phase i study of the pharmacokinetics of a radioimmunoconjugate, 90y-t101, in patients with...

1998;4:2691-2700. Published online November 1, 1998.Clin Cancer Res F M Foss, A Raubitscheck, J L Mulshine, et al. CD5-expressing leukemia and lymphoma.radioimmunoconjugate, 90Y-T101, in patients with Phase I study of the pharmacokinetics of a

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Vol. 4, 2691-2700, November 1998 Clinical Cancer Research 2691

Phase I Study of the Pharmacokinetics of a Radioimmunoconjugate,

90Y-T1O1, in Patients with CD5-expressing Leukemia

and Lymphoma

Francine M. Foss,’ Andrew Raubitscheck,

James L. Mulshine, Thomas A. Fleisher,

James C. Reynolds, Chang H. Paik,

Ronald D. Neumann, Cynthia Boland,

Patricia Perentesis, Margaret R. Brown,

James M. Frincke,2 Charles P. Lollo,

Steven M. Larson, and Jorge A. CarrasquilloNational Cancer Institute Navy Medical Oncology Branch [F. M. F..

J. L. M.. C. M.. B. K.l, and the Radiation Oncology Branch [A. R.].of the National Cancer Institute, Bethesda, Maryland 20889;Departments of Clinical Pathology [T. A. F.. M. R. B.l and NuclearMedicine [I. C. R., C. H. P., R. D. N., P. P., S. M. L., I. A. C.].Warren G. Magnuson Clinical Center, National Institutes of Health.

Bethesda, Maryland 20892; and Hybritech Inc. [J. M. F., C. P. L.],

San Diego. California 92121

ABSTRACTTen patients with advanced or refractory CD5.express.

ing hematologic neoplasms [two with chronic lymphocytic

leukemia and eight with cutaneous T-cell lymphoma

(CTCL)] were treated in a Phase I study with the radioim-

munoconjugate �#{176}Y-T101, which targets CD5+ lympho-

cytes. Prior imaging studies using “In-TiOl demonstrated

uptake in involved lymph nodes and skin in patients withCTCL, and Phase I studies with unmodified TiOl demon-strated transient responses. In this study, patients were

treated with 5 or 10 mCi of �#{176}Ychelated to TiOl via iso-

thiocyanatobenzyl diethylenetriamine pentaacetic acid,

along with tracer doses of ‘“In-TiOl for imaging. The

biodistribution of the radioimmunoconjugate was deter-

mined by measuring �#{176}Yand t1tln blood clearance, urine

excretion, and accumulation in bone marrow and in in-

volved skin lesions. The intravascular pharmacokinetics of

90Y were predicted by “ ‘In-labeled TlO1. The greatest dif-

ferences in biodistribution between “In and �#{176}Ywere in the

higher bone accumulation of �#{176}Yand its lower urinary

excretion. Imaging studies demonstrated targeting of skin

lesions and involved lymph nodes in CTCL patients. The

Received 2/27/98; revised 7/29/98; accepted 8/12/98.

The costs of publication of this article were defrayed in part by the

payment of page charges. This article must therefore be hereby marked

advertisement in accordance with 18 U.S.C. Section 1734 solely to

indicate this fact.

I To whom requests for reprints should be addressed, at HematologyOncology, Tufts New England Medical Center, 750 Washington Street,NEMC #542, Boston, MA 021 1 1. Phone: 617-636-5146; Fax: 617-636-0342.

2 Present address: Hollis Eden Pharmaceuticals, San Diego. California

92121.

predominant toxicity was bone marrow suppression. Rapid

antigenic modulation of CD5 on circulating T and B cells

was observed. Recovery of T-cell populations occurred

within 2-3 weeks; however, suppression of B-cell popula.

tions persisted after 5+ weeks. All CTCL patients developed

human antimouse antibody after one cycle and thus were

not retreated; one patient with chronic lymphocytic leuke-

mia received a second cycle of therapy. Partial responses

occurred in five patients, two with chronic lymphocytic

leukemia and three with CTCL. The median response du-

ration was 23 weeks. One CTCL patient who subsequentlyreceived electron beam irradiation to a residual lesion is

disease-free after 6 years.

