Treatment of cd20-positive b-cell lymphoma with ustutuzumab

Abstract

The present invention provides a method of treating CD20 positive B cell lymphoma with Usutuzumab, involving the rate of administration of Usutuzumab. In some embodiments, the methods comprise an intravenous drip infusion at 1000 mg of ustuzumab olbabine each administration, and are administered in two or more cycles at a specific administration rate.

Description

[0001] This application is a divisional application of the patent application with the application number 201880067120.X and the title "Treatment of CD20 positive B-cell lymphoma with obinutuzumab" filed on October 19, 2018. TECHNICAL FIELD

[0002] The present invention relates to the rate of administration of obinutuzumab. BACKGROUND

[0003] Obinutuzumab is a glycoengineered, type II anti-CD20 monoclonal antibody indicated for the treatment of B-cell malignancies. It differs from its predecessor rituximab in having lower complement-dependent cytotoxicity but enhanced antibody-dependent cellular cytotoxicity and direct B-cell death (NPLs 1-3, Figure 1 ). In the phase III GALLIUM trial comparing chemotherapy in combination with either obinutuzumab or rituximab, followed by anti-CD20 antibody maintenance therapy, obinutuzumab-based immunochemotherapy resulted in a clinically meaningful improvement in progression-free survival in patients with previously untreated follicular lymphoma (FL) (NPLs 4, 5). In the phase III GADOLIN study, obinutuzumab plus bendamustine, followed by obinutuzumab maintenance, also improved efficacy relative to bendamustine monotherapy in rituximab-ineffective patients with indolent B-cell non-Hodgkin lymphoma (NHL) (NPL 6).

[0004] LIST OF CITATIONS

[0005] NON-PATENT LITERATURE

[0006] [NPL 1] Mossner E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 2010; 115: 4393-402.

[0007] [NPL2] Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther 2013; 12: 2031-42.

[0008] [NPL3] Tobinai K, Klein C, Oya N, Fingerle-Rowson G. A review of obinutuzumab (GA101), a novel type II anti-CD20 monoclonal antibody, for the treatment of patients with B-cell malignancies. Adv Ther 2017; 34: 324-56.

[0009] [NPL4] Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017; 377: 1331-44.

[0010] [NPL5] Hiddemann W, Barbui AM, Canales Albendea MA, et al. Immunochemotherapy with obinutuzumab or rituximab in previously untreated folllicular lymphoma in the randomised phase III GALLIUM study: analysis by chemotherapy regimen. Hematol Oncol 2017; 35: 117-9.

[0011] [NPL6] Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016; 17: 1081-93. SUMMARY

[0012] Obinutuzumab is currently administered by intravenous (abbreviated in this specification as 'IV') infusion. Prolonged and / or frequent IV infusions are burdensome and inconvenient for patients, and result in the need for prolonged observation times and increased workload for nursing and management staff. The conventional IV infusion of obinutuzumab (abbreviated in this specification as 'RI') takes approximately 3 to 4 hours, and it is reasonable to consider that shortening the duration of the infusion has potential advantages in terms of patient convenience, and more efficient use of healthcare facilities and staff time. Figure 2 The main potential disadvantage of shorter infusion durations (abbreviated in this specification as 'SDI') is the potential for increased risk of infusion-related reactions (IRRs) mediated by cytokine release. However, studies in patients with rheumatoid arthritis or B-cell NHL have shown that it is feasible to shorten the rituximab infusion time from at least 4 hours to 1.5-2 hours, which in turn led to the recommendation to increase the infusion rate of rituximab and similarly to investigate SDI in patients receiving obinutuzumab.

[0013] SDI was also investigated in the GATHER trial, a phase II, open-label, multicenter, single-arm study of obinutuzumab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone (abbreviated as 'CHOP' in this specification, wherein prednisolone is interchangeable with prednisone) chemotherapy in 80 previously untreated patients with CD20-positive, completely diffuse large B-cell lymphoma (abbreviated as 'DLBCL' in this specification). Both SDI times evaluated in GATHER (120 and 90 minutes) were well tolerated with no > grade 3 IRRs. Overall, 4% of the GATHER population was of Asian ethnicity, and ethnic differences in the frequency of polymorphisms in genes involved in drug metabolism pathways have been suggested to be associated with changes in enzyme activity that can affect drug pharmacokinetics (abbreviated as 'PK' in this specification). However, data obtained in various geographic populations receiving obinutuzumab showed no relevant differences in the PK of obinutuzumab in Asian (including Chinese and Japanese) and non-Asian patients.

[0014] To further explore these concepts, a phase II GATS study (JO29737, JapicCTI-152848) was conducted in previously untreated patients with CD20-positive B-cell NHL to investigate the tolerability of obinutuzumab administration using SDI, in particular the rate of IRRs of all grades, and to assess serum obinutuzumab concentrations and PK, and the time course of cytokine release Figure 3 ) in patients.

[0015] In particular, the present invention relates to:

[0016] [1] A pharmaceutical composition comprising obinutuzumab for use in the treatment of CD20-positive B-cell lymphoma, which is administered as an intravenous infusion infusion at 1000 mg obinutuzumab per administration, and at an administration rate according to (a) and (b) below in two or more cycles:

[0017] (a) the maximum administration rate in the first cycle is equal to or greater than 200 mg obinutuzumab per hour, preferably equal to or greater than 300 mg obinutuzumab per hour, more preferably equal to or greater than 400 mg obinutuzumab per hour;

[0018] (b) the maximum administration rate in the second or later cycle is equal to or greater than 700 mg obinutuzumab per hour, preferably equal to or greater than 800 mg obinutuzumab per hour, more preferably equal to or greater than 900 mg obinutuzumab per hour.

[0019] [2] The pharmaceutical composition according to [1], wherein the duration of each administration in the second or later cycle is within 180 minutes, preferably within 150 minutes, more preferably within 120 minutes, most preferably within 90 minutes.

[0020] [3] The pharmaceutical composition according to [1] or [2], which is administered 3 times in the first cycle and once per cycle in the second or later cycle.

[0021] [4] The pharmaceutical composition according to [3], wherein the first administration in the first cycle is initiated at a rate of 50 mg of obinutuzumab per hour and the second or later administration in the first cycle is initiated at a rate of 100 mg of obinutuzumab per hour.

[0022] [5] The pharmaceutical composition according to any one of [1] to [4], wherein the rate of administration in the second or later cycle is increased to 700 mg of obinutuzumab per hour or faster, preferably 800 mg of obinutuzumab per hour or faster, more preferably up to 900 mg of obinutuzumab per hour.

