A Phase II, Multicenter, Open-label Study Evaluating Glofitamab in Combination With Venetoclax Plus Zanubrutinib or Venetoclax Alone in Subjects With Untreated or Relapsed/Refractory High-risk Mantle-cell Lymphoma
概览
- 阶段
- 2 期
- 干预措施
- Obinutuzumab
- 疾病 / 适应症
- Lymphoma, Mantle-Cell
- 发起方
- The Lymphoma Academic Research Organisation
- 入组人数
- 100
- 试验地点
- 16
- 主要终点
- PFS at the end of C17 (each cycle is 21 days)
- 状态
- 招募中
- 最后更新
- 2个月前
概览
简要总结
This open-label, multicenter, three cohorts, phase II study is designed to assess a combination of Zanubrutinib/Venetoclax/Glofitamab or Venetoclax/Glofitamab in high-risk subjects with either first line or R/R Mantle Cell Lymphoma (MCL).
Three independent cohorts will be run:
- Cohort A will include subjects with a primary refractory or progressive disease within 24 months from initiation of first line treatment (POD 24).
- Cohort B will be open for subjects with R/R MCL and refractory or progressive to a BTK inhibitor given previously (>24 months if first line).
- Cohort C will only enrol newly diagnosed and untreated MCL subjects with very high-risk features.
详细描述
Cohort A : 40 subjects will be included and treated Cohort B : 36 subjects will be included and treated Cohort C : 24 subjects will be included and treated Subjects in cohorts A and C will receive during induction phase 12 cycles of Zanubrutinib/Venetoclax/Glofitamab and during maintenance phase 23 cycles of Zanubrutinib/Venetoclax Subjects in cohort B will receive during induction phase 12 cycles of Venetoclax/Glofitamab and during maintenance phase 23 cycles of Venetoclax
研究者
入排标准
入选标准
- •In cohort A, subject must meet the following inclusion criteria:
- •Subject must be primary refractory or in progression within 24 months from initiation of first line treatment (POD24 defined as time between D1C1 of the first treatment line and ICF signature)) (including an anti-CD20 combined with chemotherapy). Subject previously exposed to BTK inhibitor at first line is eligible. Subject in failure of CAR-T cell first line is eligible.
- •Primary refractory subjects (ie with a progressive disease) to the BTKi and Venetoclax combination will not be eligible.
- •In cohort B, subject must meet the following inclusion criterion:
- •Subject must be R/R MCL and refractory or progressive to a BTK inhibitor given in a previous line of treatment (the number of treatment lines is not limited). If first progression, time from diagnosis (defined as D1C1 of the first treatment line) to inclusion (defined as the date of ICF signature) must be superior to 24 months.
- •Subject previously exposed to Bcl-2 therapy and/or relapsing post CAR-T cell therapy is eligible, except if they presented a progressive disease under BTKi and Venetoclax combination.
- •In cohort C, subject must meet the following inclusion criteria:
- •Subject not previously treated for mantle cell lymphoma.
- •Subject at high risk of relapse presenting at least two of the following risk factors:
- •TP53 mutation, del17p, or p53 expression (IHC) \> 50%,
排除标准
- •Subject who meets any of the following criteria will be excluded from enrollment in the study study for cohort A, B and C:
- •Proven or previously known CD20 negative status on FFPE IHC at time of MCL relapse or diagnosis.
- •For subjects in Cohort A and B: previously refractory to treatment by BTK inhibitor and Bcl-2 therapy combination.
- •Any prior therapy with a bispecific antibody targeting CD3 and CD
- •Current or past history of central nervous system or meningeal involvement by lymphoma.
- •Use of any standard or experimental anti-cancer drug therapy including biological agents (e.g. monoclonal antibodies) within 30 days of the start (Day 1) of study treatment, except for BTKi for subjects included in cohort B, that can be pursued until C1D
- •and except for topical treatment or hormone treatment if criterion 33 is respected. Corticosteroid treatment ≤ 1 mg/kg/day prednisone or equivalent is allowed within 2 weeks prior to Obinutuzumab infusion.
