On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11–0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy–designated drug to receive FDA approval. Clin Cancer Res; 20(15); 3902–7. ©2014 AACR.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries (1). It is estimated that there will be 15,720 new cases of CLL and 4,600 deaths because of CLL in 2014 in the United States (2). CLL is predominant in older individuals with a median age at diagnosis of 71 years. CLL has a variable natural history with a 5-year relative survival rate of approximately 82% (3).

CLL is characterized by increasing levels of clonal lymphocytes in the blood, bone marrow, and lymphatic tissues (4). The diagnosis of CLL requires at least 5 × 109 B lymphocytes/L (5,000/μL) in the peripheral blood and confirmation of clonality by flow cytometry. CLL cells coexpress the T-cell antigen CD5 and B-cell surface antigens CD19, CD20, and CD23 (5).

Approved therapies for CLL include chlorambucil, cyclophosphamide, fludarabine, alemtuzumab, bendamustine, ofatumumab, and rituximab. For previously untreated patients with progressive CLL, recommended treatment regimens primarily consist of chemoimmunotherapies. However, in patients with coexisting medical conditions, often including the elderly, aggressive treatment regimens are poorly tolerated (6). Allogeneic stem-cell transplantation is the only potentially curative treatment for CLL (7).

This report summarizes the FDA review of the Biologics License Application (BLA) for obinutuzumab used in combination with chlorambucil for the initial therapy of patients with CLL.

Obinutuzumab is an Fc-glycoengineered humanized anti-CD20 monoclonal antibody of the IgG1 subclass with a molecular mass of approximately 150 kDa (8). It recognizes the type II epitope of the CD20 antigen rather than the type I epitope recognized by rituximab. Obinutuzumab is a sterile, clear, colorless to slightly brown, preservative-free liquid concentrate for i.v. administration and is supplied at a concentration of 25 mg/mL in 1,000 mg single-use vials.

Obinutuzumab binds to CD20 expressed on the surface of pre-B and mature B lymphocytes (B-cells). Upon binding to CD20, obinutuzumab mediates B-cell lysis (i) through antibody-dependent cellular cytotoxicity and phagocytosis; (ii) by directly activating internal cell death signaling pathways; and (iii) by antibody activation of complement-dependent cytotoxicity.

Toxicology studies were conducted using cynomolgus monkeys. Obinutuzumab binds human and cynomolgus monkey CD20 with similar affinity. Repeat-dose toxicology studies of up to 26 weeks' duration using i.v. administration of obinutuzumab or 4 weeks' duration using s.c. administration were conducted. Toxicities observed from repeat-dose studies were consistent with the intended pharmacology of obinutuzumab or were the apparent result of cross-species immunogenicity effects. The primary effects of obinutuzumab included hypersensitivity reactions and marked decreases in circulating B cells, with corresponding lymphoid tissue B-cell depletion in the spleen and lymph nodes. Transient natural killer cell reductions were also observed, as were opportunistic infections secondary to immunosuppression.

Administration of obinutuzumab to pregnant monkeys during gestation was associated with complete depletion of B lymphocytes in infants. Obinutuzumab did not affect embryo–fetal development, parturition, postnatal survival, or the growth and development of infants. Obinutuzumab crosses the blood–placental barrier and is secreted in the milk of pregnant monkeys. Because of the depletion of B cells and possible opportunistic infections, use of obinutuzumab during pregnancy is not recommended.

The steady-state pharmacokinetic parameters for obinutuzumab were derived using a population-based pharmacokinetic (pop-PK) analysis. The geometric mean (CV%) volume of distribution of obinutuzumab is approximately 3.8 L (23%). The elimination of obinutuzumab is composed of a linear clearance pathway and a time-dependent nonlinear clearance pathway. As obinutuzumab treatment progresses, the impact of the time-dependent pathway diminishes in a manner suggesting target-mediated drug disposition. The geometric mean (CV%) terminal obinutuzumab clearance and half-life are approximately 0.09 (46%) L/day and 28.4 (43%) days, respectively.

Body weight, disease type, and tumor size were associated with changes in obinutuzumab exposures, but the impact of these factors on obinutuzumab exposure did not warrant a dose modification at this time. Mild or moderate renal impairment [i.e., baseline creatinine clearance (CLcr) > 30 mL/min] did not affect obinutuzumab exposure. There are insufficient data available to determine the effect of severe renal impairment (CLcr < 30 mL/min) or any degree of hepatic impairment on obinutuzumab exposure. No treatment modifications are recommended in these populations because these elimination pathways are not expected to be a major factor affecting exposure as monoclonal antibodies are generally catabolized by ubiquitous proteolytic enzymes.

