Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME AND/OR COMPOUND NUMBER: PF-05280586
PROTOCOL NO.: B3281006
PROTOCOL TITLE: A Phase 3, Randomized, Double-Blind Study of PF-05280586
Versus Rituximab for the First-Line Treatment of Patients With CD20-Positive, Low Tumor
Burden, Follicular Lymphoma
Study Center(s): A total of 160 centers took part in the study: 1 each in Austria, Peru, andPuerto Rico, 2 each in Belarus, Croatia, Georgia, South Africa, Thailand, and Poland, 3 eachin Belgium, Switzerland, United Kingdom, and Lebanon, 4 each in France, Greece, Mexico,
Portugal, and Romania, 5 each in India, and Ukraine, 7 each in Germany, and the Republic ofKorea, 8 each in Brazil, and Turkey, 10 each in the Russian Federation, and Spain, 13 in
Italy, 19 in Japan, and 21 in the United States.
Study Initiation Date and Primary Completion or Final Completion Dates:
Study Initiation Date: First subject first visit: 30 September 2014
Final Completion Date: Last subject last visit: 19 April 2018
Phase of Development:
Phase 3
Study Objective(s):Primary Objective

To compare the efficacy of PF-05280586 to rituximab-EU when administered as afirst-line treatment to subjects with CD20-positive, low tumor burden follicularlymphoma (LTB FL).

Secondary Objectives
To evaluate the safety of PF-05280586 and rituximab-EUTo evaluate the population pharmacokinetics (PK) of PF-05280586 and rituximab-EUTo evaluate the immunogenicity of PF-05280586 and rituximab-EU

To characterize CD19-positive B-cell depletion and recovery in subjects receiving
PF-05280586 and rituximab-EU.

METHODS
Study Design: This was a double-blind, randomized, comparative clinical trial evaluating
the efficacy, safety, PK and immunogenicity of PF-05280586 versus rituximab-EU insubjects with CD20 positive, LTB FL in the first-line treatment setting. Subjects were
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Protocol B3281006 – 18 October 2018 - Finalrandomized in a 1:1 ratio to receive PF-05280586 or rituximab-EU. Randomization was
stratified by low, medium, and high risk subjects using the Follicular Lymphoma
International Prognostic Index 2 (FLIPI2). During the study, subjects received 4 weekly
doses of PF-05280586 or rituximab-EU administered via intravenous infusion. The dose of
PF-05280586 or rituximab-EU was 375 mg/m2 of body surface area (BSA). The maximum
dose that could be infused in 1 day was 1125 mg.
Figure 1. Study Schematic

Abbreviations: EU=European Union; R-EU=rituximab-EU; R-Pfizer=rituximab-Pfizer (PF-05280586)

Number of Subjects (Planned and Analyzed): The primary hypothesis to be tested in thisstudy was that the difference between the overall response rate (ORR) of PF-05280586
versus that of rituximab-EU was within a pre-specified equivalence margin of -16% to 16%(-14.9% to 14.9% for Japan). A sample size of approximately 394 subjects (approximately
197 per treatment arm) provided approximately 93% power for achieving equivalence under
the specified margin with 2.5% type I error rate assuming an ORR of 77% in both treatment
arms. Overall 394 subjects were enrolled globally (196 subjects in the PF-05280586 groupand 198 subjects in the rituximab-EU group).
Diagnosis and Main Criteria for Inclusion and Exclusion: Male or female subjects aged
18 years or older with histologically confirmed, Grade 1-3a, CD20-positive FL (containing
no elements of diffuse large B-cell lymphoma) were eligible for the study. Documentation of
Ann Arbor Staging (II, III, or IV), an Eastern Cooperative Oncology Group status of 0 to 1,
and at least 1 measureable disease lesion identifiable by imaging was also required for study
eligibility. An eligible subject with LTB FL was defined as serum lactate dehydrogenase1.5 upper limit of normal (ULN), 2-microglobulin 1.5 × ULN, largest nodal or
extra-nodal mass <7 cm in diameter, no more than 3 nodal sites with a diameter >3 cm, noclinically significant serous effusions detectible on chest radiography, spleen enlargement
16 cm by computed tomography scan, no complications such as organ compression or
impairment, and no B symptoms (ie, fever >38C for 3 consecutive days; recurrent,
drenching night sweats; unintentional weight loss exceeding 10% body weight in 6 months).
Study Treatment: Blinded rituximab (PF-05280586 or rituximab-EU) was administered at
a dose of 375 mg/m2 at Visits 2, 3, 4, and 5 (Days 1, 8, 15, and 22). The BSA for the subject
was calculated using a standard formula and the subject’s weight and height. The weight andheight at Screening could have been used to calculate the BSA for all doses unless the subject
had a clinically significant change in weight from Screening at a dosing visit, in which casethe dose could be adjusted if there had been a change of more than 10%. The maximum dose

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Protocol B3281006 – 18 October 2018 - Finalof rituximab that could be infused in 1 day was 1125 mg. Infusion instructions were followed
as per the product labeling; study treatment was administered according to the local productlabeling if it differed from the following instructions:

Day 1 infusion: Infusion was initiated at a rate of 50 mg/hour. After 30 minutes and in
the absence of infusion toxicity, infusion rate was increased by 50 mg/hour increments
every 30 minutes, to a maximum of 400 mg/hour.

Day 8, 15, and 22 infusions: Infusion was initiated at a rate of 100 mg/hour. After
30 minutes and in the absence of infusion toxicity, the infusion rate was increased by
100 mg/hour increments at 30 minute intervals, to a maximum of 400 mg/hour.

Subjects were closely monitored for the onset of cytokine release syndrome. Subjects
who developed evidence of severe reactions, especially severe dyspnea, bronchospasm or
hypoxia had immediate interruption of the infusion. In all subjects, the infusion was not
to be restarted until complete resolution of all symptoms, and normalization of laboratory
values. At this time, the infusion could be initially resumed at not more than one half theprevious rate. If the same severe adverse reactions occurred for a second time, thedecision to stop the treatment was seriously considered on a case by case basis.



Mild to moderate infusion related reactions (IRRs) usually respond to a reduction in therate of infusion. The infusion rate could have been increased upon improvement ofsymptoms.

The subject was observed post-infusion if necessary based on the investigator’s medical
judgment.

Efficacy Evaluations: The primary efficacy endpoint was ORR at Week 26 of
PF-05280586 versus rituximab-EU based on central review which included radiographic
assessment and review of clinical data (B-cell depletion and bone marrow biopsy results).
As per current guidelines for staging and response assessment of lymphoma, the ORR was
defined purely for the purpose of this study as the proportion of subjects who achieved either
complete response (CR) or partial response (PR). This updated terminology has been usedthroughout and is based on the Lugano Classification, the most current response assessment
guidelines for malignant lymphoma.
Secondary efficacy evaluations included:
Time to treatment failure (TTF) defined as the time from date of randomization toprogression of disease (PD) based on central review, death due to any cause, or
permanent discontinuation from treatment, or discontinuation from study for any reason,
whichever came first.

Progression-free survival (PFS) defined as the time from date of randomization to first
PD (based on central review) or death due to any cause in the absence of documented PD.

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Protocol B3281006 – 18 October 2018 - Final

Complete response at Week 26 defined as per the revised response criteria for malignant
lymphoma (based on central review).



Duration of response (DOR) defined as the time from date of the first documentation of
overall response (CR or PR) to the first documentation of PD (central review) or to death
due to any cause in the absence of documented PD.

Overall survival (OS) defined as the time from date of randomization to death due to any
cause.

