Phase 1 study of inotuzumab ozogamicin combined with R-GDP for the treatment of patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma

Abstract

Objective: To evaluate safety, tolerability, and preliminary activity of inotuzumab ozogamicin (InO) plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL). Methods: Patients received InO plus R-GDP (21-day cycle; six-cycle maximum) using up-and-down dose-escalation schema for gemcitabine and cisplatin to define the highest dosage regimen(s) with acceptable toxicity (Part 1; n = 27). Part 2 (n = 10) confirmed safety and tolerability; Part 3 (n = 18) evaluated preliminary efficacy. Results: Among 55 patients enrolled, 42% were refractory at baseline (median 2 [range, 1-6] prior therapies); 38% had diffuse large B-cell lymphoma (DLBCL). The highest dosage regimen with acceptable toxicity was InO 0.8 mg/m2, rituximab 375 mg/m2, cisplatin 50 mg/m2, gemcitabine 500 mg/m2 (day 1 only) and dexamethasone 40 mg (days 1-4); this was confirmed in Part 2, in which three patients had dose-limiting toxicities (grade 4 thrombocytopenia [n = 2], febrile neutropenia [n = 2]). Most frequent treatment-related adverse events were thrombocytopenia (any grade, 85%; grade ≥3, 75%) and neutropenia (69%; 62%). Overall (objective) response rate (ORR) was 53% (11 complete, 18 partial responses); ORR was 71%, 33%, and 62% in patients with follicular lymphoma (n = 14), DLBCL (n = 21), and mantle cell lymphoma (n = 13), respectively. Conclusions: InO 0.8 mg/m2 plus R-GDP was associated with manageable toxicity, although gemcitabine and cisplatin doses were lower than in the standard R-GDP regimen due to hematologic toxicity. Evidence of antitumor activity was observed; however, these exploratory data should be interpreted with caution due to the small sample size and short follow-up duration (Clinicaltrials.gov number: NCT01055496).

Keywords: B-cell non-Hodgkin lymphoma; CD22+; Inotuzumab ozogamicin; antibody-conjugate; chemotherapy; rituximab.

Figures

Figure 1.

Kaplan–Meier’s estimate of (A) progression-free survival, (B) overall survival, and (C) duration of response. Progression-free survival (PFS) was defined as the time between first dose and earliest date of disease progression (including symptomatic deterioration), new anti-lymphoma therapy, or death from any cause, which ever occurred first. Patients without a PFS event were censored at the last valid post baseline tumor assessment date; patients without a PFS event and without a post baseline tumor assessment were censored at the date of first dose. Overall survival (OS) was defined as the time between the first dose and death from any cause, censored at the date the patient was last known to be alive. Duration of response (DOR) was defined as the time between the date of first response and the earliest date of disease progression (including symptomatic deterioration), new anti-lymphoma therapy, or death, which ever occurred first. Patients without an event were censored at the last valid tumor assessment date. Indolent non-Hodgkin lymphoma includes follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia, and low-grade B-cell lymphoma favoring follicular lymphoma. Aggressive non-Hodgkin lymphoma includes diffuse large B-cell lymphoma and mantle cell lymphoma. CI: confidence interval.

Figure 1.

Kaplan–Meier’s estimate of (A) progression-free survival, (B) overall survival, and (C) duration of response. Progression-free survival (PFS) was defined as the time between first dose and earliest date of disease progression (including symptomatic deterioration), new anti-lymphoma therapy, or death from any cause, which ever occurred first. Patients without a PFS event were censored at the last valid post baseline tumor assessment date; patients without a PFS event and without a post baseline tumor assessment were censored at the date of first dose. Overall survival (OS) was defined as the time between the first dose and death from any cause, censored at the date the patient was last known to be alive. Duration of response (DOR) was defined as the time between the date of first response and the earliest date of disease progression (including symptomatic deterioration), new anti-lymphoma therapy, or death, which ever occurred first. Patients without an event were censored at the last valid tumor assessment date. Indolent non-Hodgkin lymphoma includes follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia, and low-grade B-cell lymphoma favoring follicular lymphoma. Aggressive non-Hodgkin lymphoma includes diffuse large B-cell lymphoma and mantle cell lymphoma. CI: confidence interval.