Design

Study CLL11 was an open-label, three-arm, randomized, multicenter, two-stage, phase III trial in patients with previously untreated CLL. Randomization was stratified by Binet stage and country/region. The trial was conducted at 155 centers in 24 countries and in collaboration with the German CLL Study Group. In stage 1 of the trial, patients were randomly allocated (2:2:1) to obinutuzumab plus chlorambucil (GClb), rituximab plus chlorambucil (RClb), or chlorambucil (Clb) alone. In stage 2, the randomization continued between GClb and RClb (1:1). Stage 2 results were not available at the time of the BLA review.

Key eligibility criteria were age of 18 years or older, previously untreated documented CD20-positive CLL requiring treatment, and coexisting medical conditions or creatinine clearance (CrCl) < 70 mL/min or both. Exclusion criteria included CrCl < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive, patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, and immunization with live virus vaccine within 28 days before randomization.

For the purpose of analysis, stage 1 of the clinical trial was further divided into stages 1a (GClb vs. Clb) and 1b (RClb vs. Clb). In the stage 1a analysis, 356 patients were randomly allocated to GClb (n = 238) or to Clb (n = 118). The stage 1b analysis is not relevant to this approval and will not be described further. Patients in the Clb arm with disease progression during or within 6 months of end of treatment could cross over to GClb, but only 19% had done so at the time of analysis cutoff date.

The trial began with patients on the GClb arm receiving obinutuzumab, 1,000 mg by i.v. infusion on days 1, 8, and 15 of the first treatment cycle and on the first day of cycles 2 to 6. Later in the trial, because of infusion reactions, the protocol was amended to split the first dose in the first cycle only between day 1 (100 mg) and day 2 (900 mg), and this regimen was administered to 45 (19%) patients. Patients on both arms received chlorambucil, 0.5 mg/kg orally on days 1 and 15 of a 28-day cycle for a maximum of 6 cycles. After the last treatment, patients were followed until disease progression, next leukemia treatment, and death.

Dose modification of obinutuzumab was not allowed. Dose reductions for chlorambucil were allowed, and once reduced the dose could not be reescalated. Patients who experienced a grade 4 infusion reaction or a grade 3 infusion reaction at rechallenge were permanently discontinued from the study treatment, and patients with an infection, grade 3 or 4 cytopenia, or grade 2 or higher nonhematologic toxicity had their study treatment temporarily interrupted until resolution.

To reduce infusion reactions, premedication with an i.v. glucocorticoid, acetaminophen, and an antihistamine before the first infusion became mandatory during the trial. Subsequent premedications could be reduced in the absence of an infusion reaction. Consideration was given to holding antihypertensive agents before and throughout the infusion because infusion reactions sometimes included hypotension. Infusion reactions were managed by interrupting or reducing the infusion rate and administering concomitant medications such as steroids and antihistamines. Upon resolution of symptoms, the infusion was resumed at one-half the previous rate. Obinutuzumab was to be administered at a location with immediately available emergency resuscitation equipment.

Patients with a high tumor burden (WBC ≥ 25 × 109/L or bulky lymphadenopathy) were to receive adequate hydration and antihyperuricemics before the initiation of treatment for prophylaxis of tumor lysis syndrome.

Disease assessment was performed at baseline, after 3 cycles, 28 days after the last trial treatment, 3 months after the end of treatment, and then every 3 months until 3 years from last treatment. Further follow-up visits were scheduled every 6 months until 5 years, and then annually for 8 years after the last patient entered the trial. A CT scan was performed in patients who had achieved a complete response (CR) or partial response 2 to 3 months after end of treatment. In patients who had a CR (or cytopenic CR), a bone marrow aspirate and biopsy were obtained. A CT scan was also performed when progression of disease was detected by physical examination.

The primary efficacy endpoint was progression-free survival (PFS) based on investigator's assessment. However, the regulatory decision was based on independent review committee (IRC)–assessed PFS. The IRC was composed of a panel of CLL experts (each patient reviewed by two reviewers and one adjudicator if required) who assessed response and progression based on peripheral blood counts, bone marrow biopsy results, reports of physical examination, and radiology reports. Secondary efficacy endpoints included best overall response, event-free survival, duration of response, disease-free survival, time to new antileukemic therapy, and overall survival. Response was determined using the NCI/International Workshop on CLL guideline (5). End of trial was defined as 8 years after the last patient was enrolled.