Immunogenicity, Pharmacokinetic and Pharmacodynamic Evaluations
Serum samples for detection of anti-drug antibodies (ADA) and neutralizing antibodies(NAb) were collected within 4 hours prior to dose administration on Day 1 and Day 15.
Additional samples for detection of ADA and NAb were collected at Weeks 5 (Day 29), 13,
26, 39, and 52. Human serum ADA samples were analyzed using 2 validated,semi-quantitative electrochemiluminescent ADA assay methods. Human serum samples
testing positive for the presence of ADA were required to be analyzed for the presence orabsence of neutralizing anti-rituximab antibody and neutralizing anti-PF-05280586 antibody
using 2 semi-quantitative NAb cell-based assays. Both assays used a tiered approach using
screening, confirmation and titer/quantitation. The cross-reactivity sample analysis was done
for those study samples that tested positive in the assay for the administered study drug using
the alternate assay with titration and confirmatory analysis. For the immunogenicity data, thepercentage of subjects with positive ADA and NAb was summarized for each treatment andby visit. For subjects with positive ADA, the magnitude (titer), of ADA response was also
described. In addition, possible associations of ADA response with clinical data on the PK,
and safety were examined.
On days where study drug was administered (Days 1, 8, 15, and 22), serum samples formeasurement of drug concentrations were collected prior to dose administration (within
4 hours of the start of dosing). On Days 1 and 22, additional drug concentration samples
were collected within 15 minutes prior to the end of infusion. Additionally, drugconcentration samples were collected at Weeks 5 (Day 29), 13, 26, 39 and 52. Rituximab
samples were assayed using a validated, sensitive and specific enzyme-linked
immunosorbent assay. The serum specimens were stored at approximately -70C until assay.
The serum concentration-time data were summarized using descriptive statistics bytreatment.
The pharmacodynamics of PF-05280586 and rituximab-EU was evaluated using circulating
CD19-positive B-cell counts (surrogate marker for CD20+ B-cells). Rituximab is known todeplete B-cells, which can result in a decrease in circulating levels of immunoglobulin (Ig)Mand IgG. Blood samples for assessment of circulating CD19 positive B-cell counts, and IgM
and IgG were collected at Day 1 (Visit 2), Treatment Visits (Visits 3, 4, and 5: Study Days 8,
15, and 22), Follow-up Visits (Visits 6, 7, 8, and 9: Weeks 5, 13, 26, and 39), and the End of
Study/Early Termination Visit (Visit 10, Week 52). Blood samples were assayed for CD19+
B-cell counts by laser scanning cytometry. Summary statistics by treatment and visit were
provided for the biomarkers including CD19 positive B-cell counts, IgM and IgG.

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Protocol B3281006 – 18 October 2018 - Final

Safety Evaluations: Safety was characterized by type, incidence, severity, timing,
seriousness, and relationship to study treatment of adverse events (AEs), including
neutropenia, infections, IRRs, and other clinical outcomes associated with immunogenicity(hereafter referred to as immune-based adverse effects; events relating to Standardized
Medical Dictionary for Regulatory Activities Queries of Anaphylaxis and Hypersensitivity
reactions, and events meeting Sampson’s criteria), and laboratory abnormalities.
Statistical Methods:
The primary efficacy analysis for equivalence was performed after all randomized subjects
had the opportunity to complete their Week 26 visit and the assessment of overall response.
Analyses were performed with the Intent-to-Treat (ITT) Population defined as all subjects
who were randomized. The same analysis based on the Per Protocol (PP) Population,
defined as all randomized subjects who received at least 1 dose of study treatment(PF-05280586 or rituximab-EU) as planned, had adequate disease assessment at baseline asconfirmed by central review, and had no important protocol deviations that would impact theefficacy assessments significantly, was performed as a sensitivity analysis. Descriptive
statistics (frequency and percentage) for CR, PR, and ORR were presented by treatmentgroup and visit. The 95% confidence interval (CI) of these response rates within each group,and the 95% CI of the difference in the response rates between the 2 treatment groups wasconstructed.
The estimated difference in response rate between PF-05280586 and rituximab-EU wascomputed (based on the stratified Mantel-Haenszel method) and the asymptotic 95% CI ofthe difference, as proposed by Miettinen and Nurminen (published in 1985) was constructed.
The FLIPI2 categorization (low, medium, and high) was considered as the stratification
factor in the Mantel-Haenszel (for the estimated treatment difference) and Miettinen andNurminen (for the 95% CI) methods.
Progression-free survival was defined as the time from date of randomization to first PD ordeath due to any cause in the absence of documented PD and was censored as summarized inTable 1:
Table 1.

Handling of Missing Assessments and Censoring Rules for PFS Analysis

Situation
No baseline or no adequate
baseline assessment, and no death
No post-baseline or no adequate
post-baseline assessment, and nodeath
No death or disease progression
Discontinued from study
Disease progression or death

Date of Progression or Censoring
Date of Randomization

Outcome
CensoredDate of Randomization

CensoredDate of last adequate assessment
Date of last adequate assessment
Date of death or first adequate
assessment for progression,
whichever was earlier

Censored
Censored
Progressed (event)The censoring mechanisms for TTF and DOR were similar to those described for PFS above
with the exception that for TTF permanent discontinuation from treatment or discontinuationfrom study was considered as treatment failure, and for DOR when a subject had missing

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Protocol B3281006 – 18 October 2018 - Final

response assessment(s) but remained as a CR or PR responder at the time of data analysis,
the endpoint was censored at the time of the last adequate assessment where CR or PR was
declared.
A log-rank test stratified by FLIPI2 risk was used to compare the treatment groups withrespect to the secondary endpoints of PFS, OR, TTF and DOR at a 2-sided alpha level of
0.05. Secondary endpoints were also summarized using the Kaplan-Meier method. The
Kaplan-Meier 1-year estimates and the 2-sided 95% CI of the rates using the Greenwood’s
formula were reported. In addition, a Cox model stratified by FLIPI2 was used to estimate
the hazard ratio and its 95% CI for the treatment effect.
The primary efficacy endpoint (ORR at Week 26) was also analyzed within subgroups ofinterest, to evaluate consistency of results relative to overall results.
The analysis for DOR was based on central review assessment and the Response Evaluable
Population, defined as all subjects in the ITT Population who received at least 1 dose of
study drug, had adequate disease assessment at baseline, and at least 1 post-baseline response
assessment.
The safety analyses (including ADA and NAb analyses) were carried out using the Safety
Population, defined as all subjects who received at least 1 dose of study drug.
Safety data were described using descriptive statistics. Frequency and percentage of subjects
within each treatment group, risk difference, p-value, and 95% CI of risk difference were
provided for Tier-1 AEs (pre-specified events considered of potentially clinical importance)
and Tier-2 AEs (those events that occurred in at least 6 subjects in either treatment group andwere not Tier-1). Individual signs and symptoms of IRRs were documented on the electroniccase report form in addition to the preferred term (PT) of “infusion related reaction” for the
purpose of comparing the overall percentage of subjects by treatment arm. The reporting ofthese events and timing of events in relation to the infusion were determined by theinvestigator. All IRRs, potential allergic and anaphylactic reactions based on Sampson
criteria were summarized overall, by treatment group and by ADA status.
RESULTS
Subject Disposition and Demography:
A summary of subject disposition is provided in Table 2. There were 394 subjects assigned
to the double-blind treatment; 196 subjects in the PF-05280586 group and 198 subjects in therituximab-EU group. Of these, 393 subjects were actively treated including 196 treatedsubjects in the PF-05280586 group and 197 treated subjects in the rituximab-EU group.
There was 1 subject who was assigned to the rituximab-EU group who withdrew from thestudy prior to receiving treatment. Of the 393 subjects actively treated, 390 subjects hadcompleted protocol-specified therapy. They received 4 doses of study treatment given on
Days 1, 8, 15, and 22 (194 [99.0%] subjects in the PF-05280586 group and
196 [99.0%] subjects in the rituximab-EU group).
In total, 340 subjects had completed Week 52 (End of Study) of the study (170 [86.7%]
subjects in the PF-05280586 group and 170 [85.9%] subjects in the rituximab-EU group). In
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Protocol B3281006 – 18 October 2018 - Final

total, 54 (13.7%) subjects had discontinued from the study. The ITT Population(394 [100.0%] subjects) was used for the efficacy analysis, and the Safety Population(393 [99.7%] subjects) was used for the analyses of AEs (393 [99.7%] subjects) andlaboratory data (392 [99.5%] subjects), including ADA and NAb analyses. The
PP Population (342 [86.8%] subjects) was used for sensitivity analyses of the primary andsecondary efficacy endpoints. The modified ITT Population (393 [99.7%] subjects) was used
for the biomarker analyses. The Response Evaluable Population (388 [98.5%] subjects) wasused for the analysis of DOR. The PK Population (393 [99.7%] subjects), defined as subjects
who were treated with PF-05280586 or rituximab-EU and provided at least 1 post-dose drugconcentration measurement, was used for analysis of the PK endpoints. The percentage ofsubjects in each population was comparable between treatment groups.
Table 2.

