A Modular Phase I/II, Open-label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, Pharmacodynamics, and Preliminary Efficacy of AZD0305 as Monotherapy or in Combination With Anticancer Agent(s) in Participants With Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AstraZeneca
- 入组人数
- 226
- 试验地点
- 44
- 主要终点
- Occurrence of dose-limiting toxicity (DLT), as defined in the protocol (Phase Ia dose escalation only)
研究概览
简要总结
This is a Phase I/II, modular, open-label, multicenter, dose escalation, and dose expansion/optimization study to evaluate the safety, tolerability, PK, immunogenicity, pharmacodynamics and efficacy of AZD0305 as monotherapy and in combination with other anticancer agents in participants with MM.
详细描述
This study will follow a modular protocol design evaluating AZD0305 as monotherapy and in combination with other anticancer agents. The protocol may be amended in the future to incorporate further monotherapy expansion at the recommended Phase 2 dose (RP2D) in Phase II, and/or additional modules investigating AZD0305 in combination with other anticancer agents.
The study consists of 3 modules:
- Module 1 (AZD0305 monotherapy),
- Module 2 (AZD0305 in combination with elranatamab)
- Module 3 (AZD0305 in combination with pomalidomide and dexamethasone [Pd])
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
No Masking
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
- •Participants must be at least 18 years of age or the legal age of consent in the jurisdiction
- •in which the study is taking place;
- •Eastern Cooperative Oncology Group performance status of ≤ 2 in module 1, or 0 or 1 in modules 2 and 3;
- •Documentation of Multiple Myeloma (MM) as defined by International Myeloma Working Group (IMWG) Diagnostic Criteria for Multiple Myeloma. Site should ensure that Multiple Myeloma diagnosis is confirmed in accordance with the IMWG Diagnostic Criteria;
- •Participants must have one or more measurable disease criteria for Serum M-Protein, Urine M-protein, and Serum immunoglobulin free light chains as specified in the relevant module of the CSP;
- •Adequate organ and bone marrow function assessment at screening according to the hematological, hepatic, and renal parameters listed in the CSP as relevant to each module;
- •Participants must have received at least 3 prior lines of treatment in module 1, or 1-3 prior lines in modules 2 and 3, with additional module-specific requirements related to prior lines of therapy
- •The above is a summary of key criteria, other inclusion criteria details may apply
排除标准
- •Amyloidosis, plasma cell leukemia, Waldenstrom Macroglobulinemia, Polyneuropathy Organomegaly Endocrinopathy M-protein and Skin Syndrome, or Smoldering Multiple Myeloma (compliant with WHO criteria);
- •Participants exhibiting clinical signs of central nervous system involvement of MM;
- •Participants with known COPD, or previous history of ILD/pneumonitis;
- •Participants with known moderate or severe persistent asthma within the past 5 years, or uncontrolled asthma of any classification;
- •Participants who have severe cardiovascular disease which is not adequately controlled;
- •Participants who have a history of immunodeficiency disease;
- •Participants with peripheral neuropathy ≥ Grade 2;
- •Primary refractory MM;
- •Participants who have previously received anti-GPRC5D or MMAE-containing treatment;
- •Participants who have previously received allogenic stem cell transplant, or participant has received autologous stem cell transplant within 3 months before the first dose of study intervention;
- •Participants with a history of prior malignancy other than MM within 3 years prior to first dose of study intervention. some exceptions apply;
- •Participants with previous history of active JC virus infection resulting in PML;
- •Participants with a known hypersensitivity to AZD0305 or any of the excipients of the product or to any of the drugs included in the respective modules or who experienced Grade 3 or higher hypersensitivity to prior monoclonal antibody therapy;
- •Participants who have uncontrolled severe illness including but not limited to ongoing active infection requiring therapeutic antibiotics and/or other administration
- •The above is a summary of key criteria, other exclusion criteria details may apply
研究组 & 干预措施
AZD0305 + Pomalidomide and Dexamethasone
Module3:
Phase 1a: Dose escalation and Phase 1b: Backfills, AZD0305 will be administered in combination with pomalidomide and dexamethasone, following the module-specific dosing.
