part 1 - To assess preliminary antitumor activity of LOXO-338 based on progression-free survival (PFS)(Estimated up to 2 years)
- Part 1 - To assess preliminary antitumor activity of LOXO-338 based on overall response rate (ORR)(Estimated up to 2 years)
- Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on progression-free survival (PFS)(Estimated up to 2 years)
- Part 1 - To characterize the pharmacokinetics (PK) properties of LOXO-338: Area under the plasma concentration versus time curve (AUC)(Predose up to 24 hours postdose)
- Part 1 - To characterize the PK properties of LOXO-338: Maximum drug concentration (Cmax)(Predose up to 24 hours postdose)
- Part 1 - To assess preliminary antitumor activity of LOXO-338 based on duration of response (DOR)(Estimated up to 2 years)
- Part 2 - To characterize the PK properties of LOXO-338 and in combination with pirtobrutinib: Maximum drug concentration (Cmax)(Predose up to 24 hours postdose)
- Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on overall response rate (ORR)(Estimated up to 2 years)
- Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on time-to-progression (TTP)(Estimated up to 2 years)
- Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on duration of response (DOR)(Estimated up to 2 years)
- Part 1 - To assess preliminary antitumor activity of LOXO-338 based on time-to-progression (TTP)(Estimated up to 2 years)
- Part 2 - To characterize the pharmacokinetics (PK) properties of LOXO-338 in combination with pirtobrutinib: Area under the plasma concentration versus time curve (AUC)(Predose up to 24 hours postdose)
研究者
研究点 (23)
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