Demographics

Patient demographics and disease characteristics, including CLL prognostic factors were balanced at baseline between treatment arms (Table 1). The median age was 73 years, 76% of patients had multiple coexisting medical conditions and 68% had a CrCl <70 mL/min.

Table 1.

Baseline demographics and disease characteristics (CLL11, stage 1a)

CategoryParameterGClbClbTotal
Gender n 238 118 356 
 Female 98 (41%) 43 (36%) 141 (40%) 
 Male 140 (59%) 75 (64%) 215 (60%) 
Age (y) n 238 118 356 
 ≥75 107 (45%) 44 (37%) 151 (42%) 
 ≥65 196 (82%) 92 (78%) 288 (81%) 
 Median 74.0 72.0 73.0 
 Range 39–88 43–87 39–88 
Race n 238 118 356 
 Caucasian 229 (96%) 108 (92%) 337 (95%) 
ECOG PS n 238 118 356 
 0 to 1 211 (89%) 105 (89%) 316 (89%) 
Binet stage n 238 118 356 
 55 (23%) 24 (20%) 79 (22%) 
 98 (41%) 50 (42%) 148 (42%) 
 85 (36%) 44 (37%) 129 (36%) 
IgVH n 210 99 309 
 Unmutated 129 (61%) 58 (59%) 187 (61%) 
 Mutated 76 (36%) 36 (36%) 112 (36%) 
Chromosomal abnormalities n 203 96 299 
 17p− 16 (8%) 10 (10%) 26 (9%) 
 11q− 33 (16%) 14 (15%) 47 (16%) 
 +12 33 (16%) 16 (17%) 49 (16%) 
 13q− 58 (29%) 32 (33%) 90 (30%) 
ZAP-70 expression n 189 97 286 
 Positive 83 (44%) 48 (49%) 131 (46%) 
 Negative 106 (56%) 49 (51%) 155 (54%) 
CategoryParameterGClbClbTotal
Gender n 238 118 356 
 Female 98 (41%) 43 (36%) 141 (40%) 
 Male 140 (59%) 75 (64%) 215 (60%) 
Age (y) n 238 118 356 
 ≥75 107 (45%) 44 (37%) 151 (42%) 
 ≥65 196 (82%) 92 (78%) 288 (81%) 
 Median 74.0 72.0 73.0 
 Range 39–88 43–87 39–88 
Race n 238 118 356 
 Caucasian 229 (96%) 108 (92%) 337 (95%) 
ECOG PS n 238 118 356 
 0 to 1 211 (89%) 105 (89%) 316 (89%) 
Binet stage n 238 118 356 
 55 (23%) 24 (20%) 79 (22%) 
 98 (41%) 50 (42%) 148 (42%) 
 85 (36%) 44 (37%) 129 (36%) 
IgVH n 210 99 309 
 Unmutated 129 (61%) 58 (59%) 187 (61%) 
 Mutated 76 (36%) 36 (36%) 112 (36%) 
Chromosomal abnormalities n 203 96 299 
 17p− 16 (8%) 10 (10%) 26 (9%) 
 11q− 33 (16%) 14 (15%) 47 (16%) 
 +12 33 (16%) 16 (17%) 49 (16%) 
 13q− 58 (29%) 32 (33%) 90 (30%) 
ZAP-70 expression n 189 97 286 
 Positive 83 (44%) 48 (49%) 131 (46%) 
 Negative 106 (56%) 49 (51%) 155 (54%) 

Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status.

Efficacy

The IRC-assessed median PFS was 23.0 months in the GClb arm versus 11.1 months in the Clb arm [Fig. 1 (HR, 0.16; 95% CI, 0.11–0.24; P < 0.0001 stratified log-rank test)]. The investigator-assessed median PFS durations were 23.0 months in the GClb arm and 10.9 months in the Clb arm (HR, 0.14; 95% CI, 0.09–0.21; P < 0.0001 stratified log-rank test). The results of the secondary endpoints were supportive of the primary endpoint; however, there was no multiplicity adjustment plan for testing the secondary endpoints. Table 2 lists the results of the primary and key secondary endpoints. The overall survival (OS) data were not mature at the analysis cutoff date. The median observation time was 14.2 months, and the median number of treatment cycles was 6. Eighty-one percent and 67% of patients in the GClb and Clb arms, respectively, received all 6 treatment cycles.

Figure 1.

