Study Comparing Blinatumomab Alternating With Low-intensity Chemotherapy Versus Standard of Care Chemotherapy for Older Adults With Newly Diagnosed Philadelphia-negative B-cell Precursor Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Newly Diagnosed Philadelphia (Ph)-Negative B-cell Precursor Acute Lymphoblastic Leukemia (ALL)

Intervention / Treatment
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* Drug: Blinatumomab
* Drug: Low-intensity chemotherapy regimen
* Drug: SOC chemotherapy regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - 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. A medical advisory board is available to the investigators for questions/advice and includes experts in the field of adult leukemia with experience with the use of blinatumomab, the global development lead for blinatumomab and the medical monitor of the study. 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% Exclusion Criteria: Active central nervous system (CNS) leukemia not resolved with IT chemotherapy during screening. Clinically relevant CNS pathology requiring treatment (eg, unstable epilepsy). 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 pre-phase chemotherapy. Radiation to a spot lesion such as chloroma or lytic lesion of bone or vertebrae for pain or vertebral stabilization is allowed.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-in: Blinatumomab alternating with low-intensity chemotherapy<br>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. | Drug: Blinatumomab<br>* Continuous intravenous (cIV) infusion<br>* Other names: Blincyto®;Drug: Low-intensity chemotherapy regimen<br>* Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration.<br>|
| Experimental: Phase 3: Blinatumomab alternating with low-intensity chemotherapy<br>Participants will receive blinatumomab alternating with low-intensity chemotherapy. | Drug: Blinatumomab<br>* Continuous intravenous (cIV) infusion<br>* Other names: Blincyto®;Drug: Low-intensity chemotherapy regimen<br>* Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration.<br>|
| Active Comparator: Phase 3: Standard of care (SOC) chemotherapy<br>Participants will receive 1 of 2 SOC chemotherapy regimens (GMALL or HyperCVAD) per investigator's choice. | Drug: SOC chemotherapy regimen<br>* Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety run-in: Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) | Number and percentage of participants who experience one or more TEAE, serious TEAE, treatment-related adverse events, and adverse events of interest. | Up to approximately 5 years | 
| Phase 3: Event-free Survival (EFS) | 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. | Up to approximately 5 years | 
| Phase 3: Overall Survival (OS) | OS is defined as time from randomization (enrollment) until death due to any cause. | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | MRD response is defined as the percentage of participants who achieve a response of < 10^-4 measured by polymerase chain reaction (PCR). | Baseline to Week 14 | 
| Safety run-in: Relapse-free Survival (RFS) | RFS: In participants who achieve CR, the time from first achievement of this response until date of the first relapse including hematologic relapse, extramedullary relapse, or death due to any cause, whichever occurs first. | Up to approximately 5 years | 
| Safety run-in: Minimal Residual Disease (MRD) Relapse Free Survival (RFS) | MRD RFS: In participants who achieve CR with MRD response, the time from first achievement of this response until date of of the first relapse including molecular relapse, hematological relapse, and/or extramedullary relapse, or death due to any cause, whichever occurs first. (Molecular relapse will be defined 2 ways: MRD>= 10^-3 and MRD>=10^-4. Participants without an event will be censored at their last evaluable disease assessment date. | Up to approximately 5 years | 
| Safety run-in: Steady State Concentration (Css) of Blinatumomab |  | Up to approximately 34 weeks | 
| Safety run-in: Clearance (CL) of Blinatumomab |  | Up to approximately 34 weeks | 
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Fatigue Score | Fatigue score will be measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue - Short Form 7a. | Baseline to Week 14 | 
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Pain Score | Pain score will be measured by Brief Pain Inventory - Short Form (BPI-SF); Item 3: pain at its worst in the last 24 hours. | Baseline to Week 14 | 
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Global Health Status | Global health status will be measured by the Quality of Life Questionnaire (QLQ)-C30 global health status quality of life scale. | Baseline to Week 14 | 
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Physical Function | Physical function will be measured by the QLQ-C30 functional scale. | Baseline to Week 14 | 
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Nausea and Vomiting | Nausea and vomiting will be measured by the QLQ-C30 symptom scale. | Baseline to Week 14 | 
| Phase 3: Complete Remission (CR) Rate by the End of Initial Disease Assessment Period |  | Baseline to Week 14 | 
| Phase 3: Minimal Residual Disease (MRD) Response by the End of Initial Disease Assessment Period | MRD response is defined as the percentage of participants who achieve a response of < 10^4 measured by polymerase chain reaction (PCR). | Baseline to Week 14 | 
| Phase 3: Relapse-free Survival (RFS) | RFS: In participants who achieve CR, the time from first achievement of this response until the date of the first relapse including hematologic relapse, extra medullary relapse, or death due to any cause, whichever occurs first. Participants without an event will be censored at their last evaluable disease assessment date. | Up to approximately 5 years | 
| Phase 3: Minimal Residual Disease (MRD) Relapse Free Survival (RFS) | In participants who achieve CR with MRD response, the time from first achievement of this response until date of the first relapse including molecular relapse, hematologic relapse, and/or extramedullary relapse, or death due to any cause, whichever occurs first. Molecular relapse will be defined 2 ways: MRD>= 10^-3 and MRD>= 10^-4. Participants without an event will be censored at their last evaluable disease assessment date | 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) | Number and percentage of participants who experience one or more TEAE, serious TEAE, treatment-related adverse events, and adverse events of interest. | 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 | 
| Phase 3: Time to Deterioration using the Fatigue Score | Fatigue score will be measured by PROMIS Fatigue-Short Form 7a. | Up to approximately 5 years | 
| Phase 3: Time to Improvements using the Fatigue Score | Fatigue score will be measured by PROMIS Fatigue-Short Form 7a. | Up to approximately 5 years | 
| Phase 3: Time to Deterioration using the Pain Score | Pain score will be measured by BPI-SF; Item 3: pain at its worst in the last 24 hours. | Up to approximately 5 years | 
| Phase 3: Time to Improvements using the Pain Score | Pain score will be measured by BPI-SF; Item 3: pain at its worst in the last 24 hours. | 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) | EORTC QLQ-C30 will include global health status, physical functioning, emotional functioning, cognitive functioning, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, diarrhea, and financial difficulties will be measured by 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) | Global health status, physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning, fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, diarrhea, and financial difficulties will be measured by EORTC QCQ-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) | Global health status, physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning, fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, diarrhea, and financial difficulties will be measured by EORTC QCQ-C30. | Up to approximately 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly Diagnosed Philadelphia (Ph)-negative B-cell Precursor Acute Lymphoblastic Leukemia (ALL), Blinatumomab, Low-intensity Chemotherapy, GMALL HyperCVAD