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).
Completed
Phase 3
| Drug | Synonyms | Arms |
|---|---|---|
| Blinatumomab | BLINCYTO®, AMG 103, MT103 | Blinatumomab |
| Dexamthasone | Blinatumomab |
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).
| Name | Type | Description | Interventions |
|---|---|---|---|
| Blinatumomab | Experimental | 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. |
|
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Percentage of Participants With a Hematological Response of Complete Remission (CR) or Complete Remission With Partial Hematological Recovery (CRh*) Within 2 Treatment Cycles With Blinatumomab |
| Time Frame: | Within 2 cycles of treatment (12 weeks) |
| Safety Issue: | |
| Description: | A CR is defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/μL, and absolute neutrophil count [ANC] > 1,000/μL). CRh* is defined as ≤ 5% blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. CR/CRh* rate is defined as the percentage of participants who achieve CR/CRh* within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. The interim analysis was to become the primary analysis by meeting pre-specified efficacy and safety criteria based on an O'Brien-Fleming alpha spending function with the critical boundary 42.2%. |
| Measure: | Percentage of Participants With a Hematological Response of Complete Remission (CR) Within 2 Treatment Cycles With Blinatumomab |
| Time Frame: | Within 2 cycles of treatment (12 weeks) |
| Safety Issue: | |
| Description: | A CR is defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/μL, and absolute neutrophil count [ANC] > 1,000/μL). CR rate is defined as the percentage of participants who achieve CR within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. |
| Measure: | Percentage of Participants With a CR or CRh* or Complete Remission With Incomplete Hematological Recovery Without CRh* (CRi) (CR/CRh*/CRi) Within 2 Treatment Cycles With Blinatumomab |
| Time Frame: | Within 2 cycles of treatment (12 weeks) |
| Safety Issue: | |
| Description: | CRi is defined as ≤ 5% blasts in the bone marrow, no evidence of disease and incomplete recovery of peripheral blood counts: platelets > 100,000/μl or ANC > 1,000/μl (but not both). CR/CRh*/CRi rate is defined as the percentage of participants who achieve CR/CRh*/CRi within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. |
| Measure: | Pharmacokinetic (PK) Parameter: Concentration of Blinatumomab at Steady State (Css) |
| Time Frame: | Cycle 1: Days 2, 15, and 29; Cycle 2: Days 2, 15, and 29 (approximately study days 44, 57, and 71) |
| Safety Issue: | |
| Description: | Blinatumomab serum concentration was quantified using a validated enzyme- linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 50 pg/mL. Blinatumomab serum steady-state concentrations (Css) was summarized as the average of the observed concentrations collected after 24 hours from the start of continuous IV infusion for each dose level. Cycle 1 day 2 values represent Css for the initial dose of blinatumomab (9 µg/day). Values collected from other time points were used to calculate Css of 28 µg/day dose in their respective cycles. |
| Measure: | Pharmacokinetic (PK) Parameter: Clearance |
| Time Frame: | Cycle 1: Days 2, 15 and 29; Cycle 2: Days 2, 15 and 29 (approximately study days 44, 57 and 71) |
| Safety Issue: | |
| Description: | Systemic clearance (CL) calculated as the average CL value during cycle 1 and cycle 2, where CL = infusion rate (μg/hour) / Css |
| Measure: | Pharmacokinetic (PK) Parameter: Terminal Half-Life |
| Time Frame: | Cycle 1 Day 29: prior to end of infusion and after the end of infusion at 3 hours and 6 hours |
| Safety Issue: | |
| Description: | Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/lambda-z, where lambda-z was the first-order rate constant estimated via linear regression of the terminal log-linear decay phase from day 29 post-end of infusion collections. |
| Measure: | Pharmacokinetic (PK) Parameter: Volume of Distribution |
| Time Frame: | Cycle 1: Days 2, 15 and 29; Cycle 2: Days 2, 15, and 29 (approximately study days 44, 57 and 71) |
| Safety Issue: | |
| Description: | The volume of distribution (Vz) was calculated as Vz = CL/lambda-z, where lambda-z was the first-order rate constant estimated based on cycle 1 day 29 collections via linear regression of the terminal log-linear decay phase as determined from the noncompartmental analysis and where CL was the CL averaged over multiple cycles. Volume of distribution was estimated for participants who have sufficient evaluable PK data. |
| Measure: | Kaplan-Meier Estimates for Overall Survival (OS) |
