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

JRCT ID: jRCT2051210174

Registered date:10/02/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Newly Diagnosed Philadelphia (Ph)-Negative B-cell Precursor Acute Lymphoblastic Leukemia (ALL)
• Date of first enrollment: 02/11/2021
• Target sample size: 287
• Countries of recruitment: United States,Japan,Australia,Japan,Germany,Japan,Spain,Japan,Turkey,Japan,Taiwan,Japan,Austria,Japan,Belgium,Japan,Bulgaria,Japan,Canada,Japan,Denmark,Japan,Finland,Japan,France,Japan,Greece,Japan,Hungary,Japan,Italy,Japan,Mexico,Japan,Netherlands,Japan,Portugal,Japan,Romania,Japan,Sweden,Japan,Switzerland,Japan
• Study type: Interventional

Intervention(s)

- Experimental: 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.
Interventions:
Drug: Blinatumomab
Drug: Low-intensity chemotherapy regimen

- Experimental: Phase 3: Blinatumomab alternating with low-intensity chemotherapy
Participants will receive blinatumomab alternating with low-intensity chemotherapy.
Interventions:
Drug: Blinatumomab
Drug: Low-intensity chemotherapy regimen

- Active Comparator: Phase 3: Standard of care (SOC) chemotherapy
Participants will receive 1 of 2 SOC chemotherapy regimens (GMALL or HyperCVAD) per investigator's choice.
Intervention
Drug: SOC chemotherapy regimen

Outcome(s)

Primary Outcome

1. Safety run-in: Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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.
2. Phase 3: Event-free Survival (EFS) [ Time Frame: 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.
3. Phase 3: Overall Survival (OS) [ Time Frame: Up to approximately 5 years ]
OS is defined as time from randomization (enrollment) until death due to any cause.