- •LVEF \< 50% as determined by echocardiography or isotopic method.
- •Clinically significant cardiovascular disease such as uncontrolled, unstable or symptomatic arrhythmias, unstable angina, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class III (moderate) or Class IV(severe) cardiac disease as defined by the New York Heart Association Functional Classification or Objective Assessment Class C or D cardiac disease. Heart rate-corrected QT interval \> 480 milliseconds based on Fridericia's formula.; History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements, at screening, showing systolic blood pressure \> 170 mmHg and diastolic blood pressure \> 105 mmHg and/or uncontrolled hypertension with systolic blood pressure\>140mmHg despite a well conduct hypertensive treatment for at least 6 months
- •Hemoglobin level \< 8g/dL; Absolute Neutrophil count \<1 G/L (\<0,5G/L if related to lymphoma); Platelets \< 75 G/L (\< 50 G/L if related to lymphoma),
研究组 & 干预措施
Cohort A - POD24
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Obinutuzumab
Cohort A - POD24
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Glofitamab
Cohort A - POD24
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Venetoclax Oral Product
Cohort B - BTKI failure
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Obinutuzumab
Cohort B - BTKI failure
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Glofitamab
Cohort B - BTKI failure
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Venetoclax Oral Product
Cohort C - first Line
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Obinutuzumab
Cohort C - first Line
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Glofitamab
Cohort C - first Line
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Venetoclax Oral Product
Cohort C - first Line
* Obinutuzumab IV infusion 2000 mg flat dose at C1D1 or Splited in 2 doses of 1000 mg at C1D1 and C1D2 * Glofitamab IV infusion 2.5 mg C1D8 10 mg C1D15 30 mg C2D1 and C3D1 (infusion during min 4 hours ) 30 mg Each D1 for C4 to C6 (Infusion during min 2 hours ) 30 mg Each D1 for C7 to C12 (Infusion during min 90 min) * Zanubrutinib PO 320 mg total daily dose (QD) From C1D2 continuously until end C35 * Venetoclax PO 20 mg/d C2D3 to C2D7 50 mg/d C2D8 to C2D14 100 mg/d C2D15 to C2D21 200 mg/d C3D1 to C3D7 400 mg/d From C3D8 continuously until end C35
干预措施: Zanubrutinib Oral Capsule
结局指标
主要结局
PFS at the end of C17 (each cycle is 21 days)
时间窗: end of cycle 17 (each cycle is 21 days)
The primary efficacy endpoint is the PFS at 12 months (end of C17) from first dose of study treatment, in each cohort: Zanubrutinib/Venetoclax/Glofitamab for cohorts A and C, Venetoclax/Glofitamab for cohort B, as determined by imaging central review (Lugano 2014 criteria),
次要结局
- Overall Survival (OS)(74 months or death)
- Time to next anti-lymphoma treatment (TTNT)(date of next anti-lymphoma treatment (74 months))
- Safety and tolerability:(from ICF signature until 28 days after the last treatment administration)
- Overall Response Rate (ORR) and Complete Response Rate (CRR)(End of C3 (each cycle is 21 days), end of C6 (each cycle is 21 days), end of C12 (each cycle is 21 days), end of C17 (each cycle is 21 days), end of C26 (each cycle is 21 days)))
- PFS at the end of C17 as determined by investigator(end of cycle 17 (each cycle is 21 days))
- Duration of response (DOR)(72 months)
- Event-free survival (EFS)(74 months)
- Minimal Residual Disease (MRD)(before Cycle 1 Day1 (baseline), end of C3 (each cycle is 21 days), end of C6 (each cycle is 21 days), end of C17 (each cycle is 21 days))
- Disease Free Survival (DFS)(74 months)