| Time Frame: | From first infusion of blinatumomab to the data cutoff date of 12 April 2019; maximum time on follow-up for OS was 14.7 months |
| Safety Issue: | |
| Description: | Overall survival time was calculated from the time of first infusion of blinatumomab until death due to any cause. Participants still alive were censored at the date last known to be alive up until the data cut-off date. Months are calculated as days from the first treatment to death/censor date, divided by 30.5. |
| Measure: | Kaplan-Meier Estimate for Relapse-Free Survival (RFS) |
| Time Frame: | From the first infusion of blinatumomab to the data cutoff date of 12 April 2019; maximum time on follow-up for RFS was 12.4 months. |
| Safety Issue: | |
| Description: | Relapse-free survival time was calculated from the first onset of CR/CRh* within the first 2 cycles until the documented hematological relapse, extra-medullary disease, or death due to any cause, whichever occurred first. Participants who were still alive and relapse-free were censored at the date of last disease assessment up until the data cut-off date. Months were calculated as days from the first onset of CR/CRh* within the 2 cycles until the documented hematological relapse/extra-medullary disease/death/censor date, divided by 30.5. |
| Measure: | Percentage of Participants With Minimal Residual Disease (MRD) Response Within Two Cycles |
| Time Frame: | Within 2 cycles of treatment (12 weeks) |
| Safety Issue: | |
| Description: | The detection of MRD (the presence of a low number of leukemic cells that are not detectable by light microscopy) after induction therapy and/or consolidation therapy is an independent prognostic factor for poor outcome of ALL. Participants highly responsive to chemotherapy with a MRD-level < 1 × 10^-4 leukemic cells detectable by flow cytometry induced by induction treatment, have a favorable prognosis. MRD response is defined as < 1 ×10^-4 leukemic cells detectable as measured by flow cytometry. MRD complete response is defined as having no detectable leukemic cells by flow cytometry. |
| Measure: | Percentage of Participants Who Received an Allogenic Hematopoietic Stem Cell Transplant (alloHSCT) After Achieving CR/CRh* During Treatment |
| Time Frame: | Up to the data cutoff date of 12 April 2019; maximum time on follow-up was 14.7 months |
| Safety Issue: | |
| Description: | Percentage of participants who underwent allogenic HSCT while in remission among those who responded to treatment by achieving CR/CRh* during treatment. |
| Measure: | 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant |
| Time Frame: | 100 days after HSCT |
| Safety Issue: | |
| Description: | The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants still alive alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. |
| Measure: | Kaplan-Meier Estimates for Time to a ≥ Ten-Point Decrease From Baseline in Global Health Status Quality of Life |
| Time Frame: | From baseline (day 1, prior to treatment) to the data cutoff date of 12 April 2019; maximum observation time was 8.8 months. |
| Safety Issue: | |
| Description: | The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales, and 9 symptom scales/items. The GHS is reported in this outcome. For the GHS, scores range from 0 to 100 with a high score indicating better global health status/functioning. A ≥ 10-point decrease from baseline indicates a deterioration in quality of life. Months are calculated from start of blinatumomab date to deterioration/censor date, divided by 30.5. |
| Measure: | Number of Participants With Treatment-Emergent Adverse Events (TEAE) |
| Time Frame: | From day 1 to 30 days after last infusion of blinatumomab up to the data cutoff date of 12 April 2019; median (min,max) treatment duration was 29.3 (1, 142) days. |
| Safety Issue: | |
| Description: | Adverse events (AEs) were evaluated for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition. |
| Measure: | Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (TEAE) |
| Time Frame: | From day 1 to 30 days after last infusion of blinatumomab up to the data cutoff date of 12 April 2019; median (min,max) treatment duration was 29.3 (1, 142) days. |
| Safety Issue: | |
| Description: | Adverse events (AEs) were evaluated for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition. |
| Measure: | Participants With Anti-Blinatumomab Antibody Formation |
| Time Frame: | Cycle 2, day 29 (after the completion of Cycle 2) and the SFU visit (30 days after last dose of blinatumomab) |
| Safety Issue: | |
| Description: | Anti-blinatumomab binding antibodies were evaluated with a validated blinatumomab anti-drug antibody assay. |
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Amgen |
May 11, 2021