Secondary Outcome

1. Safety run-in: Complete Remission (CR) Rate by the End of Initial Disease Assessment Period [ Time Frame: Baseline to Week 14 ]
2. Safety run-in: Minimal Residual Disease (MRD) Response by the End of Initial Disease Assessment Period [ Time Frame: Baseline to Week 14 ]
MRD response is defined as the percentage of participants who achieve a response of < 10^-4 measured by polymerase chain reaction (PCR).
3. Safety run-in: Relapse-free Survival (RFS) [ Time Frame: Up to approximately 5 years ]
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.
4. Safety run-in: Minimal Residual Disease (MRD) Relapse Free Survival (RFS) [ Time Frame: Up to approximately 5 years ]
MRD 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, 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.
5. Safety run-in: Steady State Concentration (Css) of Blinatumomab [ Time Frame: Up to approximately 34 weeks ]
6. Safety run-in: Clearance (CL) of Blinatumomab [ Time Frame: Up to approximately 34 weeks ]
7. Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Fatigue Score [ Time Frame: Baseline to Week 14 ]
Fatigue score will be measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue - Short Form 7a.
8. Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Pain Score [ Time Frame: Baseline to Week 14 ]
Pain score will be measured by Brief Pain Inventory - Short Form (BPI-SF); Item 3: pain at its worst in the last 24 hours.
9. Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Global Health Status [ Time Frame: Baseline to Week 14 ]
Global health status will be measured by the Quality of Life Questionnaire (QLQ)-C30 global health status quality of life scale.
10. Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Physical Function [ Time Frame: Baseline to Week 14 ]
Physical function will be measured by the QLQ-C30 functional scale.
11. Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Nausea and Vomiting [ Time Frame: Baseline to Week 14 ]
Nausea and vomiting will be measured by the QLQ-C30 symptom scale.
12. Phase 3: Complete Remission (CR) Rate by the End of Initial Disease Assessment Period [ Time Frame: Baseline to Week 14 ]
13. Phase 3: Minimal Residual Disease (MRD) Response by the End of Initial Disease Assessment Period [ Time Frame: Baseline to Week 14 ]
MRD response is defined as the percentage of participants who achieve a response of < 10^-4 measured by polymerase chain reaction (PCR).
14. Phase 3: Relapse-free Survival (RFS) [ Time Frame: Up to approximately 5 years ]
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.
15. Phase 3: Minimal Residual Disease (MRD) Relapse Free Survival (RFS) [ Time Frame: Up to approximately 5 years ]
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
16. Phase 3: Minimal Residual Disease (MRD) Over Time [ Time Frame: Up to approximately 5 years ]
17. Phase 3: Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) [ Time Frame: 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.
18. Phase 3: Number of Participants who Experience Cluster of Differentiation (CD) 19 Positive and Negative Relapse by Flow Cytometry for Bone Marrow [ Time Frame: Up to approximately 5 years ]
19. 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 [ Time Frame: Up to end of safety follow up (approximately 44 months) ]
20. Phase 3: Number of Participants who Experience Cluster of Differentiation (CD) 19 Positive and Negative Relapse for Extramedullary Sites other than Cerebrospinal Fluid [ Time Frame: Up to end of safety follow up (approximately 44 months) ]
21. Phase 3: Rate of Lineage Switch to Acute Myeloid Leukemia (AML) [ Time Frame: Up to end of safety follow up (approximately 44 months) ]
22. Phase 3: Localization of Relapse by Clinical Assessment [ Time Frame: Up to end of safety follow up (approximately 44 months) ]
23. Phase 3: Mortality Rate in Participants who Experience Complete Remission (CR) [ Time Frame: Up to approximately 5 years ]
24. Phase 3: Number of Participants who have Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT) in Participants who Experience Continuous First Complete Remission (CR) [ Time Frame: Up to approximately 5 years ]
25. Phase 3: Mortality Rate in Participants who Experience Complete Remission (CR) after Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)[ Time Frame: Up to approximately 5 years ]
26. Phase 3: Relapse Rate Following Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) [ Time Frame: Up to approximately 5 years ]
27. Phase 3: Time to Deterioration using the Fatigue Score [ Time Frame: Up to approximately 5 years ]
Fatigue score will be measured by PROMIS Fatigue-Short Form 7a.
28. Phase 3: Time to Improvements using the Fatigue Score [ Time Frame: Up to approximately 5 years ]
Fatigue score will be measured by PROMIS Fatigue-Short Form 7a.
29. Phase 3: Time to Deterioration using the Pain Score [ Time Frame: Up to approximately 5 years ]
Pain score will be measured by BPI-SF; Item 3: pain at its worst in the last 24 hours.
30. Phase 3: Time to Improvements using the Pain Score [ Time Frame: Up to approximately 5 years ]
Pain score will be measured by BPI-SF; Item 3: pain at its worst in the last 24 hours.
31. 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) [ Time Frame: Baseline to end of study (up to approximately 5 years) ]
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.
32. 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) [ Time Frame: Up to approximately 5 years ]
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.

Key inclusion & exclusion criteria

• Age minimum: >= 40age old
• Age maximum: <= 100age old
• Gender: Both

Include criteria

1. 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) / alanineaminotransferase (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.
2. Participants with newly diagnosed Philadelphia (Ph)-negative B-cell precursor acute lymphoblastic leukemia (ALL)
3. Eastern Cooperative Oncology Group (ECOG) performance status <= 2, higher ECOG score allowed if due to underlying leukemia
4. 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 < 55years 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%

Exclude criteria

1. Active central nervous system (CNS) leukemia not resolved with IT chemotherapy during screening.
2. Clinically relevant CNS pathology requiring treatment (eg, unstable epilepsy).
3. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
4. Known infection with human immunodeficiency virus (HIV)
5. 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).
6. 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.
7. Participant with symptoms and/or clinical signs and/or radiographic and/or sonographic signs that indicate an acute or uncontrolled chronic infection.
8. 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.

Related Information

• Primary Sponsor: Kaneda Hirokazu
• Secondary ID(s): NCT04994717