Information below provided by the Pharmaceutical Company.

Blinatumomab (AMG 103, BLINCYTO^®)

Agent Description

Blinatumomab is a novel single-chain antibody derivative of the BiTE class. It is designed to target CD19 expressed on malignant B cells. It was developed by genetic engineering from 2 distinct parental murine monoclonal antibodies (mAbs): HD37, which recognizes the pan-B cell antigen CD19; and L2K-07, which specifically binds the T-cell receptor (TCR)-associated complex, CD3. The single-chain variable fragments (scFv) of these antibodies are linked to form 1 single polypeptide chain. Blinatumomab is a recombinant non-glycosylated protein, consisting of 504 amino acids with a molecular weight of approximately 54 kDa. The CD19-binding region of blinatumomab is positioned at the amino terminus, while the CD3-binding region is at the carboxy terminus. The 2 scFv are joined by a flexible linker consisting of glycine/serine amino acid residues.

Detailed information on the physical and chemical description of blinatumomab, available dosage forms, and drug supply and storage information is provided in the current country-specific prescribing information for blinatumomab. The US Prescribing Information (USPI) and EU Summary of Product Characteristics (SPC) provide detailed product information for investigators.

Mechanism of Action

The therapeutic action of the anti-CD19 BiTE blinatumomab relies on the specific redirection of cytotoxic T lymphocytes to lyse CD19-positive tumor cells. As part of this action, blinatumomab causes the formation of a cytolytic synapse between the T cell and the tumor cell, releasing the pore-forming protein perforin and the apoptosis-inducing granzyme B. In the presence of BiTE molecules, T cells can eliminate tumor cells even at very low effector-to-target cell (E:T) ratios, indicating that redirected T cells can repeatedly lyse target cells.

The binding affinity of blinatumomab to its 2 target antigens, CD19 and CD3, was measured by flow cytometry using the human B-cell precursor leukemia cell line NALM-6 for CD19 and purified human T cells for CD3. Blinatumomab binds to CD19 with a dissociation constant (Kd) of 1.49 x 10-9 M and to CD3 with a Kd of 2.6 x 10-7 M. Blinatumomab binds to both normal human peripheral B cells and cell lines derived from human B-cell lymphomas. Blinatumomab does not detectably bind to cells not expressing CD3 and CD19.

Classification

Bispecific T-cell engager (BiTE) monoclonal antibody

Molecular Target

Bispecific T-cell engager monoclonal antibody construct that directs CD-3 positive effector memory T cells to CD19-positive target cells

Monograph

Blinatumomab is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.

Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells. Blinatumomab mediates the formation of a synapse between the T-cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells.

Clinical Studies

Relapsed/Refractory Acute Lymphoblastic Leukemia

TOWER Study compared the efficacy of blinatumomab to standard of care (SOC) chemotherapy in a randomized, open-label, multicenter study (TOWER Study). Eligible patients were ≥ 18 years of age with relapsed or refractory B-cell precursor ALL. Blinatumomab was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for Cycles 2-5 in 42-day cycles and for Cycles 6-9 in 84-day cycles. SOC chemotherapy included fludarabine, cytarabine arabinoside, and granulocyte colony-stimulating factor (FLAG); high-dose cytarabine arabinoside (HiDAC); high-dose methotrexate- (HDMTX) based combination; or clofarabine/clofarabine-based regimens. There were 405 patients randomized 2:1 to receive blinatumomab or investigator-selected SOC chemotherapy. Of the 271 patients randomized to the blinatumomab arm, 267 patients received blinatumomab treatment. Of the 134 patients on the SOC arm, 25 dropped out prior to start of study treatment, and 109 patients received a median of 1 treatment cycle (range: 1 to 4 cycles). The determination of efficacy was based on overall survival (OS). The study demonstrated statistically significant improvement in OS for patients treated with blinatumomab as compared to SOC chemotherapy. See USPI for additional detail.