[0023] [6] The pharmaceutical composition according to any one of claims 1 to 5, wherein, in (b), the pharmaceutical composition is administered according to at least one of the following conditions (c) to (e):

[0024] (c) if no grade 3 or above infusion reaction occurred for the last three administrations and the number of lymphocytes in the peripheral blood prior to administration is less than 5000 / μL, administration is performed at 100 mg / hr for 30 minutes; if no infusion reaction is observed for the whole time, the rate can be increased to 900 mg / hr; depending on the patient's condition, the rate is reduced to the administration rate in cycle 1, if appropriate;

[0025] (d) if a grade 1 / 2 infusion reaction occurs, administration is restarted at half the rate before administration was stopped; if no infusion reaction is observed for 30 minutes, the rate can be increased to 900 mg / hr;

[0026] (e) if a grade 3 infusion reaction, administration is restarted at 200 mg / hr or less; if no infusion reaction is observed for 30 minutes, the rate can be increased by 50 mg / hr every 30 minutes to a maximum of 400 mg / hr.

[0027] [7] The pharmaceutical composition according to any one of [1] to [6], which is administered on days 1, 8 and 15 in the first cycle and on day 1 in the second or later cycle.

[0028] [8] The pharmaceutical composition according to any one of [1] to [7], wherein each cycle is 3 weeks.

[0029] [9] The pharmaceutical composition according to any one of [1] to [7], which is used in combination with at least one other anti-tumor agent, and the administration cycle of which is synchronized with the dosing cycle of said at least one other anti-tumor agent, wherein the dosing cycle is 4 weeks per cycle.

[0030]

[10] The pharmaceutical composition according to [9], wherein said at least one other anti-tumor agent is selected from the group consisting of CHOP, CVP, bendamustine, fludarabine, lenalidomide, an anti-PD-1 antibody, and an anti-PD-Ll antibody.

[0031]

[11] The pharmaceutical composition according to any one of [1] to

[10] , wherein the pharmaceutical composition is administered every two months for two years as a maintenance monotherapy after said two or more cycles.

[0032]

[12] The pharmaceutical composition according to any one of [1] to

[11] , wherein the concentration of obinutuzumab in the infusion solution is 10 to 40 mg / mL, preferably 20 to 30 mg / mL, more preferably 25 mg / mL, when administered as an intravenous drip infusion.

[0033]

[13] The pharmaceutical composition according to any one of [1] to

[12] , which further comprises trehalose hydrate, L-histidine, L-histidine hydrochloride hydrate, or polyoxyethylene (160) polyoxypropylene (30) glycol as an additive.

[0034]

[14] Use of obinutuzumab for the preparation of a pharmaceutical composition comprising obinutuzumab for the treatment of CD20-positive B-cell lymphoma, wherein the composition is administered as an intravenous drip infusion of 1000 mg of obinutuzumab per administration, and the administration rate is given in accordance with the following (a) and (b) in two or more cycles:

[0035] (a) the maximum administration rate in the first cycle is equal to or greater than 200 mg of obinutuzumab per hour, preferably equal to or greater than 300 mg of obinutuzumab per hour, more preferably equal to or greater than 400 mg of obinutuzumab per hour;

[0036] (b) the maximum administration rate in the second or later cycle is equal to or greater than 700 mg of obinutuzumab per hour, preferably equal to or greater than 800 mg of obinutuzumab per hour, more preferably equal to or greater than 900 mg of obinutuzumab per hour.

[0037]

[15] A method of treating CD20-positive B-cell lymphoma by a pharmaceutical composition comprising obinutuzumab, wherein the composition is intravenous infusion at 1000 mg of obinutuzumab per administration, and is administered in two or more cycles at an administration rate according to (a) and (b) below:

[0038] (a) the maximum administration rate in the first cycle is equal to or greater than 200 mg of obinutuzumab per hour, preferably equal to or greater than 300 mg of obinutuzumab per hour, more preferably equal to or greater than 400 mg of obinutuzumab per hour;

[0039] (b) the maximum administration rate in the second or later cycle is equal to or greater than 700 mg of obinutuzumab per hour, preferably equal to or greater than 800 mg of obinutuzumab per hour, more preferably equal to or greater than 900 mg of obinutuzumab per hour. SUMMARY

[0040] [ Figure 1 ]

[0041] Figure 1 Characteristics of obinutuzumab are shown. Obinutuzumab is a glycoengineered type II anti-CD20 mAb and has greater direct cell death induction and ADCC / ADCP activity than rituximab. ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cellular phagocytosis.

[0042] [ Figure 2 ]

[0043] Figure 2 Length of administration time and risk of IRR are shown. Achieving SDI would improve the clinical usefulness of obinutuzumab, taking into account the heavy burden on patients. In a phase 1 study (J021900 study) evaluating the safety, tolerability, PK, and preliminary efficacy of obinutuzumab in Japanese patients, all 12 patients administered obinutuzumab experienced infusion-related reactions (IRRs) on cycle 1 day 1.

[0044] [ Figure 3 ]

[0045] Figure 3To show the summary of the GATS study. To confirm the acceptability of shorter infusion duration (SDI) of obinutuzumab in Japanese patients. Objective population: Patients with CD20-positive B-cell NHL (DLBCL, FL, MZL) who were previously untreated. Study design: Phase II, multicenter, open-label, single-arm, G-CHOP x 8 cycles. Primary endpoints: Incidence of infusion-related reactions of grade > 3 in cycle 2; serum concentration and pharmacokinetic parameters of obinutuzumab; time course of cytokines (TNFα, IFNγ, IL-6, IL-8, IL-10). Target number of patients: 36 (enrolled).

[0046] [ Figure 4 ]

[0047] Figure 4 To show the clinical design of the GATS study. The GATS study confirmed SDI based on the GATHER study design which evaluated the safety and efficacy of G-CHOP, study drug administration, and SDI inclusion criteria. Obinutuzumab was administered by conventional infusion, 4 hours and 15 minutes on cycle 1 day 1 with CHOP, and 3 hours and 15 minutes on cycle 1 days 8 and 15. If patients met the SDI inclusion criteria (at least 3 consecutive doses of obinutuzumab by conventional infusion without any infusion-related reactions of grade > 3; peripheral lymphocyte count < 5000 / μL prior to SDI), obinutuzumab was administered by SDI from cycle 2 to 8.

[0048] [ Figure 5 ]

[0049] Figure 5 To show the comparison of the administration rate between conventional infusion and SDI in the GATS study.

