LUMOXITI Powder for solution for injection Ref.[10359] Active ingredients:

The presence of moxetumomab pasudotox-tdfk may interfere with detection of cellular CD22, therefore, total peripheral blood B-cell counts (including normal B cells and HCL cells) were quantified using a standard assay for CD19+ B cells as a surrogate. In patients with HCL, treatment with LUMOXITI at the approved recommended dosage resulted in a reduction of circulating CD19+ B cells. The circulating CD19+ B cells on Day 8 were reduced by 89% from baseline following the first three infusions of LUMOXITI. B cell reduction was sustained for at least 1-month post-treatment.

Total counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD16+/CD56 Natural Killer cells and quantitative immunoglobulin (Ig) A, G, and M levels were evaluated throughout the course of treatment. On Day 8, median cell counts were reduced from baseline for the following populations: CD3+ T cells (-21%), CD4+ T cells (-20%), CD8+ T cells (-23%), and CD16+/CD56 Natural Killer cells (-47%). All monitored cell counts returned to, or were elevated above baseline levels on Day 29 and thereafter. At baseline, the median IgA, IgG, and IgM levels were 107 mg/dL (11-260), 834 mg/dL (387-3003), and 42 mg/dL (6-380), respectively, and remained generally unchanged at the end of treatment.

The pharmacokinetics (PK) of moxetumomab pasudotox-tdfk was studied in patients with HCL at doses ranging from 0.005 to 0.05 mg/kg (about 0.1 to 1.3 times the approved recommended dosage) administered intravenously over 30 minutes on Days 1, 3, and 5 of a 28-day cycle. Moxetumomab pasudotox-tdfk concentrations increased dose-proportionally over the studied dose range. The mean steady state moxetumomab pasudotox-tdfk exposures at the approved recommended dosages were 379 ng/mL (range: 20 to 862; SD: 262) for C_max and 626 ng·hour/mL (range: 5 to 1960; SD: 610) for AUC_0-last. No systemic accumulation of moxetumomab pasudotox-tdfk was observed. Baseline CD19+ B cells were evaluated for association with the PK exposure and higher PK exposures were significantly associated with low baseline CD19+ counts (p <0.001).

Distribution

The population PK model estimated mean volume of distribution of moxetumomab pasudotox-tdfk was 6.5 L (SD 2.4).

Elimination

The mean elimination half-life of moxetumomab pasudotox-tdfk was 1.4 hours (range: 0.8 to 1.8; SD: 0.35). The population PK model estimated mean systemic clearance of moxetumomab pasudotox-tdfk after the first dose of the first cycle was 25 L/hour (SD: 29.0) and after subsequent dosing was 4 L/hour (SD: 4.4).

Metabolism

The metabolic pathway of moxetumomab pasudotox-tdfk in humans is unknown, however, other protein therapeutics generally undergo proteolytic degradation into small peptides and amino acids via catabolic pathways.

Specific Populations

No clinically significant differences in the pharmacokinetics of moxetumomab pasudotox-tdfk were observed for age (36 to 84 years), sex, race (White and non-White), body weight (42 to 152 kg), mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN, or total bilirubin >1 to 1.5 times ULN and any AST), mild renal impairment (CLcr 60-89 mL/min; n=40), or moderate renal impairment (CLcr 30-59 mL/min; n=4) based on population PK analysis.

The pharmacokinetics of moxetumomab pasudotox-tdfk in patients with moderate to severe hepatic impairment (total bilirubin >1.5 ULN) or severe renal impairment (CrCl ≤29 mL/min) is unknown.

Anti-Product Antibody Formation Affecting PK

In patients who were ADA-positive with high titers, the presence of ADA post-baseline was associated with statistically significant (p <0.05) lower PK exposure (C_max) at later cycles (Cycle 3 and beyond).

No studies have been conducted to assess the carcinogenic or genotoxic potential of moxetumomab pasudotox-tdfk. Animal fertility studies have not been conducted with moxetumomab pasudotox-tdfk.

At a human equivalent dose >3 times the recommended dose, degeneration of heart tissue was observed in cynomolgus monkeys. At a human equivalent dose >10 times the recommended dose, gliosis in the brain, axonal degeneration in the spinal cord, and body tremors were observed in cynomolgus monkeys.

The efficacy of LUMOXITI was based upon Study 1053 titled “A Pivotal Multicenter Trial of Moxetumomab Pasudotox in Relapsed/Refractory Hairy Cell Leukemia” (NCT01829711). Study 1053 was conducted in patients with histologically confirmed HCL or HCL variant with a need for therapy based on presence of cytopenias or splenomegaly and who had received prior treatment with at least 2 systemic therapies, including 1 purine nucleoside analog (PNA). Eligible patients had serum creatinine ≤1.5 mg/dL or creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft Gault equation.

A total of 80 patients were enrolled; 77 with classic HCL and 3 with HCL variant. The median age was 60 years (range: 34 to 84) years, 79% were male, and 94% were Caucasian. At baseline, 98% of patients had an ECOG performance status of 0 or 1. The median number of prior treatments was 3 (range: 2 to 11); all patients received prior PNA therapy, including 29% in combination with rituximab. The most common other prior treatment regimens were rituximab monotherapy (51%), interferon-alpha (25%), and a BRAF inhibitor (18%). At baseline, 33% (26/80) of patients had low hemoglobin (<10 g/dL), 68% (54/80) of patients had neutropenia (< 1000/mm³), and 84% (67/80) patients had baseline platelet counts < 100,000/mm³. About 35% of patients had enlarged spleens (≥14 cm, assessed by BICR) at baseline.

Patients received LUMOXITI 0.04 mg/kg as an intravenous infusion over 30 minutes on Days 1, 3, and 5 of each 28‑day cycle for a maximum of 6 cycles or until documentation of complete response (CR), disease progression, or unacceptable toxicity. The median duration of follow-up was 16.7 months (range: 2 to 49). An independent review committee (IRC) performed efficacy evaluations using blood, bone marrow, and imaging criteria adapted from previous HCL studies and consensus guidelines.

Efficacy of LUMOXITI in HCL was evaluated by the IRC-assessed rate of durable CR, as confirmed by maintenance of hematologic remission (hemoglobin ≥11 g/dL, neutrophils ≥ 1500/mm³, and platelets ≥ 100,000/mm³ without transfusions or growth factor for at least 4 weeks) more than 180 days after IRC-assessed CR. The IRC-assessed durable CR rate was 30% (24/80 patients; 95% CI: 20, 41).

Additional efficacy outcome measures included overall response rate (ORR), CR, and duration of response (see Table 6).

Table 6. Additional Efficacy Results in Patients with HCL in Study 1053:

CI=Confidence Interval; NR=Not Reached; + indicates censored observations
^* ORR defined as best overall response of CR or PR.
^† CR defined as clearing of the bone marrow of hairy cells by routine Hematoxylin & Eosin stain, radiologic resolution of pre-existing lymphadenopathy and/or organomegaly, and hematologic remission.
^‡ PR defined as ≥ 50% decrease or normalization (< 500/mm³ ) in peripheral blood lymphocyte count, reduction of pre-existing lymphadenopathy and/or organomegaly, and hematologic remission.

The median time to ORR and CR was 5.7 months (range: 1.8 to 12.9) and 5.9 months (range 1.8 to 13.2), respectively. Sixty-four patients (80%) had normalization of hematologic parameters and achieved hematologic remission, with a median time to hematologic remission of 1.1 months (range: 0.2 to 13) and with a median duration of hematologic remission not reached (range: 0.3 to 48.2+).