A Phase 2 Open-label Study of Loncastuximab Tesirine in Combination With Rituximab (Lonca-R) in Previously Untreated Unfit/Frail Patients With Diffuse Large B-cell Lymphoma (DLBCL) (LOTIS-9)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 41
- 试验地点
- 41
- 主要终点
- CR Rate
研究概览
简要总结
The main objective of the trial is to assess the efficacy and tolerability of Lonca-R in unfit and frail participants with previously untreated DLBCL.
详细描述
The primary objectives of this trial are shown below:
Cohort A: To assess the efficacy of a response-adapted treatment of Lonca-R in unfit participants with previously untreated DLBCL, high-grade B cell lymphoma (HGBCL), or Grade 3b follicular lymphoma (FL).
Cohort B: To assess the tolerability and efficacy of a response-adapted treatment of Lonca-R in frail participants with previously untreated DLBCL, or HGBCL, or Grade 3b FL who are ineligible for standard R-mini-CHOP.
The simplified geriatric assessment (sGA) developed by the Fondazione Italiana Linfomi (FIL) identifies three distinct categories (fit, unfit, and frail) based on age, activities of daily living (ADL), instrumental activities of daily living (IADL) and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Participants will be assigned to Cohort A (unfit) or B (frail) using the sGA.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 65 Years 至 —（Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Pathologic diagnosis of DLBCL, as defined by the 2016 World Health Organization (WHO) classification (including participants with DLBCL transformed from indolent lymphoma), or HGBCL, or Grade 3b FL.
- •Measurable disease as defined by the 2014 Lugano Classification.
- •Stages I-IV.
- •ECOG PS 0-2; ECOG PS 3 allowed if decline in status is deemed related to lymphoma & felt to be potentially reversible by the treating physician.
- •Adequate organ function as defined by screening laboratory values within the following parameters:
- •Absolute neutrophil count (ANC) ≥1.0 x 10^3/µL (off growth factors at least 72 hours).
- •Platelet count ≥75 x 10^3/µL without transfusion in the past 7 days.
- •Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 x the upper limit of normal (ULN).
- •Total bilirubin ≤1.5 x ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 x ULN).
- •Calculated creatinine clearance >30 mL/min by the Cockcroft and Gault equation.
- •Note: A laboratory assessment may be repeated a maximum of two times during the screening period to confirm eligibility.
- •Women of childbearing potential (WOCBP) must agree to use a highly effective method of contraception from the time of giving informed consent until at least 12 months after the last dose of study treatment. Men with female partners who are of childbearing potential must agree to use a condom when sexually active or practice total abstinence from the time of the first dose until at least 7 months after the participant receives his last dose of study treatment.
- •Inclusion Criteria specific for Cohort A:
- •Unfit as defined by the simplified geriatric assessment (sGA). Includes all of the following:
- •Aged ≥80 years
- •ADL score of 6
- •IADL score of 8
- •CIRS-G: no score of 3-4 and <5 scores of 2
- •Inclusion Criteria specific for Cohort B:
- •Frail as defined by sGA:
- •Aged ≥80 years
- •ADL score of <6 and/or
- •IADL score of <8 and/or
- •CIRS-G: ≥1 score of 3-4 and/or >5 scores of 2 OR
- •Aged ≥65 - <80 with at least one of the following cardiac comorbidities that make anthracycline-containing regimens inadvisable as determined by the investigator.
- •Left ventricular ejection fraction (LVEF) ≥30 to <50%
- •History of myocardial infarction within 6 months prior to screening
- •Ischemic heart disease
- •History of stroke within 12 months prior to screening
排除标准
- •Known history of hypersensitivity to or positive serum human anti-drug antibody to a cluster of differentiation 19 (CD19) antibody.
- •Previous therapy for DLBCL, HGBCL, or Grade 3b FL (with exception of corticosteroid course for symptom management of less than 14 days).
- •Previous therapy with loncastuximab tesirine and rituximab for any indication.