Subject Evaluation Groups
rituximab-EU

PF-05280586

Number (%) of subjects
Screened
Assigned to study
treatments
TreatedCompleted treatment
Discontinued treatment
Completed study
Discontinued study
Analyzed for efficacy
ITT
mITTa
PP
Response Evaluable
Population
Analyzed for safetyb
Safety analysis
Adverse events
Laboratory data

Total
627

198

196

394

197
196 (99.0)
1 (0.5)170 (85.9)
28 (14.1)

196
194 (99.0)
2 (1.0)170 (86.7)
26 (13.3)

393
390 (99.0)
3 (0.8)340 (86.3)
54 (13.7)

198 (100.0)
197 (99.5)
176 (88.9)
196 (99.0)

196 (100.0)
196 (100.0)
166 (84.7)
192 (98.0)

394 (100.0)
393 (99.7)
342 (86.8)
388 (98.5)

197 (99.5)
197 (99.5)
197 (99.5)

196 (100.0)
196 (100.0)
195 (99.5)

393 (99.7)
393 (99.7)
392 (99.5)

Analyzed for PK
PK analysis
197 (99.5)
196 (100.0)
393 (99.7)
Abbreviations: ADA=anti-drug antibody; EU=European Union; ITT=Intent-to-Treat; mITT=modified Intentto-Treat; NAb=neutralizing antibody; PK=pharmacokinetic; PP=per protocol.
a. Included biomarker analyses.
b. Analyzed for safety included ADA and NAb.

A summary of demographic characteristics for the ITT Population is presented in Table 3.
Demographic and baseline characteristics were comparable between the 2 treatment groups.
The majority of the treated subjects were female (216) and white (304 [77.2%]). The mean
age of all subjects was 58.5 years (range 21 to 93 years).

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Protocol B3281006 – 18 October 2018 - Final

Table 3.

Demographic Characteristics - ITT Population
rituximab-EU
198

PF-05280586
196

Total
394

92 (46.5)
106 (53.5)

86 (43.9)
110 (56.1)

178
216

Age (years)
<18
18-44
45-64
65
Mean (SD)MedianRange

029 (14.6)
101 (51.0)
68 (34.3)
58.3 (12.8)
60.0
21-93

0
27 (13.8)102 (52.0)
67 (34.2)
58.7 (12.1)
59.0
25-85

0
56 (14.2)
203 (51.5)
135 (34.3)
58.5 (12.4)
60.0
21-93

Race
White
Black
Asian
Other

146 (73.7)
044 (22.2)
8 (4.0)158 (80.6)
1 (0.5)30 (15.3)
7 (3.6)304 (77.2)
1 (0.3)74 (18.8)
15 (3.8)

Ethnicity
Hispanic/Latino
Not Hispanic/Latino

26 (13.1)
172 (86.9)

31 (15.8)
165 (84.2)

57 (14.5)
337 (85.5)

Weight (kg)N
Mean (SD)MedianRange

198 (100.0)
73.2 (18.0)
72.0
42.2-156.0

196 (100.0)
73.7 (15.6)
73.9
37.6-130.0

394 (100.0)
73.5 (16.8)
73.0
37.6-156.0

Height (cm)N
Mean (SD)MedianRange

195 (98.5)
166.1 (9.3)
165.0
146.4-190.0

194 (99.0)
166.0 (10.5)
165.0
137.0-195.0

389 (98.7)
166.0 (9.9)
165.0
137.0-195.0

Number (%) of subjects
GenderMale
FemaleBody mass index (kg/m2)
N
195 (98.5)
194 (99.0)
389 (98.7)
Mean (SD)26.3 (5.2)
26.7 (4.8)
26.5 (5.0)
Median
25.9
26.0
26.0
Range
16.0-54.7
16.1-47.6
16.0-54.7
Abbreviations: EU=European Union; ITT=Intent-to-Treat; N=number of subjects; SD=standard deviation.
Body mass index was defined as weight/(height*.01)**2

Efficacy, Pharmacokinetic, Pharmacodynamic and Immunogenicity Results:
Primary Efficacy Endpoint: The ORR was equivalent between the 2 treatment groups with148 (75.5%) subjects in the PF-05280586 group, and 140 (70.7%) subjects in therituximab-EU group achieving CR or PR at Week 26 based on central review.

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Protocol B3281006 – 18 October 2018 - Final

The analysis of ORR showed an estimated difference of 4.66% (PF-05280586 minus
rituximab-EU), with a 95% CI of (-4.16%, 13.47%), which fell entirely within the -16.0% to
16.0% pre-specified equivalence margin agreed to by the Food and Drug Administration(FDA) and European Medicines Agency (EMA), and also within the -14.9% to 14.9%
margin agreed to by the Pharmaceuticals and Medical Devices Agency (PMDA) (Table 4).
Table 4.

Summary of Overall Response Rate (ORR) at Week 26 - Central Review
Assessment - ITT Population
rituximab-EU(N=198)PF-05280586(N=196)

Difference(PF-05280586 minus
rituximab-EU)
4.66

Overall Response Rate,
140 (70.7)
148 (75.5)
n (%)(95% CI)(63.8, 76.9)(68.9, 81.4)(-4.16, 13.47)
ORR was defined as the proportion of subjects who achieved either CR or PR at the specified time point.
The stratified Miettinen and Nurminen method was used to obtain the asymptotic 95% CI of the estimateddifference (PF-05280586 minus rituximab-EU).
The stratified Mantel-Haenszel method was used to obtain the estimated difference between treatment groups.
The FLIPI2 categorization was considered as the stratification factor.
Abbreviations: CI=confidence interval; CR=complete response; EU=European Union; FLIPI2=Follicular
Lymphoma International Prognostic Index 2; ITT=Intent-to-Treat; n=number of subjects with observation;
N=total number of subjects in the analysis population; ORR=overall response rate; PR=partial response.

Secondary Efficacy Endpoints
Time to Treatment Failure (TTF): A total of 142 (72.4%) ITT subjects in the PF-05280586
and 150 (75.8%) subjects in the rituximab-EU treatment groups were censored (Table 5).
The main reason for censorship was ‘study completion without treatment failure’ for subjects
in the PF-05280586 treatment group (139 [97.9%] subjects and 149 [99.3%] subjects in the
PF-05280586 and rituximab-EU treatment groups, respectively).
Using a Cox Proportional Hazards model with FLIPI2 categorization (low, medium, andhigh) as strata, the hazard ratio for TTF for PF-05280586 versus rituximab-EU was 1.163,
with a 95% CI of (0.786, 1.720). The stratified log-rank test resulted in a 2-sided p-value of0.450.

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Protocol B3281006 – 18 October 2018 - Final

Table 5.

