Newly Diagnosed Philadelphia (Ph)-Negative B-cell Precursor Acute Lymphoblastic Leukemia (ALL)
Conditions
Keywords
Newly Diagnosed Philadelphia (Ph)-negative B-cell Precursor Acute Lymphoblastic Leukemia (ALL), Blinatumomab, Low-intensity Chemotherapy, GMALL HyperCVAD
Brief summary
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.
Interventions
DRUGBlinatumomab
Continuous intravenous (cIV) infusion
DRUGLow-intensity chemotherapy regimen
Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration.
DRUGSOC chemotherapy regimen
Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 100 Years
Healthy volunteers
No
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. * 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 3: Event-free Survival (EFS) | 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. |
| Phase 3: Overall Survival (OS) | Up to approximately 5 years | OS is defined as time from randomization (enrollment) until death due to any cause. |
| Safety run-in: Number of Participants who Experience Treatment-emergent Adverse Events (TEAEs) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to approximately 5 years | Fatigue score will be measured by PROMIS Fatigue-Short Form 7a. |
| Phase 3: Time to Improvements using the Fatigue Score | Up to approximately 5 years | Fatigue score will be measured by PROMIS Fatigue-Short Form 7a. |
| Phase 3: Time to Deterioration using the Pain Score | Up to approximately 5 years | Pain score will be measured by BPI-SF; Item 3: pain at its worst in the last 24 hours. |
| Phase 3: Time to Improvements using the Pain Score | Up to approximately 5 years | Pain score will be measured by BPI-SF; Item 3: pain at its worst in the last 24 hours. |
| 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) | 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. |
| 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 | 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. |
| 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 | 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. |
| Steady State Concentration of Blinatumomab | Up to approximately Day 36 | — |
| Clearance of Blinatumomab | Up to approximately Day 36 | — |
| Phase 3: Relapse-free Survival (RFS) | 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. |
| 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 | MRD response is defined as the percentage of participants who achieve a response of \< 10\^-4 measured by polymerase chain reaction (PCR). |
| Safety run-in: Relapse-free Survival (RFS) | 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. |
| Safety run-in: Minimal Residual Disease (MRD) Relapse Free Survival (RFS) | 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 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. |
| 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 | Baseline to Week 14 | Fatigue score will be measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue - Short Form 7a. |
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Pain Score | 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. |
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Global Health Status | 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. |
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Physical Function | Baseline to Week 14 | Physical function will be measured by the QLQ-C30 functional scale. |
| Phase 3: Change from Baseline to End of Initial Disease Assessment Period in Nausea and Vomiting | Baseline to Week 14 | Nausea and vomiting will be measured by the QLQ-C30 symptom scale. |
| Phase 3: Complete Remission (CR) Rate by the End of Initial Disease Assessment Period | Baseline to Week 14 | — |
| Phase 3: Minimal Residual Disease (MRD) Relapse Free Survival (RFS) | 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 |
| Phase 3: Minimal Residual Disease (MRD) Response by the End of Initial Disease Assessment Period | 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). |
| 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 | Number and percentage of participants who experience one or more TEAE, serious TEAE, treatment-related adverse events, and adverse events of interest. |
Countries
Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Mexico, Netherlands, Portugal, Romania, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORMD
Amgen
Outcome results
None listed