Phase I study of anti‐CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed/refractory B‐cell non‐Hodgkin lymphoma

Abstract

Inotuzumab ozogamicin (CMC‐544), a humanized anti‐CD22 antibody conjugated to the potent cytotoxic antibiotic calicheamicin, targets the CD22 antigen expressed on the majority of B‐cell non‐Hodgkin lymphomas. This phase I study assessed the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered intravenously in combination with rituximab in Japanese patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma. Ten patients were administered rituximab 375 mg/m² followed by inotuzumab ozogamicin at the maximum tolerated dose (1.8 mg/m²). Treatment was repeated every 28 days up to eight cycles, or until occurrence of disease progression or intolerable toxicity. The safety profile was similar to that of inotuzumab ozogamicin monotherapy, with hematologic adverse events occurring most frequently. The most common grade three or higher adverse events were thrombocytopenia (70%), neutropenia (50%), leukopenia (30%), and lymphopenia (30%). The overall response rate was 80% (8/10; 95% CI, 44–98%). Drug exposure increased with successive doses, similar to the pharmacokinetic profiles observed in previous phase I monotherapy studies. Efficacy results suggested promising antitumor activity, and the overall findings support the continued clinical development of this therapeutic regimen in patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma. This trial was registered at www.ClinicalTrials.gov as NCT00724971. (Cancer Sci 2012; 103: 933–938)

CD22, a B‐cell antigen expressed on >90% of B‐lymphoid malignancies,1 represents an attractive therapeutic target for treatment of B‐cell non‐Hodgkin lymphoma (NHL). CD22 is not routinely shed into the extracellular environment;2 rather, CD22 is rapidly internalized upon binding with a ligand or antibody, allowing efficient delivery of targeted cytotoxic agents.3 Inotuzumab ozogamicin (CMC‐544) is a targeted chemotherapy agent composed of a humanized anti‐CD22 antibody conjugated to calicheamicin, a potent cytotoxic antibiotic. In vitro, inotuzumab ozogamicin has demonstrated enhanced cytotoxic activity compared with untargeted uptake of calicheamicin.2 Additionally, CD22 is expressed primarily on mature B‐lymphocytes, with limited expression on lymphocyte precursor cells and no expression on memory B cells; therefore, minimal impact of inotuzumab ozogamicin on long‐term immune function is expected.

Inotuzumab ozogamicin demonstrated promising cytotoxic activity both as a single agent and in combination with rituximab in xenograft models and in vitro studies.2, 4, 5 Rituximab, an anti‐CD20 monoclonal antibody, is indicated for single‐agent use or in combination with chemotherapy for treatment of low‐grade or follicular, CD20‐positive, B‐cell NHL, and in combination with chemotherapy for treatment of diffuse large B‐cell, CD20‐positive NHL.6 Although rituximab has been effectively used in combination with chemotherapy for indolent and aggressive B‐cell NHLs, some patients are not responsive, while those who do respond often experience relapse.7 Mechanisms of rituximab resistance may include downregulation of CD20 and increased expression of complement inhibitory proteins.8 Newer monoclonal antibodies that target B‐cell antigens other than CD20 may be effective in rituximab‐resistant B‐cell NHL or work in synergistic fashion with rituximab to improve B‐cell NHL treatment efficacy.9 As both CD22 and CD20 are expressed in most patients with B‐cell NHL,1, 7 inotuzumab ozogamicin and rituximab combination therapy in B‐cell NHL may enhance the therapeutic advantage of each agent.5

Clinical activity was observed with inotuzumab ozogamicin monotherapy at the maximum tolerated dose (MTD) of 1.8 mg/m² i.v. every 28 days.10, 11 Results of inotuzumab ozogamicin at the MTD in combination with rituximab in non‐Japanese patients with relapsed or refractory B‐cell NHL has shown promising efficacy with a safety profile similar to that reported for inotuzumab ozogamicin alone.12 The current study assessed the tolerability and initial safety profile of inotuzumab ozogamicin plus rituximab in Japanese patients with relapsed or refractory B‐cell NHL. Secondary objectives included evaluating the pharmacokinetics and preliminary efficacy of this drug combination.