Kaplan-Meier Estimates, Time to Treatment Failure (TTF) - Central
Review Assessment - ITT Population

Number with event, n (%)aNumber censored, n (%)
Reason for censorship, n (%)b
Ongoing at data cutoff
No baseline assessment (or not adequate), notreatment failure
No post-baseline assessment (or not adequate), notreatment failure
Study completion without treatment failure
Probability (%) of being event-free at 1 yearc(95% CI)d
Kaplan-Meier estimates of time to event (months)
Quartiles (95% CI)e
25%
50%
75%

rituximab-EU(N=198)48 (24.2)

PF-05280586(N=196)54 (27.6)

150 (75.8)

142 (72.4)

0
0

0
0

1 (<1.0)

3 (2.1)149 (99.3)

139 (97.9)

75.3 (67.6, 81.5)

71.5 (63.7, 77.9)

12.1 (11.7, 12.6)
18.9 (12.6, 18.9)
18.9 ( - , - )11.8 (11.2, 12.3)- (12.3, - )-Versus rituximab-EU
Hazard ratiof
1.163
95% CI of hazard ratio
0.786 - 1.720
P-valueg
0.450
Abbreviations: CI=confidence interval; EU=European Union; FLIPI2=Follicular Lymphoma International
Prognostic Index 2; HR=hazard ratio; ITT=Intent-to-Treat; n=number of subjects meeting specified criteria;
N=total number of subjects.
a. Time to event was based on the first event to occur (possible events: progression, death, early treatment
discontinuation, early study discontinuation).
b. Percentage was calculated based on the number of censored subjects.
c. Estimated from the Kaplan-Meier method.
d. Calculated based on Greenwood method.
e. Kaplan-Meier method used and 2-sided 95% CI calculated based on the Brookmeyer and Crowley
method.
f. Hazard ratio and its CIs were estimated from Cox Proportional Hazards model stratified by FLIPI2 risk
categorization.
g. 2-sided p-value from the log-rank test stratified by FLIPI2 risk categorization.

Progression-Free Survival (PFS): The percentage of subjects in the ITT Population who had
disease progression or died, were censored, or were estimated to be event-free at 1 year wascomparable between the 2 treatment groups (Table 6). There were 37 (18.9%) subjects in the
PF-05280586 treatment group and 28 (14.1%) subjects in the rituximab-EU treatment group
who had an event. A total of 159 (81.1%) subjects in the PF-05280586 treatment group and
170 (85.9%) subjects in the rituximab-EU group were censored.
Using a Cox Proportional Hazards model with FLIPI2 categorization (low, medium, andhigh) as strata, the hazard ratio when comparing PF-05280586 and rituximab-EU was 1.393,

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Protocol B3281006 – 18 October 2018 - Finalwith a 95% CI of (0.847, 2.291). The stratified log-rank test resulted in a 2-sided p-value of
0.189.
Table 6.

Kaplan-Meier Estimates, Progression-Free Survival (PFS) - Central
Review Assessment - ITT Population

Number with event, n (%)

Rituximab-EU(N=198)28 (14.1)

PF-05280586(N=196)37 (18.9)

Type of event, n (%)aProgression
Death without progression

27 (96.4)
1 (3.6)36 (97.3)
1 (2.7)170 (85.9)

159 (81.1)

1 (<1.0)
2 (1.2)0
6 (3.8)17 (10.0)

14 (8.8)150 (88.2)

139 (87.4)

83.0 (75.0, 88.6)

78.2 (70.2, 84.2)

12.6 (12.1, 18.9)
18.9 (12.6, 18.9)
18.9 ( - , - )12.1 (11.8, - )-Number censored, n (%)
Reason for censorshipb
No baseline assessment (or not adequate), no death
No post-baseline assessment (or not adequate), no
death
Early study discontinuation without
progression/death
Study completion without progression/death
Probability (%) of being event-free at 1 yearc(95% CI)d
Kaplan-Meier estimates of time to event (months)
Quartiles (95% CI)e
25%
50%
75%

Versus rituximab-EU
Hazard ratiof
1.393
95% CI of hazard ratio
0.847 - 2.291
P-valueg
0.189
Abbreviations: CI=confidence interval; EU=European Union; FLIPI2=Follicular Lymphoma International
Prognostic Index 2; ITT=Intent-to-Treat; n=number of subjects meeting specified criteria; N=total number ofsubjects.
a. Percentage was calculated based on the number of subjects with event.
b. Percentage was calculated based on the number of censored subjects.
c. Estimated from the Kaplan-Meier method.
d. Calculated based on Greenwood method.
e. Kaplan-Meier method used and 2-sided 95% CI calculated based on the Brookmeyer and Crowley
method.
f. Hazard ratio and its CIs were estimated from Cox Proportional Hazards model stratified by FLIPI2 risk
categorization.
g. 2-sided p-value from the log-rank test stratified by FLIPI2 risk categorization.

Complete Response (CR) at Week 26: The percentage of all subjects who achieved CR at
Week 26 was comparable between the 2 treatment groups. The proportion of subjects in the
ITT Population achieving a CR at Week 26 based on central review was 51 (26.0%) subjects
in the PF-05280586 group and 57 (28.8%) subjects in the rituximab-EU group, with
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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

97 (49.5%) subjects in the PF-05280586 group and 83 (41.9%) subjects in the rituximab-EUgroup achieving a PR at Week 26. The analysis of CR derived from central review
assessments showed a difference of -2.80% (PF-05280586 minus rituximab-EU), with a
95% CI of (-11.60%, 6.03%) and a difference of 7.46% (-2.41%, 17.18%) for subjects having
achieved a PR (Table 7).
Table 7.

Summary of Complete Response (CR) and Partial Response (PR) at
Week 26 - Central Review Assessment - ITT Population

Complete Responsen (%)(95% CI)

Rituximab-EU(N=198)PF-05280586(N=196)

Difference(PF-05280586 minus
Rituximab-EU)

57 (28.8)(22.6, 35.6)

51 (26.0)(20.0, 32.8)-2.80(-11.60, 6.03)

Partial Responsen (%)
83 (41.9)
97 (49.5)
7.46(95% CI)(35.0, 49.1)(42.3, 56.7)(-2.41, 17.18)
The stratified Miettinen and Nurminen method was used to obtain the asymptotic 95% CI of the estimateddifference (PF-05280586 minus rituximab-EU).
The stratified Mantel-Haenszel method was used to obtain the estimated difference between treatment groups.
The FLIPI2 categorization was considered as the stratification factor.
Abbreviations: CI=confidence interval; EU=European Union; FLIPI2=Follicular Lymphoma International
Prognostic Index 2; ITT=Intent-to-Treat; n=number of subjects with observation; N=total number of subjects
in the analysis population.

Duration of Response (DOR): Using a Cox Proportional Hazards model with FLIPI2
categorization (low, medium, and high) as strata, the hazard ratio between PF-05280586 andrituximab-EU was 1.492, with a 95% CI of (0.823, 2.704). The stratified log-rank test
resulted in a 2-sided p-value of 0.185 (Table 8).

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Protocol B3281006 – 18 October 2018 - Final

Table 8.

