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Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

ABSTRACT: Background:This two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells. Patients and methods:Patients aged??18?years, with R-R NHL progressing after??1 prior rituximab-containing regimen were enrolled into subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent (i)NHL and mantle cell lymphoma (MCL). Treatment was MOR208, 12?mg/kg intravenously, weekly, for 8?weeks. Patients with at least stable disease could continue treatment for an additional 4?weeks. Those with a partial or complete response after 12?weeks could receive extended MOR208 treatment (12?mg/kg, either monthly or every second week) until progression. The primary end point was overall response rate. Results:Ninety-two patients were enrolled: DLBCL (n?=?35), FL (n?=?34), other iNHL (n?=?11) and MCL (n?=?12). Responses were observed in DLBCL, FL and other iNHL cohorts (26%, 29% and 27%, respectively). They lasted??12?months in 5/9 responding patients with DLBCL, 4/9 with FL and 2/3 with other iNHL. Responses in nine patients are ongoing (>26?months in five instances). Patients with rituximab refractory disease showed a similar response rate and progression-free survival time to patients with non-refractory disease. The most common adverse events (any grade) were infusion-related reactions (12%) and neutropenia (12%). One patient experienced a grade 4 infusion-related reaction and eight patients (9%) experienced grade 3/4 neutropenia. No treatment-related deaths were reported. Conclusions:MOR208 monotherapy demonstrated promising clinical activity in patients with R-R DLBCL and R-R FL, including in patients with rituximab refractory tumors. These efficacy data and the favorable safety profile support further investigation of MOR208 in phase II/III combination therapy trials in R-R DLBCL. ClinicalTrials.gov number:NCT01685008.

SUBMITTER: Jurczak W

PROVIDER: S-EPMC5961010 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

Jurczak W W Zinzani P L PL Gaidano G G Goy A A Provencio M M Nagy Z Z Robak T T Maddocks K K Buske C C Ambarkhane S S Winderlich M M Dirnberger-Hertweck M M Korolkiewicz R R Blum K A KA

Annals of oncology : official journal of the European Society for Medical Oncology 20180501 5

<h4>Background</h4>This two-stage, phase IIa study investigated the antitumor activity and safety of MOR208, an Fc-engineered, humanized, CD19 antibody, in patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is broadly expressed across the B-lymphocyte lineage, including in B-cell malignancies, but not by hematological stem cells.<h4>Patients and methods</h4>Patients aged ≥18 years, with R-R NHL progressing after ≥1 prior rituximab-containing regimen were enrolle ...[more]

PMID: 29444231

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Project description:BackgroundRelapsed or refractory classical Hodgkin lymphoma (cHL) remains a difficult treatment challenge. Although checkpoint inhibitors (CPI) have provided clinical benefit for these patients, responses are generally not durable, and progression eventually occurs. Discovering combination therapies which maximize the immune response of CPI therapy may overcome this limitation. We hypothesized that adding ibrutinib to nivolumab will lead to deeper and more durable responses in cHL by promoting a more favorable immune microenvironment leading to enhanced T-cell-mediated anti-lymphoma responses.MethodsWe conducted a single arm, phase II clinical trial testing the efficacy of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who had received at least one prior line of therapy. Prior treatment with CPIs was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for up to 16 cycles. The primary objective was complete response rate (CRR) assessed per Lugano criteria. Secondary objectives included overall response rate (ORR), safety, progression free survival (PFS), and duration of response (DoR).ResultsA total of 17 patients from two academic centers were enrolled. The median age of all patients was 40 (range 20-84). The median number of prior lines of treatment was five (range 1-8), including 10 patients (58.8%) who had progressed on prior nivolumab therapy. Most treatment related events were mild (<Grade 3) and expected from the individual side effect profiles of ibrutinib and nivolumab. In the intent to treat population (n = 17), the ORR and CRR were 51.9% (9/17) and 29.4% (5/17), which did not meet the prespecified efficacy endpoint of a CRR of 50%. In patients who received prior nivolumab therapy (n = 10), the ORR and CRR were 50.0% (5/10) and 20.0% (2/10), respectively. At a median follow up of 8.9 months, the median PFS was 17.3 months, and the median DOR was 20.2 months. There was no statistically significant difference in median PFS between patients who received previous nivolumab therapy versus patients who were nivolumab naïve (13.2 months vs. 22.0 months, p = 0.164).ConclusionsCombined nivolumab and ibrutinib led to a CRR of 29.4% in R/R cHL. Although this study did not meet its primary efficacy endpoint of a CRR of 50%, likely due to enrollment of heavily pretreated patients including over half of who had progressed on prior nivolumab treatment, responses that were achieved with combination ibrutinib and nivolumab therapy tended to be durable even in the case of prior progression on nivolumab therapy. Larger studies investigating the efficacy of dual BTK inhibitor/immune checkpoint blockade, particularly in patients who had previously progressed on checkpoint blockade therapy, are warranted.

Dataset Information

Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

Publications

Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

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