INTRODUCTIONTlOl is a monoclonal belonging to the IgG2a subclass,

which recognizes CD5, a surface antigen present on circulating

normal T lymphocytes, a subset of B cells, as well as on

nonsecretory CLL3 cells and CTCL cells ( 1). Tl0l recognizes

the same antigen as the monoclonal antibodies anti-Leu- I and

OKT1. Previous imaging studies using � ‘ ‘In-TlOl and ‘�‘I-

Tl0l have demonstrated uptake of the antibody radioconjugates

in malignant skin and lymph node infiltrates in CTCL patients

and binding to and uptake by circulating CD5-positive neoplas-

tic lymphocytes in CLL patients (2-4). Early Phase I studies

using unmodified Tl0l at doses of 1-140 mg by slow iv.

infusion demonstrated rapid but transient responses in patients

with CLL and CTCL with minimal toxicity (5).

The observation of clinical improvement in patients treated

with unmodified antibody together with the excellent localiza-

tion of � ‘ ‘In-TlOl in sites of disease has prompted further

clinical investigation of radioimrnunoconjugates of T 10 1 . Rosen

et a!. (3) demonstrated clinical responses in CTCL patients

treated with ‘31I-Tl0l in therapeutic doses of 100-150 mCi;

however, the specificity of the therapeutic response was in

question due to associated rapid dehalogenation of the radio-

conjugate (6).

We have conducted a Phase I trial using the radioimmu-

noconjugate 90Y-TlOl in patients with CDS-expressing CTCL

and CLL. #{176}“Yis a high energy �3-emitter without any associated

.Y emission on decay. It was anticipated that w)y would behave

similarly to ‘ ‘ ‘ In in remaining intracellular once internalized as

part of an antigen-antibody complex. The high antigen density

3 The abbreviations used are: CLL, chronic lymphocytic leukemia:

CTCL, cutaneous i-cell lymphoma; HAMA. human antimouse anti-body; HPLC, high-performance liquid chromatography; DTPA. dieth-

ylenetriamine pentaacetic acid; AUC. area under the curve: %ID/g,

percent of injected dose/g; CR. complete response: PR, partial response.




2692 Phase I Study of ‘�#{176}YTl0I in CD5� Lymphoma

in circulating neoplastic cells rapidly decreases free isotope

blood levels and minimizes nonspecific toxicity secondary to

bone accumulation (7). Tracer doses of � � ‘In-TlOl were coad-

ministered for localization and biodistribution studies, and the

uptake of ‘ ‘ ‘ In and 90Y was measured in biopsies of bone

marrow and clinically involved skin to validate that ‘ ‘ ‘In-TlOl

distribution also reflects #{176}#{176}Y-TlOldistribution. Significant dis-

ease regression was documented in 5 of 10 patients treated at

very low dose levels. We performed an extensive pharmacoki-

netic analysis of both ‘ � ‘In- and 90Y-TlOl and also used imag-

ing results to evaluate the ‘ ‘ ‘Infl#{176}Y biodistribution. Although

other radioimmunotherapy studies have been performed using

90y and ‘ ‘ ‘In for imaging, this study represents the most de-

tailed pharmacokinetic analyses including biopsies to determine

the similarities in biodistribution between ‘ ‘ ‘In and 9#{176}Y.

MATERIALS AND METHODSPatients. Adults with CTCL or CLL who had failed prior

therapy and whose tumor cells expressed CD5 were eligible.

