An Open-Label, Multicenter, Phase I Trial Evaluating the Safety and Pharmacokinetics of Escalating Doses of Cevostamab (BFCR4350A) in Patients With Relapsed or Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 355
- 试验地点
- 33
- 主要终点
- Percentage of Participants with Adverse Events (AEs)
研究概览
简要总结
This is a phase I, multicenter, open-label, dose-escalation study of cevostamab administered as a single agent by IV infusion to participants with relapsed or refractory multiple myeloma (R/R MM).
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
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- •Life expectancy of at least 12 weeks
- •Participants must have relapsed or refractory (R/R) multiple myeloma (MM) for which no established therapy for MM is appropriate and available or be intolerant to those established therapies
- •Adverse events from prior anti-cancer therapy resolved to Grade < or = 1, except any grade alopecia and/or peripheral sensory or motor neuropathy which must have resolved to Grade < or = 2
- •Measurable disease defined by laboratory test results
- •Female participants of childbearing age must agree to remain abstinent or use reliable contraceptive methods during the treatment period, and at least 5 months after last dose of study drug. Women must refrain from breastfeeding during the same period.
- •Male participants must agree to refrain from donating sperm, to abstain or use a condom during the treatment period, and for at least 2 months after the last dose of tocilizumab (if applicable).
排除标准
- •Inability to comply with protocol-mandated hospitalization and activities restrictions
- •Pregnant or breastfeeding, or planning to become pregnant during the study or within 5 months after the last dose of cevostamab or within 3 months after the last dose of of tocilizumab (if applicable)
- •Prior use of any monoclonal antibody, radioimmunoconjugate, or antibody-drug conjugate as anti-cancer therapy within 4 weeks before first infusion
- •Prior treatment with systemic immunotherapeutic agents within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first infusion
- •Prior treatment with chimeric antigen receptor (CAR) T-cell therapy within 12 weeks before first cevostamab infusion
- •Known treatment-related, immune-mediated adverse events associated with prior immunotherapeutic agents
- •Treatment with radiotherapy, any chemotherapeutic agent, or treatment with any other anti-cancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first cevostamab infusion
- •Autologous stem cell transplantation (SCT) within 100 days prior to first infusion
- •Prior allogeneic SCT or solid organ transplantation
- •Absolute plasma cell count exceeding 500/micro L or 5% of the peripheral blood white cells
- •History of autoimmune disease or of confirmed progressive multifocal leukoencephalopathy
- •Known history of hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS)
- •History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
- •Patients with known history of amyloidosis (e.g., positive Congo Red stain or equivalent in tissue biopsy)
- •Patients with lesions in proximity of vital organs that may develop sudden decompensation/deterioration in the setting of a tumor flare
- •History of other malignancy that could affect compliance with the protocol or interpretation of results
- •Current or past history of central nervous system (CNS) disease, or CNS involvement by MM
- •Significant cardiovascular disease that may limit a patient's ability to adequately respond to a CRS event
- •Symptomatic active pulmonary disease requiring supplemental oxygen
- •Within 14 days prior to first cevostamab infusion: known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics within 4 weeks prior to first infusion
- •Positive and quantifiable Epstein-Barr virus (EBV) polymerase chain reaction (PCR) or cytomegalovirus (CMV) PCR prior to first study treatment
- •Known or suspected chronic active EBV infection, acute or chronic hepatitis C virus (HCV) infection
- •Positive serologic or PCR test results for acute or chronic hepatitis B virus (HBV) infection
- •Recent major surgery within 4 weeks prior to first infusion
- •Human Immunodeficiency Virus (HIV) positive
- •Any episode of active, symptomatic COVID-19 infection, or requiring treatment with IV antivirals for COVID-19 (not including COVID-19 primary prophylaxis) within 14 days, prior to first study treatment
- •Administration of a live, attenuated vaccine within 4 weeks before first cevostamab infusion or anticipation that such a live attenuated vaccine will be required during the study
- •Received systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents), with the exception of corticosteroid treatment <=10 mg/day prednisone or equivalent within 2 weeks prior to first dose of cevostamab and, if applicable, tocilizumab premedication prior to first dose of cevostamab
- •History of illicit drug or alcohol abuse within 12 months prior to screening
- •Any medical condition or laboratory test abnormality that precludes the participant's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results
研究组 & 干预措施
Arm A: Single Step Dose Escalation for Cevostamab
Study drug will be administered intravenously on a 21-day cycle. The step-up dose will be given on Cycle 1 Day 1 and the target dose will be given on C1D8. Subsequently the target dose will be administered on Day 1 of each 21-day cycle.
干预措施: Cevostamab (Drug)
Arm B: Double Step Dose Escalation for Cevostamab
In Cycle 1, participants will receive 2 step-up doses and a target dose. The step-up dose will be given on Cycle 1 Day 1 and C1D8. The target dose will be given on C1D15. Subsequently the target dose will be administered on Day 1 of each 21-day cycle.
