Phase 3 Randomized, Controlled Study of Blinatumomab Alternating With Low-intensity Chemotherapy Versus Standard of Care for Older Adults With Newly Diagnosed Philadelphia-negative B-cell Precursor Acute Lymphoblastic Leukemia With Safety Run-in (Golden Gate Study)
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- Amgen
- 入组人数
- 303
- 试验地点
- 359
- 主要终点
- Phase 3: Event-free Survival (EFS)
研究概览
简要总结
The safety run-in part of the study aims to evaluate the safety and tolerability of blinatumomab alternating with low-intensity chemotherapy. The phase 3 part of the study aims to compare event-free survival (EFS) and overall survival (OS) of participants receiving blinatumomab alternating with low-intensity chemotherapy to EFS and (OS) of participants receiving standard of care (SOC) chemotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 40 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •- Age ≥ 55 years at the time of informed consent. OR
- •Age 40 to < 55 years of age if at least 1 of the following comorbidities at the time of informed consent:
- •history of grades 3 and 4 pancreatitis
- •diabetes mellitus with end-organ damage
- •severe liver disease such as cirrhosis stage 2 with portal hypertension or history of esophageal variceal bleeding and aspartate transaminase (AST)/alanine aminotransferase (ALT) > 10 x upper limit of normal (ULN) (liver cirrhosis must be confirmed by biopsy)
- •body mass index (BMI) ≥ 40 combined with relevant comorbidities such as metabolic syndrome
- •Any further combination of documented severe comorbidities that the investigator judges to be incompatible with administering an intensive pediatric based, adult adapted standard chemotherapy regimen but still compatible with the suggested protocol for older participants in both the experimental and the SOC arm. The participant history will be reviewed by the medical monitor during screening to determine enrollment acceptability based on a standard list with types of comorbidities allowed.
- •Participants with newly diagnosed Philadelphia (Ph)-negative B-cell precursor acute lymphoblastic leukemia (ALL)
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, higher ECOG score allowed if due to underlying leukemia
- •All participants must have adequate organ function as defined below:
- •renal: estimated glomerular filtration rate based on MDRD calculation ≥ 50 mL/min/1.73 m^2
- •liver function: total bilirubin ≤ 2x upper limit of normal (ULN; unless Gilbert's Disease or if liver involvement with leukemia); exception for participants 40 to < 55 years of age if they have a comorbidity listed above: severe liver disease such as cirrhosis stage 2 with portal hypertension or history of esophageal variceal bleeding and AST/ALT > 10 x ULN (liver cirrhosis must be confirmed by biopsy)
- •cardiac: left ventricular ejection fraction (LVEF) ≥ 50% and no clinically significant, uncontrolled, or active cardiovascular disease (eg, myocardial infarction or stroke within 3 months). Consult with medical monitor as needed.
排除标准
- •Active central nervous system (CNS) leukemia (i.e., CNS 3 leukemia, confirmed by lumbar puncture) not resolved with IT chemotherapy during screening.
- •History of other malignancy within the past 3 years, with the following exceptions:
- •Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician Note: History of other malignancy (eg, multiple myeloma) treated with immunomodulatory drugs (eg, lenalidomide, thalidomide) in the past 3 years is an exclusion.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated cervical carcinoma in situ without evidence of disease
- •Adequately treated breast ductal carcinoma in situ without evidence of disease
- •Prostatic intraepithelial neoplasia without evidence of prostate cancer
- •Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ
- •Clinically relevant CNS pathology or event such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychiatric conditions that preclude the use of high dose of corticosteroids
- •Current autoimmune disease or history of autoimmune disease with potential CNS involvement
- •Known infection with human immunodeficiency virus (HIV)
- •Known infection with chronic or active infection with hepatitis B (eg, hepatitis b surface [HBs] antigen reactive or quantifiable hepatitis b virus [HBV] viral load) or hepatitis C virus (HCV) (eg, HCV RNA [qualitative] is detected).
- •Active hepatitis B and C based on the following results:
- •positive for hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B)
- •negative HepBsAg and positive for hepatitis B core antibody: negative HBV DNA by PCR result is necessary to enroll.
- •positive Hepatitis C virus antibody (HepCAb): negative hepatitis C virus RNA by PCR result is necessary to enroll.
- •Participant with symptoms and/or clinical signs and/or radiographic and/or sonographic signs that indicate an acute or uncontrolled chronic infection.
- •Cancer chemotherapy for this newly diagnosed B cell ALL before the start of protocol-required therapy with the exception of IT chemotherapy or optional pre-phase (debulking) chemotherapy. Radiation to a spot lesion such as chloroma or lytic lesion of bone or vertebrae for pain or vertebral stabilization is allowed.
研究组 & 干预措施
Phase 3: Standard of care (SOC) chemotherapy
Participants will receive 1 of 2 SOC chemotherapy regimens (GMALL or HyperCVAD) per investigator's choice.
干预措施: SOC chemotherapy regimen (Drug)
Phase 3: Blinatumomab alternating with low-intensity chemotherapy
Participants will receive blinatumomab alternating with low-intensity chemotherapy.
干预措施: Low-intensity chemotherapy regimen (Drug)
Phase 3: Blinatumomab alternating with low-intensity chemotherapy
Participants will receive blinatumomab alternating with low-intensity chemotherapy.
干预措施: Blinatumomab (Drug)
Safety Run-in: Blinatumomab alternating with low-intensity chemotherapy
The safety run-in will be performed prior to initiating the phase 3 randomized part of the study. This safety run-in is to evaluate the safety and tolerability of blinatumomab alternating with low-intensity chemotherapy.