Materials and Methods

Patients

Eligible patients were aged 20–74 years, with a diagnosis of CD20‐ and CD22‐positive B‐cell NHL according to the World Health Organization classification.13 The disease must have progressed after one or two prior therapies, and prior treatment must have included one or more doses of rituximab therapy (monotherapy or combined with chemotherapy). Maintenance therapy with rituximab was considered part of the preceding induction regimen, and patients could not be refractory to rituximab (i.e. progressive disease [PD] under treatment or <6 months of protocol therapy initiation). Other inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1; life expectancy ≥12 weeks; adequate organ function (absolute neutrophil count [ANC] ≥1.5 × 10⁹/L and platelet count ≥100 × 10⁹/L; serum creatinine ≤1.5 × upper limit of normal [ULN] and urine protein to creatinine ratio of ≤0.2; total bilirubin ≤1.5 × ULN, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤2.5 × ULN); and ≥1 measurable lesion ≥1.5 × 1.5 cm by computed tomography (CT) scan. Patients who had received radioimmunotherapy or prior treatment with anti‐CD22 antibodies were excluded. Prior allogeneic hematopoietic stem cell transplant was not allowed, and patients with prior autologous transplant were eligible if it occurred >6 months before the first study dose. No chemotherapy, anti‐lymphoma immunosuppressive therapy, growth factors (except erythropoietin), or investigational agents <28 days before the first study dose (<6 weeks for nitrosoureas or mitomycin C) was allowed.

The study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent, and the protocol was approved by institutional review board at each site. This trial was registered at www.ClinicalTrials.gov (Identifier: NCT00724971).

Study design

This phase I, open‐label, single‐arm study evaluated the tolerability, safety, pharmacokinetics, and preliminary efficacy of inotuzumab ozogamicin administered i.v. with rituximab to Japanese patients with B‐cell NHL. Screening procedures were performed within 21 days of study treatment initiation and included: medical history and physical examination; ECOG Performance Status; CD20/CD22 immunophenotyping of the B‐cell lymphoma; electrocardiogram (ECG) and echocardiogram; complete chemistry panel; complete blood count (CBC) with differential; chest radiograph; CT scans of the chest, abdomen, and pelvis; clinical disease and tumor site assessments; bone marrow aspiration and/or biopsy; urinalysis; and testing for serum antibodies to inotuzumab ozogamicin and rituximab.

A fixed standard dose of rituximab 375 mg/m² was administered i.v. on day 1 of a 28‐day (±2 days) cycle followed by inotuzumab ozogamicin 1.8 mg/m² i.v. on day 2 of the cycle. Treatment was repeated for up to eight cycles or until the occurrence of PD, intolerable toxicity, or patient refusal. Patients were followed for a minimum period of 1 year from the first dosing to assess progression‐free survival (PFS). Six patients were to be enrolled in the first cohort; if two or fewer patients experienced a dose‐limiting toxicity (DLT) within 28 days after the first dose, the dose and administration schedule would be considered reasonable and an additional four patients would be enrolled in an expanded cohort (10 patients total). If more than two of six patients experienced a DLT in the first 28 days, the tolerability of lower doses of inotuzumab ozogamicin (e.g. 1.3 mg/m²) would be explored.

A DLT was defined as any of the following that were at least possibly related to study treatment: any grade 3/4 nonhematologic toxicity (except grade 3 nausea or vomiting, unless the patient had received optimal supportive therapy); febrile neutropenia (grade 4 ANC and temperature ≥38.0°C); grade 4 ANC ≥7 days duration; grade 4 thrombocytopenia ≥3 days duration or grade 3/4 thrombocytopenia associated with bleeding tendency requiring platelet transfusion; and delayed recovery (to grade ≤1 or baseline, except alopecia) from toxicity related to the study drug that delayed initiation of the next dose by > 2 weeks.

