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In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 2 ( 2020-02), p. 522-532

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-019-0559-9

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1814-1814

Abstract: Rituximab-based chemoimmunotherapy is standard treatment for non-Hodgkin’s lymphoma (NHL), but some patients relapse or do not respond to treatment. GA101, the first glycoengineered, humanized, anti-CD20 monoclonal antibody, was developed to induce increased direct cell death and antibody-dependent cellular cytotoxicity relative to rituximab. Phase 1 and 2 studies of patients with NHL have shown that GA101 monotherapy has promising activity. The phase 1b GAUDI study (NCT00825149, BO21000) evaluated the safety and efficacy of induction treatment with GA101 plus chemotherapy in patients with relapsed/refractory follicular lymphoma (FL). GA101 was partnered with cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP) or with fludarabine and cyclophosphamide (G-FC). The end-of-induction overall response rate was 96% for G-CHOP and 93% for G-FC (Radford et al. Blood. 2013). Here we report results from the cohort of patients who received GA101 maintenance monotherapy after responding to induction treatment. During induction, patients with relapsed/refractory FL received G-CHOP (every 3 weeks, 6–8 cycles) or G-FC (every 4 weeks, 4–6 cycles). Chemotherapy backbone was selected by the investigator on the basis of patient characteristics and treatment history. Patients were randomized to either high-dose GA101 (1600 mg on days 1 and 8 of cycle 1, 800 mg on day 1 of subsequent cycles) or to low-dose GA101 (400 mg on days 1 and 8 of cycle 1 and day 1 of subsequent cycles). Patients with complete response (CR) or partial response after induction were eligible to receive GA101 monotherapy (at the same dose used for induction) as maintenance treatment every 3 months for 2 years or until disease progression. Patients who completed maintenance therapy were followed for 2 years after the last GA101 dose or until progression/initiation of a new antilymphoma treatment. The primary end point was safety. Progression-free survival (PFS) was a secondary end point. Median observation time from study start in the G-CHOP and G-FC cohorts was 31.8 and 37.5 months, respectively. In the G-CHOP cohort, 82% (23/28) and 65% (15/23) of patients started and completed maintenance therapy, respectively. There were 7 discontinuations due to stable disease (SD) or progressive disease (PD) and 1 due to an adverse event (AE; hepatosplenic T-cell lymphoma). In the G-FC cohort, 61% (17/28) and 53% (9/17) of patients started and completed maintenance therapy, respectively. There were 4 discontinuations due to AEs (pancytopenia/septicemia, n=1; diarrhea/weight loss, n=1; neutropenia, n=2), 2 due to SD or PD, 1 due to administrative/other (patient moved away), and 1 due to death (chronic obstructive pulmonary disease, which was considered unrelated to GA101). During the maintenance period, 3 and 6 patients in the G-CHOP and G-FC cohorts, respectively, experienced a serious AE. No grade ≥3 AEs occurred in 〉 1 patient in the G-CHOP cohort; in the G-FC cohort, the most common grade ≥3 AE was neutropenia (n=3). The proportion of patients with CR as a best overall response increased between the end of induction and the end of maintenance in the G-CHOP (39% [9/23] to 52% [12/23] ) and G-FC cohorts (59% [10/17] to 82% [14/17] ). Median PFS was not reached for G-CHOP; median PFS in the G-FC cohort was 46.0 months (95% CI: 24.4–46.0 months). Pharmacokinetic data will be presented. In this phase 1b study, maintenance treatment with GA101 monotherapy was well tolerated and CR rates increased compared with the end of the induction phase. This suggests that GA101 could be used to sustain and extend the clinical response achieved after induction with GA101 plus chemotherapy in patients with relapsed/refractory FL. The majority of responders completed maintenance treatment. No new safety signals emerged during maintenance treatment with GA101 monotherapy. In summary, data from the GAUDI study show that GA101 maintenance monotherapy is well tolerated and confers clinical benefit after induction with GA101 plus chemotherapy. Disclosures: Davies: Roche: Consultancy, Honoraria, Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. Cartron:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Morschhauser:Roche, Celgene, Mundipharma, Spectrum: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Salles:Roche: Consultancy, Honoraria, Research Funding. Marcus:Roche: Consultancy, Honoraria. Wenger:Genentech: Employment. Lei:Roche: Employment. Wassner-Fritsch:Roche: Employment. Vitolo:Roche, Celgene, Takeda: Membership on an entity’s Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1814.1814

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 7 ( 2013-08-15), p. 1137-1143

