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

An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

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).

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).

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.