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Published OnlineFirst May 13, 2014.Clin Cancer Res
Hyon-Zu Lee, Barry W. Miller, Virginia E. Kwitkowski, et al.
Untreated Chronic Lymphocytic Leukemia
Combination with Chlorambucil for the Treatment of Previously
U.S. Food and Drug Administration Approval: Obinutuzumab in
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1
U.S. Food and Drug Administration Approval: Obinutuzumab in Combination with
Chlorambucil for the Treatment of Previously Untreated Chronic Lymphocytic Leukemia
Hyon-Zu Lee1, Barry W. Miller1, Virginia E. Kwitkowski1, Stacey Ricci1, Pedro DelValle1,
Haleh Saber1, Joseph Grillo2, Julie Bullock2, Jeffry Florian2, Nitin Mehrotra2, Chia-Wen Ko3, Lei
Nie3,Marjorie Shapiro4, Mate Tolnay4, Robert C. Kane1, Edvardas Kaminskas1, Robert Justice1,
Ann T. Farrell1, and Richard Pazdur1.
Author Affiliations: 1Office of Hematology and Oncology Products, Office of New Drugs;
2Office of Clinical Pharmacology, 3Office of Biostatistics, 4Office of Biotechnology Products,
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring,
Maryland.
Running Title: FDA Approval of Obinutuzumab for CLL
Corresponding Author: Hyon-Zu Lee, Division of Hematology Products, U.S. Food and Drug
Administration, 10903 New Hampshire Avenue, Silver Spring MD 20993. Phone: 301-796-
2192; Fax 301-796-9849; E-mail: Hyon.Lee@fda.hhs.gov
Note: This is a U.S. Government work. There are no restrictions on its use.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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Abstract
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 here. There was a clinically meaningful and statistically significant improvement in
PFS with medians of 23.0 months and 11.1 months in the GClb and Clb arms, respectively
[HR=0.16 (95% CI: 0.11, 0.24), p-value <0.0001log-rank test]. The ORR was 75.9% and 32.1%
in the GClb and Clb arms, respectively, and the complete response rate was 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.
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Introduction
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 due to CLL in 2014 in
the U.S (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 x 109 B
lymphocytes/L (5000/µL) in the peripheral blood and confirmation of clonality by flow
cytometry. CLL cells co-express 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
chronic lymphocytic leukemia.
Chemistry
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
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sterile, clear, colorless to slightly brown, preservative-free liquid concentrate for intravenous
administration and is supplied at a concentration of 25 mg/mL in 1000 mg single use vials.
Pharmacology and Toxicology
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 IV administration of obinutuzumab or four weeks duration using
subcutaneous 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, 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.
Clinical Pharmacology
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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 (23%) L. The elimination of obinutuzumab is comprised of a
linear clearance pathway and a time-dependent non-linear 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.
Clinical Trial
Design
Study CLL11 was an open-label, three-arm, randomized, multicenter, two-stage, phase 3 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
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(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 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 prior to randomization.
For the purpose of analysis, stage 1of 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 1000 mg by
intravenous infusion on days 1, 8 and 15 of the first treatment cycle and on the first day of cycles
2-6. Later in the trial, due to 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 re-escalated. Patients who experienced a
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grade 4 infusion reaction or a grade 3 infusion reaction at re-challenge were permanently
discontinued from the study treatment and patients with an infection, grade 3 or 4 cytopenia or a
grade 2 or higher non-hematologic toxicity had their study treatment temporarily interrupted
until resolution.
To reduce infusion reactions, premedication with an intravenous glucocorticoid,
acetaminophen and an antihistamine prior to the first infusion became mandatory during the trial.
Subsequent pre-medications 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 x109/L or bulky lymphadenopathy) were
to receive adequate hydration and anti-hyperuricemics prior to 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 CR or PR 2-3 months after end of treatment. In patients who had a CR (or
cytopenic CR), a bone marrow aspirate and biopsy was obtained. A CT scan was also performed
when progression of disease was detected by physical examination.
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The primary efficacy endpoint was 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 anti-leukemic therapy and overall survival. Response was
determined using the NCI/International Workshop on CLL (IWCLL) guideline (5). End of trial
was defined as 8 years after the last patient was enrolled.
Results
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.
