Background: Patients with relapsed/refractory B-cell lymphomas have limited treatment options. GERSHWIN is an open-label, single-arm, phase Ib study of obinutuzumab monotherapy in Chinese patients with histologically docu- mented CD20 relapsed/refractory chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL). The primary outcome measure of pharmacokinetics has been previously reported. We now present data on the secondary endpoint measures (e.g., safety, and efficacy and pharmacodynamics). Methods: Patients received 1000 mg obinutuzumab intravenously on days 1, 8, and 15 of cycle 1 (CLL patients; first dose split over 2 days), and on day 1 of cycles 2–8. Each cycle lasted for 21 days; the treatment period was 24 weeks. All subjects receiving at least one dose of obinutuzumab were included in the analysis of safety, efficacy, as well as pharmacodynamics. Results: A total of 48 patients (> 18 years of age) were enrolled (CLL: 12; DLBCL: 23; FL: 13). The subjects received a median of two lines of anticancer treatment prior to the enrollment. Thirty-five patients (72.9%) had at least one adverse event (AE). The most frequent AE was infusion-related reactions (15 patients; 31.3%), followed by pyrexia (11 patients; 22.9%). Treatment-related AEs were reported in 28 patients (58.3%), and included one death (interstitial lung disease). End-of-treatment (EoT ) response rate was 33.3%. Best overall response rate was 47.9%. Most CLL patients achieved a partial response at EoT (58.3%). CD19 depletion occurred in 75.0% of the patients with CLL, and all patients with FL and DLBCL. Conclusions: The safety and efficacy of obinutuzumab monotherapy in Chinese patients with B-cell lymphomas were similar to that observed in previous studies in non-Chinese patients; no new safety signals were observed. Clinical trial registration ID NCT01680991 Keywords: Obinutuzumab, B-cell lymphoma, Chronic lymphocytic leukemia, Chinese patients Background population is approximately one-tenth of that in West- B-cell lymphoproliferative disorders range from slow- ern countries . In a nationwide collaborative study of growing indolent diseases, such as chronic lymphocytic 10,002 lymphoma patients by Li and colleagues in , leukemia (CLL) and follicular lymphoma (FL), to more DLBCL accounted for 50.2% of all cases of common aggressive diseases, such as diffuse large B-cell lym - B-cell lymphoma in China; FL and CLL/small lympho- phoma (DLBCL). The incidence of CLL in the Chinese cytic leukemia accounted for 8.3% and 6.4%, respectively. Most B-cell lymphomas are characterized by the expres- sion of C D20 , a membrane antigen implicated in cell- *Correspondence: email@example.com cycle initiation and differentiation [ 3]. Anti-CD20 Department of Medical Oncology, Beijing Key Laboratory of Clinical monoclonal antibodies, such as rituximab, have been Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union shown to be effective for B-cell lymphomas when used Medical College, Beijing 100021, P. R. China in combination with chemotherapeutic agents [4–7]. Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Qin et al. Cancer Commun (2018) 38:31 Page 2 of 9 However, many patients eventually relapse or become guidelines for Good Clinical Practice. Approval from refractory upon repeated exposure. Thus, there is an Institutional Review Boards and/or Independent Ethics ongoing need to develop more therapies that could effec - Committees was obtained before the trial started. tively prolong remission and/or improve survival. Patients received a maximum of eight treatment Obinutuzumab (GA101; GAZYVA/GAZYVARO) is a cycles (24 weeks), each lasting for 21 days. On day 1 of novel glycol-engineered type II anti-CD20 monoclonal each cycle, obinutuzumab was given intravenously at a antibody, and has shown promising activity in phase Ib/ dose of 1000 mg. In cycle 1, additional doses of obinutu- II studies in patients with B-cell malignancies [8–11]. In zumab were administered on days 8 and 15. In patients stage II of the pivotal phase III CLL11 study in previously with CLL, the first infusion of obinutuzumab on cycle 1 untreated CLL patients receiving background chloram- was given as a split dose over 2 days (100 mg at a rate of bucil, obinutuzumab significantly prolonged progression- 25 mg/h over 4 h on day 1; 900 mg starting at 50 mg/h free survival (PFS) in comparison to rituximab (median on day 2, increasing by 50 mg/h every 30 min, to a maxi- PFS 29.2 vs. 15.4 months; hazard ratio 0.40; 95% confi - mum of 400 mg/h) to minimize the risk of infusion- dence interval, 0.33–0.50, P < 0.001) [12, 13]. Based on related reactions (IRRs). For the first infusion in patients results from the CLL11 study, obinutuzumab in combina- with NHL, obinutuzumab was administered at an initial tion with chlorambucil has been approved for the treat- rate of 50 mg/h, and increased by 50 mg/h every 30 min ment of patients with previously untreated CLL in more to a maximum of 400 mg/h if there were no signs of IRRs. than 60 countries [14, 15]. Obinutuzumab has also shown If the first obinutuzumab infusion was well tolerated by activity in patients with relapsed CD20 indolent non- all study subjects, subsequent infusions were initiated at Hodgkin lymphoma (NHL). In the phase II GAUSS study 100 mg/h and increased by 100 mg/h increments every in relapsed CD20 indolent NHL patients, obinutuzumab 30 min to a maximum of 400 mg/h. produced a higher overall response rate than rituximab (44.6% vs. 33.3%; P = 0.08) . The efficacy and safety Study population of obinutuzumab has also been assessed in the phase III Adult patients (> 18 years of age) with histologically doc- GADOLIN study in patients with rituximab-refractory umented CD20 relapsed/refractory CLL, DLBCL, or FL; indolent NHL . In this study, obinutuzumab plus an Eastern Cooperative Oncology Group performance bendamustine was associated with a 45% reduction in the status of 0 or 1; and a life expectancy of > 6 months were risk of disease progression or death (assessed by an inde- eligible. With the exception of CLL, all patients had at pendent review committee) vs. bendamustine induction least one bidimensionally measurable lesion (> 1.5 cm alone. Based on the results from GADOLIN, obinutu- in its largest dimension by computed tomography). For zumab has been approved for rituximab-refractory FL in patients with CLL, circulating lymphocyte cell assess- the US and Europe [14, 15]. In all three trials, the adverse ments were an acceptable method of measurement. events (AEs) related to obinutuzumab alone, or in combi- To be eligible, patients with DLBCL or FL must have nation with other chemotherapeutic agents, were gener- relapsed after, or had been refractory to, at least one ally manageable. standard chemotherapy, with or without rituximab. CLL To date, no ethnic sensitivity associated with the use of patients must have relapsed after, or had been refrac- obinutuzumab has been reported. We have completed a tory to at least one chemotherapy regimen. Relapse was trial (GERSHWIN; trial registration ID: NCT01680991) defined as disease recurrence after any documented to evaluate obinutuzumab in Chinese patients with history of response [complete response (CR), CR with CD20 relapsed/refractory malignant B-cell lymphomas. incomplete bone marrow recovery (CRi; CLL patients The primary outcome measure of pharmacokinetic pro - only) or partial response (PR)] that lasted ≥ 6 months. file of obinutuzumab following repeated intravenous dos - Refractoriness was defined as progression or stable dis - ing has been previously reported . Here, we report ease (SD) on treatment, or any response that was fol- the results of secondary outcome measures: safety, toler- lowed by progression < 6 months after treatment. All ability, efficacy, and pharmacodynamics. patients provided written informed consent to partici- pate in the study. Patients and methods Key exclusion criteria included the following: use of Study design and treatment any investigational monoclonal antibody therapy within GERSHWIN was an open-label, multicenter, single-arm, 6 months before the trial started; use of any anticancer phase Ib study, conducted in four sites in China between vaccine; prior treatment with rituximab or radioimmuno- September 6, 2012 and August 15, 2013. The study was therapy within 3 months of study entry; history of severe conducted in accordance with the Declaration of Helsinki anaphylactic reactions to humanized or murine mono- and the International Conference on Harmonization clonal antibodies; central nervous system lymphoma; and Qin et al. Cancer Commun (2018) 38:31 Page 3 of 9 history of other malignancy or evidence of significant, Results uncontrolled concomitant diseases (including cardiovas- Patients cular and pulmonary diseases). Full inclusion and exclu- A total of 56 patients were screened for eligibility, among sion criteria are shown in Additional file 1. which 48 were enrolled (Fig. 1): 12 (25.0%) with CLL, 23 (47.9%) with DLBCL, and 