Kaplan-Meier Estimates, Duration of Response (DOR) - Central Review
Assessment - Response Evaluable Population
rituximab-EU(N=196)166 (84.7)

PF-05280586(N=192)165 (85.9)

Number with event, n (%)
Type of eventa
Progression
Death without progression

19 (11.4)

28 (17.0)

18 (94.7)
1 (5.3)28 (100)
0

Number censored, n (%)
Reason for censorshipb
Ongoing at data cutoff
Early study discontinuation without
progression/death
Study completion without progression/death

147 (88.6)

137 (83.0)0
11 (7.5)

0
10 (7.3)

136 (92.5)

127 (92.7)

10.4 (9.2, 15.4)
15.4 (10.4, 15.4)
15.4 ( - , - )9.3 (9.1, 9.8)
- (9.6, - )-Number of subjects with response (CR or PR), n (%)

Response duration (months)c
Quartiles (95% CI)d
25%
50%
75%

Versus rituximab-EU
Hazard ratioe
1.492
95% CI of hazard ratio
0.823 - 2.704
P-valuef
0.185
Abbreviations: CI=confidence interval; CR=complete response; DOR=duration of response; EU=European
Union; FLIPI2=Follicular Lymphoma International Prognostic Index 2; HR=hazard ratio; n=number ofsubjects meeting specified criteria; N=total number of subjects; PD=progressive disease; PR=partial response.
a. Percentage was calculated based on the number of subjects with event.
b. Percentage was calculated based on the number of censored subjects.
c. The DOR was defined as the time from date of the first documentation of objective tumor response (CRor PR) to the first documentation of PD or to death due to any cause in the absence of documented PD.
d. Kaplan-Meier method used and 2-sided 95% CI calculated based on the Brookmeyer and Crowley
method.
e. Hazard ratio and its CIs were estimated from Cox Proportional Hazards model stratified by FLIPI2 risk
categorization.
f. 2-sided p-value from the log-rank test stratified by FLIPI2 risk categorization.

Overall Survival (OS): In the ITT Population, there was 1 (<1.0%) subject who died in eachtreatment group. The cause of death for both subjects was disease progression. As there
were very few deaths during the reporting period the Kaplan-Meier estimates of OS bytreatment group for subjects in the ITT Population these data are of limited value and were
not interpreted.

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Pharmacokinetics: A summary of serum concentrations of PF-05280586 and rituximab-EUby visit is provided for subjects in the PK Population in Table 9. On days where study drug
was administered (Days 1, 8, 15, and 22), serum samples for measurement of drugconcentrations were collected prior to dose administration (within 4 hours of the start ofdosing). On Days 1 and 22, additional drug concentration samples were collected within
15 minutes prior to the end of infusion. Additionally, drug concentration samples werecollected at Weeks 5 (Day 29), 13, 26, 39, and 52 (hours not specified).
In general, data indicated similar rituximab serum concentrations at each visit between the
2 treatment groups. The highest (peak) serum concentration (mean [SD]) was observed at
Day 22, within 15 minutes prior to the end of the infusion, and were comparable between the
2 treatment groups.
At visits following completion of study treatment, serum concentrations decreased steadily
from Week 5 to Week 52 (End of Study; Table 9) and were comparable between the
2 treatment groups.

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Table 9.
Visit

Summary Statistics for Serum Drug Concentrations by Visit, All Subjects - PK Population

PlannedN
Time
Post-Dose
Treatment Group: rituximab-EU
Day 1
0
195
Day 1
3h 30m
137
Day 8
0
197
Day 15
0
195
Day 22
0
193
Day 222h 30m132
Week 5
Hours NS
194
Week 13
Hours NS
192
Week 26
Hours NS
185
Week 39
Hours NS
170
Week 52a
Hours NS
188
Treatment Group: PF-05280586
Day 1
0
192
Day 1
3h 30m
138
Day 8
0
194
Day 150
193
Day 22
0
194
Day 222h 30m138
Week 5
Hours NS
193
Week 13
Hours NS
188
Week 26
Hours NS
181
Week 39
Hours NS
171
Week 52a
Hours NS
177

NALQ

Mean

SD

%CV

Geometric
MeanMedian

Min

Max

4
133
197
195
193
132
193
190
170
104
48

756.73
200618.76
67011.83
117438.46
159424.35
351173.48
198907.73
33496.71
3115.96496.051780.239256.505
71560.981
21536.811
37652.513
53665.005
107275.604
62110.162
21601.456
3675.020
1208.771
11727.062

1223
36
32
32
34
31
31
64
118
244
659

0.01
119755.43
62311.74
109706.91
149878.23
334848.88
173747.94
20996.36
710.05
6.98
0.16

0.00
198000.00
68800.00
120000.00
156000.00
340000.00
202000.00
31200.00
1740.00
166.50
0.00

0.0
0.0
3610.014500.041400.089900.0
0.0
0.0
0.0
0.0
0.0

128000.0467000.0
165000.0218000.0389000.0
757000.0375000.0
126000.0
18600.012500.0108000.0

4
128
194
193
194
138
193
187
172
112
48

3104.84
185994.13
70761.03
123894.30
164903.61
354592.03
206477.20
36887.58
3868.45526.70703.6225782.027
78045.677
19656.723
38216.182
41894.323
96770.732
55455.820
22731.513
5345.666
902.2984743.707

830
42
28
31
25
27
27
62
138
171
674

0.01
55560.74
66669.15
119026.91
158294.91
337708.05
197858.84
26154.60
1266.97
12.06
0.18

0.00
198000.00
71800.00
122000.00
168500.00
359000.00
209000.00
35600.00
2360.00
227.00
0.00

0.0
0.0
1540.033300.037800.036200.065800.0
0.0
0.0
0.0
0.0

243000.0
481000.0138000.0410000.0289000.0762000.0335000.0134000.046500.06010.059900.0

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Table 9.

Summary Statistics for Serum Drug Concentrations by Visit, All Subjects - PK Population

Visit

Planned
N
NALQ
Mean
SD
%CV
Geometric
Median
Min
Max
Time
Mean
Post-Dose
Summary statistics were not presented if NALQ=0.
Summary statistics were calculated by setting concentration values below the lower limit of quantification (<100 ng/mL) to zero.
‘Hours not specified’ was displayed for visits that did not have planned time for serum PK sampling.
Only samples collected at the scheduled times were included in the above table.
Trough drug concentrations were collected on Days 1, 8, 15, and 22 (within 4 hours prior to the start of dosing). Samples were also collected within 15 minutes
prior to the end of the infusion on Days 1 and 22. Additionally, drug concentration samples were collected at Weeks 5 (Day 29), 13, 26, 39, and 52.
Abbreviations: %CV=percent coefficient of variation; EU=European Union; h=hour; m=minute; max=maximum; min=minimum; N=number of observations(non-missing concentrations [ng/mL]); NALQ=number of observations above lower limit of quantification; NS=not specified; PK=pharmacokinetic;
SD=standard deviation.
a. End of Treatment/End of Study

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Pharmacodynamics: At baseline, the serum CD19-positive B-cell counts results ranged
from 0.6 to 2313.1 cells/L across the 2 treatment groups. The median baseline
CD19-positive B-cell count was 119.9 cells/L in the PF-05280586 group and 114.2 cells/L
in the rituximab-EU group. A decrease from baseline in mean serum CD19-positive B-cellcounts was observed at all subsequent time points through Week 26, and was comparable
between both treatment groups. The median percentage reduction from baseline at Week 2
was >99% for subjects in both the PF-05280586 and rituximab-EU groups. CD19-positive
B-cells showed recovery at Week 39 in both treatment groups, the increase in cell countcontinued through End of Study (Week 52).
Mean (SD) serum IgG concentrations were comparable between the 2 treatment groups atbaseline (10.43 [3.137] G/L in the PF-05280586 group and 10.73 [2.642] G/L in therituximab-EU group). A small decrease from baseline in median serum IgG concentrations
was observed at all subsequent time points, and was comparable between both treatmentgroups. The greatest median percentage change from baseline was observed at Week 4 inboth treatment groups (median percent change of -4.31% for subjects in the PF-05280586
group and -5.54% in the rituximab-EU group).
Mean (SD) serum IgM concentrations were comparable between the 2 treatment groups atbaseline (1.06 [1.381] G/L in the PF-05280586 group and 0.99 [0.646] G/L in therituximab-EU group). In general, mean serum IgM concentrations decreased throughout the
duration of the study and were comparable between the 2 treatment groups. The greatest
median percentage change from baseline was observed at Week 52 (End of Study; medianpercent change of 24.00% for subjects in the PF-05280586 group and -21.00% in therituximab-EU group).
Immunogenicity: A summary of ADA incidence by visit and overall is presented inTable 10. For subjects in the Safety Population, there were 14 (7.2%) subjects in the
PF-05280586 group and 17 (8.7%) subjects in the rituximab-EU group who had a positive
ADA test (titer 1.88) prior to initiation of study drug at baseline (Day 1). One (0.5%)
subject in the PF 05280586 group and 2 (1.0%) subjects in the rituximab-EU group had apositive ADA test pre-dose on Day 15.
Following initiation of treatment, the percentage of subjects with ADA increased over theduration of the study from Week 5 through Week 52 (End of Study), and was similar
between treatments. Overall, there were 43 (22.1%) subjects in the PF-05280586 group and
39 (19.8%) subjects in the rituximab-EU group with at least 1 post-dose sample that tested
positive for ADA.
In general, of the samples that tested positive for ADA, the majority tested positive in both
ADA assays, indicating that the ADA that developed was against shared epitopes between
the study treatments with 40/43 (93.0%) subjects with positive ADA cross-reactivity in the
PF-05280586 group, and 30/39 (76.9%) subjects in the rituximab-EU group. A titer booster
response (an increase in titer upon repeated treatment) was not observed.