干预措施: Cevostamab (Drug)
Arm C: Single Step Dose Expansion for Cevostamab
The single step dose expansion stage of the study may use the dosing and assessment schedule from the single dose escalation arm in Cycle 1, based on data from Arm A.
干预措施: Cevostamab (Drug)
Arm D: Double Step Dose Expansion for Cevostamab
The double step dose expansion stage of the study may use the dosing and assessment schedule from the double step dose escalation arm in Cycle 1, based on data from Arm B.
干预措施: Cevostamab (Drug)
Arm E: Expansion Phase for Tocilizumab Pretreatment
All participants will receive a single dose of tocilizumab intravenously. An additional dose of tocilizumab may be instituted as premedication for subsequent Cycle 1 dose(s) of cevostamab and Cycle 1 cevostamab doses for other treatment arms.
干预措施: Cevostamab (Drug)
Arm E: Expansion Phase for Tocilizumab Pretreatment
All participants will receive a single dose of tocilizumab intravenously. An additional dose of tocilizumab may be instituted as premedication for subsequent Cycle 1 dose(s) of cevostamab and Cycle 1 cevostamab doses for other treatment arms.
干预措施: Tocilizumab (Drug)
Arm F: Single Step Dose Expansion for Cevostamab
The single step dose expansion stage of the study may use the dosing and assessment schedule from the single dose escalation arm in Cycle 1, based on data from Arm A.
干预措施: Cevostamab (Drug)
Arm G: Double Step Dose Expansion for Cevostamab
The double step dose expansion stage of the study may use the dosing and assessment schedule from the double step dose escalation arm in Cycle 1, based on data from Arm B.
干预措施: Cevostamab (Drug)
Arm H: Triple Step Dose Escalation for Cevostamab
In Cycle 1, participants will receive 3 step-up doses and a target dose. The doses will be given on Cycle 1 Days 1, 2-4, 8, and 9-11. Subsequently the target dose will be administered on Day 1 of each 21-day cycle.
干预措施: Cevostamab (Drug)
Arm I: Triple Step Dose Expansion for Cevostamab
The triple step dose expansion stage of the study may use the dosing and assessment schedule from the triple step dose escalation arm in Cycle 1, based on data from Arm H.
干预措施: Cevostamab (Drug)
Arm J: Expansion Phase for Tocilizumab Pretreatment
All participants will receive a single dose of tocilizumab intravenously. An additional dose of tocilizumab may be instituted as premedication for subsequent Cycle 1 dose(s) of cevostamab and Cycle 1 cevostamab doses for other treatment arms.
干预措施: Cevostamab (Drug)
Arm J: Expansion Phase for Tocilizumab Pretreatment
All participants will receive a single dose of tocilizumab intravenously. An additional dose of tocilizumab may be instituted as premedication for subsequent Cycle 1 dose(s) of cevostamab and Cycle 1 cevostamab doses for other treatment arms.
干预措施: Tocilizumab (Drug)
Arm K: Compressed Double Step Dose Expansion for Cevostamab
In Cycle 1, participants will receive 2 step-up doses and a target dose. The doses will be given on Cycle 1 Days 1, 4, and 8. Subsequently the target dose will be administered on Day 1 of each 21-day cycle.
干预措施: Cevostamab (Drug)
结局指标
主要结局
Percentage of Participants with Adverse Events (AEs)
时间窗: Up to approximately 8 years
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure.
Arms E and J Only: Incidence and Severity of Cytokine-release Syndrome (CRS) Following Tocilizumab Premedication Followed by Treatment with Cevostamab
时间窗: Up to approximately 8 years
Cytokine release syndrome was recorded as an AE that generally occurs \>30 minutes after the start of Cevostamab administration and at any time afterward in a given cycle.
Percentage of Participants With Dose-Limiting Toxicities (DLTs)
时间窗: Up to approximately 8 years
Dose-Limiting Toxicities (DLTs) will be reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0), except for Cytokine release syndrome (CRS), which will be graded according to the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine Release Syndrome.
次要结局
- AUC of Tocilizumab(Up to approximately 8 years)
- Minimum Observed Serum Concentration (Cmin) of Cevostamab(Up to approximately 8 years)
- Objective Response Rate (ORR)(Up to approximately 8 years)
- Clearance (CL) of Cevostamab(Up to approximately 8 years)
- Cmax of Tocilizumab(Up to approximately 8 years)
- Serum Concentration of Tocilizumab(Up to approximately 8 years)
- Duration of Response(Up to approximately 8 years)
- Area Under the Concentration-Time Curve (AUC) of Cevostamab(Up to approximately 8 years)
- Maximum Observed Serum Concentration (Cmax) of Cevostamab(Up to approximately 8 years)
- Cmin of Tocilizumab(Up to approximately 8 years)
- CL of Tocilizumab(Up to approximately 8 years)
- Volume of Distribution at Steady State (Vdss) of Cevostamab(Up to approximately 8 years)
- Serum Concentration of Cevostamab(Up to approximately 8 years)
- Change from Baseline in the Presence Anti-Drug Antibodies (ADAs)(Up to approximately 8 years)
- Vdss of Tocilizumab(Up to approximately 8 years)