13 (27.1%) with FL. Most Study endpoints and procedures patients had advanced disease [Binet B or C (CLL); Ann Safety and tolerability Arbor III or IV (NHL)] (Table 1). The median number of Safety assessments included AEs, serious AEs (SAEs) and previous anticancer treatments was 2 or 3 depending on AEs of special interest [AESI; e.g., IRRs, serious neutro- disease type. Twenty-eight subjects (58.3%; 28/48) com- penia, infections, and tumor lysis syndrome (TLS)]. AEs pleted the planned treatment. Obinutuzumab was dis- were summarized using the Medical Dictionary for Regu- continued in 17 (35.4%) patients during cycles 1–4 and latory Activities system organ class, and graded using the three (6.3%) patients during cycles 5–8. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included Safety and tolerability laboratory assessments (hematology, biochemistry, and All 48 enrolled patients received at least one dose of urinalysis), vital signs, and electrocardiograms (ECGs); obinutuzumab and were included in the safety analy- tests for immunogenicity [human antichimeric antibod- sis. Median treatment duration was 20.8 weeks, with ies (HACA) and human antihuman antibodies (HAHA)] a median cumulative dose of 10,000 mg (Additional were also performed. file 2). A total of 141 AEs were reported, mostly grade I–II (116/141, 82.3%). The number of patients who Efficacy experienced at least one AE was 35 (CLL: 10/12, 83.3%; Treatment response was assessed according to the DLBCL: 18/23, 78.3%; FL: 7/13, 53.8%). The most com - International Workshop to Standardize Response cri- mon AE was IRR (CLL: 7/12, 58.3%; DLBCL: 5/23, 21.7%; teria for NHL , and 2008 Guidelines of the Interna- FL: 3/13, 23.1%), with the highest rate in CLL patients tional Workshop on CLL . End-of-treatment (EoT) (Additional file 3). Other common AEs included pyrexia response was assessed 1 month after the cycle 8, day 1 (CLL: 6/12, 50.0%; DLBCL: 3/23, 13.0%; FL: 2/13, 15.4%) infusion, or for treatment withdrawals after cycle 4. For and cough (CLL: 4/12, 33.3%; DLBCL: 1/23, 4.3%; FL: 0). patients with CLL, a further confirmation of response No patients withdrew from treatment as a result of treat- was performed 2 months after EoT. Best overall response ment-related AEs. was assessed at any time point during the study, prior to Twenty-five grade III–V AEs were reported, with a new anti-lymphoma/leukemia therapy. For both EoT and seemingly higher rate in the CLL subgroup (CLL: 7/12, best overall response, patients were regarded as respond- 58.3%; DLBCL: 5/23, 21.7%; FL: 3/13, 23.1%; Additional ers if they demonstrated CR, CR unconfirmed (CRu), CRi file 4). Infections and infestations were the most common (CLL patients only), or PR. Patients were considered to grade III–V AEs across all three subgroups (CLL: 3/12, be non-responders if they demonstrated SD or progres- 25.0%; DLBCL: 2/23, 8.7%; FL: 2/13, 15.4%) (Additional sive disease (PD), or were missing response assessments. file 4), with pneumonia accounting for two of the three Follow-up was carried out up to 1 year after the last dose. events in the CLL subgroup. Grade III–V thrombocyto- penia occurred in 16.7% (2/12) of the CLL patients. Neu- Pharmacodynamics tropenia occurred in 15.4% (2/13) of the FL patients. + + CD19 depletion was defined as CD19 cell count Thirteen SAEs were reported in nine patients, of 9 9 < 0.07 × 10 /L; recovery was defined as ≥ 0.07 × 10 /L. which five were infections and infestations (CLL: 3/12, The duration of depletion was defined as the time 25.0%; DLBCL: 1/23, 4.3%; FL: 1/13, 7.7%; Additional between the first assessment of depletion and the first file 5). One SAE (grade III, pneumonia) led to the with- assessment when C D19 B-cell count returned to at least drawal of treatment in a patient with CLL, but was the depletion level from baseline and was not followed considered unrelated to treatment with obinutuzumab. by any further depletion time to recovery was defined In this case, pneumonia started on day 52, treatment as the time between the beginning of depletion and the was discontinued on day 66, and the patient was with- first value after EoT that was ≥ 0.07 × 10 /L, not followed drawn from the study on day 90 (Table 2). The total rate exclusively by depleted values. of SAEs appeared higher in the CLL subgroup (Addi- tional file 5). Six (6/48; 12.5%) patients reported a total Analytical plan of eight AESIs, including serious IRR (CLL: 1/12, 8.3%), Only descriptive analyses were performed; no