干预措施: AZD0305 (Drug)
AZD0305 monotherapy
Module 1:
Phase Ia: Dose Escalation Phase Ib: Dose Expansion/Optimization AZD0305 will be administered at specified dose levels.
干预措施: AZD0305 (Drug)
AZD0305 + Elranatamab
Module2:
Phase 1a: Dose escalation and Phase 1b: Backfills, AZD0305 will be administered in combination with elranatamab, following the module-specific dosing.
干预措施: Elranatamab (Drug)
AZD0305 + Elranatamab
Module2:
Phase 1a: Dose escalation and Phase 1b: Backfills, AZD0305 will be administered in combination with elranatamab, following the module-specific dosing.
干预措施: AZD0305 (Drug)
AZD0305 + Pomalidomide and Dexamethasone
Module3:
Phase 1a: Dose escalation and Phase 1b: Backfills, AZD0305 will be administered in combination with pomalidomide and dexamethasone, following the module-specific dosing.
干预措施: Dexamethasone (Drug)
AZD0305 + Pomalidomide and Dexamethasone
Module3:
Phase 1a: Dose escalation and Phase 1b: Backfills, AZD0305 will be administered in combination with pomalidomide and dexamethasone, following the module-specific dosing.
干预措施: Pomalidomide (Drug)
结局指标
主要结局
Occurrence of dose-limiting toxicity (DLT), as defined in the protocol (Phase Ia dose escalation only)
时间窗: From first dose of AZD0305 until the end of Cycle 1. Cycle 1 (the DLT assessment period is 21 days for Module 1 Group A and 28 days for Module 1 Group B, Module 2, and Module 3)
A DLT is any toxicity occuring from the first dose of AZD0305 up to and including the planned end of Cycle 1 (the DLT assessment period) that is assessed as unrelated to the disease or disease-related processes under investigation and which includes, any death not clearly due to the underlying disease or extraneous causes, pre-defined haematological and non-haematological toxicities
Frequency of dose modifications, dose delays, and treatment discontinuations due to AEs (Module 2 and Module 3)
时间窗: From first dose of study treatment until End of treatment (EOT), assessed up to approximately 2 years (each cycle is 28 days)
Number and percentage of participants with dose modifications, dose delays, and permanent discontinuations due to adverse events (for AZD0305 and combination agent\[s\], as applicable), per protocol-defined dose modification rules.
Occurrence of dose-limiting toxicity (DLT), as defined in the protocol (Phase Ia dose escalation only)
时间窗: From first dose of study treatment until the end of Cycle 1
A DLT is defined as any toxicity that occurs from the first dose of study treatment up to and including the planned end of Cycle 1 (the DLT assessment period) that is assessed as unrelated to the disease or disease-related processes under investigation and which includes, any death not clearly due to the underlying disease or extraneous causes, pre-defined haematological and non-haematological toxicities
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: From time of Informed consent to 30 days post end of treatment
Number of patients with adverse events and serious adverse events by system organ class and preferred term
次要结局
- Phase Ia: Immunogenicity of elranatamab(From the first dose, at predefined intervals until Cycle 24 administration of elranatamab(approximately 2 years))
- Phase Ia: MRD negative CR rate(From first dose of AZD0305 to progressive disease or death in the absence of disease progression (approximately 2 years))
- Phase Ib: Objective Response Rate (ORR)(From randomization/cohort assignment to progressive disease or Initiation of subsequent MM therapy (approximately 2 years))
- Phase Ib: Duration of response (DoR)(From randomization/cohort assignment to confirmed progressive disease or death (approximately 2 years))
- Phase Ib: Progression free Survival (PFS)(From randomization/cohort assignment to progressive disease or death in the absence of disease progression (approximately 2 years))
- Phase Ib: Overall Survival (OS)(From randomization/cohort assignment to death (approximately 2 years))