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Only positive ADA samples were analyzed for NAb. The ADA negative samples wereautomatically assigned a negative NAb test result. In this study, all ADA positive samples
tested negative for NAb.

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Table 10. Summary of Anti-Drug Antibody (ADA) Incidence by Visit and Overall - Safety Population
Visit

Criteria

Day 1 (baseline)

ADA Positive
ADA Cross-Reactivity Positive
ADA Cross-Reactivity Negative

Day 8aADA Negative
ADA Positive
ADA Cross-Reactivity Positive
ADA Cross-Reactivity Negative

Day 15ADA Negative
ADA Positive
ADA Cross-Reactivity Positive
ADA Cross-Reactivity Negative

Day 22b

ADA Negative
ADA Positive
ADA Cross-Reactivity Positive
ADA Cross-Reactivity Negative

Week 5ADA Negative
ADA Positive
ADA Cross-Reactivity Positive
ADA Cross-Reactivity Negative

Week 13ADA Negative
ADA Positive
ADA Cross-Reactivity Positive
ADA Cross-Reactivity Negative

Week 26

ADA Negative
ADA Positive
ADA Cross-Reactivity Positive
ADA Cross-Reactivity Negative

Week 39ADA Negative
ADA Positive
ADA Cross-Reactivity Positive
ADA Cross-Reactivity Negative
ADA Negative

Page 19

rituximab-EU(N=197)n/N1 (%)
17/195 (8.7)
10/17 (58.8)
7/17 (41.2)
178/195 (91.3)
2/192 (1.0)
0/2
2/2 (100.0)
190/192 (99.0)
0/1
NA
NA
1/1 (100.0)
0/193
NA
NA
193/193 (100.0)
1/192 (0.5)
1/1 (100.0)
0/1
191/192 (99.5)
12/191 (6.3)
8/12 (66.7)
4/12 (33.3)
179/191 (93.7)
25/175 (14.3)
22/25 (88.5)
3/25 (12.0)
150/175 (85.7)

PF-05280586(N=196)n/N1 (%)
14/195 (7.2)
12/14 (85.7)
2/14 (14.3)
181/195 (92.8)
0/1
NA
NA
1/1 (100.0)
1/192 (0.5)
1/1 (100.0)
0/1
191/192 (99.5)
0/3
NA
NA
3/3 (100.0)
0/192
NA
NA
192/192 (100.0)
2/189 (1.1)
1/2 (50.0)
1/2 (50.0)
187/189 (98.9)
10/184 (5.4)
9/10 (90.0)
1/10 (10.0)
174/184 (94.6)
23/174 (13.2)
22/23 (95.7)
1/23 (4.3)
151/174 (86.8)

Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Table 10. Summary of Anti-Drug Antibody (ADA) Incidence by Visit and Overall - Safety Population
Visit

Criteria

rituximab-EU
PF-05280586(N=197)(N=196)n/N1 (%)
n/N1 (%)
Week 52
ADA Positive
30/168 (17.9)
35/163 (21.5)
ADA Cross-Reactivity Positive
25/30 (83.3)
35/35 (100.0)
ADA Cross-Reactivity Negative
5/30 (16.7)
0/35
ADA Negative
138/168 (82.1)
128/163 (78.5)
Overall
ADA Positive
39/197 (19.8)
43/195 (22.1)
ADA Cross-Reactivity Positive
30/39 (76.9)
40/43 (93.0)
ADA Cross-Reactivity Negative
9/39 (23.1)
3/43 (7.0)
ADA Negative
158/197 (80.2)
152/195 (77.9)
Serum samples for detection of anti-drug antibodies (ADA) and neutralizing antibodies (NAb) were collected within 4 hours prior to dose administration on
Day 1 and Day 15. Additional samples for detection of ADA and NAb were to be collected at Weeks 5 (Day 29), 13, 26, 39, and 52.
Percentages have as their numerator (n) the number of subjects tested at a given visit with a sample that met the specified criteria, and denominator (N1) the
number of subjects tested who had an observed result at the specified visit. Only subjects with a positive ADA result were further tested for ADA
cross-reactivity and NAb. For the Overall row, percentages have as their numerator (n) the number of subjects tested who had at least 1 post-dose (ie, post
Day 1) sample that met the specified criteria, and the denominator (N1) was the number of subjects tested who had at least 1 observed post-dose result.
Only subjects with a positive ADA result were further tested for ADA cross-reactivity and NAb. None of the ADA positive samples were NAb positive at any
time during the study and in any treatment group.
Abbreviations: ADA=anti-drug antibody; NA=not applicable; NAb=neutralizing antibody; N=number of subjects in the analysis population.
a. Day 8 was an unplanned visit.
b. Sample collected prior to protocol Amendment 1.

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Safety Results:
Treatment-Emergent Serious AEs (SAEs): The number of all-causality, treatment-emergent
SAEs is summarized in Table 11. A total of 17 (8.67%) subjects in the PF-05280586 groupand 15 (7.61%) subjects in the rituximab-EU group experienced a treatment-emergent SAE.
The most common all-causality treatment-emergent SAEs by system organ class (SOC) were
Infections and infestations (4 [2.04%] subjects in the PF-05280586 group and3 [1.52%] subjects in the rituximab-EU group).

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Table 11. Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (All Causalities andTreatment-Related)n (%)
Number (%) of Subjects:
Evaluable for adverse events
With adverse events

197
15 (7.61)

Cardiac disorders
Angina unstable
Atrial fibrillation
Intracardiac thrombus
Gastrointestinal disorders
Abdominal pain
Ileus
Inguinal hernia
Mesenteric artery stenosis
General disorders and administration site conditions
Disease progression
Non-cardiac chest pain
Pyrexia
Hepatobiliary disorders
Cholelithiasis
Immune system disorders
Serum sickness
Infections and infestations
Appendicitis
Clostridium difficile infection
Diverticulitis
Escherichia sepsis
Hepatitis B
Kidney infection
Peritonitis
Urinary tract infection
Viral sinusitis
Injury, poisoning and procedural complications
Contusion

2 (1.02)
1 (0.51)01 (0.51)
1 (0.51)001 (0.51)02 (1.02)
1 (0.51)
1 (0.51)01 (0.51)
1 (0.51)
1 (0.51)
1 (0.51)
3 (1.52)000
1 (0.51)
1 (0.51)
1 (0.51)001 (0.51)
1 (0.51)0

rituximab-EU
n1

n2

n (%)