Abstract: Obinutuzumab is a novel type II anti-CD20 monoclonal antibody under early-stage clinical investigation. Obinutuzumab plus CHOP or FC has an acceptable safety profile and is effective in relapsed/refractory follicular lymphoma.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2013-01-481341

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1743-1743

Abstract: Obinutuzumab (GA101; G) is an anti-CD20 monoclonal antibody with activity in relapsed/refractory follicular lymphoma (FL) as a single agent and in combination with chemotherapy. G-chemotherapy induction followed by G-maintenance has not been evaluated for untreated FL. The open-label, randomized, phase Ib GAUDI study (NCT00825149) investigated safety and efficacy of G + CHOP (G-CHOP) or bendamustine (G-B) as first-line treatment for FL. We report data from patients (pts) who received G-maintenance after responding to G-chemotherapy induction. Pts with treatment-naïve CD20+ B-cell FL and ≥1 bi-dimensionally measurable lesion (CT scan; largest dimension 〉 1.5cm) were allocated on a per-center basis to receive induction G IV 1000mg + standard CHOP (3-weekly, 6–8 cycles) or B IV 90mg/m2(4-weekly, 4–6 cycles). Induction responders received G-maintenance every 3 months for 2 years or until disease progression (PD). Pts completing maintenance were followed for a further 2 years, until PD or start of new anti-lymphoma therapy. Anti-infective prophylaxis was used at investigator discretion. The primary objective was safety. Secondary objectives included progression-free survival (PFS) and response rates. The overall safety population comprised 81 pts (G-B: n=41; G-CHOP: n=40). Baseline characteristics (age, sex, FLIPI status, bone marrow involvement, bulky disease [lesion ≥7cm], time from diagnosis) were balanced between arms. Median observation time from study start was 31 months (G-B) and 33 months (G-CHOP). The maintenance safety population comprised 72 pts (n=36 from each induction therapy arm). Most pts completed maintenance (G-B: 81%; G-CHOP: 72%). There were 17 discontinuations (24%; G-B: n=7; G-CHOP: n=10), due to an adverse event (AE)/intercurrent illness (n=9), insufficient therapeutic response (n=5), administrative/other (n=2) and death (n=1). During 2 years’ maintenance most pts had AEs: G-B, 100% (44% grade ≥3); G-CHOP, 78% (31% grade ≥3). The most common AE (all grades) was cough (G-B: 17%; G-CHOP: 11%). The grade ≥3 AEs mainly reflected infections and cytopenia. Six G-B pts (17%) experienced 7 grade ≥3 infections; 4 were considered treatment related (genital infection, oral herpes, pneumonia klebsiella, neutropenic infection). Five G-CHOP pts (14%) had one grade ≥3 infection each; 4 were considered treatment related (viral meningitis, respiratory tract infection [RTI], bacterial pneumonia [2 events] ). Six G-B pts (17%) experienced 10 grade ≥3 cytopenia AEs; 7 were considered treatment related (anemia, febrile neutropenia, pancytopenia, neutropenia [2 events], thrombocytopenia [2 events] ). No G-CHOP pt experienced a grade ≥3 cytopenia AE. AEs led to dose delays in 17% (G-B) and 6% (G-CHOP) of pts. Three pts (G-B: n=1; G-CHOP: n=2) had treatment-related AEs during, or within 24 hours of, an infusion (all grade 1–2). Two deaths (both G-CHOP) occurred during maintenance or maintenance follow-up; 1 due to PD and 1 due to a G-related AE (RTI leading to fatal lactic acidosis). At the end of maintenance, all pts with data available (G-B: n=41; G-CHOP: n=39) had experienced B-cell depletion ( 〈 0.07x109 cells/L). At data cut-off, only 22 pts (28%) had a B-cell assessment within 6–9 months of follow-up after the end of maintenance treatment; all remained B-cell depleted. Six of 12 pts (G-B: n=2; G-CHOP: n=4) assessed between 9 and 24 months after the end of maintenance recovered ( 〉 0.07x109cells/L). Median IgG levels remained within normal range during maintenance. In the overall safety population, complete response (CR) rate (based on CT scan rather than PET) as best overall response increased from end of induction (G-B: 37%; G-CHOP: 35%) to end of maintenance (G-B: 61%; G-CHOP: 70%). PFS rate at 32 months after first study drug was 92% (G-B) and 84% (G-CHOP). Median PFS was not reached; 10 pts (G-B: n=4; G-CHOP: n=6) had PD, including one transformation to diffuse large B-cell lymphoma. G-maintenance after G-chemotherapy induction was associated with a high CR rate in pts with previously untreated FL. Opportunistic infections occurred infrequently. Clinically relevant neutropenia was experienced by 14% of pts who received G-B induction but was not observed in G-CHOP pts. A phase III trial (GALLIUM) is investigating G versus rituximab in chemoimmunotherapy induction followed by immunotherapy maintenance in pts with untreated indolent non-Hodgkin lymphoma. Disclosures Off Label Use: Obinutuzumab is a type II CD20 monoclonal antibody which is licensed for use in combination with chlorambucil in untreated patients with CLL but is not currently approved for use in follicular lymphoma.. Grigg:Roche: Consultancy. Dreyling:Roche: Honoraria, Research Funding. Rule:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lei:Roche Products Ltd.: Employment. Wassner-Fritsch:Roche: Employment. Fingerle-Rowson:F. Hoffmann–La Roche: Employment. Marlton:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1743.1743