formal serious neutropenia (CLL: 1/12, 8.3%; FL: 2/13, 15.4%), hypothesis was tested. and serious infections (CLL: 3/12, 25.0%; DLBCL: Qin et al. Cancer Commun (2018) 38:31 Page 4 of 9 Assessed for eligibility (n = 56) Screening failures (n = 8) Enrolled and started obinutuzumab treatment (n = 48) CLL (n = 12) DLBCL (n = 23) FL (n = 13) Disconnued study during treatment (n = 20) CLL (n = 3) DLBCL (n = 15) FL (n = 2) Completed obinutuzumab treatment (n = 28) CLL (n = 9) DLBCL (n = 8) FL (n = 11) Disconnued study during follow-up (n = 11) CLL (n = 6) DLBCL (n = 3) FL (n = 2) Completed the study (n = 17) Fig. 1 Patient flow through the study. Reasons for screening failures: three patients tested positive for Hepatitis B core antibody, two patients did not meet inclusion criteria number 1 (histologically documented CD20 malignant disease), one patient did not meet inclusion criteria number 2 (relapsed/refractory CLL, FL, or DLBCL), one patient had positive hepatitis serology, and one patient had a hemoglobin value of 56 g/L. Reasons for discontinuation during treatment: AE (pneumonia), n = 1; PD, n = 9; protocol violation, n = 1; withdrawal by the patient, n = 3; physician decision, n = 6. Reasons for discontinuation during follow-up: death, n = 2; withdrawal by the patient, n = 4; PD, n = 1; physician decision, n = 2; other, n = 2 (patient could not visit due to poor physical condition, progression of disease confirmed in another hospital). CLL chronic lymphocytic leukemia, DLBCL diffuse large B-cell lymphoma, FL follicular lymphoma 1/23, 4.3%; FL: 1/13, 7.7%). The patient with a serious There were no clinically significant abnormal labora - IRR also developed a serious infection (pneumonia). tory test results, ECGs, or vital signs during the treat- No cases of TLS were reported. Two deaths occurred ment period. Three clinically significant abnormal ECGs during the follow-up period: one in the CLL subgroup were recorded prior to dosing. On cycle 1, day 1, two [interstitial lung disease (interstitial pneumonia; no patients with CLL and one with DLBCL had detectable testing for Pneumocystis jiroveci was performed), which HACA. At the 6-month follow-up visit, one with FL had occurred 60 days after the last treatment dose] was detectable HAHA. considered treatment-related; the other after disease No evidence of hepatitis B virus (HBV) reactivation progression in the FL group was considered unrelated was observed in any subject. Patients with CLL who were to treatment. positive for hepatitis B core antibodies (anti-HBc) and Qin et al. Cancer Commun (2018) 38:31 Page 5 of 9 Table 1 Demographics and disease characteristics of the subject who received at least one dose of obinutuzumab Variable CLL (n = 12) DLBCL (n = 23) FL (n = 13) Overall (n = 48) Age at baseline (years) Mean (sd) 60.7 (12.0) 53.3 (15.8) 55.1 (8.8) 55.6 (13.4) Gender [n (%)] Male 7 (58.3) 11 (47.8) 8 (61.5) 26 (54.2) Female 5 (41.7) 12 (52.2) 5 (38.5) 22 (45.8) Weight (kg) Mean (sd) 60.83 (11.44) 62.33 (9.86) 64.27 (12.49) 62.48 (10.85) Height (cm) Mean (sd) 161.0 (5.0) 164.1 (7.1) 166.3 (10.7) 163.9 (7.9) ECOG at baseline [n (%)] 0 2 (16.7) 8 (34.8) 8 (61.5) 18 (37.5) 1 10 (83.3) 15 (65.2) 5 (38.5) 30 (62.5) Ann Arbor stage at diagnosis [n (%)] I N/A 0 2 (15.4) 2 (5.6) II N/A 4 (17.4) 0 4 (11.1) III N/A 8 (34.8) 5 (38.5) 13 (36.1) IV N/A 7 (30.4) 3 (23.1) 10 (27.8) Missing N/A 4 (17.4) 3 (23.1) 7 (19.4) Binet stage [n (%)] Stage A 1 (8.3) N/A N/A 1 (8.3) Stage B 6 (50.0) N/A N/A 6 (50.0) Stage C 2 (16.7) N/A N/A 2 (16.7) Unknown 3 (25.0) N/A N/A 3 (25.0) Number of previous lines of treatment Median 2.0 2.0 3.0 2.0 Minimum–maximum 1–7 1–11 1–6 1–11 Best response of prior treatment [n (%)] CR 1 (8.3) 9 (39.1) 2 (15.4) 12 (25.0) PR 8 (66.7) 9 (39.1) 7 (53.8) 24 (50.0) SD 1 (8.3) 2 (8.7) 0 3 (6.3) PD 0 2 (8.7) 0 2 (4.2) Missing 2 (16.7) 1 (4.3) 4 (30.8) 7 (14.6) Duration of best response n 6 18 7 31 Mean (sd) (days) 355.2 (604.2) 152.5 (119.2) 159.4 (136.4) 193.3 (281.3) CLL chronic lymphocytic leukemia, CR complete response, DLBCL diffuse large B-cell lymphoma, ECOG Eastern Cooperative Oncology Group, FL follicular lymphoma, N/A not applicable, PR partial response, SD stable disease, sd standard deviation Patients were assessed according to Ann Arbor staging criteria for non-Hodgkin lymphoma and Binet staging criteria for CLL negative for hepatitis B surface antigen were eligible for Efficacy participation if HBV DNA was undetectable, but were The efficacy dataset included all 48 patients. EoT