Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab

Abstract

Purpose: Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20(+)/CD22(+) B-cell non-Hodgkin lymphoma (NHL).

Patients and methods: A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles.

Results: In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m(2)) was confirmed to be the same as that for single-agent INO (1.8 mg/m(2)). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL.

Conclusion: R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20(+)/CD22(+) B-cell NHL.

Trial registration: ClinicalTrials.gov NCT00299494.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram. DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MTD, maximum-tolerated dose; q4wk, every 4 weeks. (*) An additional patient was enrolled over the six planned patients because one patient was unevaluable for safety (increased aminotransferase levels at screening in violation of study eligibility criteria and confirmed alcohol abuse). (†) All patients who received one or more doses of rituximab plus inotuzumab ozogamicin. One patient with DLBCL who was enrolled onto part 2 did not receive study treatment. (‡) All patients enrolled to receive MTD treatment (intent-to-treat): seven in part 1, 104 in part 2. One patient with DLBCL enrolled onto part 2 did not receive study treatment.

Fig 2.

(A-B) CD19+ B-cell count and CD22 expression versus time after rituximab plus inotuzumab ozogamicin (R-INO) treatment (1.8 mg/m2 dose). (A) Total CD19+ B-cell count after treatment with rituximab (time, −24 hours) and INO (time, 0 hours). Inset magnifies the plot area between times 0 and 672 hours. As shown, CD19+ B-cell count declined rapidly after rituximab treatment and further declined after INO treatment, indicating that R-INO targeted the B-cell population. (B) Whole blood was drawn during cycles 1, 2, and 3 for measurement of CD22 saturation in B cells. Analysis was performed by using a differential binding flow cytometry technique as previously described. CD22 expression levels were detected with either the fluorescein isothiocyanate (FITC; uninhibited by INO) or phycoerythrin (PE; inhibited by INO) antibody clones. Response is expressed in units of molecular equivalents of soluble fluorescence (MESF) of phycoerythrin CD22+ cells determined from flow cytometry in which samples exhibited at least 300 events that were CD19+ at baseline. Length of box denotes 25th and 75th percentile; horizontal line within box denotes the median of observed data. As shown, CD22 expression declined with R-INO treatment, indicating that the total amount of CD22 receptor available for binding declined with INO treatment. The consistently lower signal of the PE clone indicates the direct binding activity of INO to CD22. (C-F) Serum INO and total calicheamicin exposure by study (this R-INO study, and prior INO monotherapy study) and treatment cycle after the 1.8 mg/m2 dose. (C) INO maximum concentration (Cmax); (D) INO partial area under the curve (AUCT); (E) total calicheamicin Cmax; (F) total calicheamicin AUCT. Length of box denotes 25th and 75th percentile, and horizontal line within box denotes the median of observed data. These data show some cycle-related increases in exposure with greater increase in AUCT than in C[inf]max[r]. Although potential interstudy variability factors are not specifically accounted for, the data also show that exposures to INO and total calicheamicin tended to be modestly higher for R-INO compared with INO monotherapy. Because INO is thought to undergo target-mediated drug disposition, INO and calicheamicin exposures increase with additional cycles of therapy. Because rituximab therapy has the potential to deplete B cells and reduce the target for INO, we have hypothesized that this clearance of target by rituximab could result in increased INO and calicheamicin exposures.

Fig 3.

In this study, tumor assessments were performed at screening after every two cycles and at end-of-treatment visit. Tumor assessments continued after end-of-treatment visit every 12 weeks until progression, death, or administration of another anticancer therapy, whichever occurred first. After progression or new therapy, patients were observed for survival for up to 5 years. (A-C) Waterfall plots for patients enrolled to receive maximum-tolerated dose (MTD) treatment by best investigator-reported objective response. Nodal lesion sizes were normalized for normal nodal structures (defined as 100 mm2 for nodal lesions with maximum diameter < 15 mm at baseline and 150 mm2 for those with diameters > 15 mm at baseline). Objective response rate (ORR) is defined as complete response (CR) plus unconfirmed complete response (CRu) plus partial response (PR). (A) ORR and CR/CRu rates and change in lesion size for all relapsed patients with follicular lymphoma (FL) enrolled to receive MTD treatment (n = 39); (B) ORR and CR/CRu rates for all relapsed patients with diffuse large B-cell lymphoma (DLBCL) enrolled to receive MTD treatment (n = 42), with change in lesion size shown for 40 patients. (*) Not shown for two patients: one because of incomplete radiographic tumor assessment at screening, and one, who did not receive inotuzumab ozogamicin [INO], because of no postscreening radiographic tumor assessment); (C) ORR and CR/CRu rates for all patients with refractory aggressive non-Hodgkin lymphoma (NHL) enrolled to receive MTD treatment (n = 30), with change in lesion size shown for 24 patients. (*) Not shown for six patients [five DLBCL, one mantle cell] because there was no or incomplete postscreening radiographic tumor assessment). Kaplan-Meier curves of (D) progression-free survival; (*) includes one patient who did not receive INO. (E) Overall survival for all patients enrolled to receive MTD treatment by NHL type; (*) includes one patient who did not receive INO. N/A, not applicable; PD, progressive disease; SD, stable disease.