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4674-4674

Abstract: Background: Infusion related reactions (IRR) are commonly seen with administration of biologic therapies but remain relatively poorly understood. Rituximab is thought to induce cell death upon binding to CD20 primarily by complement dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Obinutuzumab (GA101, Gazyva®, Gazyvaro®) is a new generation humanised IgG1 Type II anti-CD20 mAb with contrasting properties to rituximab. The Fc portion has been glycoengineered (afucosylated) to increase binding affinity to Fcgamma receptor 3(FcγRIII). These features result in higher direct cell killing activity, enhanced ADCC and phagocytosis (ADP) and less complement activation compared with rituximab. Early experience with rituximab has shown that release of pro-inflammatory cytokines occurs with initial administration and is higher in patients experiencing IRRs compared to those who are not. We report on the cytokine release in a subset of 38 patients with chronic lymphocytic leukemia (CLL) treated with obinutuzumab monotherapy pooled from the earlier Phase I (GAUSS) trial (NCT00576758) and Phase I/II (GAUGUIN) trial (NCT00517530). Methods: Eligible patients for both studies had relapsed/refractory CLL with no alternative, higher priority therapy available. All patients were treated sequentially with intravenous (IV) obinutuzumab monotherapy and were universally pre-medicated with an oral anti-pyretic (paracetamol/acetaminophen) and an IV anti-histamine 30 minutes prior to starting the infusion. Steroid pre-medication was not mandated in either study. Cytokine serum samples (quantitatively measured using the Becton-Dickinson (BD) Cytometric Bead Array) were taken from each patient prior to each obinutuzumab infusion, mid-way through the infusion, at the end of infusion and 2-5 hours after completion. Samples for complement analysis were also taken at these same time points (C3/C4 analysed using Siemens BNII Nephelometer, C3a/C5a using BD Pharmingen ELISA kit). Peripheral blood samples for immunophenotyping were also taken at baseline, prior to and at the end of each infusion. The development of an IRR with the first infusion was defined as the occurrence of related signs and symptoms within 24 hours of administration of antibody and graded according to the CTCAE guidelines v4.0. Results: Of the 38 patients treated, 35 developed symptoms of IRR (Grade 1/2=25, Grade 3/4=10) with the first infusion accompanied by a rapid decrease in circulating CD19+ B cells, a drop in the measurable natural killer (NK) CD16+56+ cells and an increase of pro-inflammatory cytokines IL6, IL8, TNFα and IFNγ (see figures 1 and 2). There were no meaningful differences between pre-treatment baseline cytokine levels across all subgroups. At the mid-infusion time-point, patients with absolute lymphocyte count (ALC) at baseline ≥50x109/L released higher levels of IL6 (mean IL6(log10) 3.16 vs 2.41), IL-8 (mean IL8(log10)3.57 vs 2.91), TNFα (mean TNFα(log10) 2.59 vs 1.92), IFNγ (mean IFNγ(log10)2.38 vs 1.8) and IL10 (mean IL10(log10) 2.03 vs 1.69) than those with ALC 〈 50x109. Patients who had higher grade IRR (≥grade 3) had higher baseline values for lymphocyte count and β-2microglobulin, lower baseline platelet count and higher Binet stage than those without severe grade IRR, however none of these differences were statistically significant at p≤0.05. . Markers of complement activation, C5a and C3a, did not increase and C3/C4 levels remained stable across all groups. Cytokine release was limited to the first infusion of obinutuzumab only and did not recur with subsequent infusions (Fig . 1). Conclusions: This sub-analysis demonstrates that the first obinutuzumab administration triggers immediate and strong release of cytokines (IL6, IL8, TNFα, IFNγ and IL10) in association with rapid destruction of circulating B cells in patients with CLL. The close temporal relationship between release of pro-inflammatory cytokines (especially IL6 and IL8) and development of IRRs, in addition to the lack of complement activation induced by obinutuzumab, suggest that cytokine release is part of the IRR pathophysiology. Intervention strategies targeting cytokines may therefore be a promising strategy to reduce the incidence and severity of IRRs. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Freeman: Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart's) Other. Off Label Use: Presentation may refer to mitigation strategies such as the use of tocilizumab in patients with cytokine release syndrome. Morschhauser:Bayer: Honoraria; Mundipharma: Honoraria; Genentech: Honoraria; Spectrum: Honoraria; Gilead: Honoraria. Sehn:Roche: Research Funding. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Wassner-Fritsch:Roche Pharmaceuticals: Employment. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Salles:Roche Pharmaceuticals: Honoraria, Research Funding. Cartron:Roche: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.4674.4674

