Subjects with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (B-NHL) MedDRA version: 20.0 Level: PT Classification code 10020067 Term: High grade B-cell lymphoma Burkitt-like lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10036710 Term: Primary mediastinal large B-cell lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and poly
Conditions
Sponsors
Amgen Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: studyspecific activities/procedures OR subject's 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. 2. Age = 18 at the time of informed consent 3. Biopsy proven aggressive B-NHL, including DLBCL NOS, follicular lymphoma Grade 3B, Primary Mediastinal B-Cell Lymphoma, T-cell rich B-cell lymphoma, or DLBCL that represents transformation of indolent NHL, (including follicular, marginal zone, and lymphoplasmacytoid lymphoma) excluding chronic lymphocytic leukemia or Hodgkin Lymphoma. Subjects with prior indolent lymphoma must have received therapy after a diagnosis of transformation that is appropriate for aggressive histology as described in 4. The following histologies are not eligible: • Lymphoblastic lymphoma • Burkitt lymphoma • Mantle cell lymphoma Any histologies not specifically mentioned must be discussed with the medical monitor. For subjects enrolled in the phase 3 portion of study, pathologic samples will be submitted for central confirmation of disease histology. 4. Refractory (no prior CMR) or relapsed (prior CMR) following front line treatment of standard multiagent chemotherapy containing an anthracycline AND an approved anti-CD20 agent. Examples of appropriate therapy include but are not limited to R-CHOP (14 or 21), RCHOEP, and DA-R-EOCH. For subjects with refractory disease and who have received radiotherapy, PET positivity should be demonstrated no less than 6 weeks after the last dose of radiotherapy 5. Biopsy-proven confirmation of relapsed disease. For subjects with de novo aggressive B-cell lymphoma and primary refractory disease (ie never achieving CMR), biopsy of persistent disease is preferred but persistent PET positivity (ie Deauville = 4) is acceptable at a minimum. For all subjects that have received radiotherapy for DLBCL, PET should be performed no less than 42 days (6 weeks) after the last dose of radiotherapy. For subjects with transformed disease that has been characterized as refractory, rebiopsy (core or excisional biopsy) with demonstration of persistent aggressive B-NHL is required 6. Received a minimum of 2 cycles of standard of care platinum-based chemotherapy in the S1 setting and had a response of PMD, NMR, PMR as centrally assessed by PET-CT scan or received at least 1 cycle of S1 chemotherapy and had evidence of PD as centrally assessed. A presalvage scan is required to be submitted to the central reader if a subject had only 1 cycle of pre-salvage chemotherapy. 7. Radiographically measurable disease with a clearly demarcated nodal lesion at least 1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm in its largest dimension 8. Eastern Cooperative Oncology Group (ECOG) performance status = 2 9. Intention to proceed to HDT and autologous HSCT per institutional standards 10. Laboratory parameters (completed within 14 days prior to enrollment and after the last cycle of S1 chemotherapy): Hematology: • Absolute neutrophil count (ANC) = 1.0 x 1000000000/L • Platelets = 75 x 1000000000/L Chemistry: • Creatinine clearance = 50 mL/min (calculated using Cockcroft Gault equation) •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3X upper limit of normal (ULN) •Total bi
Exclusion criteria
Exclusion criteria: 1. CMR following S1 chemotherapy 2. Treatment within 30 days prior to randomization with another investigational device or drug study (ies). Other investigational procedures while participating in this study are excluded 3. Prior anti-CD19-directed therapies 4. Prior HDT with autologous HSCT 5. Prior allogeneic HSCT 6. Presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis 7. Evidence of CNS involvement by NHL 8. Known infection with human immunodeficiency virus or chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (anti-hepatitis C virus positive) 9. History of malignancy other than B-NHL within the past 3 years with the exception of: • 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 • 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 10. Subject has known sensitivity to immunoglobulins or any of the products or components to be administered during dosing. 11. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge. 12. 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. 13. Female subjects who are pregnant or breastfeeding or planning to become pregnant or breastfeed while receiving blinatumomab and for an additional 48 hours after the last dose of blinatumomab. (Females of child bearing potential should only be included after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test.) 14. Female subjects of childbearing potential unwilling to use an effective method of contraception while receiving blinatumomab and for an additional 48 hours after the last dose of blinatumomab. Note: The pregnancy, breastfeeding and contraceptive requirements are specific for blinatumomab. The investigator is responsible for providing the subject (male and female) with pregnancy and breastfeeding (female only) avoidance requirements for other medications given during the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 2: • estimate the complete metabolic response (CMR) rate following blinatumomab monotherapy administered in the second salvage (S2) treatment of transplant-eligible subjects with relapsed or refractory (R/R) aggressive B-NHL who have not achieved CMR1 following 2 cycles of standard platinum-based first salvage (S1) chemotherapy Phase 3: • compare the CMR rates following blinatumomab to those following investigator’s choice (IC) S2 chemotherapy;Secondary Objective: Phase 2: • To evaluate the efficacy parameters following blinatumomab treatment, of: - Response duration - The rate of successful hematopoietic stem cell mobilization • To evaluate the safety of blinatumomab in the S2 setting Phase 3: • To compare the efficacy of blinatumomab to investigator’s choice chemotherapy (ICC) in: - Overall survival - Response duration - Rate of successful HSCs mobilisation - Ability to proceed to hematopoietic stem cell transplant (both autologous and allogeneic) rates among responding subjects (CMR) or those in sustained partial metabolic response (PMR) - Objective response rate (ORR; CMR + PMR) • To compare the safety profile of blinatumomab to that of ICC • To compare the quality of life reported by subjects treated with blinatumomab or ICC Phases 2 and 3 • To characterize the pharmacokinetic parameters of blinatumomab administered to subjects with R/R aggressive B-NHL • Progression-free survival;Primary end point(s): Phases 2 and 3: • CMR as determined by central radiographic assessment of positron emission tomography-computed tomography (PET-CT) scans using the Lugano Classification;Timepoint(s) of evaluation of this end point: From first subject randomised: 8, 13, 18, 23 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary Endpoint: Phase 3: • OS Other Secondary Endpoints: Phase 2: • ORR • PFS • Duration of response (DOR) • Successful mobilization rate • HSCT (both autologous and allogeneic) rates among subjects with post-blinatumomab complete response (CMR) + partial response (PMR) • 100-day non-relapse mortality (NRM) after autologous HSCT • Blinatumomab concentration steady state, clearance, and half life • Incidence and severity of adverse events Phase 3: • Objective response rate (ORR; CMR+PMR) • PFS • DOR • Successful mobilization rate following protocol assigned therapy • HSCT (both autologous and allogeneic) rates among responding subjects (CMR or PMR) • 100-day NRM after autologous HSCT rate • Patient-reported clinical outcome assessments quality of life (QOLCOA) using the EQ-5D and FACT-Lymphoma tools • Blinatumomab steady state concentration and clearance • Safety: - Overall incidence and severity of treatment-emergent adverse events Exploratory Endpoints (Phase 2 and 3): • Pharmacodynamics, including descriptive analysis of quantitative and qualitative features of lymphocyte populations and serum or plasma concentrations of cytokines • Response rates and duration according to COO designation and c-myc and bcl-2 rearrangement and overexpression, R-IPI, Secondary IPI, NCCN IPI, as determined from pretreatment specimens • Quantitative analysis of CF CT-DNA as determined by analysis of tumor-associated mutations in CF CT-DNA from plasma collected at various timepoints before, during, and after treatment;Timepoint(s) of evaluation of this end point: From first subject randomised: 18, 26 months | — |
Countries
Australia, Belgium, European Union, Spain, United Kingdom, United States
Contacts
Public ContactMedical Information
Amgen Limited
Outcome results
None listed