Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

NCT ID: NCT03476239

Last Updated: 2023-02-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 121 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-18
• Study Completion Date: 2021-04-08

Brief Summary

This study is being done to evaluate the rate of hematological response (complete remission/complete remission with partial hematological recovery [CR/CRh*]) induced by blinatumomab in Chinese adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).

Detailed Description

This is an open label, single-arm, multicenter phase 3 study to evaluate efficacy and safety of the BiTE (bispecific T cell engager) antibody blinatumomab in Chinese adults with relapsed/refractory B-precursor ALL. The study will consist of a screening period, a treatment period, and a follow-up period.

Treatment will consist of up to 5 cycles of blinatumomab. Participants who achieve a bone marrow (BM) response (≤ 5% BM blasts) or CR/CRh*/CRi within 2 induction cycles of treatment may continue to receive up to 3 additional consolidation cycles of blinatumomab. Thirty days after end of the last dose of protocol-specified therapy, participants will have a safety follow-up visit.

If subjects are suitable for allogeneic stem cell transplantation (alloHSCT) after treatment with blinatumomab, they may undergo alloHSCT instead of receiving further consolidation cycles with blinatumomab.

Participants will be followed via clinic visit or telephone contact every 3 months after their safety follow-up visit until death has been observed or a maximum of 2 years after start of treatment, whichever occurs first.

A planned interim analysis to assess efficacy and safety of blinatumomab was to be based on the interim analysis set (N = 90). The efficacious benefit assessment based on an O'Brien-Fleming alpha spending function (O'Brien and Fleming, 1979) with the critical boundary 42.2% at the interim analysis and 39.2% at the primary analysis in CR/CRh* rate. If the interim analysis showed statistically efficacious and overall benefit-risk analysis to be promising per the data review team review, then the interim analysis could become the primary analysis of this study. In addition, the study would continue its enrollment until 120 participants had been enrolled and continued their participation in the study to complete protocol-specified procedures.

The data cutoff date of 12 April 2019 allowed for the 90th participant enrolled before 21 February 2019 to have had the opportunity to complete 2 cycles of treatment and the safety follow-up visit (if the participant had discontinued treatment after 2 cycles).

Conditions

Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Blinatumomab

Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders.

In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for Days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4). This is followed by two weeks without blinatumomab treatment.

In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.

Group Type: EXPERIMENTAL

Blinatumomab

Intervention Type: DRUG

Blinatumomab will be supplied as single-use glass injection vials as a sterile, preservative-free, white to off-white, lyophilized powder for reconstitution and administration by continuous intravenous infusion (CIVI).

A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of blinatumomab CIVI followed by a 2 week treatment-free interval. The treatment-free interval may be prolonged by up to 7 days, if deemed necessary by the investigator.

Dexamthasone

Intervention Type: DRUG

Premedication with dexamethasone was intended to prevent cytokine release syndrome (CRS) events associated with blinatumomab treatment. Treatment could start pre-study. Dexamethasone 20 mg IV was administered within 3 hours before start of blinatumomab in each treatment cycle, and within 3 hours before dose step increase.

Interventions

Blinatumomab

Blinatumomab will be supplied as single-use glass injection vials as a sterile, preservative-free, white to off-white, lyophilized powder for reconstitution and administration by continuous intravenous infusion (CIVI).

A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of blinatumomab CIVI followed by a 2 week treatment-free interval. The treatment-free interval may be prolonged by up to 7 days, if deemed necessary by the investigator.

Intervention Type: DRUG

Dexamthasone

Premedication with dexamethasone was intended to prevent cytokine release syndrome (CRS) events associated with blinatumomab treatment. Treatment could start pre-study. Dexamethasone 20 mg IV was administered within 3 hours before start of blinatumomab in each treatment cycle, and within 3 hours before dose step increase.

Intervention Type: DRUG

Other Intervention Names

BLINCYTO®; AMG 103; MT103

Eligibility Criteria

Inclusion Criteria

• Subjects have provided informed consent/assent prior to initiation of any study-specific activities/procedures or subjects legally acceptable representative has provided informed consent prior to any study-specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent.
• Subjects with Ph-negative B-precursor ALL, with any of the following:
• Primary refractory after induction therapy or who had relapsed within 12 months of first remission or
• Relapsed within 12 months of receiving allogeneic hematopoietic stem cell transplantation (alloHSCT) or
• Relapsed or refractory after first salvage therapy or beyond
• > 5% blasts in bone marrow (by morphology)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
• Age ≥ 18 years at the time of informed consent

Exclusion Criteria

Disease Related

• Subjects with Ph-positive ALL
• Subjects with Burkitt´s Leukemia according to World Health Organization (WHO) classification.
• History or presence of clinically relevant CNS pathology as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, and psychosis
• Active ALL in the central nervous system (CNS) (confirmed by cerebrospinal fluid [CSF] analysis) or testes
• Isolated extramedullary disease
• Current active autoimmune disease or history of autoimmune disease with potential CNS involvement