and required to undergo monthly HBV DNA testing during best overall response rate were higher in the CLL and the study period. Among the four patients with positive FL subgroups than in the DLBCL subgroup (Table 3). In anti-HBc at screening, one patient refused to undergo the CLL subgroup, the PR rate at EoT and best overall monthly HBV DNA testing and withdrew from the study, response rate were 58.3% (7/12) and 75.0% (9/12), respec- one patient withdrew before the protocol requirement tively. In the FL subgroup, PR rate at EoT and best overall for HBV DNA testing was implemented, and the remain- response rate were 46.2% (6/13) and 61.5% (8/13), respec- ing two patients underwent monthly testing with no indi- tively. In the DLBCL subgroup, EoT and best overall cation of HBV reactivation. response rate were 13.0% (1/23 CRu; 2/23 PR) and 26.1% Qin et al. Cancer Commun (2018) 38:31 Page 6 of 9 Table 2 Adverse events Variable CLL (n = 12) DLBCL (n = 23) FL (n = 13) Overall (n = 48) Number of patients with at least one AE 10 (83.3) 18 (78.3) 7 (53.8) 35 (72.9) Number of AEs 71 45 25 141 Number of deaths 1 (8.3) 0 1 (7.7) 2 (4.2) Number of patients withdrawn from study due to an AE 1 (8.3) 0 0 1 (2.1) Number of patients with at least one AE with fatal outcome 1 (8.3) 0 0 1 (2.1) SAE 5 (41.7) 3 (13.0) 1 (7.7) 9 (18.8) SAE leading to withdrawal from treatment 1 (8.3) 0 0 1 (2.1%) Related SAE 4 (33.3) 1 (4.3) 1 (7.7) 6 (12.5) AE leading to withdrawal from treatment 1 (8.3) 0 0 1 (2.1) AE leading to treatment interruption 4 (33.3) 3 (13.0) 2 (15.4) 9 (18.8) Related AE 9 (75.0) 12 (52.2) 7 (53.8) 28 (58.3) Related AE leading to treatment interruption 4 (33.3) 3 (13.0) 2 (15.4) 9 (18.8) Grade III–V AE (at greatest intensity) 7 (58.3) 5 (21.7) 3 (23.1) 15 (31.3) Percentages are based on n in the column headings. Multiple occurrences of the same AE in one individual are counted only once except for the ‘total number of AEs’ row, in which multiple occurrences of the same AE are counted separately Data are shown as n (%) AE adverse event, CLL chronic lymphocytic leukemia, DLBCL diffuse large B-cell lymphoma, FL follicular lymphoma, SAE serious adverse event Table 3 End of treatment and best overall response rate Variable CLL (n = 12) DLBCL (n = 23) FL (n = 13) Overall (n = 48) EoT response Best overall EoT response Best overall EoT response Best overall EoT response Best overall response response response response Responders, 7 (58.3) 9 (75.0) 3 (13.0) 6 (26.1) 6 (46.2) 8 (61.5) 16 (33.3) 23 (47.9) n (%) Non-respond- 5 (41.7) 3 (25.0) 20 (87.0) 17 (73.9) 7 (53.8) 5 (38.5) 32 (66.7) 25 (52.1) ers, n (%) 95% CI for 27.67–84.83 42.81–94.51 2.78–33.59 10.23–48.41 19.22–74.87 31.58–86.14 20.40–48.41 33.29–62.81 response rate CR, n 0 0 0 0 0 0 0 0 95% CI 0.00–26.46 0.00–26.46 0.00–14.82 0.00–14.82 0.00–24.71 0.00–24.71 0.00–7.40 0.00–7.40 CRi, n 0 0 0 0 0 0 0 0 95% CI 0.00–26.46 0.00–26.46 0.00–14.82 0.00–14.82 0.00–24.71 0.00–24.71 0.00–7.40 0.00–7.40 CRu, n (%) 0 0 1 (4.3) 1 (4.3) 0 0 1 (2.1) 1 (2.1) 95% CI 0.00–26.46 0.00–26.46 0.11–21.95 0.11–21.95 0.00–24.71 0.00–24.71 0.05–11.07 0.05–11.07 PR, n (%) 7 (58.3) 9 (75.0) 2 (8.7) 5 (21.7) 6 (46.2) 8 (61.5) 15 (31.3) 22 (45.8) 95% CI 27.67–84.83 42.81–94.51 1.07–28.04 7.46–43.70 19.22–74.87 31.58–86.14 18.66–46.25 31.37–60.83 SD, n (%) 1 (8.3) 1 (8.3) 2 (8.7) 6 (26.1) 4 (30.8) 4 (30.8) 7 (14.6) 11 (22.9) 95% CI 0.21–38.48 0.21–38.48 1.07–28.04 10.23–48.41 9.09–61.43 9.09–61.43 6.07–27.76 12.03–37.31 PD, n (%) 2 (16.7) 0 15 (65.2) 9 (39.1) 3 (23.1) 1 (7.7) 20 (41.7) 10 (20.8) 95% CI 2.09–48.41 0.00–26.46 42.73–83.62 19.71–61.46 5.04–53.81 0.19–36.03 27.61–56.79 10.47–34.99 Missing or non- 2 (16.7) 2 (16.7) 3 (13.0) 2 (8.7) 0 0 5 (10.4) 4 (8.3) evaluable, n (%) 95% CI for rates were constructed using Clopper–Pearson method. Patients were classified as missing or non-evaluable if no post-baseline response assessments were available or all post-baseline response baseline assessments were un-evaluable CLL chronic lymphocytic leukemia, CI confidence interval, CR complete response, CRi CR with incomplete bone marrow recovery (CRi; CLL patients only), CRu CR unconfirmed, DLBCL diffuse large B-cell lymphoma, EoT end of treatment, FL follicular lymphoma, PR partial response, SD stable disease Qin et al. Cancer Commun (2018) 38:31 Page 7 of 9 (1/23 CRu; 5/23 PR), respectively. No CR was reported in trials may have contributed the lower IRR rate in the GER- any patient. SHWIN study. However, it is important to note that such