Kaplan–Meier estimates of IRC-assessed PFS (CLL11, stage 1a). Clb, chlorambucil; GClb, obinutuzumab + chlorambucil.

Figure 1.

Kaplan–Meier estimates of IRC-assessed PFS (CLL11, stage 1a). Clb, chlorambucil; GClb, obinutuzumab + chlorambucil.

Close modal
Table 2.

Summary of efficacy results (CLL11, stage 1a)

EndpointsGClbClb
Median PFS by IRC (months) 23.0 11.1 
HR, P-value (stratified log-rank testa0.16 (0.11, 0.24), <0.0001 
Median PFS by investigator (months) 23.0 10.9 
HR, P-value (stratified log-rank testa0.14 (0.09, 0.21), <0.0001 
Best overall response rate 75.9% 32.1% 
Complete response 27.8% 0.9% 
Median duration of response (months)b 15.2 3.5 
EndpointsGClbClb
Median PFS by IRC (months) 23.0 11.1 
HR, P-value (stratified log-rank testa0.16 (0.11, 0.24), <0.0001 
Median PFS by investigator (months) 23.0 10.9 
HR, P-value (stratified log-rank testa0.14 (0.09, 0.21), <0.0001 
Best overall response rate 75.9% 32.1% 
Complete response 27.8% 0.9% 
Median duration of response (months)b 15.2 3.5 

aStratified by Binet stage at baseline.

bAmong patients who had response.

Safety

The safety dataset included 240 patients who received one or more doses of obinutuzumab with Clb and 116 patients who received Clb only. Although Clb dose modifications or delays occurred twice as often in the GClb arm (32% vs. 15%), the median cumulative dose was comparable in the two arms (370 mg vs. 384 mg). The most frequently reported adverse reactions with an incidence of 5% or greater and occurring at least 2% more frequently in the GClb arm were infusion-related reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, leukopenia, and musculoskeletal pains (Table 3). The most common serious adverse reaction was infusion-related reaction (11%). Grade 3 to 4 neutropenia was more common in the GClb arm (34%) than in the Clb arm (16%). The incidence of infections was not higher in the GClb arm, but 32% of patients in the GClb arm received G-CSF compared with 14% in the Clb arm. Growth factors were allowed for neutropenia per investigator or institutional guidelines. Tumor lysis syndrome occurred in 4% of patients in the GClb arm.

Table 3.

Treatment-emergent adverse reactions with ≥5% incidence and ≥2% difference between the two arms (CLL11, stage 1a)

Obinutuzumab + chlorambucil, n = 240Chlorambucil, n = 116
Grades 1–4Grades 3 and 4Grades 1–4Grades 3 and 4
Adverse Eventn%n%n%n%
Injury, poisoning, and procedural complications 
 Infusion-related reaction 165 69 50 21 
Blood and lymphatic system disorders 
 Neutropenia 96 40 82 34 21 18 18 16 
 Thrombocytopenia 36 15 26 11 
 Anemia 29 12 12 10 
 Leukopenia 16 13 
Respiratory, thoracic, and mediastinal disorders 
 Cough 23 10 <1 
General disorders and administration site conditions 
 Pyrexia 25 10 <1 
Musculoskeletal and connective tissue disorders 
 Arthralgiasa 13 
 Musculoskeletal painsb 23 10 
Obinutuzumab + chlorambucil, n = 240Chlorambucil, n = 116
Grades 1–4Grades 3 and 4Grades 1–4Grades 3 and 4
Adverse Eventn%n%n%n%
Injury, poisoning, and procedural complications 
 Infusion-related reaction 165 69 50 21 
Blood and lymphatic system disorders 
 Neutropenia 96 40 82 34 21 18 18 16 
 Thrombocytopenia 36 15 26 11 
 Anemia 29 12 12 10 
 Leukopenia 16 13 
Respiratory, thoracic, and mediastinal disorders 
 Cough 23 10 <1 
General disorders and administration site conditions 
 Pyrexia 25 10 <1 
Musculoskeletal and connective tissue disorders 
 Arthralgiasa 13 
 Musculoskeletal painsb 23 10 

aIncludes the preferred terms: arthralgia, gouty arthritis, arthritis, and osteoarthritis.

bIncludes the preferred terms: musculoskeletal pain, musculoskeletal chest pain, bone pain, myalgia intercostal, neck pain, pain in extremity, and back pain.