- •Known history of hypersensitivity to any component of study treatment (loncastuximab tesirine and rituximab)
- •Human immunodeficiency virus (HIV) seropositive with any of the following:
- •CD4+ T-cell (CD4+) counts <350 cells/µL
- •Acquired immunodeficiency syndrome (AIDS) - defining opportunistic infection within 12 months prior to screening
- •Not on anti-retroviral therapy, or on anti-retroviral therapy for <4 weeks at the time of screening
- •HIV viral load ≥400 copies/mL
- •Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load.
- •Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load.
- •History of Stevens-Johnson syndrome or toxic epidermal necrolysis.
- •Lymphoma with active central nervous system involvement at the time of screening, including leptomeningeal disease.
- •Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath).
- •Major surgery, radiotherapy, chemotherapy, or other anti-neoplastic therapy within 14 days prior to start of study drug (Cycle 1 Day 1 [C1D1]), except shorter if approved by the Sponsor.
- •Use of any other experimental medication within 14 days prior to start of study drug (C1D1).
- •Received live vaccine within 4 weeks of C1D
- •Congenital long QT syndrome or a corrected Fridericia correction of the QT measure (QTcF) interval of >480 ms at screening (unless secondary to pacemaker or bundle branch block).
- •Active second primary malignancy other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy that the Sponsor's Medical monitor and Investigator agree, and document should not be exclusionary.
- •Any other significant medical illness, abnormality, or condition that would, in the Investigator's judgment, make the participant inappropriate for study participation or put the participant at risk.
研究组 & 干预措施
Cohort A : Loncastuximab Tesirine + Rituximab (Lonca-R)
Participants who are unfit (per sGA) will receive Lonca-R for 3 cycles. Participants who achieve a complete response (CR) will receive Lonca-R for 1 additional cycle. Participants who achieve a partial response (PR) will receive Lonca-R for 3 additional cycles.
Lonca-R will be administered as rituximab 375 mg/m^2 on Day 1 of Cycle 1 and loncastuximab tesirine 150 µg/kg on Day 2 of Cycle 1. During Cycle 2, Lonca-R will be administered as rituximab* 375 mg/m^2 and loncastuximab tesirine 150 µg/kg on Day 1. For cycles 3 and beyond, Lonca-R will be administered as rituximab 375 mg/m^2 and loncastuximab tesirine 75 µg/kg on Day 1.
*subcutaneous rituximab 1400mg/dose may be used during Cycle 2 and beyond
干预措施: Loncastuximab Tesirine (Drug)
Cohort A : Loncastuximab Tesirine + Rituximab (Lonca-R)
Participants who are unfit (per sGA) will receive Lonca-R for 3 cycles. Participants who achieve a complete response (CR) will receive Lonca-R for 1 additional cycle. Participants who achieve a partial response (PR) will receive Lonca-R for 3 additional cycles.
Lonca-R will be administered as rituximab 375 mg/m^2 on Day 1 of Cycle 1 and loncastuximab tesirine 150 µg/kg on Day 2 of Cycle 1. During Cycle 2, Lonca-R will be administered as rituximab* 375 mg/m^2 and loncastuximab tesirine 150 µg/kg on Day 1. For cycles 3 and beyond, Lonca-R will be administered as rituximab 375 mg/m^2 and loncastuximab tesirine 75 µg/kg on Day 1.
*subcutaneous rituximab 1400mg/dose may be used during Cycle 2 and beyond
干预措施: Rituximab (Drug)
Cohort B : Loncastuximab Tesirine + Rituximab (Lonca-R)
Participants who are frail (per sGA) or participants with cardiac comorbidities will receive Lonca-R for 3 cycles. Participants who achieve a CR will receive Lonca-R for 1 additional cycle. Participants who achieve a PR will receive Lonca-R for 3 additional cycles for a total of up to 6 cycles. Only participants enrolled in Cohort B, who achieve stable disease (SD) and deriving clinical benefit per the treating physician, may also receive Lonca-R for an additional 3 cycles.