PF-05280586
n1

n2

1
0
1
0
3
1
1
0
1
2
1
0
1
0
0
0
0
5
1
1
1
0
0
0
1
1
0
1
1

0
0
0
0
0
0
0
0
0
1
0
0
1
0
0
0
0
1
0
1
0
0
0
0
0
0
0
0
0

196
17 (8.67)
2
1
0
1
1
0
0
1
0
2
1
1
0
1
1
1
1
4
0
0
0
1
1
1
0
0
1
1
0

Page 22

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0
0
0
0
0
0
0
0
0
1
0

1 (0.51)01 (0.51)03 (1.53)
1 (0.51)
1 (0.51)01 (0.51)
2 (1.02)
1 (0.51)01 (0.51)00004 (2.04)
1 (0.51)
1 (0.51)
1 (0.51)0001 (0.51)
1 (0.51)01 (0.51)
1 (0.51)

Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Table 11. Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (All Causalities andTreatment-Related)n (%)
1 (0.51)
2 (1.02)0
1 (0.51)
1 (0.51)
2 (1.02)

rituximab-EU
n1
1
2
0
1
1
2

n (%)
0
1 (0.51)
1 (0.51)004 (2.04)

PF-05280586
n1
0
1
1
0
0
4

n2
Infusion related reaction
0
Musculoskeletal and connective tissue disorders
0Intervertebral disc disorder0
Polyarthritis
0
Spinal column stenosis0
Neoplasms benign, malignant and unspecified (incl.
0cysts and polyps)
Bladder cancer
1 (0.51)
100
00Colon adenoma
000
1 (0.51)
10Lung adenocarcinoma stage I000
1 (0.51)
10
Prostate cancer
000
1 (0.51)
1
0
Squamous cell carcinoma of lung1 (0.51)
100
00
Uterine cancer
000
1 (0.51)
1
0
Nervous system disorders000
2 (1.02)
2
0
Paraesthesia
00
0
1 (0.51)
1
0Transient ischaemic attack000
1 (0.51)
10
Respiratory, thoracic and mediastinal disorders
2 (1.02)2
1
0
0
0
Dyspnoea
1 (0.51)1
1
0
00
Pulmonary embolism
1 (0.51)
10
0
0
0
Except for ‘n1’ and ‘n2’ subjects are only counted once per treatment for each row.
Includes data up to 999 days after last dose of study drug.
MedDRA (v21.0) coding dictionary applied.
Abbreviations: EU=European Union; MedDRA=Medical Dictionary for Regulatory Activities; n=number of subjects in this reporting group affected byany occurrence of this adverse event, all causalities; n1=number of occurrences of treatment-emergent all causalities adverse events; n2=number ofoccurrences of treatment-emergent causally related to treatment adverse events.

Page 23

n2
1
0
0
0
0
0

Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Non-Serious Treatment-Emergent AEs (TEAEs): The number of all-causality, non-serious
TEAEs in >5% of subjects are summarized in Table 12. A total of 93 (47.45%) subjects in
the PF-05280586 group and 95 (49.24%) subjects in the rituximab-EU group experienced anon-serious TEAE.
For subjects in the PF-05280586 group, the most common all-causality non-serious TEAEs
by SOC group were Injury, poisoning and procedural complications (49 [25.00%] subjects),
General disorders and administration site conditions (30 [15.31%] subjects), andGastrointestinal disorders (25 [12.76%] subjects).
For subjects in the rituximab-EU group, the most common all-causality non-serious TEAEs
by SOC were Injury, poisoning and procedural complications (58 [29.44%] subjects),
General disorders and administration site conditions (33 [16.75%] subjects), and Respiratory,
thoracic and mediastinal disorders (30 [15.23%] subjects).
The most common treatment-related non-serious TEAEs by PT, for subjects in the
PF-05280586 group, were infusion related reaction (58 subjects), throat irritation(15 subjects), and pruritus (11 subjects).
For subjects in the rituximab-EU group, the most common treatment-related non-serious
TEAEs by PT were infusion related reaction (63 subjects), pruritus (18 subjects), andoropharyngeal pain (12 subjects).

Page 24

Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Table 12. Treatment-Emergent Non-Serious Adverse Events by System Organ Class and Preferred Term in >5%
Subjects (All Causalities and Treatment-Related)
Number (%) of subjects with adverse events by:
System Organ ClassMedDRA Preferred Term
Number (%) of Subjects:
Evaluable for adverse events
With adverse eventsn (%)

rituximab-EU
n1

197
97 (49.24)

n2

n (%)

PF-05280586
n1

n2

196
93 (47.45)

Gastrointestinal disorders
27 (13.71)
37
17
25 (12.76)
35
16
Diarrhoea
12 (6.09)15
7
14 (7.14)
16
7
Nausea17 (8.63)
22
10
15 (7.65)
19
9
General disorders and administration site conditions
33 (16.75)
43
18
30 (15.31)
37
19
Asthenia
13 (6.60)
15
89 (4.59)
11
5
Fatigue
13 (6.60)
16
9
12 (6.12)
15
6
Pyrexia
11 (5.58)
121
11 (5.61)
11
8
Injury, poisoning and procedural complications
58 (29.44)
63
63
49 (25.00)
58
58
Infusion related reaction
58 (29.44)
63
63
49 (25.00)
58
58
Musculoskeletal and connective tissue disorders
10 (5.08)
11
1
8 (4.08)
8
1
Back pain
10 (5.08)
11
1
8 (4.08)
8
1
Nervous system disorders
19 (9.64)
31
8
16 (8.16)
18
5
Headache19 (9.64)
31
8
16 (8.16)
18
5
Respiratory, thoracic and mediastinal disorders
30 (15.23)
33
22
24 (12.24)
30
20
Cough
11 (5.58)
111
11 (5.61)
13
4
Oropharyngeal pain
10 (5.08)
12
12
2 (1.02)
2
1
Throat irritation
10 (5.08)10
9
14 (7.14)
15
15
Skin and subcutaneous tissue disorders
28 (14.21)
32
25
22 (11.22)
28
20
Pruritus
22 (11.17)
23
18
13 (6.63)
14
11
Rash
8 (4.06)97
10 (5.10)
14
9
Except for ‘n1’ and ‘n2’ subjects are only counted once per treatment for each row.
Includes data up to 999 days after last dose of study drug.
MedDRA (v21.0) coding dictionary applied.
Abbreviations: EU=European Union; MedDRA=Medical Dictionary for Regulatory Activities; n=number of subjects in this reporting group affected byany occurrence of this adverse event, all causalities; n1=number of occurrences of treatment-emergent all causalities adverse events; n2=number ofoccurrences of treatment-emergent causally related to treatment adverse events.

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Protocol B3281006 – 18 October 2018 - Final

Immune-Based Adverse Effects: A summary of ADA and immune-based adverse effects
overall is presented in Table 13.
Overall, the percentage of subjects reporting immune-based adverse effects post-treatment
was comparable between treatment groups, and also between ADA positive and ADA
negative subjects.
The percentage of treatment-emergent IRR AEs (all causalities) was comparable between thetreatment groups with 49 (25.0%) subjects in the PF-05280586 group and
59 (29.9%) subjects in the rituximab-EU group with reported IRRs.
The incidence of treatment-emergent (all causalities) anaphylactic reaction/hypersensitivity
AEs was comparable between the treatment groups. Overall, there were 39 (19.9%) subjects
in the PF-05280586 group and 48 (24.4%) subjects in the rituximab-EU group with an event
meeting the broad and narrow SMQ of Anaphylaxis/Hypersensitivity.
Overall, there were 17 (8.7%) subjects in the PF-05280586 group and 17 (8.6%) subjects in
the rituximab-EU group with an event potentially meeting Sampson criteria. Medical review
of events utilizing Sampson criteria did not identify any subject meeting the criteria ofanaphylaxis as described in the Second Symposium on the Definition of Anaphylaxis.
The percentage of IRRs (as assessed by the investigator), events retrieved utilizing the SMQof Anaphylaxis/Hypersensitivity (broad and narrow), and events potentially meeting theSampson Criteria occurring in ADA positive subjects was comparable between the treatmentgroups:

In the PF-05280586 group: 11/43 (25.6%) subjects with IRRs, 7/43 (16.3%) subjects with
events of Anaphylaxis/Hypersensitivity (broad and narrow), and 5/43 (11.6%) subjects
with events potentially meeting the Sampson Criteria.