Efficacy
The IRC-assessed median PFS was 23.0 months in the GClb arm versus 11.1 months in the Clb
arm [HR=0.16 (95% CI: 0.11, 0.24), p-value <0.0001 stratified log-rank test] (Fig. 1). The
investigator-assessed median PFS was 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-value <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 median number of
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treatment cycles was six. Eighty-one percent and 67% of patients in the GClb and Clb arms,
respectively, received all 6 treatment cycles.
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/delays occurred
twice as often in the GClb arm (32% vs. 15%), the median cumulative dose was comparable in
the two arms (370 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 3-4 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 to 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.
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 1000 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) appeared to reduce the incidence of infusion reactions.
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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. While 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.
Discussion
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 to the Clb arm and
in PFS for the GClb arm compared to the RClb arm (10). These data have not been reviewed by
the Agency.
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
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median age was 73 years and 81% of the patients were 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 plus 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 (FDASIA)
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.
Acknowledgment
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The authors thank Beatrice Kallungal for her assistance in coordinating the review of this
Biologics License Application.
References
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8. Mössner E, Brünker P, Moser S, Püntener U, Schmidt C, Herter S, et al. Increasing the
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Table 1. Baseline Demographics and Disease Characteristics (CLL11, stage 1a)
Category Parameter GClb Clb Total
Gender n 238 118 356
Female 98 (41%) 43 (36%) 141 (40%)
Male 140 (59%) 75 (64%) 215 (60%)
Age (years) 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
A 55 (23%) 24 (20%) 79 (22%)
B 98 (41%) 50 (42%) 148 (42%)
C 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%)
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Table 2. Summary of Efficacy Results (CLL11, stage 1a)
Endpoints GClb Clb
Median PFS by IRC (months) 23.0 11.1
HR, p-value (stratified log-rank test a) 0.16 (0.11, 0.24), <0.0001
Median PFS by investigator (months) 23.0 10.9
HR, p-value (stratified log-rank test a) 0.14 (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
a Stratified by Binet stage at baseline.
b Among patients who had response.
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Table 3. Treatment-Emergent Adverse Reactions with ≥ 5% Incidence and ≥ 2%
Difference between the Two Arms (CLL11, stage 1a)
Adverse Event
Obinutuzumab +
Chlorambucil
n=240
Chlorambucil
n=116
Grades
1-4
Grades
3&4
Grades
1-4
Grades
3&4
n % n % n % n %
Injury, Poisoning and Procedural
Complications
Infusion-Related Reaction 165 69 50 21 0 0 0 0
Blood and Lymphatic System
Disorders
Neutropenia 96 40 82 34 21 18 18 16
Thrombocytopenia 36 15 26 11 8 7 4 3
Anemia 29 12 9 4 12 10 6 5
Leukopenia 16 7 13 5 0 0 0 0
Respiratory, Thoracic and Mediastinal
Disorders
Cough 23 10 0 0 8 7 1 <1
General Disorders and Administration
Site Conditions
Pyrexia 25 10 1 <1 8 7 0 0
Musculoskeletal and Connective
Tissue Disorders
Arthralgias (a) 13 5 2 1 3 3 1 1
Musculoskeletal Pains (b) 23 10 2 1 8 7 0 0
(a) Includes the Preferred Terms: Arthralgia, Gouty Arthritis, Arthritis, Osteoarthritis
(b) Includes the Preferred Terms: Musculoskeletal Pain, Musculoskeletal Chest Pain, Bone Pain, Myalgia
Intercostal, Neck Pain, Pain In Extremity, Back Pain
Research.
on May 19, 2014. © 2014 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Author Manuscript Published OnlineFirst on May 13, 2014; DOI: 10.1158/1078-0432.CCR-14-0516
17
Figure 1. Kaplan-Meier Estimates of IRC-Assessed PFS (CLL11, stage 1a)
Clb: Chlorambucil; GClb: Obinutuzumab plus chlorambucil
Research.
on May 19, 2014. © 2014 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Author Manuscript Published OnlineFirst on May 13, 2014; DOI: 10.1158/1078-0432.CCR-14-0516
© 2014 American Association for Cancer Research
0
10
20
30
40
50
60
70
80
90
100
0369121518212427
Study month
Progression-free survival (%)
Clb
Clb
118
GClb
GClb
238
91
208
76
201
46
146
21
111
6
69
2
39
0
16
0
2
0
0
Figure 1:
Research.
on May 19, 2014. © 2014 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Author Manuscript Published OnlineFirst on May 13, 2014; DOI: 10.1158/1078-0432.CCR-14-0516