[0050] [ Figure 6 ]

[0051] Figure 6 To show the disposition of patients in the GATS study.

[0052] [ Figure 7 ]

[0053] Figure 7 To show the patient characteristics in the GATS study.

[0054] [ Figure 8 ]

[0055] Figure 8 To show the safety profile in the GATS study. No infusion-related reactions of grade > 3 occurred in SDI transition patients. The safety profile under SDI was comparable to that under conventional infusion.

[0056] [ Figure 9]

[0057] Figure 9 This shows the number of patients with IRR in the GATS and GATHER studies. The same trend is shown between the GATS and GATHER studies.

[0058] [ Figure 10 ]

[0059] Figure 10 This study demonstrates the pharmacokinetic (PK) profile of olibutuzumab in Japanese patients after SDI conversion in the GATS study compared to routine infusion administration in the GOYA study. Serum olibutuzumab concentrations in patients with SDI conversion in the GATS study followed a similar time course as in patients receiving routine infusion in the GOYA study.

[0060] [ Figure 11 ]

[0061] Figure 11 This study shows oxetuzumab PK in SDI patients from the GATS and GATHER studies. Considering individual variability, no racial differences were observed, although the timing of blood sampling differed between the GATS and GATHER studies. Serum concentrations immediately after cycle 2 under SDI were similar to those in cycle 8; therefore, PK reached steady state at cycle 2 and was unaffected by SDI.

[0062] [ Figure 12 ]

[0063] Figure 12 This study showed IL-6 release following administration of olibutuzumab in the GATS study. The peak increase in cytokines occurred during the infusion on day 1 of cycle 1, and they rapidly decreased 2–5 hours post-infusion. No significant changes were observed after the start of SDI. Similar trends were observed in TNFα, IFNγ, IL-8, and IL-10.

[0064] [ Figure 13 ]

[0065] Figure 13 The GATAS study demonstrated the therapeutic efficacy of oxetuzumab against DLBCL and FL.

[0066] [ Figure 14 ]

[0067] Figure 14The acceptability of SDI based on GATS study of obinutuzumab was shown. No > grade 3 IRRs occurred in SDI transitioning patients. IRRs most commonly occurred on cycle 1 day 1 under routine infusion, but were all grade 1 or 2. Three IRRs were observed under SDI on cycles 6, 7, and 8, but were all classified as grade 1. Similar trends were observed in the GATHER study. There appeared to be no impact of administration time and race on the PK of obinutuzumab. Cytokine elevations were observed during the first obinutuzumab infusion, but decreased immediately at the end of infusion. Overall, the SDI of obinutuzumab showed to be acceptable. DETAILED DESCRIPTION

[0068] DETAILED DESCRIPTION

[0069] I. Summary of doses and administration of obinutuzumab

[0070] In the present application, obinutuzumab is a glycoengineered, genetically recombinant and humanized anti-CD20 monoclonal antibody, a glycoprotein, exhibiting the characteristics of a type II anti-CD20 antibody and comprising two heavy chains of 449 amino acid residues and two light chains of 219 amino acid residues, and having a molecular weight of about 148,000-150,000. Specifically, obinutuzumab includes not only those specified under "obinutuzumab (genetically recombinant)" in the Japanese Approved Drug Names (JAN) in the present application, but also biosimilars and biobetters thereof.

[0071] Hereinafter, a pharmaceutical composition comprising obinutuzumab shall be referred to as "the present formulation".

[0072] <Effects and efficacy>

[0073] - Examples of "effects and efficacy" of the present formulation are provided below as one embodiment.

[0074] - One example of a disease targeted by the present formulation is CD20-positive B-cell lymphoma. That is, the present formulation is a pharmaceutical composition comprising obinutuzumab for treating CD20-positive B-cell lymphoma. Examples of CD20-positive B-cell lymphoma include follicular lymphoma, low-grade lymphoma, intermediate-grade lymphoma, and high-grade lymphoma. The CD20-positive B-cell lymphoma is preferably CD20-positive B-cell follicular lymphoma.

[0075] <Dosage and administration>

[0076] - Examples of "dosage and administration" of the present formulation are provided below as one embodiment. The tolerability of the dosage and administration exemplified below, including the rate of administration, has been proven by GATS studies.

[0077] - Normally, olibutuzumab is administered intravenously infusion at a dose of 1000 mg per administration in adults.

[0078] - For induction therapy, each cycle is three weeks, and administration is performed on days 1, 8, and 15 of cycle 1, and on day 1 of cycles 2 through 8. In cases of combined use and administration of antitumor agents at four-week intervals, each cycle is four weeks, and administration is performed on days 1, 8, and 15 of cycle 1, and on day 1 of cycles 2 through 6.

[0079] - After 24 weeks of induction therapy, maintenance therapy is performed by administering this formulation alone every two months for up to two years.

[0080] - Administer this formulation at the following rates. Furthermore, the grading criteria are in accordance with NCI-CTCAE version 4.03.

[0081] (During the first application)

[0082] Initiate intravenous infusion at a rate of 50 mg / hr. Increase the rate to 50 mg / hr every 30 minutes, while monitoring the patient's condition as appropriate, and may increase to a maximum of 400 mg / hr.

[0083] (During or after the second application in cycle 1)

[0084] If no grade 2 or higher infusion response has been observed in previous administration, start administration at 100 mg / hr. If no infusion response is observed, the rate can be increased from 100 mg / hr every 30 minutes to a maximum of 400 mg / hr.

[0085] (In or after cycle 2)

[0086] If no grade 3 or higher infusion reaction occurs during the last three administrations and the peripheral blood lymphocyte count is less than 5000 / μL before administration, administer at 100 mg / hr over 30 minutes. If no infusion reaction is observed, the rate can be increased to 900 mg / hr. Depending on the patient's condition, the rate may be reduced to, for example, the administration rate in cycle 1, if appropriate.

[0087] - If an infusion reaction occurs, take the following response.

[0088] (If a grade 2 or lower infusion reaction occurs)

[0089] Stop application or reduce the application rate.

[0090] (If a grade 3 infusion reaction occurs)

[0091] Stop application and take appropriate measures.

[0092] If the infusion is stopped, after the patient's infusion reaction has resolved / abated, the rate of administration is adjusted as described below and administration is resumed.

[0093] (if a Grade 4 infusion reaction occurs)

[0094] Administration of the formulation is immediately stopped and appropriate measures are taken.