Safety assessment

All patients who received one or more doses of inotuzumab ozogamicin or rituximab were included in the safety analysis (safety population). Safety was monitored through physical examinations, interim history, and laboratory tests. Interim physical examinations, including liver and spleen assessments, occurred every cycle before treatment administration if deemed necessary. Vital signs were measured on each day of inotuzumab ozogamicin administration. Complete chemistry panel and CBC with differential were assessed weekly during the first four cycles and biweekly during the last four cycles. Complete spot urinalysis was performed on day 1 of every other cycle beginning with cycle 2. ECG and chest radiograph were conducted at treatment completion. Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients were monitored for AEs for 28–42 days after the last dose of inotuzumab ozogamicin, regardless of causality, and patients with evidence of treatment‐related AEs at the end of treatment visit were followed until the AEs resolved or were determined to be irreversible.

Efficacy evaluation

Efficacy analyses were based on the intention‐to‐treat (ITT) and evaluable populations. The ITT population included all patients who were enrolled into the intended dose scheme, and the evaluable population included all patients who received two or more cycles of the study treatment, had a baseline tumor CT scan, and had undergone one or more post‐baseline tumor assessments. Tumor responses were evaluated by investigator's assessment according to the International Response Criteria for NHL.14 Overall response rate (ORR) was defined as the proportion of patients achieving complete response (CR), unconfirmed complete response (CRu), or partial response (PR). Duration of overall response was defined as the interval between first CR, CRu, or PR, until relapse or PD. PFS was defined as the interval between the first study dose and relapse, PD, or death, censored at the last tumor evaluation date. PFS rate at 1 year, defined as the proportion of patients without an event (relapse, PD, or death), was used as an early determination of PFS. Overall survival (OS) was defined as the interval between the first study dose and death, censored at the last date known alive.

Tumor responses were determined from CT scans, clinical information (e.g. liver and spleen size), “B‐symptoms” (e.g. fever, night sweats, and weight loss), laboratory assessments (e.g. bone marrow biopsies), and biochemical markers of disease activity (e.g. lactate dehydrogenase). Tumor sites and clinical disease measurements were assessed: approximately every 8 weeks during treatment (or earlier with clinical evidence of tumor response), at the end of treatment visit, and approximately every 12 weeks during follow‐up visits. If clinically indicated, CT scans were performed earlier than scheduled, and a confirmatory assessment was performed within 4 weeks of a documented tumor response. Tumor assessments continued until PD or death occurred, or subsequent anti‐lymphoma treatment was administered.

Pharmacokinetic analyses

Serum concentrations of inotuzumab ozogamicin, total calicheamicin, and free (unconjugated) calicheamicin were determined using a validated ELISA.10 The quantitation ranges for inotuzumab ozogamicin, total calicheamicin, and free calicheamicin were 52.2–1400, 5–100, and 1.25–150 ng/mL, respectively. Timed blood samples for pharmacokinetic analyses were collected from cycles 1 to 3, at 0 (pre‐dose), 1 (before the end of infusion), 4, 48, 144, 192, 312, 480, and 648 h relative to the start of inotuzumab ozogamicin infusion; sample collection for pharmacokinetics was not collected beyond cycle 3. Pharmacokinetic parameters of inotuzumab ozogamicin and total calicheamicin were estimated by a non‐compartmental method using WinNonlin, version 5.1 (Pharsight, Mountain View, CA, USA). Validated ELISAs were used for the detection of antibodies to inotuzumab ozogamicin and rituximab. The pharmacokinetic profile of rituximab was not evaluated.

Statistics

The safety and antitumor activity of inotuzumab ozogamicin plus rituximab were evaluated on an exploratory basis and summarized using descriptive statistics. Clopper‐Pearson methodology was used to estimate the confidence interval (CI) for the ORR, and Kaplan–Meier methodology was used to analyze the duration of overall response, PFS, and OS.

