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Pharmacodynamics: Circulating B Cell Count: Peripheral B cell counts decreased to undetectable levels (< 5 cells/microliter) in 86.5% of patients by Cycle 1 Day 7 after obinutuzumab pretreatment of 1,000 mg on Cycle 1 Day 1, and in 88.2% of patients by Cycle 1 Day 10 after the first glofitamab dose of 2.5 mg on Cycle 1 Day 8.
Cytokine Concentrations: Plasma concentrations of cytokines (IL-2, IL-6, IL-10, TNF-α, and IFN-γ) were measured and transient elevation of cytokines was observed at doses of 0.045 mg and above. After administration of the recommended dosage of COLUMVI, the highest elevation of cytokines was generally observed within 6 hours after the first glofitamab dose of 2.5 mg on Cycle 1 Day 8. The elevated cytokine levels generally returned to baseline within 48 hours after the first 30 mg dose on Cycle 2 Day 1.
Clinical Studies: Relapsed or Refractory DLBCL, NOS or LBCL Arising from Follicular Lymphoma: The efficacy of COLUMVI was evaluated in Study NP30179 (NCT03075696), an open-label, multicenter, multicohort, single-arm clinical trial that included patients with relapsed or refractory LBCL after two or more lines of systemic therapy. The trial required an ECOG performance status of 0 or 1, absolute neutrophil count ≥ 1,500/µL, platelet count ≥ 75,000/µL independent of transfusion, serum creatinine ≤ 1.5 x ULN or CLcr ≥ 50 mL/min, and hepatic transaminases ≤ 3 x ULN. The trial excluded patients with active or previous CNS lymphoma or CNS disease, acute infection, recent infection requiring intravenous antibiotics, or prior allogeneic HSCT.
Following pretreatment with obinutuzumab on Cycle 1 Day 1, patients received COLUMVI by intravenous infusion, starting with a 2.5 mg step-up dose on Cycle 1 Day 8, followed by a 10 mg step-up dose on Cycle 1 Day 15, then 30 mg on Cycle 2 Day 1 and on Day 1 of each subsequent cycle. The cycle length was 21 days. COLUMVI was administered for up to 12 cycles unless patients experienced progressive disease or unacceptable toxicity.
The efficacy population consists of 132 patients with de novo DLBCL, NOS (80%) or LBCL arising from follicular lymphoma (20%) who received at least one dose of COLUMVI. The median age was 67 years (range: 21 to 90 years), 64% were male, 77% were White, 4.5% were Asian, 0.8% were Black or African American, 5% were Hispanic or Latino. The median number of prior lines of systemic therapy was 3 (range: 2 to 7). Most patients (83%) had refractory disease to the last therapy, 55% had primary refractory disease, 30% had received CAR-T cell therapy, and 19% had received autologous HSCT.
Efficacy was based on objective response rate (ORR) and duration of response (DOR), as determined by an Independent Review Committee (IRC) using the 2014 Lugano criteria.
Efficacy results are summarized in Table 1. The median time to first response was 42 days (range: 31 to 178 days). Among responders, the estimated median follow-up for DOR was 11.6 months. (See Table 1.)
Click on icon to see table/diagram/imagePharmacokinetics: The pharmacokinetics of glofitamab was determined following pretreatment with a single dose of obinutuzumab of 1,000 mg and the pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise specified. Glofitamab exposure increased dose-proportionally over the dose range from 0.005 to 30 mg (0.000167 to 1 time the recommended treatment dosage). Glofitamab exposure parameters are summarized in Table 2 for the approved recommended dosage of COLUMVI. (See Table 2.)
Click on icon to see table/diagram/imageDistribution: The glofitamab total volume of distribution is 5.6 L (24%).
Elimination: At steady state, the glofitamab terminal half-life is 7.6 days (24%) and the clearance is 0.617 L/day (33%).
Metabolism: Glofitamab is expected to be metabolized into small peptides by catabolic pathways.
Specific Populations: No clinically significant changes in the pharmacokinetics of glofitamab were observed based on age (21 to 90 years), body weight (31 to 148 kg), sex, mild to moderate renal impairment (CLcr 30 to < 90 mL/min as estimated by Cockcroft-Gault formula) and mild hepatic impairment (total bilirubin > ULN to ≤ 1.5 x ULN or AST > ULN).
The effects of severe renal impairment (CLcr 15 to < 30 mL/min), end-stage renal disease (CLcr < 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and any AST), and race/ethnicity on the pharmacokinetics of glofitamab are unknown.
Drug Interaction Studies: No clinical studies evaluating the drug interaction potential of glofitamab have been conducted.
Immunogenicity: The observed incidence of antidrug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the study described as follows with the incidence of ADA in other studies, including those of glofitamab.
During treatment in Study NP30179 (up to 9 months) [see Pharmacology: Pharmacodynamics: Clinical Studies: Relapsed or Refractory DLBCL, NOS or LBCL Arising from Follicular Lymphoma as previously mentioned], using an enzyme-linked immunosorbent assay (ELISA), the incidence of anti-glofitamab antibody formation was 1.1% (5/448) in patients treated with COLUMVI. Because of the low occurrence of ADAs, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of glofitamab is unknown.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity or genotoxicity studies have been conducted with glofitamab.
Fertility studies have not been conducted with glofitamab.
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