- Phase Ib: Pharmacokinetics of AZD0305: Area Under the concentration-time curve (AUC)(From randomization/cohort assignment , at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Pharmacokinetics of AZD0305: Maximum plasma concentration of the study drug (Cmax)(From randomization/cohort assignment , at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Pharmacokinetics of AZD0305: Time to maximum plasma concentration of the study drug (tmax)(From randomization/cohort assignment , at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Pharmacokinetics of AZD0305: Clearance(From randomization/cohort assignment , at predefined intervals throughout the administration of AZD0305 (approximately 2 years)
- Phase Ib: Pharmacokinetics of AZD0305: Terminal elimination half-life (t 1/2)(From randomization/cohort assignment, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Immunogenicity of AZD0305(From randomization/cohort assignment, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Immunogenicity of elranatamab(From the first dose, at predefined intervals until Cycle 24 administration of elranatamab(approximately 2 years))
- Phase 1b: MRD negative CR rate(From first dose of AZD0305 to progressive disease or death in the absence of disease progression (approximately 2 years))
- Complete Response Rate (CRR) - Mod2&3 only(From first dose of combination treatment to progressive disease or initiation of subsequent multiple myeloma therapy (approximately 2 years))
- Pre-Dose Plasma Concentration of Elranatamab (pharmacokinetics - Module 2 only)(From the first dose of study intervention, at predefined intervals until Cycle 24 administration of elranatamab(approximately 2 years; 1 cycle = 28 days))
- Phase Ia: Objective Response Rate (ORR)(From first dose of AZD0305 to progressive disease or Initiation of subsequent MM therapy (approximately 2 years))
- Phase Ia: Duration of response (DoR)(From the first documented response to confirmed progressive disease or death (approximately 2 years))
- Phase Ia: Progression free Survival (PFS)(From first dose of AZD0305 to progressive disease or death in the absence of disease progression (approximately 2 years))
- Phase Ia: Overall Survival (OS)(From first dose of AZD0305 to death (approximately 2 years))
- Phase Ia: Pharmacokinetics of AZD0305: Area Under the concentration-time curve (AUC)(From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ia: Pharmacokinetics of AZD0305: Maximum plasma concentration of the study drug (Cmax)(From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ia: Pharmacokinetics of AZD0305: Time to maximum plasma concentration of the study drug (tmax)(From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ia: Pharmacokinetics of AZD0305: Clearance(From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ia: Pharmacokinetics of AZD0305: Terminal elimination half-life (t 1/2)(From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ia: Immunogenicity of AZD0305(From the first dose of study intervention, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Objective Response Rate (ORR)(From randomization to progressive disease or Initiation of subsequent MM therapy (approximately 2 years))
- Phase Ib: Duration of response (DoR)(From randomization to confirmed progressive disease or death (approximately 2 years))
- Phase Ib: Progression free Survival (PFS)(From randomization to progressive disease or death in the absence of disease progression (approximately 2 years))
- Phase Ib: Overall Survival (OS)(From randomization to death (approximately 2 years))
- Phase Ib: Pharmacokinetics of AZD0305: Area Under the concentration-time curve (AUC)(From randomization, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Pharmacokinetics of AZD0305: Maximum plasma concentration of the study drug (Cmax)(From randomization, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Pharmacokinetics of AZD0305: Time to maximum plasma concentration of the study drug (tmax)(From randomization, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Pharmacokinetics of AZD0305: Clearance(From randomization, at predefined intervals throughout the administration of AZD0305 (approximately 2 years)
- Phase Ib: Pharmacokinetics of AZD0305: Terminal elimination half-life (t 1/2)(From randomization, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))
- Phase Ib: Immunogenicity of AZD0305(From randomization, at predefined intervals throughout the administration of AZD0305 (approximately 2 years))