CD5 expression was determined on circulating neoplastic cells

by flow cytometry or on skin biopsies by immunohistochemical

analysis using TlOl and Leu-l and peroxidase-labeled anti-

mouse IgG. Patients were eligible if 25% or more of the tumor

cells stained for TIOl. All patients had bilateral iliac crest bone

marrow biopsies to assess tumor involvement and adequacy of

bone marrow reserve, pulmonary function testing with a forced

expiratory volume at 1 s and vital capacity >65% of predicted

value and P#{176}2 >65, no cardiovascular disease, or if cardiac

history was present, a gated cardiac blood pool ejection fraction

of >35%. Hematologic parameters included WBC > 2000/

mm3, platelets > 100,000/mm3, bilirubin < 1.5 mg/dl, and

creatinine < 2 mg/dl. Patients were required to have a Karnof-

sky performance status of at least 60%, measurable disease, a

life expectancy of at least 3 months, and no HAMAs as deter-

mined by an HPLC method (8). The protocol was approved by

the National Cancer Institute Institutional Review Board, and all

patients gave their written informed consent to participate. A

total of 10 patients were e,nrolled; 9 patients were treated once

and 1 patient received two courses of therapy. Patients were

accrued from July 1989 to October 1991, and the last follow-up

date was April 1998. The trial was discontinued before maxi-

mum tolerated dose was reached due to unavailability of the

antibody.

Antibody Preparation. TlOl was provided by Hy-

britech Incorporated (La Jolla, CA) and was prepared from the

ascites of BALB/c mice injected with the hybridoma. The an-

tibody was purified by 1 8% sodium sulfate precipitation and

subsequent fractionation on a DEAE-Sephacel column (Phar-

macia Fine Chemicals, Piscataway, NJ). The purified antibody

was conjugated to the chelating agent, isothiocyanatobenzyl-

DTPA (9). The antibody was labeled with 911Y, purified through

a sizing column, shipped overnight on ice, and used within 24 h

of preparation. The specific activity of the final product was 40

mCi/mg. Prior to patient injection, the material was checked for

endotoxin by standard limulus lysate assay and protein-bound

radioactivity by ITLC. In all cases, >97% (97.8 ± 0.6%,

mean ± SD) of the 9#{176}Ywas bound to TlOl. The ‘ ‘ ‘In-labeled

T 10 1 ( ‘ ‘ ‘ In-T 10 1 ) was prepared on site by incubating the che-

late-conjugated TlOl with buffered indium chloride. The reac-

tion was quenched with excess DTPA to bind any ionic ‘ ‘ ‘In.

This resulted in >75% (87.8 ± 8.4%) protein-bound ‘ ‘ ‘In, and

no further purification was performed. The preparation for the

last patient consisted of the same conjugated TIOl but differed

from the others in that both ‘ ‘ ‘ In and #{176}#{176}Ylabeling were per-

formed on site, followed by purification through a size exclusion

HPLC.

Immunoreactivity. The immunoreactivity of the ‘ ‘ ‘In-

TlOl and #{176}#{176}Y-TlOlwas determined by a cell-binding assay.

Serial dilutions of the antibody were incubated with a CD5-

positive T-cell line, and the immunoreactivity was expressed as

the maximum percentage of radioactivity bound to the cells at

antigen excess (10). The ‘�#{176}Y-Tl0l was 63 ± 10% immunore-

active and the ‘ ‘ ‘In-TlOl was 58 ± 12% immunoreactive when

corrected for the protein-bound fraction determined from ITLC.

Antibody Administration. All patients received co-in-

jections of a mixture of ‘ ‘ ‘In-TlOl and 9#{176}Y-TlOl and unlabeled

(DTPA-conjugated) TIOl to achieve the total protein mass

desired. Each patient received approximately 1.0 mg of Tl0l

labeled with a mean of 5 mCi of ‘ ‘ ‘ In (4.95 ± 0. 1 7 mCi). The

first three patients received 0.5 mg of TlOl with 10 mCi of 9()y

formulated to a total dose of 2 mg with unlabeled TlOl. Because

grade 4 bone marrow toxicity was observed in one patient, the

next six patients received 5 mCi of9#{176}Y-TlOl, with the total dose

of TlOl increased to 10 mg. The 10-mg dose was selected

because prior studies suggested lower bone marrow concentra-

tion when 1 mg versus 10 or 50 mg were utilized (1 1).