Lonca-R will be administered as rituximab 375 mg/m^2 on Day 1 of Cycle 1 and loncastuximab tesirine 150 µg/kg on Day 2 of Cycle 1. During Cycle 2, Lonca-R will be administered as rituximab* 375 mg/m^2 and loncastuximab tesirine 150 µg/kg on Day 1. For cycles 3 and beyond, Lonca-R will be administered as rituximab 375 mg/m^2 and loncastuximab tesirine 75 µg/kg on Day 1.
*subcutaneous rituximab 1400mg/dose may be used during Cycle 2 and beyond
干预措施: Loncastuximab Tesirine (Drug)
Cohort B : Loncastuximab Tesirine + Rituximab (Lonca-R)
Participants who are frail (per sGA) or participants with cardiac comorbidities will receive Lonca-R for 3 cycles. Participants who achieve a CR will receive Lonca-R for 1 additional cycle. Participants who achieve a PR will receive Lonca-R for 3 additional cycles for a total of up to 6 cycles. Only participants enrolled in Cohort B, who achieve stable disease (SD) and deriving clinical benefit per the treating physician, may also receive Lonca-R for an additional 3 cycles.
Lonca-R will be administered as rituximab 375 mg/m^2 on Day 1 of Cycle 1 and loncastuximab tesirine 150 µg/kg on Day 2 of Cycle 1. During Cycle 2, Lonca-R will be administered as rituximab* 375 mg/m^2 and loncastuximab tesirine 150 µg/kg on Day 1. For cycles 3 and beyond, Lonca-R will be administered as rituximab 375 mg/m^2 and loncastuximab tesirine 75 µg/kg on Day 1.
*subcutaneous rituximab 1400mg/dose may be used during Cycle 2 and beyond
干预措施: Rituximab (Drug)
结局指标
主要结局
CR Rate
时间窗: Up to a maximum of 17.1 months
Defined as percentage of participants with a best overall response (BOR) of CR as determined by the Investigator according to the 2014 Lugano Classification criteria. CR was defined as achieving: * Complete metabolic response for positron emission tomography (PET)-computed tomography (CT) OR * Complete radiologic response (target node regress to \<1.5 cm, no non-measured lesions, no organ enlargement, no new lesions and normal bone marrow morphology) for CT if disease was not fluorodeoxyglucose (FDG)-avid at baseline.
Cohort B: Percentage of Participants Who Completed 4 Cycles of Treatment
时间窗: Up to 12 weeks (3 week cycle length)
Defined by the number of participants who completed a total of 4 cycles of therapy divided by the total number of participants \* 100.
次要结局
- Overall Response Rate (ORR)(Up to a maximum of 17.1 months)
- 2-year Progression-free Survival (PFS)(2 years)
- 3-year Overall Survival (OS)(3 years)
- Duration of Response (DoR)(Up to a maximum of 17.1 months)
- Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)(Up to approximately 8 months)
- Maximum Observed Concentration (Cmax) of Conjugated Antibody(Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion) and at the end (within -5 to +10 min) of loncastuximab tesirine infusion; Cycles 2-6 Day 1 predose and at the end of loncastuximab tesirine infusion (3 week cycle length))
- Cmax of Total Antibody(Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion) and at the end (within -5 to +10 min) of loncastuximab tesirine infusion; Cycles 2-6 Day 1 predose and at the end of loncastuximab tesirine infusion (3 week cycle length))
- Trough Concentration (Ctrough) of Conjugated Antibody(Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion); Cycles 2-6 Day 1 predose (3 week cycle length))
- Ctrough of Total Antibody(Cycle 1 Day 2: predose (preferably within 2 h prior to start of infusion); Cycles 2-6 Day 1 predose (3 week cycle length))
- Number of Participants With Confirmed Positive Anti-Drug Antibody (ADA) Response(Cycle 1 Day 2 pre-dose (preferably within 2 h prior to start of infusion) then Day 1 pre-dose of Cycles 2, 4, and 6 (3 week cycle length))
- Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale and Composite Scores(Baseline and End of Treatment Visit (a maximum of 19 weeks))