Results

Patients

Ten patients (five males, five females) were enrolled; patient characteristics are summarized in Table 1. Clinical stages at screening were IIIA in five patients, IVA in three patients, and IA and IIA in one patient each. Five patients had experienced one prior lymphoma regimen and five patients had two prior regimens (including two patients who had single‐agent rituximab as the second regimen); two patients had prior radiotherapy. All 10 patients received one or more cycles of both inotuzumab ozogamicin and rituximab, with a median number of four cycles (range, 1–8 cycles), and were included in the safety and ITT populations. Eight patients were included in the evaluable population for efficacy analyses, as two patients did not complete two or more cycles of the study treatment.

Table 1.

Patient characteristics

Characteristic	Inotuzumab ozogamicin 1.8 mg/m2 + rituximab 375 mg/m2 (N = 10)
Median age (range), years	60.5 (46–74)
Male sex, n (%)	5 (50)
ECOG Performance Status, n (%)
0	10 (100)
Histologic subtype, n (%)
Follicular lymphoma	6 (60)
Mantle cell lymphoma	2 (20)
Diffuse large B‐cell lymphoma	1 (10)
Mucosa‐associated lymphoid tissue lymphoma	1 (10)
Stage IIIA/IVA disease	8 (80)
No. prior anti‐lymphoma regimens, n (%)
1	5 (50)
2	5 (50)
Prior radiotherapy, n (%)	2 (20)

ECOG, Eastern Cooperative Oncology Group.

Safety

In the initial cohort of six patients, two patients experienced DLTs (grade 4 thrombocytopenia persisting ≥3 days and grade 3 increased AST). Since two or fewer patients experienced DLTs during the first cycle, an additional four patients were enrolled at the same dose level (inotuzumab ozogamicin 1.8 mg/m² and rituximab 375 mg/m²). Three of the four patients in the expanded cohort experienced DLTs (grade 4 thrombocytopenia persisting ≥3 days).

Of the four patients who experienced thrombocytopenia qualifying as a DLT, the patient in the initial cohort had grade 4 thrombocytopenia persisting for 5 days that required a subsequent dose reduction; the patient experienced persistent grade 1–3 thrombocytopenia thereafter but continued treatment until cycle 7. Two patients in the expansion cohort experienced grade 4 thrombocytopenia persisting for 4 days and 5 days; both experienced recovery after discontinuing treatment after cycle 1 due to neutropenia. The remaining patient experienced grade 4 thrombocytopenia persisting for 3 days that required platelet transfusion and subsequent dose reduction; this patient experienced persistent grade 1–3 thrombocytopenia thereafter but remained on therapy until cycle 5. Although an additional three patients experienced grade ≥3 thrombocytopenia during the study, no dose delays, dose reductions, platelet transfusions, or treatment discontinuations due to thrombocytopenia were required. In addition, no grade ≥3 bleeding events were reported.

All 10 patients experienced one or more treatment‐emergent AE, and nine patients experienced grade three or higher treatment‐emergent AEs (Table 2). The most commonly reported grade ≥3 treatment‐emergent AEs were hematologic abnormalities; other grade ≥3 events included hypophosphatemia (n = 2) and increased AST (n = 1; Table 3). Neutropenia led to dose delays in two patients. AEs leading to dose reductions (to inotuzumab ozogamicin 1.3 mg/m²) included thrombocytopenia (n = 2) and increased AST (n = 1). Five patients had AEs (neutropenia [n = 3] and hyperbilirubinemia [n = 2]) that did not recover to grade ≤1 within 21 days of the scheduled dosing day and were discontinued from treatment. No serious AEs or deaths occurred during the study.

Table 2.

Summary of adverse events, safety population

Event, n (%)	Inotuzumab ozogamicin 1.8 mg/m2 + rituximab 375 mg/m2 (N = 10)
Any TEAE	10 (100)
Grade ≥3 TEAE	9 (90)
AE leading to dose delays	2 (20)
AE leading to dose reduction	3 (30)
AE leading to treatment discontinuation	5 (50)
Serious AE	0
Death within 28 days from last dose	0

AE, adverse event; TEAE, treatment‐emergent adverse event.

Table 3.