In the rituximab-EU group: 10/39 (25.6%) subjects with IRRs, 5/39 (12.8%) subjects
with events of Anaphylaxis/Hypersensitivity (broad and narrow), and 4/39 (10.3%)
subjects with events potentially meeting the Sampson Criteria.

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Protocol B3281006 – 18 October 2018 - Final

Table 13. Summary of ADA and Immune-Based Adverse Effects Overall - Safety
Population
Overall

Criteria

rituximab-EU(N=197)n/N1 (%)
59/197 (29.9)
17/197 (8.6)
48/197 (24.4)

Total IRR reported
Total Sampson’s criteria fulfilled
Total Anaphylaxis/Hypersensitivity (SMQ)a

PF-05280586(N=196)n/N1 (%)
49/196 (25.0)
17/196 (8.7)
39/196 (19.9)

ADA Positive

39/197 (19.8)
43/195 (22.1)
10/39 (25.6)
11/43 (25.6)
4/39 (10.3)
5/43 (11.6)
5/39 (12.8)
7/43 (16.3)
ADA Negative
158/197 (80.2)
152/195 (77.9)
IRR reported
46/158 (29.1)
36/152 (23.7)
Sampson’s criteria fulfilled
13/158 (8.2)
12/152 (7.9)
Anaphylaxis/Hypersensitivity (SMQ)a35/158 (22.2)
22/152 (14.5)
Serum samples for detection of ADA and NAb were to be collected within 4 hours prior to dose
administration on Day 1 and Day 15. Additional samples for detection of ADA and NAb were to be collected
at Weeks 5 (Day 29), 13, 26, 39 and 52.
Events of interest: IRR adverse events, adverse events which fulfill Sampson’s criteria, and adverse events
which belong to the Anaphylaxis or Hypersensitivity SMQs.
Events must have occurred during the study to be counted.
The ADA positive subgroup refers to subjects who had a sample positive for ADA.
Abbreviations: ADA= anti-drug antibodies; EU=European Union; IRR=infusion related reaction;
MedDRA=Medical Dictionary for Regulatory Activities; n=the corresponding number of those subjects
represented in each denominator with at least 1 specified event during the study; n=number of subjects in theanalysis population; NAb=neutralizing antibodies; N1=the number of subjects in the analysis population (andwithin the ADA status subgroup where applicable) for the study; SMQ=Standardized MedDRA Query.
a. Standardized MedDRA Query from the MedDRA dictionary (v20.1).
IRR reported
Sampson’s criteria fulfilled
Anaphylaxis/Hypersensitivity (SMQ)aDiscontinuations: The number of TEAEs leading to withdrawal from the study aresummarized in Table 14.
There were 2 (1.0%) subjects in the PF-05280586 group who permanently discontinued fromthe study due to treatment-related AEs.
In total, there were 27 (13.6%) subjects who discontinued from the study in the PF-05280586
group and 23 (11.7%) subjects in the rituximab-EU group. The most frequent reason for
discontinuation was progressive disease (14 [7.1%] subjects and 20 [10.1%] subjects in the
PF-05280586 and rituximab-EU groups, respectively).
There were 3 (1.5%) subjects in the PF-05280586 group and 1 (0.5%) subject in therituximab-EU group who permanently discontinued from the study due to TEAEs (infusion
related reaction and angioedema, rash maculo-papular, and Non-Hodgkin’s lymphoma in the
PF-05280586 group; and Grade 2 bladder cancer in the rituximab-EU group).

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final

Table 14. Discontinuations from Study

Number of subjects
Completed
Discontinuations:
Relation to study drug not definedInsufficient clinical response
Lost to follow-up
No longer willing to participate in study
Progressive disease
Protocol violation

rituximab-EU
n (%)
198
170 (85.9)

PF-05280586
n (%)
196
170 (86.7)

27 (13.6)
4 (2.0)03 (1.5)20 (10.1)
023 (11.7)
3 (1.5)1 (0.5)4 (2.0)14 (7.1)
1 (0.5)00

2 (1.0)2 (1.0)1 (0.5)0
1 (0.5)1 (0.5)1 (0.5)0

Related to study drug
Adverse event, not serious
Not related to study drug
Adverse event, not serious
Adverse event, serious non-fatal

Total
28 (14.1)
Abbreviations: EU=European Union; n=number of subjects in this reporting group.

26 (13.3)

Deaths: Two subjects, 1 in each treatment group, died during the study due to diseaseprogression (Table 15), which occurred outside the active reporting period (through andincluding 28 calendar days after the last study visit) and were not considered to be related totreatment.

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Protocol B3281006 – 18 October 2018 - Final

Table 15. Summary of Deaths
Number of subjects evaluable for adverse events
System organ class
General disorders and administrationsite conditions

Preferred term
Disease progression

Neoplasms benign, malignant andunspecified (incl cysts and polyps)

Rituximab-EU
N=197
n
n1
0
0

PF-05280586
N=196
n
n1
1
0

0
1

1
0

0
0

0
0

Neoplasm progression
10
00
Total number of fatalities from adverse
1
1
eventsa
Total number of deaths all causesb
1
1
A subject death could be associated with more than 1 treatment if the first onset date of the case fell within
multiple treatment group periods.
A fatality could be associated with multiple events.
MedDRA v.21.0J coding dictionary applied.
Abbreviations: MedDRA=Medical Dictionary for Regulatory Activities; N=total number of subjects;
n=number of adverse events associated with a fatality; n1=number of adverse events associated with a fatality
and thought to be associated or related to treatment; SAE=serious adverse event.
Source of Actual treatment Group is Oracle Clinical or Phase I Management System. Source of SAE is Safety
Data Warehouse.
a. Total number of deaths in this reporting group thought to be causally related to adverse events.
b. Total number of deaths (all causes) in this reporting group. This includes deaths not related to the trial.

CONCLUSION(S):

Equivalence between PF-05280586 and rituximab-EU was statistically demonstrated in
the ITT Population for the primary efficacy endpoint, ORR. The analysis of ORR at
Week 26 derived from central review assessments showed an estimated difference of
4.66% (PF-05280586 minus rituximab-EU), with a 95% CI of (-4.16%, 13.47%), whichfell entirely within the -16.0% to 16.0% pre-specified equivalence margin agreed to by
the FDA and EMA, and also within the -14.9% to 14.9% margin agreed to by the PMDA.



There were no clinically meaningful or statistically significant differences in thesecondary endpoint results for CR rate at Week 26, PFS, OS, and TTF, which werecomparable between the 2 treatment groups, in the ITT Population. There were also no
clinically meaningful or statistically significant differences in the secondary endpoint of
DOR in the Response Evaluable Population.



A comparable safety profile was observed between the treatment groups and with thesafety information described in the reference product label.

The observed rate of ADA was comparable between the 2 treatment groups. A titerbooster response (an increase in titer upon repeated treatment) was not observed. No
ADA positive subjects tested positive for NAb.



The serum concentrations of PF-05280586 and rituximab-EU groups were comparable.

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Public Disclosure Synopsis
Protocol B3281006 – 18 October 2018 - Final



No notable differences were observed in mean serum concentrations between
ADA positive and ADA negative subjects in either treatment group.



CD19 positive B-cell depletion and recovery were comparable between the treatmentgroups and consistent with the reference product label.



No clinically meaningful differences were observed in terms of potential immunogenicity
associated AEs in those who were treatment-emergent ADA positive versus those who
were ADA negative.

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