[0095] (if a Grade 3 infusion reaction occurs again and if a Grade 4 infusion reaction occurs)

[0096] The formulation will not be administered again.

[0097] - When administration is resumed after stopping administration following an infusion reaction, the rate of administration at the time of resumption is manipulated as follows.

[0098] (at the first administration and at the second administration in Cycle 1 or thereafter)

[0099] Administration is resumed at half the rate prior to stopping administration. If no infusion reaction is observed in 30 minutes, the rate can be increased by 50 mg / hr every 30 minutes to a maximum of 400 mg / hr.

[0100] (if a Grade ½ infusion reaction occurs in Cycle 2 or thereafter)

[0101] Administration is resumed at half the rate prior to stopping administration. If no infusion reaction is observed in 30 minutes, the rate can be increased to 900 mg / hr.

[0102] (if a Grade 3 infusion reaction occurs in Cycle 2 or thereafter)

[0103] Administration is resumed at 200 mg / hr or less. If no infusion reaction is observed in 30 minutes, the rate can be increased by 50 mg / hr every 30 minutes to a maximum of 400 mg / hr.

[0104] II. Pharmaceutical Compositions

[0105] In the present application, a pharmaceutical composition comprises obinutuzumab. In one embodiment, the pharmaceutical composition comprises a pharmaceutically effective amount of obinutuzumab. Obinutuzumab is a glycoengineered, genetically recombinant and humanized anti-CD20 monoclonal antibody, a glycoprotein, exhibiting the characteristics of a type II anti-CD20 antibody and comprising two heavy chains of 449 amino acid residues and two light chains of 219 amino acid residues, and having a molecular weight of about 148,000-150,000. Specifically, obinutuzumab in the present application includes not only those specified under "obinutuzumab (genetically recombinant)" in the Japanese Approved Drug Names (JAN), but also biosimilars thereof (in which the amino acid sequence of the heavy chain is shown in SEQ No. 1 and the amino acid sequence of the light chain is shown in SEQ No. 2) and biobetters derived from those amino acid sequences.

[0106] The pharmaceutical composition is used for the treatment of CD20-positive B-cell lymphoma. Examples of CD20-positive B-cell lymphoma include follicular lymphoma, low-grade lymphoma, intermediate-grade lymphoma, and high-grade lymphoma. The CD20-positive B-cell lymphoma is preferably CD20-positive B-cell follicular lymphoma.

[0107] In one embodiment, the concentration of obinutuzumab in the pharmaceutical composition as an infusion solution at the time of intravenous drip infusion is generally 10 to 40 mg / mL. In another embodiment, the concentration is 20 to 30 mg / mL. In another embodiment, the concentration is 25 mg / mL. In a preferred embodiment, the concentration is 20 to 30 mg / mL. In a more preferred embodiment, the concentration is 25 mg / mL.

[0108] In one embodiment, the pharmaceutical composition can further comprise at least one additive selected from trehalose hydrate, L-histidine, L-histidine hydrochloride hydrate, or polyoxyethylene (160) polyoxypropylene (30) glycol. In a preferred embodiment, the pharmaceutical composition comprises trehalose hydrate, L-histidine, L-histidine hydrochloride hydrate, and polyoxyethylene (160) polyoxypropylene (30) glycol as additives.

[0109] In one embodiment, the pharmaceutical composition is administered in two or more cycles. The period of the cycle can be determined by one of ordinary skill in the art to be 3 to 5 weeks. Examples of the period are 3 weeks or 4 weeks. In the case where the pharmaceutical composition is administered as a monotherapy, the period is preferably 3 weeks. In the case where the pharmaceutical composition is administered in combination with at least one anti-tumor agent, the period is preferably 4 weeks. In the combination of the pharmaceutical composition with such an anti-tumor agent, the administration cycle of the pharmaceutical composition is preferably synchronized with the dosing cycle of the anti-tumor agent.

[0110] In one embodiment, the pharmaceutical composition is administered one or more times per cycle. The frequency of administration varies per cycle. In another embodiment, the pharmaceutical composition is administered three times in the first cycle. In another embodiment, the pharmaceutical composition is administered once per cycle in the second or later cycle. In a preferred embodiment, the pharmaceutical composition is administered three times in the first cycle and once per cycle in the second or later cycle.

[0111] In one embodiment, the dates of administration in a cycle are arranged by one of ordinary skill in the art. In another embodiment, the dates are days 1, 8, and 15 in the first cycle, and day 1 in the second or later cycle.

[0112] In one embodiment, the amount of obinutuzumab administered per administration is varied by one of ordinary skill in the art in the range of 1 to 2000 mg. In a particular embodiment, the pharmaceutical composition is administered as a 1000 mg obinutuzumab intravenous drip infusion per administration.

[0113] In one embodiment, the pharmaceutical composition is administered in two or more cycles at an administration rate according to (a) and (b) below.

[0114] (a) the maximum administration rate in the first cycle is equal to or greater than 200 mg obinutuzumab per hour, preferably equal to or greater than 300 mg obinutuzumab per hour, or more preferably equal to or greater than 400 mg obinutuzumab per hour.

[0115] (b) the maximum administration rate in the second or later cycle is equal to or greater than 700 mg obinutuzumab per hour, preferably equal to or greater than 800 mg obinutuzumab per hour, or more preferably equal to or greater than 900 mg obinutuzumab per hour.

[0116] In another embodiment of (a) above, the maximum administration rate in the first cycle is preferably equal to or greater than 300 mg obinutuzumab per hour, or more preferably equal to or greater than 400 mg obinutuzumab per hour.

[0117] In another embodiment of (b) above, the maximum administration rate in the second or later cycle is preferably equal to or greater than 800 mg obinutuzumab per hour, or more preferably equal to or greater than 900 mg obinutuzumab per hour. In this embodiment, the duration of each administration in the second or later cycle is preferably within 180 minutes. The duration is preferably within 150 minutes, more preferably within 120 minutes, or most preferably within 90 minutes.

[0118] In one embodiment, the first administration in the first cycle is initiated at a rate of 50 mg of obinutuzumab per hour. The second or later administration in the first cycle is initiated at a rate of 100 mg of obinutuzumab per hour.

[0119] In one embodiment, the rate of administration in the second or later cycle is increased to 700 mg of obinutuzumab per hour or more, preferably 800 mg of obinutuzumab per hour or more, more preferably up to 900 mg of obinutuzumab per hour.