HAMA. A size exclusion HPLC-based assay was used to

detect evidence ofa human immune response to TlOl. lodinated

TlOl was incubated with patient serum and then assayed on an

HPLC equipped with a TSK 2000 column. Immune complexes

were separated from intact IgG, and quantitation was done by

integrating the free and complexed peaks. When complexes

were detected, specificity was determined by competition assays

with unlabeled Tl0l or an excess of unlabeled IgG (8).

Flow Cytometric Analysis. Flow cytometry was per-

formed using a whole blood lysis technique, which included two

prewashes in PBS to eliminate any nonbound monoclonal anti-

body in the plasma. The cells were then resuspended to the

original blood volume, and 100 ul of cell suspension was incu-

bated with the specific antibody or antibodies for 30 mm at 4#{176}C.

The incubation mix was treated with FACS Lyse (Becton Dick-

inson, San Jose, CA) according to manufacturer’s instructions,

washed twice in PBS, and fixed in 0. 1% paraformaldehyde. A

minimum of 10.000 events was acquired on each sample using

a FACScan (Becton Dickinson) equipped with an air-cooled

laser. The photomultiplier tubes for side angle scatter, FLi (515

nm), and FL2 (585 nm) were operated using logarithmic ampli-

fication. Instrument calibration was performed daily using Ca-

librite beads (Becton Dickinson) according to manufacturer’s

instructions, and the data were analyzed using a Consort 32

computer system using Lysis II software. The cells were eval-

uated for CD5 expression using unconjugated TlOl followed by

a wash step and incubation with goat antimouse FITC (Caltag,

Burlingame, CA). Cells incubated with an unconjugated plas-

macytoma of the same subclass served as the control for the

TIOl . The directly conjugated monoclonal antibodies were ob-

tamed from Becton Dickinson and included CD3 for T cells,




Clinical Cancer Research 2693

CD4 and CD8 for T-cell subsets, CD2O for B cells, and CD45/

CD14 as gating reagents. The cells were collected in a modified

lymphocyte gate, and additional gating was done on the basis of

forward and side angle scatter. This was confirmed using the

combination of CD45 and CDI4 monoclonal antibodies. The

percentage of positive cells was determined using the subclass

control for positive-negative discrimination. The number of

cells staining for each marker was determined using the total

lymphocyte count determined with a hematology instrument and

the percentage of cells staining positive by flow cytometry. The

TlOl staining pattern was followed by monitoring the geometric

mean channel fluorescence (FL1). Studies were planned to be

performed prior to therapy, 1 , 2, 3, 4, and 5 days, and I, 2, 3, and

5 weeks posttherapy.

Imaging. Analog scintillation camera images as well as

digital images were recorded with a General Electric 500

gamma camera. Anterior and posterior whole body images and

four spot views of the anterior and posterior chest and abdomen

were acquired with a medium energy collimator using a 20%

window centered around the 173-keV and 247-keV X-ray peaks

of ‘ ‘ ‘In. Typical spot views contained 300,000 to 1,000,000

counts, whereas the whole body views were acquired over 1060

s/side.

Pharmacokinetics. In addition to gamma scans, blood

samples were taken following the infusion, typically at the end

of infusion, 30 and 60 mm, and 2, 6, and 12 h after infusion, and

then daily for 1 week. The retention of 90Y and ‘ ‘ ‘In in blood

and plasma were determined by sampling both blood and

plasma, with sequential counting in a X and then in a beta

counter. Because Cerenkov counting is sensitive to quench and

geometry, all samples were processed in a similar and repro-

ducible manner. Samples of 0. 1 ml of blood, plasma, and urine

were first treated with 0.5 ml of SDS at 56#{176}Cfor 15 mm,

followed by cooling for 10 mm at 5#{176}C.The samples were then

bleached with 0.4 ml of 30% hydrogen peroxide. The counts in

the samples were referred back to a standard of the injected

dose. To mimic the quench observed in the patient samples,

separate standards were prepared by mixing with 0.1 ml of the

patient’s baseline blood or serum. These standards underwent

the same processing and resulted in quench similar to the patient

samples. All samples were then brought up to I 1 ml with

distilled water. Beta counting of Cerenkov radiation was per-

formed using a 0-200 keV range (A4530D; Packard, Downes

Grove, IL). The samples were also counted in a gamma counter

using a 100-500 keV window. The counts were corrected for

cross-talk and decay-corrected accounting for the time differ-

ences between counting in the gamma and beta counters.