comparisons are limited by the differences in patient numbers and design between these studies. No TLS was Pharmacodynamics + 9 reported in the current study. Previous studies in Cauca- CD19 B-cell depletion (count < 0.07 × 10 /L) occurred in sian patients, including CLL11  and GAUGUIN [9, 11], 75.0% (9/12) with CLL, 100% (13/13) of the patients with reported neutropenia as a major AE after obinutuzumab FL, and 100% (23/23) with DLBCL. The FL subgroup treatment. In the current study, grade III–V neutropenia had the longest median duration of depletion, 465 days, was reported in three cases, but resolved spontaneously compared with 244 days for CLL and 92 days for DLBCL. or with treatment; none required dose adjustment/discon- Subsequently, 33.3% (4/12) of patients with CLL, 7.7% tinuation. One patient with CLL died of interstitial lung (1/13) with FL, and 4.3% (1/23) with DLBCL experienced + 9 disease on day 252 (82 days after the last dose of obinutu- B-cell recovery (CD19 B-cell count ≥ 0.07 × 10 /L). zumab); the infection started 60 days after the last dose and One patient with CLL and one with FL who experienced was considered treatment-related. B-cell recovery had PD: time to recovery was 419 days Obinutuzumab efficacy in the current study was simi - (CLL) and 331 days (FL), respectively. For the three lar to that seen in non-Chinese patients in previous stud- patients with CLL who did not have PD, the median time ies (e.g., GAUGUIN and the phase I Japanese dose-finding to recovery was 182 days, and for DLBCL (one patient study). The EoT response rate in the overall analysis was only), it was 515 days. 33.3% (CLL: 58.3%; DLBCL: 13.0%; FL: 46.2%) and the best overall response rate was 47.9% (CLL: 75.0%; DLBCL: Discussion 26.1%; FL: 61.5%). Most patients with CLL achieved a PR GERSHWIN showed that obinutuzumab monotherapy at EoT (7/12; 58.3%). In GAUGUIN phase II (of relapsed/ has acceptable safety and tolerability profiles in Chinese refractory CD20 indolent NHL patients; 85.0% had FL), patients with relapsed/refractory B-cell lymphomas; no overall response rates ranged from 21.4% to 50.0% in the FL new safety signals were observed. Obinutuzumab also subgroup (dependent on obinutuzumab dosage), and best showed encouraging efficacy, particularly in subjects with overall response rate ranged from 35.7% to 60.0% . In CLL. the phase I Japanese dose-finding study (66.7% of patients Consistent with previous reports in Caucasian popula- had FL), the EoT response rate was 58.3% . By com- tions , IRRs, pyrexia, and cough were the most com- parison, in GAUGUIN phase II (in patients with relapsed/ mon AEs in all three disease types in the current study. All refractory CD20 DLBCL and mantle cell lymphoma, IRRs occurred during or within 24 h after the end of the 62.5% DLBCL), EoT and best overall response rate in the obinutuzumab infusion; all were grade I or II, and manage- DLBCL subgroup were 28.0% and 32.0%, respectively . able. The rate of IRRs appeared to be highest in patients Limitations of the current study include the small sam- with CLL (58.3%). Recent findings by Illidge et al. in  ple size (n = 48) and lack of a control arm. Nevertheless, the and Freeman et al. in  suggest that CLL patients with + results are encouraging and are generally comparable with higher CD20 expression are at greater risk of develop- previous studies in non-Chinese patients. ing severe IRRs to obinutuzumab. The IRR rate observed in the current study was lower than reported by the GAU- Conclusions GUIN study despite similar intervention (monotherapy) The safety profile and efficacy of obinutuzumab monother - and patient characteristics (relapsed/refractory B-cell lym- apy in Chinese patients with CD20 malignant B-cell lym- phomas). In GAUGUIN, the rate of IRR in patients with + phomas was similar to that observed in previous studies relapsed/refractory CD20 CLL was 100% (13/13 and in non-Chinese patient populations. No new safety signals 20/20 in phase I and II, respectively) . In patients with + were observed. relapsed/refractory CD20 DLBCL/mantle cell lymphoma and indolent NHL in the GAUGUIN study, the IRR rate Additional files was 75.0% and 72.5%, respectively, and the majority were grade I or II and manageable [10, 11]. The IRR rate in our Additional file 1. Detailed inclusion and exclusion criteria. study was also lower than that reported in a phase I dose- Additional file 2. Study drug exposure. finding study of obinutuzumab in 12 Japanese patients Additional