A Phase I/II Open-Label Multi-Centre Master Protocol to Evaluate the Safety and Efficacy of AZD0486 Monotherapy or in Combination With Other Anticancer Agents in Participants With Mature B-Cell Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 408
- 试验地点
- 65
- 主要终点
- Number of Participants with Adverse Events, Serious Adverse Events and Adverse Events of Special Interest
研究概览
简要总结
The purpose of this study is to assess the safety and efficacy of surovatamig (formerly AZD0486) administered as monotherapy or in combination with other anticancer agents in participants with hematological malignancies
详细描述
This is open-label, multi-center study to evaluate the safety and preliminary efficacy of surovatamig administered as monotherapy and in combination with other anticancer agents in participants with mature B-cell hematologic malignancies.
This master study currently includes 3 substudies and each substudy focusing on a defined population:
Substudy 1: Relapsed/refractory (R/R) Chronic lymphocytic leukaemia (CLL)/ Small lymphocytic lymphoma (SLL) Substudy 2: R/R Mantle-cell lymphoma (MCL) Substudy 3: Large B-cell lymphoma (LBCL) or R/R B-cell non-Hodgkin lymphoma (B-NHL) (not applicable to US)
The study will have the following sequential periods:
- Screening period of 28 days
- Treatment period
- Follow-up period
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Master Inclusion Criteria applicable to all substudies:
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Contraception use during treatment and at least 90 days after final dose.
- •Confirmed CD19 expression if prior anti-CD19 therapy.
- •Substudy 1 Specific Inclusion Criteria:
- •Participants with CLL must require treatment according to the international workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.
- •SLL: at least 1 measurable site per Lugano.
- •Absolute lymphocyte count (ALC) <25000 cells/mcL.
- •Cohort 1A and 1C: at least 2 prior lines of systemic therapy for CLL/SLL.
- •Cohort 1B: at least 1 prior line of therapy and is bruton tyrosine kinase inhibitor (BTKi)-sensitive.
- •Substudy 2 Specific Inclusion Criteria:
- •MCL diagnosis per WHO.
- •Clinical Stage II, III, or IV by Ann Arbor Classification.
- •At least 1 measurable site per Lugano.
- •ALC < 25000 cells/mcL.
- •Cohort 2A and 2C: Relapse or progressed after 2 or more lines of therapy including BTKi.
- •Substudy 3 Specific Inclusion Criteria:
- •At least 1 measurable site as per Lugano.
- •Left ventricular ejection fraction (LVEF) ≥50%.
- •Participant must be no older than 79 years of age at the time of signing ICF.
- •Contraception at least 90 days after last dose of surovatamig or 4 months after last dose of vincristine, and 6 months after the last dose of cyclophosphamide, or doxorubicin.
- •Cohort 3A:
- •Histologically confirmed diagnosis of previously untreated large B-cell Lymphoma (LBCL) per WHO
- •R/R B-NHL after at least 1 prior lines of systemic therapy.
- •International Prognostic Index (IPI) 2-
- •Cohort 3B:
- •Histologically confirmed diagnosis of previously untreated large B-cell Lymphoma (LBCL) per WHO
- •IPI score of 2 to 5.
排除标准
- •Master Exclusion Criteria applicable to all substudies:
- •Central nervous system (CNS) lymphoma.
- •Surgery within 14 days of study drug.
- •Clinically significant cardiovascular (CV) disease.
- •Unresolved Grade >2 AEs from prior anticancer therapy (except alopecia or fatigue).
- •Any systemic therapy within 5 half-lives or 21 days (whichever is shorter) prior to treatment.
- •Radiation therapy within 28 days.
- •Prior CAR T-cell therapy or autologous-haematopoietic stem cell transplant (HSCT) within 12 weeks or prior T-cell engager (TCE) within 8 weeks.
- •Prior Grade > 3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) event.
- •Prior allogeneic HSCT or solid organ transplantation within 24 weeks of starting Cycle 1 Day
- •Active, significant, uncontrolled infection or autoimmune disease requiring systemic therapy including participants with known history of haemophagocytic lymphohistiocytosis (HLH).
- •Substudy 1 Specific Exclusion Criteria:
- •CLL/SLL transformation to more aggressive form of lymphoma.
- •Cohort 1B: bleeding diathesis, CYP3A inhibitor or inducer, history of ICH or stroke within 24 weeks, GI malabsorption, receiving vitamin K antagonist.
- •Substudy 3 Specific Exclusion Criteria:
- •Mediastinal grey-zone lymphoma, Burkitt, Richter's transformation, primary effusion large B-cell lymphoma (LBCL).
- •Cumulative dose of anthracycline >150 mg/m2.