[0120] In other embodiments, at least one agent is suitably selected from the agents known hitherto in combination with the pharmaceutical composition and the antitumor agent. The other antitumor agent is at least one selected from the group consisting of CHOP, CVP, bendamustine, fludarabine, lenalidomide, anti-PD-1 antibody, and anti-PD-Ll antibody.

[0121] In one embodiment, the maintenance monotherapy of obinutuzumab is implemented as an additional therapy. The maintenance monotherapy is implemented every two months after the treatment of the pharmaceutical composition for two years, which treatment is called 'induction therapy' in this case.

[0122] III. Production method

[0123] Obinutuzumab can be manufactured by a person of ordinary skill according to the known method shown in WO 2005 / 044859. The pharmaceutical composition is also manufactured by a person of ordinary skill by mixing obinutuzumab with other components.

[0124] The present application also provides the use of obinutuzumab in the manufacture of a pharmaceutical composition for the treatment of CD20-positive B-cell lymphoma. The pharmaceutical composition is administered in the same manner as mentioned in 'II. Pharmaceutical composition'.

[0125] IV. Treatment method

[0126] The present application also provides a method of treating CD20-positive B-cell lymphoma by a pharmaceutical composition comprising obinutuzumab. In the method, the pharmaceutical composition is intravenously infused at 1000 mg of obinutuzumab per administration, and is administered in two or more cycles according to the rate of administration of (a) and (b) below:

[0127] (a) the maximum rate of administration in the first cycle is equal to or more than 200 mg of obinutuzumab per hour, preferably equal to or more than 300 mg of obinutuzumab per hour, more preferably equal to or more than 400 mg of obinutuzumab per hour;

[0128] (b) the maximum rate of administration in the second or later cycle is equal to or greater than 700 mg of obinutuzumab per hour, preferably equal to or greater than 800 mg of obinutuzumab per hour, more preferably equal to or greater than 900 mg of obinutuzumab per hour.

[0129] The method of using the pharmaceutical composition is the same as mentioned in 'II. Pharmaceutical composition'.

[0130] It was not clear before the present invention whether SDI is suitable for administering obinutuzumab to humans, since the possibility of the sugar engineering in obinutuzumab causing any abnormal immunological reactions cannot be ruled out. In summary, based on the findings of the GATS study, the above pharmaceutical composition was found to be safe and tolerable for administration, and to reduce the therapeutic burden suffered by patients and medical staff from the long time of administration in conventional infusion. Examples

[0131] <Overview of the GATS clinical study>

[0132] Title: Safety and tolerability of obinutuzumab (GA101) SDI in Japanese patients with non-Hodgkin's lymphoma

[0133] Background: Obinutuzumab (GA101, G) is a novel anti-CD20 monoclonal antibody. Immunochemotherapy with G led to a clinically meaningful improvement in progression-free survival (PFS) in patients with follicular lymphoma (FL) (ASH 2016, #6). Conventional infusion (RI) of G takes approximately 3-4 hours. Shortening the duration of administration can be more convenient for patients.

[0134] Methods: The GATS study (JapicCTI-152848) included patients with previously untreated CD20-positive B-cell non-Hodgkin's lymphoma. Treatment consisted of 8 cycles (C) of G plus CHOP in C1-C6 (additional G on days 8 and 15 of C1). From C2, SDI was performed, and infusion of G was in 90 minutes. The primary endpoint was tolerability of SDI, pharmacokinetics (PK), and cytokine release. Tolerability was assessed by the incidence of infusion-related reactions (IRRs).

[0135] Results: Of 36 enrolled patients, 35 patients were treated, including 19 with diffuse large B-cell lymphoma, 13 with FL, and 3 with other histologies. Overall, 17 / 35 patients (49%) experienced IRRs. All were Grade 1 / 2 and most commonly occurred at C1 Day 1 (RI). Two patients started SDI at C3 or C4 due to deviation or AE. Under SDI, 3 IRRs were observed, but all were Grade 1. Serum G levels just after C2 under SDI were similar to those in C8. This shows that PK reached steady state at C2 and was not affected by the shortened administration. Cytokine elevations were observed during the first G infusion, but decreased immediately at the end of the infusion.

[0136] Conclusions: SDI of G over 90 minutes was acceptable in Japanese patients. The PK and serum cytokine profiles were comparable to those under RI.

[0137] Detailed description of the GATS clinical study

[0138] Study design and treatment

[0139] This was a Phase II, multicenter, open-label, single-arm study conducted in Japan. Eligible patients were > 20 years of age with previously untreated and histologically confirmed CD20-positive B-cell NHL (DLBCL, FL, or marginal zone lymphoma); Eastern Cooperative Oncology Group performance status of 0-2; life expectancy of > 12 months from the date of enrollment; adequate cardiovascular function defined as left ventricular ejection fraction > 50%; adequate organ function defined as hemoglobin > 9 g / dL, absolute neutrophil count > 1.5 x 10 9 cells / l, peripheral lymphocytes < 5.0 x 10 9 cells / l, and platelet count > 75 x 10 9 cells / l; serum bilirubin, serum creatinine, and prothrombin time or activated partial thromboplastin time < 1.5 times the site-specific upper limit and liver enzymes < 2.5 times the site-specific upper limit. Patients were also required to have not experienced major surgery or received immunosuppressive therapy, live vaccines, or other investigational drugs within 4 weeks prior to enrollment; monoclonal antibody therapy was not allowed within the previous 12 weeks.

[0140] Exclusion criteria included prior therapy for NHL (except needle biopsy or localized irradiation); primary central nervous system (CNS) lymphoma, secondary CNS involvement or leptomeningeal lymphoma; history of recent (≤ 4 weeks) major infection that would affect the outcome of this study, history of other malignancy or autoimmune disease; ongoing corticosteroid therapy with prednisolone > 30 mg / day equivalent for any condition other than lymphoma; any prior use of cytotoxic agents or rituximab or any other anti-CD20 antibody; positive test for hepatitis B surface (HBs) antigen, HBs antibody, hepatitis B core (HBc) antibody, or hepatitis C virus (HCV) antibody; HIV or human T-cell lymphotrophic virus type I, and uncontrolled diabetes mellitus. Patients with apparently attributable to vaccination HBs antibody and hepatitis B virus DNA test not positive (irrespective of antibody status) were allowed to enroll, as were patients with positive HCV antibody test but with HCV RNA negative status. The study was approved by local institutional review boards and was conducted in accordance with the Declaration of Helsinki and good clinical practice. Informed consent was given by all patients.