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 14 ( 2014-10-02), p. 2196-2202

Abstract: In this phase 1/2 study, obinutuzumab (GA101) monotherapy was active in patients with relapsed or refractory CLL. Best overall response was lower in phase 2 vs phase 1, possibly due to higher baseline tumor burden resulting in lower treatment exposure.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2014-07-586610

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1907-1907

Abstract: Introduction: Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway is insufficient to induce clinical response in relapsed or refractory (R/R) multiple myeloma (MM). We postulated that combining atezolizumab (A; anti-PD-L1) with daratumumab (D; anti-CD38), which targets myeloma cells and has immunomodulatory activity, may alter the tumor microenvironment (TME) to favor cytotoxic T-cell activation and clinical activity. To assess the immunologic efficacy of this combination, we studied changes in CD8+ T cells in D-naïve and D-refractory pts from a Phase Ib study (GO29695; NCT02431208). Methods: Flow cytometry was performed using longitudinal peripheral blood (PB) and bone marrow aspirates (BMA) to characterize CD8+ cytotoxic T cells using 8 color flow panels. RNA sequencing (RNAseq) and dual-plex immunohistochemistry (IHC) (CD138/CD8, CD8/Ki-67, CD138/osteoclast) were performed using longitudinal CD138+ fraction and bone biopsies, respectively. For IHC, CD138+ cell masses of 〉 5000μm2 were defined as tumor clusters. Osteoclasts were enumerated based on TRAP positivity and morphology. Table 1 shows on-treatment changes in Cohorts D1-D3. Table 2 shows baseline data in Cohorts A, B, D1-D3, and E. The median (bootstrap 95% CI) is used to describe the data. Results: 9/36 (25%) pts in cohorts D1-3 showed clinical efficacy (partial response or better); all were D-naïve. We studied CD8+ T-cell activation and proliferation (%CD8+HLA-DR+Ki-67+), the pharmacodynamic marker for A (Herbst et al. Nature 2014), in PB. All D-naive pts showed on-treatment increase in %CD8+HLA-DR+Ki-67+ cells in the periphery (C1D15-C2D1) compared to baseline, which was not observed in D-refractory pts (Table 1). In BMA, the increase in %CD8+HLA-DR+Ki-67+ (C2D15-C4D1) was observed in D-naïve pts with clinical response to A-D (sensitive), but not in non-responders (resistant) or D-refractory pts (all resistant), suggesting that sensitive pts have an immune-supportive TME. Preliminary IHC staining also showed an increase in CD8+Ki-67+ T cells in two responders after treatment. Gene enrichment analysis (RNAseq data, n=20) showed upregulation of an innate immune response signature, which appeared to be driven by a 'macrophage activation' gene signature post-treatment, in the CD138+ fraction of responders. To understand the mechanisms regulating sensitivity to treatment, we studied the spatial localization of CD8+ T cells with respect to CD138+ tumor cells by IHC. A higher density of CD8+ T cells within tumor clusters was seen at baseline in sensitive versus resistant pts, but this was not observed outside of tumor clusters (Table 1). In addition, the number of osteoclasts in the tumor region was higher in resistant pts, suggesting that these cells may contribute to the inhibition of T-cell function as reported(An et al. Blood 2016). This hypothesis was further supported by higher osteoclast numbers in D-refractory pts at baseline (Table 2), for whom an on-treatment increase in %CD8+HLA-DR+Ki-67+ cells was not observed