研究组 & 干预措施
Substudy 3 (LBCL): Cohort 3B 3SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 3SUD (triple step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Doxorubicin (Drug)
Substudy 3 (LBCL): Cohort 3B 3SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 3SUD (triple step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Vincristine (Drug)
Substudy 1 (RR CLL/SLL): Cohort 1A (Surovatamig Monotherapy)
Participants will receive surovatamig monotherapy as subcutaneous (SC) injection.
干预措施: Surovatamig (Drug)
Substudy 2 (RR MCL): Cohort 2C (Surovatamig Monotherapy)
Participants will receive surovatamig monotherapy as IV infusion.
干预措施: Surovatamig (Drug)
Substudy 1 (RR CLL/SLL): Cohort 1B (Surovatamig + Acalabrutinib)
Participants will receive surovatamig as SC injection. Participants will receive acalabrutinib tablet orally twice daily.
干预措施: Surovatamig (Drug)
Substudy 1 (RR CLL/SLL): Cohort 1C (Surovatamig Monotherapy)
Participants will receive surovatamig monotherapy as intravenous (IV) infusion.
干预措施: Surovatamig (Drug)
Substudy 2 (RR MCL): Cohort 2A (Surovatamig Monotherapy)
Participants will receive surovatamig monotherapy as SC injection.
干预措施: Surovatamig (Drug)
Substudy 3 (LBCL): Cohort 3A 2SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 2SUD (double step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Surovatamig (Drug)
Substudy 3 (LBCL): Cohort 3B 3SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 3SUD (triple step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Surovatamig (Drug)
Substudy 3 (LBCL): Cohort 3B 3SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 3SUD (triple step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Cyclophosphamide (Drug)
Substudy 3 (LBCL): Cohort 3A 2SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 2SUD (double step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Vincristine (Drug)
Substudy 1 (RR CLL/SLL): Cohort 1B (Surovatamig + Acalabrutinib)
Participants will receive surovatamig as SC injection. Participants will receive acalabrutinib tablet orally twice daily.
干预措施: Acalabrutinib (Drug)
Substudy 3 (LBCL): Cohort 3A 2SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 2SUD (double step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Rituximab (Drug)
Substudy 3 (LBCL): Cohort 3A 2SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 2SUD (double step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Cyclophosphamide (Drug)
Substudy 3 (LBCL): Cohort 3A 2SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 2SUD (double step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Prednisone (or equivalent) (Drug)
Substudy 3 (LBCL): Cohort 3A 2SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 2SUD (double step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Doxorubicin (Drug)
Substudy 3 (LBCL): Cohort 3B 3SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 3SUD (triple step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Rituximab (Drug)
Substudy 3 (LBCL): Cohort 3B 3SUD (Surovatamig + RCHOP)
Participants will receive surovatamig as IV infusion with a 3SUD (triple step-up dosing) schedule for priming in combination with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy.
干预措施: Prednisone (or equivalent) (Drug)
结局指标
主要结局
Number of Participants with Adverse Events, Serious Adverse Events and Adverse Events of Special Interest
时间窗: Up to 6 years 4 months
Safety and tolerability of surovatamig as monotherapy and in combination with other anticancer agents across mature B-cell malignancies.
Number of Participants with Dose Limiting Toxicity (DLTs)
时间窗: Up to 2 months
Safety and tolerability of surovatamig as monotherapy and in combination with other anticancer agents across mature B-cell malignancies.
次要结局
- Duration of Response (DoR)(Up to 6 years 4 months)
- Number of Participants with Anti-drug Antibody (ADA) for AZD0486(Up to 90 days after last dose)
- Objective Response Rate (ORR)(Up to 6 years 4 months)
- Half Life (t1/2) of AZD0486(Up to 90 days after last dose)
- Clearance (CL) of AZD0486(Up to 90 days after last dose)
- Complete Response (CR) Rate(Up to 6 years 4 months)
- Time to Reach Maximum Concentration (Tmax)(Up to 90 days after last dose)
- Maximum Observed Concentration (Cmax)(Up to 90 days after last dose)
- Area Under the Concentration-time Curve (AUC)(Up to 90 days after last dose)
- Minimum Observed Concentration (Cmin)(Up to 90 days after last dose)
- Trough Plasma Concentration (Ctrough)(Up to 90 days after last dose)
- Overall Response Rate (ORR)(Up to 6 years 4 months)
- Time to Reach Maximum Concentration (tmax)(Up to 90 days after last dose)
- Half Life (t1/2) of surovatamig(Up to 90 days after last dose)
- Clearance (CL) of surovatamig(Up to 90 days after last dose)
- Number of Participants with Anti-drug Antibody (ADA) for surovatamig(Up to 90 days after last dose)