[0141] Treatment consisted of eight 21 -day cycles of obinutuzumab (given as 1000 mg IV on days 1, 8, and 15 of cycle 1) plus standard CHOP on cycle 1-6 day 1. Figure 4 Obinutuzumab was administered as RI (3-4 hours) in cycle 1 and then as 90-minute SDI from cycle 2 onwards in patients who reached SDI criteria. Figure 5 SDI criteria were patient safety at the time of confirmation of RI rate and included no > grade 3 IRRs during any of the three RIs in cycle 1 and peripheral lymphocyte count < 5.0 x 10 9 Patients who did not reach these criteria before cycle 2 could still be switched from RI to SDI if they reached the criteria in any of the subsequent cycles.

[0142] Standard CHOP consisted of cyclophosphamide 750 mg / m 2 , doxorubicin 50 mg / m 2 and vincristine 1.4 mg / m 2 IV on day 1, and prednisolone 100 mg / day orally or IV on days 1-5. When obinutuzumab and CHOP were scheduled to be administered on the same day, prednisolone was given prior to the obinutuzumab infusion. Dose reductions were allowed to accommodate the patient's condition.

[0143] Study endpoints

[0144] The primary endpoint of the study was the incidence of grade >3 IRRs in Cycle 2 in patients who initiated SDI in Cycle 2, serum concentrations and PK parameters of obinutuzumab after SDI until Cycle 2 Day 12, and the time course of cytokine release of tumor necrosis factor alpha (TNFa), interferon gamma (IFNy), and interleukins 6, 8, and 10 (IL6, IL8, and IL10). IRR was defined as an adverse event (AE) judged by the investigator to be related to obinutuzumab and reported during the infusion or within 24 hours.

[0145] Secondary endpoints included all other AEs regardless of the relevance to obinutuzumab treatment, IRRs reported during SDI, tumor response at the end of treatment, and best response (at any time during the follow-up period).

[0146] The PK analysis population included all patients who received obinutuzumab by SDI in Cycle 2. The PK parameters for obinutuzumab were assessed for each patient using non-compartmental analysis (NCA; Phoenix WinNonlin® version 6.4, USA, Inc.). The following PK parameters were calculated: maximum observed serum concentration (Cmax), area under the serum concentration-time curve from 0 to Day 7 (AUC0-7), elimination half-life (t½), and AUC from 0 to the last measurable point (AUC0-inf). 最大 0-7 1 / 2 最后

[0147] Statistical and Analytical Methods

[0148] The sample size was based on an estimate of the true probability that the incidence of grade >3 IRRs in Cycle 2 would exceed 5%. Depending on the estimate used, the probability that the IRR would exceed 5% if 30 patients were enrolled would be 2.2% assuming one patient had a grade >3 IRR. This number was increased to 36 assuming that 20% of patients would be unable to be transitioned to SDI. The sample size was therefore set at 36 patients.

[0149] The incidence of grade >3 IRRs in Cycle 2 was obtained by dividing the number of patients who experienced such reactions by the number of patients who were transitioned to SDI. The probability of experiencing a grade >3 IRR was determined according to a Bayesian approach using the incidence of grade >3 IRRs in Cycle 2 of the GATHER study as the prior distribution. The probability of experiencing a grade >3 IRR was assumed to be the same between Japanese and non-Japanese patients regardless of the infusion rate. We assumed that SDI would be adequately tolerated if the true probability of experiencing a grade >3 IRR was <5%.

[0150] ​​​​​Summary statistics, including arithmetic mean, geometric mean, standard deviation, coefficient of variation, median, minimum, and maximum, were calculated for cytokine concentrations at each study visit using serum cytokine concentrations from SDI transitioning patients through Cycle 2. Time course of cytokine concentrations was also assessed. The same summary data were generated for PK parameters based on serum obinutuzumab concentrations in SDI transitioning patients through Cycle 2 Day 12. NCA was used. Cycle 2 serum concentrations were compared with additional samples obtained before and after dosing at Cycle 8.

[0151] Patient Population

[0152] A total of 36 Japanese patients were enrolled, of which 35 were treated (Safety Population; Figure 6 ); 28 (80%) completed all eight cycles of treatment. Thirty-one patients initiated SDI in Cycle 2 (SDI transitioning patients), and an additional 2 patients initiated SDI in a subsequent cycle (1 in Cycle 3, 1 in Cycle 4), constituting a total of 33 SDI-treated patients. Two patients discontinued prior to initiating SDI. Adequate intensity of treatment was achieved; the median dose intensity of obinutuzumab was 100%.

[0153] The median age of patients was 66 years, with just over half of the study population between the ages of 60 and 70 Figure 7 ). Approximately two-thirds were male, and the majority of patients had DLBCL (54%) or FL (37%). One-fifth of patients (20%) had bone marrow involvement.

[0154] Infusion-Related Reactions

[0155] Overall, 17 / 35 patients (49% of the Safety Population) experienced a total of 21 IRRs; all were Grade 1 or 2, and the majority [18 / 21 IRRs (86%)] occurred during Cycle 1 (in which RI was used). No SDI-related IRRs occurred in SDI transitioning patients in Cycle 2, so it was not possible to estimate the probability that the true probability of a Grade >3 IRR in SDI transitioning patients in Cycle 2 would exceed the 5% level inferred using the GATHER study data as a prior distribution. Moreover, the probability that the true probability of a Grade >3 IRR in SDI transitioning patients in Cycle 2 would exceed the 5% level inferred using a non-informative prior distribution was 0.05%. There were 2 patients with reports of IRRs during SDI in Cycles 6, 7, and 8; both were Grade 1 severity (1 patient experienced nasopharyngitis in Cycle 6, and the other experienced headache in Cycles 7 and 8 and palpitations in Cycle 7).

[0156] Other Safety and Tolerability Endpoints

[0157] AEs were observed in all 35 patients Figure 8). All patients had at least one AE judged by the investigator to be related to the treatment. Grade >3 AEs were observed in 30 patients (86%) and judged to be treatment related in 29 patients (83%). Among the treatment related Grade >3 AEs, blood and lymphatic system disorders (neutropenia, leukopenia, and thrombocytopenia) were the most frequently reported. Serious AEs were reported in 9 patients (26%). All were judged to be treatment related.