Study MT103-211 was an open-label, multicenter, single-arm study. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL. Blinatumomab was administered as a continuous intravenous infusion. The recommended dose for this study was determined to be 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. The treated population included 185 patients who received at least 1 infusion of blinatumomab; the median number of treatment cycles was 2 (range: 1 to 5). Patients who responded to blinatumomab but later relapsed had the option to be retreated with blinatumomab. Among treated patients, the median age was 39 years (range: 18 to 79 years), 63 out of 185 (34.1%) had undergone HSCT prior to receiving blinatumomab, and 32 out of 185 (17.3%) had received more than 2 prior salvage therapies. Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with blinatumomab. The HSCT rate among those who achieved CR/CRh* was 39% (30 out of 77). See USPI for additional detail.

ALCANTARA Study evaluated the efficacy of blinatumomab for treatment of Philadelphia chromosome-positive B-cell precursor ALL in an open-label, multicenter, single-arm study. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-positive B-cell precursor ALL, relapsed or refractory to at least 1 second generation or later tyrosine kinase inhibitor (TKI), or intolerant to second generation TKI, and intolerant or refractory to imatinib mesylate. Blinatumomab was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. The treated population included 45 patients who received at least one infusion of blinatumomab; the median number of treatment cycles was 2 (range: 1 to 5). Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with blinatumomab. Five of the 16 responding (31%) patients underwent allogeneic HSCT in CR/CRh* induced with BLINCYTO. There were 10 patients with document T315I mutation; four achieved CR within 2 cycles of treatment with blinatumomab. See USPI for additional detail.

Study MT103-205 was an open-label, multicenter, single-arm study in pediatric patients with relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogeneic HSCT, or refractory to other treatments, and had > 25% blasts in bone marrow). Binatumomab was administered at 5 mcg/m2/day on Days 1-7 and 15 mcg/m2/day on Days 8-28 for Cycle 1, and 15 mcg/m2/day on Days 1-28 for subsequent cycles. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with blinatumomab. Among the 70 treated patients, the median age was 8 years (range: 7 months to 17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and 39 out of 70 (55.7%) had refractory disease. The median number of treatment cycles was 1 (range: 1 to 5). Twenty-three out of 70 (32.9%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out of 23 (73.9%) occurring within Cycle 1 of treatment. The HSCT rate among those who achieved CR/CRh* was 48% (11 out of 23). See USPI for additional detail.

Blinatumomab is being further evaluated in both adult and pediatric and adolescent subjects with Ph-negative relapsed/refractory B-cell precursor ALL, adults with Ph-positive relapsed/refractory B-cell precursor ALL, adults with minimal residual disease (MRD) ALL, and adults with non-Hodgkin lymphoma (NHL). More than 900 subjects (predominantly adults) in company-sponsored clinical studies have been exposed to blinatumomab as a continuous intravenous (cIV) infusion at doses ranging from 0.5 to 90 mcg/m2/day or 9 to 112 mcg/day.

Package insert: http://pi.amgen.com/united_states/blincyto/blincyto_pi_hcp_english.pdf

Studies of Interest

Areas of Interest:

• Ph(-) Relapsed/Refractory ALL
  • Study proposals for mode of resistance may be considered
  • Study proposals for combination therapy may be considered
• Ph(+) Relapsed/Refractory ALL
  • Study proposals for combination therapy may be considered
• Pediatric Relapsed/Refractory ALL
  • Not a priority except — study proposals in the post allo-HSCT setting or combination studies may be considered
• Non-Hodgkin Lymphoma
  • Study proposals for NHL other than DLBCL may be considered
• Minimal Residual Disease
  • Not a priority except — study proposals with MRD endpoints that are different from current Amgen program may be considered
• HSCT (Allo and Auto)
  • Study proposals in post-HSCTs setting may be considered
• Multiple Myeloma
• Other
  • Study proposals pre/post CAR T-cell therapy
  • Study proposals of mutual medical/scientific interest

Areas NOT of Interest:

• Ph(+) Relapsed/Refractory ALL
  • Not a priority to support new studies for mono-therapy
• Adult ALL frontline setting (Ph- or +)
  • Not a priority due to ongoing activities
• Pediatric Relapsed/Refractory ALL
  • Not a priority to support new studies in relapsed/refractory setting due to ongoing activities
• Minimal Residual Disease
  • Not a priority to support new studies

Information collaborator would like included in investigator proposals

Amgen is considering proposals for drug only support.