file 3. Incidence of AEs of any grade reported in ≥10% of with relapsed/refractory CD20 NHL, in which all patients patients (in any patient population). experienced an IRR . Awareness of recommended Additional file 4. Summary of patients with AEs NCI-CTCAE grade III–V. measures to prevent the development of IRR and other Additional file 5. Summary of SAEs. AEs during obinutuzumab therapy gained by some of the investigators in the current study during previous clinical Qin et al. Cancer Commun (2018) 38:31 Page 8 of 9 Abbreviations References AE: adverse event; AESI: AEs of special interest; CLL: chronic lymphocytic 1. Mak V, Ip D, Mang O, Dalal C, Huang S, Gerrie A, et al. Preservation of leukemia; CR: complete response; CRi: CR with incomplete bone marrow lower incidence of chronic lymphocytic leukemia in Chinese residents in recovery; CRu: CR unconfirmed; DLBCL: diffuse large B-cell lymphoma; ECGs: British Columbia: a 26-year survey from 1983 to 2008. Leuk Lymphoma. electrocardiograms; EoT: end-of-treatment; FL: follicular lymphoma; HACA 2014;55(4):824–7. : human antichimeric antibodies; HAHA: human antihuman antibodies; IRRs: 2. Li XQ, Li GD, Gao ZF, Zhou XG, Zhu XZ. Distribution pattern of lymphoma infusion-related reactions; NHL: non-Hodgkin lymphoma; PFS: progression- subtypes in China: a nationwide multicenter study of 10002 cases. J free survival; PR: partial response; SAEs: serious AEs; SD: stable disease; TLS: Diagn Concepts Pract. 2012;11(2):111–5. tumor lysis syndrome; PD: progressive disease. 3. Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non- Hodgkin’s lymphoma. N Engl J Med. 2008;359(6):613–26. Authors’ contributions 4. Coiffier B, Haioun C, Ketterer N, Engert AA, Tilly H, Ma D, et al. Rituximab Professor Y. Shi is the principal investigator. All authors contributed to the (anti-CD20 monoclonal antibody) for the treatment of patients with study design and data collection, and were responsible for the final inter - relapsing or refractory aggressive lymphoma: a multicenter phase II pretation of the data, development of the manuscript. All authors read and study. Blood. 1998;92(6):1927–32. approved the final manuscript. 5. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy Author details for relapsed indolent lymphoma: half of patients respond to a four-dose Department of Medical Oncology, Beijing Key Laboratory of Clinical Study treatment program. J Clin Oncol. 1998;16(8):2825–33. on Anticancer Molecular Targeted Drugs, National Cancer Center/Cancer 6. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof Hospital, Chinese Academy of Medical Sciences and Peking Union Medi- JE, et al. Single-agent rituximab as first-line and maintenance treatment cal College, Beijing 100021, P. R. China. Department of Lymphoma, Beijing for patients with chronic lymphocytic leukemia or small lymphocytic Cancer Hospital, Peking University, Beijing 100142, P. R. China. Department lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J of Hematology, Ruijin Hospital, Shanghai Jiaotong University, Shang- Clin Oncol. 2003;21(9):1746–51. hai 200025, P. R. China. Department of Hematology, Guangdong General 7. Keating GM. Rituximab: a review of its use in chronic lymphocytic leu- Hospital/Guangdong Academy of Medical Sciences, Guangzhou 510030, kaemia, low-grade or follicular lymphoma and diffuse B-cell lymphoma. Guangdong, P. R. China. Clinical Science, Shanghai Roche Pharmaceuticals Drugs. 2010;70(11):1445–76. Ltd, Shanghai 201203, P. R. China. Statistics, Roche (China) Holding Ltd, 8. Grigg A, Dyer MJS, González Díaz M, Dreyling M, Rule S, Lei G, et al. Safety Shanghai 201203, P. R. China. and efficacy of obinutuzumab with CHOP or bendamustine in previously untreated follicular lymphoma. Haematologica. 2017;102:765–72. Acknowledgements 9. Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis The authors thank all the patients who participated in the GERSHWIN study, J, et al. Obinutuzumab (GA101) in relapsed/refractory chronic lympho- and acknowledge all of the study investigators and their staff. GERSHWIN was cytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. sponsored by F. Hoffmann-La Roche Ltd. Editorial support, under the direction 2014;124(14):2196–202. of the lead author Y. Shi, was provided by Lucy Carrier and Elizabeth Johnson 10. Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, of Gardiner-Caldwell Communications, and Clare Cox (Ph.D.) of Edanz Medical Bouabdallah R, et al. Obinutuzumab (GA101) monotherapy in relapsed/ Writing. Editorial support was funded by F. Hoffmann-La Roche Ltd. refractory diffuse large B-cell lymphoma or mantle cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013;31(23):2912–9. Competing interests 11. Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Y. Shi, Y. Qin, Y. Song, X. Du, W Ji, J. Zhu and Z. Shen have no potential compet- et al. Obinutuzumab (GA101) in patients with relapsed/refractory indo- ing interests to disclose. W. Hsu is employed by F. Hoffmann-La Roche Ltd. lent non-Hodgkin’s lymphoma: results of the phase II GAUGUIN study. J The GERSHWIN study was sponsored by F. Hoffmann-La Roche Ltd. The study Clin Oncol. 2013;31(23):2920–6. sponsor designed the study and contributed to the collection, analysis, and 12. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. interpretation of the data. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10. Availability of data and materials 13. Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, et al. The data that support the findings are held by F. Hoffmann-La Roche Ltd. Due Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: to restrictions, the full dataset is not publicly available. Data supporting the updated results of the CLL11 study. Leukemia. 2015;29(7):1602–4. conclusions of this article are included within the article and its additional files. 14. GAZYVA prescribing information. http://www.acces sdata .fda.gov/scrip ts/ cder/drugs atfda /index .cfm/index .cfm?fusea ction =Searc h.DrugD etail s. Ethics approval and consent to participate Accessed 1 July 2016. The present study was approved by the Institutional Review Boards and/or 15. GAZYVARO summary of product characteristics. http://www.medic ines. Independent Ethics Committees of National Cancer Center/Cancer Hospital, org.uk/emc. Accessed 1 July 2016. Chinese Academy of Medical Sciences and Peking Union Medical College, 16. Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Beijing Cancer Hospital, Ruijin Hospital, Shanghai Jiaotong University, and et al. Randomized phase II trial comparing obinutuzumab (GA101) Guangdong General Hospital/Guangdong Academy of Medical Sciences. It with rituximab in patients with relapsed CD20+ indolent B-cell non- was conducted in accordance with the Declaration of Helsinki and the Inter- Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. national Conference on Harmonization guidelines for Good Clinical Practice. 2015;33(3):3467–74. 17. Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, et al. Funding Obinutuzumab plus bendamustine versus bendamustine monotherapy GERSHWIN was sponsored by F. Hoffmann-La Roche Ltd. Medical Writing sup - in patients with rituximab-refractory indolent non-Hodgkin lymphoma port, under the direction of the lead author, was provided by Elizabeth John- (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 son of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La trial. Lancet Oncol. 2016;17(8):1081–93. Roche Ltd. 18. Zhai J, Qin Y, Zhu J, Song Y, Shen Z, Du X, et al. Pharmacokinetics of obinu- tuzumab in Chinese patients with B-cell lymphomas. Br J Clin Pharmacol. Received: 23 October 2017 Accepted: 28 March 2018 2017. https ://doi.org/10.1111/bcp.13232 (Epub ahead of print). 19. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol. 1999;17(4):1244–53. 20. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lympho- cytic leukemia: a report from the International Workshop on Chronic Qin et al. Cancer Commun (2018) 38:31 Page 9 of 9 Lymphocytic Leukemia updating the National Cancer Institute-Working factors in the development of infusion-related reactions in patients with Group 1996 Guidelines. Blood. 2008;111(12):5446–56. CLL treated with obinutuzumab. Leukemia. 2016;30(8):1763–6. 21. Illidge T, Klein C, Sehn LH, Davies A, Salles G, Cartron G. Obinutuzumab 23. Ogura M, Tobinai K, Hatake K, Uchida T, Suzuki T, Kobayashi Y, et al. Phase in hematologic malignancies: lessons learned to date. Cancer Treat Rev. I study of obinutuzumab (GA101) in Japanese patients with relapsed or 2015;41(9):784–92. refractory B-cell non-Hodgkin lymphoma. Cancer Sci. 2013;104(1):105–10. 22. Freeman CL, Dixon M, Houghton R, Kreuzer KA, Fingerle-Rowson G, Herling M, et al. Role of CD20 expression and other pre-treatment risk Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your ﬁeld rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions
Cancer Communications – Springer Journals
Published: May 30, 2018
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