[0158] There were no AEs (Grade 5) that resulted in death during the study. Obinutuzumab treatment was discontinued in three patients due to AEs: skin cyst with infection, bronchiolitis, and aspiration pneumonia, one each. Aspiration pneumonia was not treatment related. AEs that resulted in dose reduction or discontinuation of obinutuzumab treatment occurred in three patients, while AEs that resulted in dose reduction or discontinuation of any study drug occurred in nine patients. AEs that resulted in discontinuation of any study drug (n=4) were neutropenia, cellulitis, IRR, cerebral infarction, or pneumonia (one each). Dose reductions of any study drug (n=7) were due to neutropenia / neutrophil count decrease (n=4), leukopenia / white blood cell count decrease (n=3), thrombocytopenia / platelet count decrease (n=3), alanine aminotransferase elevation, aspartate aminotransferase elevation, peripheral neuropathy, peripheral sensory neuropathy, or steroid withdrawal syndrome (one each).

[0159] Pharmacokinetics

[0160] Serum obinutuzumab concentrations in SDI transition patients in the GATS study followed a similar time course as patients under routine infusion in the GOYA study ( Figure 10 ).

[0161] Mean serum obinutuzumab concentrations at cycle 8 were similar to those in cycle 2 in 17 evaluable SDI transition patients. This indicates that steady-state PK was reached at cycle 2 and was not affected by the shortened infusion duration. AUC 最后 (AUC 7天 ) was 4770 ± 898 pg day / ml at cycle 2 (compared to 3590 ± 1060 pg day / ml at cycle 8 in GATHER) Figure 11 ). The mean t 1 / 2 was 15.4 ± 7.55 days (based on 17 evaluable SDI patients; compared to 23.0 ± 15 days in GATHER). AUC 最后 (AUC 11天 ) values at cycle 2 day 1 were 6790 ± 1450 pg day / ml, and C 最大 was 925 ± 221 pg / ml.

[0162] Cytokines

[0163] In all 35 patients (including 31 with SDI conversion), an increase in cytokines was observed during the first olibutuzumab infusion, followed by an immediate decrease 2–5 hours after the infusion. Figure 12 (Indicating IL-6 levels). No changes were observed after the start of SDI. There was also a rapid decrease in CD19-positive B cells after the first olibutuzumab infusion, with the count decreasing to <0.07x10⁻⁶. 9 Cells / L and maintained at this level throughout the study period.

[0164] effect

[0165] At the end of treatment, the overall response rate based on computed tomography was 77% (10 / 13) in patients with flaccid paralysis and 68% (13 / 19) in patients with diabetic leukemia (DLBCL) (including complete and partial responses). Figure 13 The best overall response rates were 92% (12 / 13) and 79% (15 / 19), respectively. Complete response (CR) was achieved at the end of treatment in 8 / 13 patients with FL (62%) and 11 / 19 patients with DLBCL (58%), and the best complete response was assessed in 8 / 13 patients with FL (62%) and 12 / 19 patients with DLBCL (63%).

[0166] This study aimed to investigate the tolerability (specific IRR ratio), PK, and cytokine release profile of olibutuzumab plus CHOP chemotherapy with SDI in patients with untreated CD20-positive B-cell NHL. The vast majority of IRRs with olibutuzumab plus CHOP were observed during cycle 1 of treatment, during which RI was administered. No grade IRR was observed during cycle 2, and only two patients experienced grade 1 IRR in subsequent cycles during olibutuzumab treatment with SDI.

[0167] The observed rate of IRRs (49%) was consistent with other reports of obinutuzumab administration by RI. While this is not a direct comparison, it suggests that there is no increased risk of IRRs in patients treated with SDI obinutuzumab. In the phase III GALLIUM trial of obinutuzumab versus rituximab immunotherapy in 1202 previously untreated patients with FL, IRRs were the most common any-grade AE (68% of patients treated with obinutuzumab immunotherapy) and grade >3 AE (12% of patients treated with obinutuzumab immunotherapy) and were generally occurring during the first infusion. Similarly, in the phase III GOYA study in 1418 patients with untreated DLBCL, IRRs occurred in 45% (any grade) and 10% (grade >3) of patients receiving obinutuzumab plus CHOP. In the phase Ib GAUDI study, IRRs occurred in 18 / 28 patients (64%) receiving obinutuzumab plus CHOP; while this incidence was more common than in the current study, IRRs were also predominantly confined to the first infusion and 3-4 grade IRRs were infrequent, occurring in 2 patients (7%). IRRs also predominated in studies in patients with B-cell malignancies where obinutuzumab was tested as monotherapy, with most responses being grade 1 or 2. Notably, in the GATHER study in 100 predominantly non-Asian patients with DLBCL receiving obinutuzumab plus CHOP, no grade >3 IRRs were recorded in patients receiving SDI over 120 or 90 minutes. The pattern of IRRs seen in GATHER was similar to GATS, with most responses (77%) occurring during cycle 1 (during which the RI is given) Figure 9 ). Other safety and tolerability findings were similar between the GATHER and GATS populations. No new safety signals were identified in the current study.

[0168] PK and serum cytokine data were also found to be comparable to the results of the GATHER study. The order of magnitude of exposure to obinutuzumab following SDI in the current study was also the same as in GATHER, with similar AUC 0-7 and t 1 / 2 values. The order of magnitude of the AUC 最后 values reported from cycle 2 day 1 onwards in this study (4770 ± 885 pg day / ml) was also the same as reported by Ogura et al in their dose-finding phase I study in 12 Japanese patients with relapsed or refractory B-cell NHL, with AUC 最后 values on cycle 1 day 8 of 4190 ± 1190 pg day / ml for patients receiving obinutuzumab 800 mg or 6540 ± 1070 pg day / ml for patients receiving obinutuzumab 1200 mg.

[0169] The pattern of inflammatory cytokine release (rapid peak during the first infusion, followed by rapid decrease and stabilization at baseline levels) was also similar to previous reports. The phase II GAUSS study in 175 patients with relapsed indolent B-cell NHL showed peak cytokine levels of IL6, IL8, IL10, TNFα and IFNγ that increased significantly during the first infusion of obinutuzumab but then returned to baseline without any increase during subsequent infusions. The same pattern was reported in the cohort of 33 patients with relapsed or refractory CLL in the phase I / II GAUGUIN study. Like the authors of GAUGUIN, we noted that these early increases in inflammatory cytokine levels were consistent with the increased IRR reported during the first cycle of treatment in GATS and the other studies mentioned. The pattern of CD 19-positive B-cell response was also similar to previous reports. Ogura et al. showed a rapid decrease after the first infusion of obinutuzumab, with the nadir achieved in most patients after the infusion on day 1. The same rapid B-cell depletion was reported in cycle 1 in the CLL cohort and the indolent B-cell NHL cohort of GAUGUIN.