in PB or BMA. Interestingly, higher median fluorescence intensity of PD-1 on CD8+ T-effector cells and on CD8+ T-effector memory cells was observed at baseline in D-naïve relative to D-refractory pts, while the level of PD-L1 expression on tumor cells was similar. An increase in activated proliferating T cells (%CD8+HLA-DR+Ki-67+) observed after treatment in D-naïve responders suggests that high PD-1 expression in this subset is not a marker of CD8+ T-cell exhaustion, but of functional capability. Conclusions: Clinical efficacy of A-D therapy in R/R MM pts is associated with higher CD8+ cell density in tumor clusters and lower osteoclast numbers in the tumor region at baseline, and an on-treatment increase in activated CD8+ T-cell populations in the bone marrow. The lack of a D-monotherapy arm in this study makes it difficult to assess the individual contribution of A to T-cell activation. The data presented, albeit a small number of samples from a Phase Ib study, support the hypothesis that the TME, including CD8+ T cells, tumor cells, and cells of myeloid lineage such as osteoclasts, has significant impact on the immunologic and clinical efficacy of combination therapy. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential for long-term disease control. Disclosures Raval: Roche: Employment, Equity Ownership. Cho:Agenus: Research Funding; Genentech: Honoraria, Research Funding; Takeda: Research Funding; BMS: Consultancy; The Multiple Myeloma Research Foundation: Employment; Celgene: Honoraria, Research Funding; GSK: Consultancy. Green:Genentech Inc.: Employment. Wassner Fritsch:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ma:Genentech: Employment. Chang:Roche Canada: Employment. Yan:F. Hoffmann-La Roche Ltd, Mississauga, Canada: Employment. Kockx:HistoGeneX: Equity Ownership. Shen:Genentech, Inc.: Employment. Huw:Roche/ Genentech: Employment, Equity Ownership. Balestiere:Genentech: Employment. Lipkind:Roche/Genentech: Employment. Huang:F. Hoffmann-La Roche Ltd: Employment. Byrtek:Genentech: Employment; Roche: Equity Ownership. Colburn:Genentech: Employment; Roche: Equity Ownership. Wong:Celgene Corporation: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Fortis: Research Funding; Juno: Research Funding. Venstrom:F. Hoffmann-La Roche Ltd: Employment. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. OffLabel Disclosure: Atezolizumab (atezo) is a programmed death-ligand 1 (PD-L1) blocking antibody. In the United States, atezo is approved for treatment of pts with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy (chemo) and whose tumors express PDââ‚â'¬Ã'ÂL1, or are not eligible for any platinumââ‚â'¬Ã'Âcontaining chemo regardless of PDââ‚â'¬Ã'ÂL1 status, or have disease progression during or following any platinum-containing chemo, or within 12 months of neoadjuvant or adjuvant chemo. Atezo is also approved: in combination with bevacizumab, paclitaxel and carboplatin for first-line treatment of pts with metastatic non-squamous non-small-cell lung carcinoma (NSCLC) with no EGFR or ALK genomic tumor aberrations, and for pts with metastatic NSCLC who have disease progression during or following platinum-containing chemo; in combination with paclitaxel protein-bound for the treatment of adults with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1; and in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer. Atezo is not approved for treatment of pts with multiple myeloma.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123652