The safety run-in also evaluates a shorter dose step interval from (4 days instead of 7 days) and a 1-week (instead of 2-week) drug free interval between blinatumomab cycles. Blinatumomab will be infused at a lower dose for 4 days and increase to a higher dose on Day 5 of the infusion for the remainder of the infusion.
干预措施: Low-intensity chemotherapy regimen (Drug)
Safety Run-in: Blinatumomab alternating with low-intensity chemotherapy
The safety run-in will be performed prior to initiating the phase 3 randomized part of the study. This safety run-in is to evaluate the safety and tolerability of blinatumomab alternating with low-intensity chemotherapy.
The safety run-in also evaluates a shorter dose step interval from (4 days instead of 7 days) and a 1-week (instead of 2-week) drug free interval between blinatumomab cycles. Blinatumomab will be infused at a lower dose for 4 days and increase to a higher dose on Day 5 of the infusion for the remainder of the infusion.
干预措施: Blinatumomab (Drug)
结局指标
主要结局
Phase 3: Event-free Survival (EFS)
时间窗: Up to approximately 5 years
Time from randomization (enrollment) until treatment failure, relapse or death from any cause, whichever is earlier. Treatment failure is defined as not achieving a hematological complete CR with MRD response \<10-4 by the end of the initial disease assessment period. Relapse is defined as hematologic relapse, extramedullary relapse, and/or molecular relapse (MRD positivity \>= 10\^-3), whichever occurs earlier, in participants with prior achievement of hematologic CR with MRD response \<10\^-4. Participants without an event will be censored at their last evaluable disease assessment date.
Safety run-in: Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs)
时间窗: Up to approximately 5 years
Number and percentage of participants who experience one or more TEAE, serious TEAE, treatment-related adverse events, and adverse events of interest.
Phase 3: Overall Survival (OS)
时间窗: Up to approximately 5 years
OS is defined as time from randomization (enrollment) until death due to any cause.
次要结局
- Safety run-in: Complete Remission (CR) Rate by the End of Initial Disease Assessment Period(Baseline to Week 14)
- Safety run-in: Minimal Residual Disease (MRD) Response by the End of Initial Disease Assessment Period(Baseline to Week 14)
- Safety run-in: Clearance (CL) of Blinatumomab(Up to approximately 34 weeks)
- Safety run-in: Relapse-free Survival (RFS)(Up to approximately 5 years)
- Safety run-in: Minimal Residual Disease (MRD) Relapse Free Survival (RFS)(Up to approximately 5 years)
- Safety run-in: Steady State Concentration (Css) of Blinatumomab(Up to approximately 34 weeks)
- Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Fatigue Score(Baseline to Week 14)
- Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Pain Score(Baseline to Week 14)
- Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Global Health Status(Baseline to Week 14)
- Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Physical Function(Baseline to Week 14)
- Phase 3: Complete Remission (CR) Rate by the End of Initial Disease Assessment Period(Baseline to Week 14)
- Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Nausea and Vomiting(Baseline to Week 14)
- Phase 3: Minimal Residual Disease (MRD) Response by the End of Initial Disease Assessment Period(Baseline to Week 14)
- Phase 3: Relapse-free Survival (RFS)(Up to approximately 5 years)
- Phase 3: Minimal Residual Disease (MRD) Relapse Free Survival (RFS)(Up to approximately 5 years)
- Phase 3: Minimal Residual Disease (MRD) Over Time(Up to approximately 5 years)
- Phase 3: Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs)(Up to approximately 5 years)
- Phase 3: Number of Participants who Experience Cluster of Differentiation (CD) 19 Positive and Negative Relapse by Flow Cytometry for Bone Marrow(Up to approximately 5 years)
- Phase 3: Number of Participants who Experience Cluster of Differentiation (CD) 19 Positive and Negative Relapse Identified by Immunohistochemistry or Flow Cytometry for Cerebrospinal Fluid(Up to end of safety follow up (approximately 44 months))
- Phase 3: Number of Participants who Experience Cluster of Differentiation (CD) 19 Positive and Negative Relapse for Extramedullary Sites other than Cerebrospinal Fluid(Up to end of safety follow up (approximately 44 months))
- Phase 3: Rate of Lineage Switch to Acute Myeloid Leukemia (AML)(Up to end of safety follow up (approximately 44 months))
- Phase 3: Localization of Relapse by Clinical Assessment(Up to end of safety follow up (approximately 44 months))
- Phase 3: Mortality Rate in Participants who Experience Complete Remission (CR)(Up to approximately 5 years)
- Phase 3: Number of Participants who have Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT) in Participants who Experience Continuous First Complete Remission (CR)(Up to approximately 5 years)
- Phase 3: Mortality Rate in Participants who Experience Complete Remission (CR) after Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)(Up to approximately 5 years)
- Phase 3: Relapse Rate Following Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)(Up to approximately 5 years)
- Clearance of Blinatumomab(Up to approximately Day 36)
- Steady State Concentration of Blinatumomab(Up to approximately Day 36)
- Phase 3: Time to Deterioration using the Fatigue Score(Up to approximately 5 years)
- Phase 3: Time to Improvements using the Fatigue Score(Up to approximately 5 years)
- Phase 3: Time to Deterioration using the Pain Score(Up to approximately 5 years)
- Phase 3: Time to Improvements using the Pain Score(Up to approximately 5 years)
- Phase 3: Change from Baseline in Global Health Status, Physical Function, Nausea/Vomiting, and All Other Subscales of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)(Baseline to end of study (up to approximately 5 years))
- Phase 3: Time to Deterioration for Global Health Status, Physical Function, Nausea/Vomiting, and All Other Subscales of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)(Up to approximately 5 years)
- Phase 3: Time to Improvements for Global Health Status, Physical Function, Nausea/Vomiting, and All Other Subscales of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)(Up to approximately 5 years)