[0170] The magnitude of the overall and complete response rates in patients with DLBCL at the end of treatment (68 and 58%, respectively) was similar to those obtained in GATHER (82 and 55%, respectively), where SDI was also used in patients with DLBCL. No data are available to compare the response rates in FL patients treated with obinutuzumab using SDI so far.

[0171] A limitation of the current study is the small patient population; a definitive safety evaluation of obinutuzumab SDI would require a much larger sample, although the results obtained do appear to be consistent with the findings in both the Japanese patients and the patients treated with SDI previously. We also note that the GATS study lacked a control arm, where for example patients could have received a regular full cycle of obinutuzumab by RI other than CHOP.

[0172] In summary, obinutuzumab given by SDI was well tolerated in this Japanese patient cohort ( Figure 14 ). No SDI-related IRRs were observed in treatment of the second cycle (i.e. the first SDI cycle); a small number of IRRs were observed with SDI in later cycles, but were tolerable and manageable. The rate of IRRs was consistent with the findings from other studies of obinutuzumab given by RI, indicating that there was no increase in the risk of IRRs when obinutuzumab is given by SDI. In summary, this finding suggests that obinutuzumab can be safely administered by SDI.

Claims

1. A pharmaceutical composition comprising obinutuzumab for use in the treatment of CD20 positive B-cell lymphoma, which is administered as an intravenous infusion infusion at 1000 mg obinutuzumab per administration, and in two or more cycles at an administration rate according to (a) and (b) below: (a) in the first cycle at a maximum administration rate of equal to or greater than 200 mg obinutuzumab per hour, preferably equal to or greater than 300 mg obinutuzumab per hour, more preferably equal to or greater than 400 mg obinutuzumab per hour; (b) in the second or later cycle at a maximum administration rate of equal to or greater than 700 mg obinutuzumab per hour, preferably equal to or greater than 800 mg obinutuzumab per hour, more preferably equal to or greater than 900 mg obinutuzumab per hour.

2. The pharmaceutical composition according to claim 1, wherein the duration of each administration in the second or later cycle is within 180 minutes, preferably within 150 minutes, more preferably within 120 minutes, most preferably within 90 minutes.

3. The pharmaceutical composition according to claim 1 or 2, which is administered 3 times in the first cycle and once per cycle in the second or later cycle.

4. The pharmaceutical composition according to claim 3, wherein the first administration in the first cycle is initiated at a rate of 50 mg obinutuzumab per hour and the second or later administration in the first cycle is initiated at a rate of 100 mg obinutuzumab per hour.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the administration rate in the second or later cycle is increased to 700 mg obinutuzumab per hour or faster, preferably 800 mg obinutuzumab per hour or faster, more preferably up to 900 mg obinutuzumab per hour.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein in (b) the pharmaceutical composition is administered according to at least one of the following conditions (c) to (e): (c) if no grade 3 or higher infusion reactions occurred in the last three administrations and the number of lymphocytes in the peripheral blood prior to administration is less than 5000 / μL, administration is performed at 100 mg / hr for 30 minutes; if no infusion reactions are observed for the entire time, the rate can be increased to 900 mg / hr; depending on the patient's condition, the rate is reduced to the administration rate in cycle 1, if appropriate; (d) if a grade 1 / 2 infusion reaction occurs, administration is resumed at half the rate before administration was stopped; if no infusion reactions are observed for 30 minutes, the rate can be increased to 900 mg / hr; (e) if a grade 3 infusion reaction, administration is resumed at 200 mg / hr or less; if no infusion reactions are observed for 30 minutes, the rate can be increased by 50 mg / hr every 30 minutes to a maximum of 400 mg / hr.

7. The pharmaceutical composition according to any one of claims 1 to 6, which is administered on days 1, 8 and 15 in the first cycle and on day 1 in the second or later cycle. ​ ​ ​ ​ ​ 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein each cycle is 3 weeks.

9. The pharmaceutical composition according to any one of claims 1 to 7, which is used in combination with at least one other anti-neoplastic agent, and wherein the administration cycle of the pharmaceutical composition is synchronized with the dosing cycle of the at least one other anti-neoplastic agent, wherein the dosing cycle is 4 weeks per cycle.

10. The pharmaceutical composition according to claim 9, wherein the at least one other anti-neoplastic agent is selected from the group consisting of CHOP, CVP, bendamustine, fludarabine, lenalidomide, an anti-PD-1 antibody, and an anti-PD-Ll antibody.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is administered every two months for two years as maintenance monotherapy after the two or more cycles.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the concentration of obinutuzumab in the infusion solution is 10 to 40 mg / mL, preferably 20 to 30 mg / mL, more preferably 25 mg / mL, when administered as intravenous infusion.

13. The pharmaceutical composition according to any one of claims 1 to 12, further comprising trehalose hydrate, L-histidine, L-histidine hydrochloride hydrate, or polyoxyethylene (160) polyoxypropylene (30) glycol as an additive.

14. Use of obinutuzumab for the manufacture of a pharmaceutical composition comprising obinutuzumab for the treatment of CD20-positive B-cell lymphoma, wherein the composition is administered as intravenous infusion with 1000 mg obinutuzumab per administration, and wherein the administration rate in two or more cycles is according to (a) and (b) below: (a) the maximum administration rate in the first cycle is equal to or greater than 200 mg obinutuzumab per hour, preferably equal to or greater than 300 mg obinutuzumab per hour, more preferably equal to or greater than 400 mg obinutuzumab per hour; (b) the maximum administration rate in the second or later cycle is equal to or greater than 700 mg obinutuzumab per hour, preferably equal to or greater than 800 mg obinutuzumab per hour, more preferably equal to or greater than 900 mg obinutuzumab per hour.

15. A method for the treatment of CD20-positive B-cell lymphoma by a pharmaceutical composition comprising obinutuzumab, wherein the composition is administered as intravenous infusion with 1000 mg obinutuzumab per administration, and wherein the administration rate in two or more cycles is according to (a) and (b) below: (a) the maximum administration rate in the first cycle is equal to or greater than 200 mg obinutuzumab per hour, preferably equal to or greater than 300 mg obinutuzumab per hour, more preferably equal to or greater than 400 mg obinutuzumab per hour; (b) the maximum administration rate in the second or later cycle is equal to or greater than 700 mg obinutuzumab per hour, preferably equal to or greater than 800 mg obinutuzumab per hour, more preferably equal to or greater than 900 mg obinutuzumab per hour. ​ ​ ​ ​

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