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3655-3655

Abstract: Abstract 3655 Obinutuzumab (GA101) is a type II glycoengineered, humanized anti-CD20 monoclonal antibody that has increased antibody-dependent cellular cytotoxicity and direct cell death activity but lower complement-dependent cytotoxicity compared with type I anti-CD20 antibodies such as rituximab and ofatumumab. GA101 is in clinical development for the treatment of lymphoma and chronic lymphocytic leukemia. The Phase I/II study BO20999 has evaluated the efficacy and safety of GA101 monotherapy in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (aNHL). Here, we report updated Phase II results including progression-free survival (PFS) and best overall response (BOR). Patients (n = 40) were randomized to receive GA101 (D1, D8 and D22, then 3-weekly for total of 9 infusions) at either a high dose (1,600 mg on D1 and D8, then 800 mg thereafter; 1,600/800 mg cohort; n = 19), or a flat low dose of 400 mg (400/400 mg cohort; n = 21). Baseline patient characteristics were similar for both cohorts (Table 1). The median observation time for all patients was 9.5 months (0.3–26.1 months). BOR rates are given in Table 2, with 8/25 diffuse large B-cell lymphoma (DLBCL) patients (32%) and 4/15 mantle cell lymphoma (MCL) patients (27%) responding to GA101. Among the patients with rituximab-refractory disease, a response was observed in 1/13 patients (7.7%) and 4/12 patients (33.3%) treated in the 400/400 mg and 1,600/800 mg cohorts, respectively. Of these, 4 patients (1,600/800 mg cohort) had a response duration 〉 6 months, with 2 patients having an ongoing response (response duration: 9.8, 16.5+, 19.5 and 20.0+ months). Median PFS for patients with DLBCL (Figure 1) was 1.9 months (range: 0.3–15.7 months) for the 400/400 mg cohort and 2.7 months (range: 0.2–22.3) months) for the 1,600/800 mg cohort (hazard ratio: 0.70; 95% CI: 0.30–1.66). For the DLBCL subgroup, response duration was 3.1, 3.1+, 5.8, 16.5+ and 19.5 months for the 5 responders in the 1,600/800 mg cohort, compared with 6.3, 8.6 and 9.8 months for the 3 responders in the 400/400 mg cohort. Individual response data indicated that 2 MCL patients had an ongoing response for ≥ 20 months (20.0 and 20.4 months). GA101 was well tolerated in both cohorts. Infusion-related reactions (IRRs; all grades) were the most common adverse event (AE), occurring in 81% of patients in the 400/400 mg cohort and 68% of patients in the 1600/800 mg cohort. Grade 3/4 AEs occurring in 〉 5% of patients across both cohorts included IRRs (10%), tumor lysis syndrome (10%), cardiac failure (not treatment-related; 10%), anemia (14%) and thrombocytopenia (14%) in the 400/400 mg cohort and IRRs (5%) and anemia (5%) in the 1,600/800 mg cohort.Table 1.Baseline patient characteristicsCharacteristic400/400 mg (n = 21)1,600/800 mg (n = 19)All (n = 40)Median age, years (range)70 (43–80)72 (22–85)71 (22–85)Histology, nDLBCL101525MCL11415Median number of prior treatments, n (range)4 (1–17)3 (1–6)3 (1–17)Previous rituximab, n211940Rituximab refractory*, n131225Prior stem cell transplant, n268DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.*Rituximab refractory defined as patients who had a response of 〈 6 months or who failed to respond to a rituximab-containing regimen (rituximab monotherapy or in combination with chemotherapy) at any point during their treatment history.Table 2.Best overall response according to diagnosis and cohortDLBCLMCLResponse, n (%)400/400 mg (n = 10)1,600/800 mg (n = 15)400/400 mg (n = 11)1,600/800 mg (n = 4)Complete response (CR)0 (0.0)3 (20.0)2 (18.2)0 (0.0)CR unconfirmed1 (10.0)0 (0.0)0 (0.0)0 (0.0)Partial response2 (20.0)2 (13.3)0 (0.0)2 (50.0)Stable disease1 (10.0)1 (6.7)3 (27.3)0 (0.0)Progressive disease5 (50.0)9 (60.0)6 (54.5)2 (50.0)No response assessment1 (10.0)0 (0.0)0 (0.0)0 (0.0)DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.Figure 1.Progression-free survival for patients with diffuse large B-cell lymphomaFigure 1. Progression-free survival for patients with diffuse large B-cell lymphoma In conclusion, GA101 shows encouraging single-agent efficacy in these heavily pretreated patients with relapsed/refractory aNHL (DLBCL or MCL). A Phase III trial of rituximab plus CHOP vs GA101 plus CHOP in first-line DLBCL has recently started. Disclosures: Morschhauser: Roche: Honoraria; Celgene: Consultancy, Honoraria. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria; LFB: Honoraria. Milpied:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wenger:Roche: Employment. Wassner-Fritsch:Roche: Employment. Asikanius:Roche: Employment. Salles:Roche: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.3655.3655