Treatment‐emergent adverse events in ≥30% of patients (all grades) and all grade 3/4 treatment‐emergent adverse events, safety population

Event, n (%)	Inotuzumab ozogamicin 1.8 mg/m2 + rituximab 375 mg/m2 (N = 10)
	All grades	Grade 3/4
Thrombocytopenia	10 (100)	7 (70)
Increased AST	9 (90)	1 (10)
Leukopenia	8 (80)	3 (30)
Nausea	8 (80)	0
Increased ALT	8 (80)	0
Neutropenia	7 (70)	5 (50)
Lymphopenia	6 (60)	3 (30)
Increased LDH	6 (60)	0
Fatigue	5 (50)	0
Increased alkaline phosphatase	5 (50)	0
Decreased appetite	5 (50)	0
Hyperbilirubinemia	4 (40)	0
Headache	4 (40)	0
Decreased hemoglobin	3 (30)	0
Increased GGT	3 (30)	0
Nasopharyngitis	3 (30)	0
Pyrexia	3 (30)	0
Stomatitis	3 (30)	0
Hypophosphatemia	2 (20)	2 (20)

Adverse events (AEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (Bethesda, MD, USA). Patients were monitored for AEs for 28–42 days after the last dose of inotuzumab ozogamicin. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma‐glutamyltransferase; LDH, lactate dehydrogenase.

Efficacy

Eight of 10 patients were followed for more than 52 weeks; one patient with mantle cell lymphoma progressed during the study, and one patient with diffuse large B‐cell lymphoma discontinued due to lack of efficacy. OS at 1 year (52 weeks) was 100%, as no deaths were observed during the study. In the ITT population, the ORR was 80% (95% CI, 44–98%; Table 4). In the eight evaluable patients who received two or more cycles of study treatment and had one or more post‐baseline tumor assessment, ORR was 88% (95% CI, 47– >99%). The duration of response ranged from 346 to 540 days; median duration of response could not be estimated, as no relapse or PD was observed among responders. In the ITT population, the best overall responses (from the start of treatment until PD) were CR in six patients, CRu and PR in one patient each, and stable disease (SD) in two patients. In the evaluable population, CR was achieved in six patients and CRu and SD were achieved in one patient each. Median PFS and OS could not be estimated because the number of events observed was limited during the study. The PFS rate at 1 year was 89% (95% CI, 43–98%) in the ITT population and 88% (95% CI, 39–98%) in the evaluable population.

Table 4.

Best overall response, intention‐to‐treat population

Best overall response, n (%)	FL (n = 6)	DLBCL (n = 1)	MCL (n = 2)	MALT (n = 1)	Total (N = 10)
Overall response	6 (100)	0	1 (50)	1 (100)	8 (80)
Complete response (confirmed)	5 (83)	0	0	1 (100)	6 (60)
Complete response (unconfirmed)	0	0	1 (50)	0	1 (10)
Partial response	1 (17)	0	0	0	1 (10)
Stable disease	0	1 (100)	1 (50)	0	2 (20)

Tumor responses were determined by the investigator according to the International Response Criteria for Non‐Hodgkin Lymphoma. Tumor assessments occurred approximately every eight weeks during treatment (or sooner), at the end of treatment visit, and every 12 weeks during follow‐up visits. Overall response included complete confirmed, complete unconfirmed and partial response. DLBCL, diffuse large B‐cell lymphoma; FL, follicular lymphoma; MALT, mucosa‐associated lymphoid tissue; MCL, mantle cell lymphoma.

Pharmacokinetics

Pharmacokinetic data were collected from all 10 patients. Three patients who received AE‐related dose reductions of inotuzumab ozogamicin after cycle 1 and 2 patients who discontinued treatment after cycle 1 were excluded from pharmacokinetic analyses for cycles 2 and 3. Two patients who discontinued treatment after cycle 2 were also excluded from analyses for cycle 3. Drug exposure for inotuzumab ozogamicin and total calicheamicin (peak observed concentration [C _max] and area under the concentration‐time curve [AUC]) increased with the number of doses, coinciding with a prolonged terminal half‐life (t _1/2) and a commensurate decrease in apparent clearance (Table 5). The C _max of inotuzumab ozogamicin was typically observed at termination or shortly after completion of infusion. The C _max of total calicheamicin was usually observed within 4 h after the initiation of inotuzumab ozogamicin. Mean concentrations and standard deviations of inotuzumab ozogamicin and total calicheamicin in serum over time are shown in Figure 1. Concentrations of free calicheamicin were much lower than other analytes, and pharmacokinetic parameters could not be calculated. No antibodies to inotuzumab ozogamicin or rituximab were detected during the course of the study.