This counting technique yielded a crossover of ‘ ‘ ‘In into

the �#{176}Ywindow of < 1 % and a crossover of 90Y into the ‘ ‘ ‘ In

window of <5%. The percentage of injected activity retained in

blood and plasma volume was then estimated using the patient’s

height and weight to estimate the volumes. Because the infusion

time was short compared with the disposition half-life (T,,,), the

intravascular data were treated similarly to an intravenous bolus.

The percentage of the injected dose per ml was fitted to a

biexponential curve to obtain both the alpha and beta phase T,,2,

using a least squares fit algorithm (SigmaPlot; Jandel Scientific,

Duarte, CA). Conventional pharmacokinetic parameters were

then derived (12). The AUCs for the blood or plasma curves

were calculated in two steps. First the AUC from the end of

infusion to 168 h was obtained by trapezoidal integration of the

decay-corrected blood and plasma data, and then the terminal

AUC was estimated using the terminal clearance rate to extrap-

olate from the activity retained at 168 h. These data were

expressed on %ID x h/ml to allow comparison between doses.

Using these data we then estimated additional pharmacokinetic

parameters including V�. Vd,,�, and maximum retained dose (12).

Whole-body retention of ‘ ‘ ‘In was determined by counting the

patient immediately after the end of the infusion and daily using

a sodium iodide counter. Urine was collected serially for a 96-h

period.

Bone marrow biopsies were taken at 7 days after infusion

in eight patients and on days 6 and 8 in one patient each.

Individual core biopsies were obtained from each iliac crest.

Both samples were weighed on an analytical balance, placed in

PBS, and counted in both the gamma and beta counters to allow

an estimate of sampling-site variability of radioactivity concen-

tration. One core was then sent for routine pathology, and the

other was further processed in 8 of the 10 patients. The biopsy

core to be processed was put in a conical tube with 10 ml of PBS

for 1 h, and the core was broken with a jagged-edge glass rod.

The core was centrifuged for 10 mm at 640 X g, and the

supernatant was removed and counted (saline fraction). The

pelleted core was broken with a jagged-edge glass rod and then

mixed with 0.5 ml of 10% SDS for 30 mm at 56#{176}Cin an attempt

to remove any cell-bound activity. After the sample cooled, 0.4

ml of 30% hydrogen peroxide was added and incubated at 56#{176}C

for 1 h to bleach the sample. Ten ml of distilled water were

added, and the sample was again centrifuged for 10 mm. The

supernatant was separated for counting (SDS fraction). Perchlo-

ric acid (0.2 ml) was then added to the remaining bone chips and

incubated at 56#{176}Cuntil the chips dissolved. This sample was

again treated with hydrogen peroxide, as described above. After

cooling, the sample was transferred to a counting vial with 10 ml

of distilled water (bone fraction). All samples were then counted

on both the beta and gamma counters, as described above, and

the %ID/g was determined on the basis of the protein-bound

injected activity (i.e., corrected for ITLC).

Response and Toxicity. Responses were assessed at the

end of each cycle of therapy and monthly thereafter. A CR was

defined as the complete resolution of all clinically evident

disease confirmed pathologically by appropriate biopsies and

lasting at least 1 month. A PR was at least a 50% reduction in

the sum of all measurable and evaluable disease lasting at least

1 month. Stable disease was a minor improvement in disease

insufficient to meet the criteria for PR. Progressive disease was

defined as a 25% or greater increase in the sum of measurable

and evaluable lesions or the development of new extracutaneous

lesions. Progression-free survival was calculated on the patients

who achieved a PR or CR from the first day of therapy until

progressive disease was documented.

Toxicity was scored according to the National Cancer

Institute’s Common Toxicity Criteria (13). Complete blood

counts were obtained immediately after the infusion, at 1 , 2, 6,

and 12 h after the infusion, and weekly thereafter until recovery

from nadir.