The incidence of infusion reactions was 69% with the first infusion of obinutuzumab, and the incidence of reactions with subsequent infusions was 3% with the second 1,000 mg and <1% thereafter. Symptoms of infusion-related reactions occurring in greater than 20% of patients included hypotension, nausea, chills, and pyrexia. Changes to the administration of obinutuzumab during the trial (including glucocorticoid, analgesic, and antihistamine treatment, omission of antihypertensive medications in the morning of the first infusion, and administration of the cycle 1 day 1 dose over 2 days) seemed to reduce the incidence of infusion reactions.

Late-occurring neutropenia (≥28 days after treatment) was seen in 16% of patients on the GClb arm and 12% of patients on the Clb arm. Although there were no instances of hepatitis B reactivation or progressive multifocal leukoencephalopathy in the randomized trial, there were rare cases of each on other trials using obinutuzumab.

The regular approval (licensing) of obinutuzumab for use in combination with chlorambucil for the treatment of patients with previously untreated CLL was based on the demonstration of a clinically meaningful and statistically robust improvement in PFS in a single randomized trial. For diseases such as CLL, PFS may be considered an acceptable endpoint for regular approval as it takes considerable time to reach the OS endpoint and additional subsequent therapies may confound an OS analysis (9). However, a recent update of study CLL11, including an analysis of stage 2, reported significant improvements in OS for the GClb arm compared with the Clb arm and in PFS for the GClb arm compared with the RClb arm (10). These data have not been reviewed by the FDA.

The main adverse reactions that occurred in the GClb arm were infusion reactions and myelosuppression. Other important toxicities included in the labeling were the risks of hepatitis B virus reactivation and JC virus infection resulting in progressive multifocal leukoencephalopathy, which were observed in patients treated with obinutuzumab in other clinical trials. The FDA review of the randomized trial comparison of GClb to Clb concluded that there was a favorable benefit–risk outcome for the treatment of patients with previously untreated CLL.

CLL largely affects older patients who often have multiple comorbidities. However, this population is not sufficiently enrolled in most pivotal clinical trials (6). In the CLL11 trial, the median age was 73 years, and 81% of the patients were aged 65 years or older; thus, this was one of the few randomized trials that adequately represented the typical age of the CLL population. The results of trial CLL11 indicate that the combination of obinutuzumab + chlorambucil is more effective than chlorambucil alone, has an acceptable safety profile, and is an appropriate regimen for elderly patients with previously untreated CLL and comorbidities. Because aggressive treatments for older patients with comorbidities are poorly tolerated, chlorambucil was considered an acceptable active control for this trial. However, in future trials in this patient population the GClb regimen would be an appropriate control.

In July 2012, the Food and Drug Administration Safety and Innovation Act was signed to provide designation of a drug as a Breakthrough Therapy for serious or life-threatening diseases. This designation is intended to expedite the development of new drugs with preliminary clinical evidence that indicates the drug may offer a substantial improvement over available therapies (11). Obinutuzumab was the first Breakthrough Therapy product to receive FDA approval. Because the Breakthrough Therapy designation request for obinutuzumab was received close to the time of BLA submission, the development plan could not receive the full benefits of the program. Drugs that receive Breakthrough Therapy designation earlier in their development are eligible to receive intensive interaction and guidance from the FDA.

Obinutuzumab is the third CD20-directed cytolytic antibody (after ofatumumab and rituximab) to receive FDA approval and provides a major advance in the treatment of patients with CLL.

No potential conflicts of interest were disclosed.

Conception and design: H.-Z. Lee, A.T. Farrell, R. Pazdur

Development of methodology: A.T. Farrell, R. Pazdur

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): J. Grillo, A.T. Farrell, R. Pazdur

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): H.-Z. Lee, B.W. Miller, V.E. Kwitkowski, S. Ricci, P. DelValle, J. Grillo, J. Bullock, J. Florian, N. Mehrotra, C.-W. Ko, L. Nie, M. Tolnay, R.C. Kane, A.T. Farrell

Writing, review, and/or revision of the manuscript: H.-Z. Lee, B.W. Miller, V.E. Kwitkowski, S. Ricci, P. DelValle, H. Saber, J. Grillo, J. Bullock, J. Florian, N. Mehrotra, C.-W. Ko, M. Shapiro, M. Tolnay, R.C. Kane, E. Kaminskas, R. Justice, A.T. Farrell, R. Pazdur

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): V.E. Kwitkowski, J. Grillo, A.T. Farrell, R. Pazdur

Study supervision: A.T. Farrell

The authors thank Beatrice Kallungal for her assistance in coordinating the review of this Biologics License Application.

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