Table 5.

Pharmacokinetic parameters^a of inotuzumab ozogamicin and total calicheamicin

Treatment period (day)	C max (ng/mL)	t 1/2 (h)	AUCT (ng·h/mL)	AUC (ng·h/mL)	CL (L/h)	V ss (L)
Inotuzumab ozogamicin
Cycle 1 (day 1/2)	559 (24%) (n = 10)	18.8 (6%) (n = 2)	12 300 (51%) (n = 10)	22 300 (13%) (n = 2)	0.120 (15%) (n = 2)	2.33 (3%) (n = 2)
Cycle 2 (day 29/30)	822 (19%) (n = 5)	29.1 (75%) (n = 2)	27 000 (28%) (n = 5)	34 800 (35%) (n = 2)	0.078 (25%) (n = 2)	2.26 (77%) (n = 2)
Cycle 3 (day 57/58)	958 (7%) (n = 3)	51.7 (40%) (n = 3)	50 100 (13%) (n = 3)	54 800 (13%) (n = 3)	0.050 (2%) (n = 3)	3.02 (41%) (n = 3)
Total calicheamicin
Cycle 1 (day 1/2)	67.7 (22%) (n = 10)	61.2 (57%) (n = 7)	2850 (49%) (n = 10)	4060 (27%) (n = 7)	0.746 (28%) (n = 7)	47.6 (24%) (n = 7)
Cycle 2 (day 29/30)	80.2 (14%) (n = 5)	96.4 (32%) (n = 5)	6490 (35%) (n = 5)	7360 (33%) (n = 5)	0.424 (31%) (n = 5)	45.6 (15%) (n = 5)
Cycle 3 (day 57/58)	96.6 (3%) (n = 3)	167.9 (43%) (n = 3)	10 700 (44%) (n = 3)	11 600 (35%) (n = 3)	0.249 (28%) (n = 3)	47.8 (14%) (n = 3)

^aData are shown as mean values at the time points indicated (CV%); the numbers of patients evaluable for each parameter or time point are also provided. AUC, area under the concentration‐time curve evaluated to infinity (cycle 1) or dosing interval (672 h; cycles 2 and 3); AUC_T, area under the concentration‐time curve evaluated to the last measurable observation; CL, apparent clearance; C _max, peak observed concentration; CV, coefficient of variation; t _1/2, terminal half‐life; V _ss, apparent steady‐state volume of distribution.

Figure 1.

Mean concentrations of inotuzumab ozogamicin (a) and total calicheamicin (b) in serum after i.v. treatment with inotuzumab ozogamicin 1.8 mg/m² and rituximab 375 mg/m², 28‐day cycle. Error bars denote standard deviations. Cycle 1 (); cycle 2 (); cycle 3 ().

Discussion

This is the first full paper to report on clinical results of inotuzumab ozogamicin therapy in combination with rituximab. The different modes of action between inotuzumab ozogamicin and rituximab may potentially provide synergistic cytotoxicity when used in combination against B‐cell NHL. Upon internalization of CD22‐bound inotuzumab ozogamicin, calicheamicin diffuses into the nucleus and causes cell death.3 By contrast, CD20‐bound rituximab does not undergo constitutive endocytosis, but rather induces cytotoxic mechanisms that occur at the cell surface: complement‐dependent cytotoxicity and antibody‐dependent cell mediated cytotoxicity.9, 15 Thus, in addition to targeting different antigens, inotuzumab ozogamicin and rituximab use non‐overlapping and perhaps complementary mechanisms of action.