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 270-270

Abstract: Abstract 270 Obinutuzumab (GA101), the first type II, glycoengineered, humanized anti-CD20 monoclonal antibody in clinical development, has shown single-agent activity in Phase I and II studies in follicular lymphoma (FL), but no studies have so far examined the safety and activity of GA101 in combination with chemotherapy, or compared GA101 dose levels in large cohorts. This study evaluates the feasibility, safety and efficacy of GA101 in combination with standard chemotherapy regimens for FL at two different doses of GA101. Patients with relapsed or refractory FL (n=56) were stratified by chemotherapy regimen based upon prior treatment history (cyclophosphamide/doxorubicin/vincristine/prednisone [6–8 21 day cycles; n=28] or fludarabine/cyclophosphamide [4–6 28 day cycles; n=28] ). Patients were then randomized to one of two GA101 dosing regimens: 1,600 mg on Days 1 and 8 of cycle 1 then 800 mg for subsequent cycles (1,600/800 mg) or 400 mg in all cycles (400/400 mg). These regimens represent a range of active doses in indolent lymphoma, based upon Phase I and II trials in which there were no dose-limiting toxicities. Responding patients were offered maintenance treatment for 2 years or until progression. The primary objective was safety, with response rate a secondary objective. Response was assessed at the end of induction using International Working Group response criteria (Cheson, et al. J Clin Oncol 1999), modified to classify unconfirmed complete response as partial response. Baseline characteristics were similar for both groups (G-CHOP and G-FC, respectively): median age 62.5 and 61.0 years; low-risk FLIPI 29% in both groups; median prior treatments (range) 1 (1–3) and 2 (1–6); bone marrow involvement 25% and 26%; Ann Arbor stage III–IV at study entry 64% and 82%. All patients (28/28) in the G-CHOP arm and 22/28 patients in the G-FC arm completed treatment. Reasons for withdrawal (G-FC arm) were neutropenia (n=3), rash (n=1), infection (n=1) and insufficient response (n=1). The most common AEs in both groups were infusion-related reactions (all grades: 64% G-CHOP; 79% G-FC; Grade 3/4: 7% G-CHOP; 7% G-FC), mostly during the first infusion. Grade 3 or 4 neutropenia was reported in 39% of G-CHOP patients and 50% of G-FC patients. Of 190 cycles of G-CHOP delivered, 11 cycles (6%) were delayed in 8 patients for neutropenia or infection (6 cycles delayed by 1 week; 5 cycles delayed by 2 weeks). Dose of any CHOP component was reduced in 29% of patients, in 5 patients for neuropathy and in 1 patient each because of neutropenia, infection and allergic rhinitis. In the G-FC group, 14 of 135 delivered cycles (10%) were delayed in 10 patients for hematologic toxicity or infections (10 cycles delayed by 1 week; 4 cycles delayed by 2 weeks). Nine of these patients also had a dose reduction in both cytostatic components of the regimen with a further patient having a dose reduction only, for an overall dose reduction in 36% of patients. Three deaths were reported following G-FC induction treatment (progressive disease, n=1; underlying Parkinson's disease, n=1; and chronic obstructive pulmonary disease during maintenance, n=1), with none considered to be treatment-related. There was no evidence for increased toxicity with the 1,600/800 mg dose compared with the 400/400 mg dose of GA101. The overall response rate (ORR) at the end of induction was 96.4% in the G-CHOP group (39.3% complete response [CR]) and 92.9% in the G-FC group (50.0% CR) (Table). Data from the G-CHOP cohort were compared in a matched-pair analysis to the rituximab plus CHOP (R-CHOP) arm from study M39022 (EORTC 20981) in a similar patient population. Response rates to G-CHOP compared favorably with response rates to R-CHOP.Response rates at end of inductionResponse, n (%)G-CHOPG-FCOverall response27 (96.4)26 (92.9)Complete response11 (39.3)14 (50.0)Partial response16 (57.1)12 (42.9)Stable disease1 (3.6)0Progressive disease01 (3.6)Not assessed01 (3.6) In conclusion, GA101 can be combined safely with chemotherapy regimens used in the treatment of FL, and demonstrates a high level of activity compared with historical controls. G-CHOP could be delivered at the protocol-specified 3-weekly interval in most patients. G-FC in a more heavily pretreated population showed worse tolerability. Following these promising results, GA101 will be studied in combination with CHOP and other chemotherapies in a randomized Phase III study against the standard of care, R-CHOP. Disclosures: Cartron: Roche: Consultancy, Honoraria. Morschhauser:Roche: Honoraria; Celgene: Consultancy, Honoraria. Salles:Roche: Consultancy, Honoraria. Wenger:Roche: Employment. Asikanius:Roche: Employment. Wassner-Fritsch:Roche: Employment. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.270.270

