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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04994717
Recruitment Status : Recruiting
First Posted : August 6, 2021
Last Update Posted : July 26, 2022
Sponsor:
Information provided by (Responsible Party):
Amgen

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.

Condition or disease Intervention/treatment Phase
Newly Diagnosed Philadelphia (Ph)-Negative B-cell Precursor Acute Lymphoblastic Leukemia (ALL) Drug: Blinatumomab Drug: Low-intensity chemotherapy regimen Drug: SOC chemotherapy regimen Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 287 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : November 2, 2021
Estimated Primary Completion Date : October 6, 2025
Estimated Study Completion Date : May 5, 2030


Arm Intervention/treatment
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.

Drug: Blinatumomab
Continuous intravenous (cIV) infusion
Other Name: Blincyto®

Drug: Low-intensity chemotherapy regimen
Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration.

Experimental: Phase 3: Blinatumomab alternating with low-intensity chemotherapy
Participants will receive blinatumomab alternating with low-intensity chemotherapy.
Drug: Blinatumomab
Continuous intravenous (cIV) infusion
Other Name: Blincyto®

Drug: Low-intensity chemotherapy regimen
Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration.

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.
Drug: SOC chemotherapy regimen
Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration.




Primary Outcome Measures :
  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, 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 Measures :
  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 of the first relapse including molecular relapse, hematological relapse, and 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 extramedullary relapse, or death due to any cause, whichever occurs first. Molecular relapse will be defined 2 ways: MRD>= 10^-13 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.

  33. 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) [ 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04994717


Contacts
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Contact: Amgen Call Center 866-572-6436 medinfo@amgen.com

Locations
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Sponsors and Collaborators
Amgen
Investigators
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Study Director: MD Amgen
Additional Information:
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT04994717    
Other Study ID Numbers: 20190360
2020-004498-29 ( EudraCT Number )
First Posted: August 6, 2021    Key Record Dates
Last Update Posted: July 26, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
URL: http://www.amgen.com/datasharing

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amgen:
Newly Diagnosed Philadelphia (Ph)-negative B-cell Precursor Acute Lymphoblastic Leukemia (ALL)
Blinatumomab
Low-intensity Chemotherapy
GMALL HyperCVAD
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Blinatumomab
Antineoplastic Agents