Other Medical Conditions

• History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:
• Malignancy treated with curative intent and with no known active disease present for 5 years before enrollment and felt to be at low risk for recurrence by the treating physician.
• 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.
• Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive)

Medications or Other Treatments

• Autologous HSCT within 6 weeks prior to start of blinatumomab treatment
• AlloHSCT within 3 months prior to start of blinatumomab treatment
• Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
• Any systemic therapy against active GvHD within 2 weeks prior to start of blinatumomab treatment
• Cancer chemotherapy within 2 weeks prior to start of blinatumomab treatment (intrathecal chemotherapy and dexamethasone are allowed until start of blinatumomab treatment). In addition, any subject whose organ toxicity (excluding hematologic) from prior ALL treatment has not resolved to common terminology criteria for adverse events (CTCAE) ≤ grade 1.
• Radiotherapy within 2 weeks prior to start of blinatumomab treatment
• Immunotherapy (eg, rituximab) within 4 weeks prior to start of blinatumomab treatment
• Currently receiving treatment in another investigational device or drug study, or less than 4 weeks prior to start of blinatumomab treatment.
• Previous treatment with anti-CD19 therapy

General

• Known hypersensitivity to immunoglobulins or to any other component of the IMP formulation
• Pregnant women and women planning to become pregnant should not participate in this study. Subjects who are breast feeding prior to start of blinatumomab treatment may be enrolled if they stop breast feeding with breast milk produced during blinatumomab treatment and for an additional 48 hours after the last dose of blinatumomab.
• Male participants are not required to use birth control during treatment with blinatumomab. However, you should let your female partner know you are in this study.
• Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.
• History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the Investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
• Previous treatment with blinatumomab
• Abnormal screening laboratory values as defined below:
• Aspartate aminotransferase (AST) and/or alanine aminotransferase ALT and/or alkaline phosphatase (ALP) ≥ 5 * upper limit of normal (ULN)
• Total bilirubin (TBL) ≥ 1.5 * ULN (unless related to Gilbert´s or Meulengracht disease)
• Creatinine ≥ 1.5 ULN or creatinine clearance < 60 ml/min (calculated)
• Woman of childbearing potential and is not willing to use 2 effective methods of contraception during treatment and for an additional 48 hours after the last dose of blinatumomab. Birth control is not required for postmenopausal women, or women with uterus/or both ovaries/ or both fallopian tubes removed.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

Peking University Third Hospital

Beijing, Beijing Municipality, China

Peking Union Medical College Hospital

Beijing, Beijing Municipality, China

Chinese People Liberation Army General Hospital

Beijing, Beijing Municipality, China

Fujian Medical University Union Hospital

Fuzhou, Fujian, China

Guangdong Provincial Peoples Hospital

Guangzhou, Guangdong, China

The First Affiliated Hospital of Sun Yat-sen University

Guangzhou, Guangdong, China

Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Guangzhou, Guangdong, China

Nanfang Hospital, Southern Medical University

Guangzhou, Guangdong, China

Henan Cancer Hospital

Zhengzhou, Henan, China

Tongji Hospital Tongji Medical College Huazhong University of Science and Technology

Wuhan, Hubei, China

Xiangya Hospital Central South University

Changsha, Hunan, China

Jiangsu Province Hospital

Nanjing, Jiangsu, China

The First Affiliated Hospital of Soochow University

Suzhou, Jiangsu, China

The First Hospital of Jilin University

Changchun, Jilin, China

The First Hospital of China Medical University

Shenyang, Liaoning, China

The Second Affiliated Hospital of Xi an Jiaotong University

Xi'an, Shaanxi, China

West China Hospital, Sichuang University

Chengdu, Sichuan, China

Institute of Hematology and Blood Diseases Hospital Peking Union Medical College

Tianjin, Tianjin Municipality, China

The First Affiliated Hospital, College of Medicine, Zhejiang University

Hangzhou, Zhejiang, China

Second Affiliated Hospital Zhejiang University College of Medicine

Hangzhou, Zhejiang, China

Peking University International Hosipital

Beijing, , China

Anhui Provincial Hospital

Hefei, , China

Huashan Hospital Affiliated to Fudan University

Shanghai, , China

Countries

China

References

Zhou H, Yin Q, Jin J, Liu T, Cai Z, Jiang B, Li D, Sun Z, Li Y, He Y, Ma L, Gao S, Hu J, He A, Du X, Liu D, Zhang X, Ke X, Zhuang J, Han Y, Wang X, Chen Y, Gordon P, Yu D, Zugmaier G, Wang J. Efficacy and safety of blinatumomab in Chinese adults with Ph-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia: A multicenter open-label single-arm China registrational study. Hematology. 2022 Dec;27(1):917-927. doi: 10.1080/16078454.2022.2111992.

Reference Type: DERIVED

PMID: 36000952 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.amgentrials.com

AmgenTrials clinical trials website

Other Identifiers

20130316

Identifier Type: -

Identifier Source: org_study_id