The safety profile of this drug combination was similar to that observed with inotuzumab ozogamicin alone;10, 11 this is consistent with the fact that safety profiles of rituximab and chemotherapy versus chemotherapy alone are similar.16 The major treatment‐related AEs in a phase I study of Japanese patients with follicular lymphoma pretreated with rituximab and administered inotuzumab ozogamicin monotherapy at the MTD of 1.8 mg/m² were thrombocytopenia, leukopenia, lymphopenia, neutropenia, increased AST, anorexia, and nausea.11 A similar toxicity profile was observed during a phase I study of non‐Japanese patients with B‐cell NHL (predominately follicular lymphoma or diffuse large B‐cell lymphoma) treated with inotuzumab ozogamicin 1.8 mg/m².10 The most common toxicities in the current study included thrombocytopenia, leukopenia, nausea, and elevated liver function tests. Five of 10 patients had AEs that met the criteria for DLTs. However, these events were all transient laboratory abnormalities without other associated clinical sequelae. Therefore, the independent data monitoring committee considered inotuzumab ozogamicin at 1.8 mg/m² plus rituximab to be tolerable and safe and recommended continued clinical development with careful attention for thrombocytopenia in subsequent studies.

Patients in this study had relatively few prior treatments (one to two regimens), but included three patients with aggressive lymphoma diagnoses: two with mantle cell lymphoma and one with diffuse large B‐cell lymphoma. In efficacy analyses, most patients achieved CR/CRu (7/10) or PR (1/10) and remained progression‐free at 52 weeks. The clinical response in this study compares favorably to responses observed with inotuzumab ozogamicin or rituximab monotherapy. In previous phase I studies of patients with B‐cell NHL administered inotuzumab ozogamicin monotherapy at the MTD, the ORRs were 39%10 and 80%,11 while rituximab monotherapy in patients with relapsed or refractory, low‐grade or follicular, B‐cell NHL was associated with an ORR of 48%.17 The clinical activity demonstrated in this trial is consistent with the robust antitumor activity of this drug combination observed in preclinical models. In vitro, inotuzumab ozogamicin plus rituximab suppressed the growth of B‐cell lymphoma xenografts by >90%; this effect was additive compared with either agent alone.5

The efficacy results were also comparable with reported results of epratuzumab, a humanized anti‐CD22 monoclonal antibody, plus rituximab in patients with post‐chemotherapy, relapsed or refractory, indolent B‐cell NHL (ORR of 54% in 41 patients with follicular lymphoma [24% achieving a CR/CRu], and 57% in seven patients with small lymphocytic lymphoma [43% with CR/CRu]).18 Although a definite comparison of this study with our study cannot be made due to the limited number of patients in our phase I study, the combination use of inotuzumab ozogamicin plus rituximab may have increased efficacy over combination use of two monoclonal antibodies due to the addition of a targeted chemotherapy agent.

Pharmacokinetic analyses revealed that drug exposure (C _max, AUC) to inotuzumab ozogamicin increased with the number of doses of combination therapy, displaying a nonlinear disposition similar to the pharmacokinetic profile observed in phase I studies of inotuzumab ozogamicin monotherapy.10, 11 No effect of rituximab on the pharmacokinetic profile of inotuzumab ozogamicin was apparent. Serum concentration increases may be partially attributable to accumulation; such nonlinearities in drug disposition are common for antibodies.19

Inotuzumab ozogamicin in combination with rituximab showed an acceptable safety profile in Japanese patients with relapsed or refractory B‐cell NHL that is similar to the observed single‐agent profile. Preliminary but encouraging evidence of clinical activity of inotuzumab ozogamicin plus rituximab was also demonstrated, and the findings support the continued clinical development of this therapeutic regimen.

Disclosure Statement

M. Ogura, K. Hatake, K. Ando, and K. Tobinai are currently conducting research sponsored by Pfizer Inc. K. Tokushige, C. Ono, and T. Ishibashi are employees of Pfizer Japan Inc. E. Vandendries is an employee of Pfizer Inc.