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3686-3686

Abstract: Abstract 3686 GA101 is a glycoengineered, humanized type II anti-CD20 monoclonal antibody (mAb) anticipated to have superior B-cell-depleting activity to rituximab in vivo on the basis of its enhanced FcR binding and because of the direct cell death induced by type II CD20 mAbs. GA101 has shown significant single-agent activity in Phase I and II studies in patients with FL, and activity in combination with CHOP and fludarabine plus cyclophosphamide in patients with resistant/refractory FL in the first part of this Phase I trial (Radford et al. ASH 2011; abstract 270). This report describes the safety, toxicity, and efficacy of remission induction of GA101 in combination with CHOP or bendamustine in 81 patients aged 〉 18 years with treatment-naïve CD20+ grade 1–3b FL with at least one measurable lesion (longest diameter 〉 1.5 cm by CT scan). All patients received a flat dose of GA101 (1,000 mg on Days 1 and 8 of Cycle 1 and Day 1 of subsequent cycles) combined with either 6–8 cycles of CHOP (every 3 weeks) or 4–6 cycles of bendamustine (90 mg/m2Days 1 and 2 every 4 weeks) on a per center choice basis. Patients achieving complete response (CR) or partial response (PR) were eligible to receive GA101 maintenance therapy (1,000 mg) every 3 months for 2 years or until progression. The primary objective was safety, and secondary objectives included overall response rate (ORR), CR rate, and pharmacokinetics. Response was assessed at the end of induction using International Working Group response criteria; unconfirmed CRs were classified as PRs. 40 patients received G-CHOP and 41 G-bendamustine. Baseline characteristics were similar for both groups: median age 53.5 and 57 years; bone marrow involvement 53% and 49%; bulky disease (≥ 7 cm) 45% and 41%; Median time from diagnosis was only 1.20 months for both groups, high-risk FLIPI status (3–5) 45% and 46%, and intermediate risk (FLIPI 2) 38% and 34%. 38 G-CHOP and 37 G-bendamustine patients completed all cycles of planned induction therapy. Three patients withdrew without any response assessment. In the G-CHOP arm, one withdrawal was due to a GA101-associated infusion-related reaction [IRR] after Cycle 1 and another patient was found to be ineligible and withdrawn after Cycle 1. In the G-bendamustine arm one patient withdrew consent after Cycle 2. Three other patients were withdrawn after interim response assessment, none for safety reasons (insufficient response in the G-bendamustine arm and administrative reasons for two in the G-CHOP arm). The most frequent adverse events were IRRs (all grades: 58% G-CHOP; 59% G-bendamustine; grade 3/4: 5% G-CHOP; 10% G-bendamustine). No Grade 3/4 IRRs occurred after cycle 3. Grade 3/4 neutropenia was reported in 43% of patients in the G-CHOP arm and 29% of patients in the G-bendamustine arm during induction, resulting in delayed delivery of 7.0% and 4.8% of chemotherapy cycles. All delays but one were no longer than 2 weeks. Grade 3/4 infections occurred in 23% of patients receiving G-CHOP and 10% of patients receiving G-bendamustine. Approximately half of these were neutropenic infections or sepsis and all resolved with appropriate management. ORR at the end of the induction period was 95% (38/40) in the G-CHOP arm (CR rate 35%) and 92.7% (38/41) in the G-bendamustine arm (CR rate 39%) (Table). Serum GA101 concentrations increased during the induction period and were similar for both regimens. Mean Cmax was 300–600 μg/mL and Cmin100–300 μg/mL. Following the final administration, a decline in GA101 serum concentration was seen that was similar for the two treatment combinations. In conclusion, efficacy and safety data for GA101 combined with CHOP and bendamustine are encouraging for first-line treatment of patients with FL. Based on these promising results GA101 is now being studied in combination with various chemotherapy regimens in a randomized Phase III study against the standard of care, rituximab-based immunochemotherapy. Patients, n (%) G-CHOP (n = 40) G-bendamustine (n = 41) Efficacy     Overall response 38 (95.0) 38 (92.7)     Complete response* 14 (35.0) 16 (39.0)     Partial response 24 (60.0) 22 (53.7)     Stable disease 0 1 (2.4)     Progressive disease 0 1 (2.4)     Not assessed 2 (5.0) 1 (2.4) Safety     Grade 3/4 IRRs 2 (5.0) 4 (9.8)     Grade 3/4 neutropenia 17 (43) 12 (29)     Grade 3/4 infections 9 (23) 4 (10) * CRu were classified as PR Disclosures: Dyer: Roche: Consultancy, Research Funding. Off Label Use: Obinutuzumab (GA101) in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) or Bendamustine in Patients with Previously Untreated Follicular Lymphoma (FL). Grigg:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Support of (other) clinical trials and Scientific Advisory Boards Other. Rule:Roche: Consultancy, Research Funding. Lei:Roche: Employment. Wassner-Fritsch:Roche: Employment. Wenger:Roche: Employment. Marlton:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.3686.3686

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7