Statistics. When the differences between ‘ ‘ ‘ In and �‘#{176}Y

were compared, paired t tests were performed.




BLOOD RETENTION PLASMA RETENTION

wU)

00

0wI-.0w-)

z

10075

45

15

107.5

4.5

1.5

0 7�

0.45

0.15

0.1

10075

45

15

107.5

4.5

1.5

0.75

0.45

0 15

0.1

(UU)00

0wI-0

. w� -2z

.-.1.�--.I.-_.I � � V� �

0 20 40 60 80 100 120 140 160 180

TIME (h)

- , ... �1..�--1--...1

0 20 40 60 80 100 120 140 160 180

TIME (h)

2694 Phase I Study of �#{176}YTlOl in CD5� Lymphoma

Ta ble I Pati ent characteristics

Age Skin LN PaIp Bone Circulating Disease duration Prior

Patient (yr) Disease/stage” stage stage” nodes marrow cells’ (yr) therapy

1 57 CLL IV - + + 1 Chemo2 54 CTCL IVA T2 LN3 + - - 7 Chemo, XRT,d IFN3 62 CTCL IVA i3 LN4 + - - 4 Chemo, XRT4 61 CTCLIVB T2 + + - 3 Chemo

5 62 CLL IV + + + 1 .5 Chemo6 30 CTCL IVA T, LN3 + - - 9 Chemo, XRT, IFN7 52 CTCL/SS IVA T,, LN3 + - + 2 Chemo8 34 CTCL IVA T3 LN3 + - - 2 Chemo, PUVA, XRT9 59 CTCL IVA T4 LN3 - - + 3 Chemo, XRT, IFN

10 47 CTCL IVB T� LN3 + - - 13 Chemo, XRT

“ Staging system according to Sausville et a!. (21).

I, LN classification according to Sausville et al. (21).

( Circulating malignant cells determined by light microscopic analysis of peripheral smear.

‘I XRT, X-ray therapy; IFN, interferon-a; PUVA, methylpsoralen with UV A.

Fig. 1 The %ID/g of ‘ ‘ ‘In (#{149})or ‘�#{176}Y(#{149})remaining in the blood (left panel) or plasma (right panel) was plotted as the mean; (bars) SD.

RESULTSDisease Characteristics of Patients. Ten patients were

entered onto the study, one with B-CLL, one with T-CLL, and

eight with CTCL. Patient characteristics are shown in Table 1.

All patients had refractory disease. Both CLL patients and seven

of eight patients with CTCL had failed cytotoxic chemotherapy

regimens. Bone marrow involvement was noted in one patient

with CLL and one with CTCL. Circulating neoplastic cells were

present in the B-CLL patient (50,000/ul), in the T-CLL patient

(46,000/al), and in two of the CTCL patients, one with <2000

Sezary cells/ul and one with >4000/ul.

Biodistribution Data. Serial gamma imaging obtained

after antibody administration demonstrated rapid clearance of

‘ ‘ ‘In-TIOl from the blood (Fig. 1) and prominent uptake into

the liver, spleen and bone marrow (Fig. 14). Imaging of known

nodal-involved sites was not seen in the initial 2-h images but

was consistently present at 24 h in patients with CTCL. Not all

lymph node regions were visualized, suggesting that there may

have been some selectivity for involved nodes. There was no

nodal uptake in the patient with B-CLL. The patient with T-CLL

had some lymph node visualization in the early images (2 h) but

much better visualization at 24 h (Fig. 2B). Uptake in clinically

involved skin sites was noted in six of the eight patients with

CTCL (Fig. 3A). One of the two patients without skin uptake

had very minimal patch-stage skin disease, and the other had

nodal involvement but no visible skin disease at the time of

therapy. The patient with circulating Sezary cells had diffuse

infiltrative erythroderma, and imaging studies showed diffuse





B

�. - �

A

Immediate

C

f

Immediate

Anterior Chest

24 hr

Anterior Pelvis Anterior Chest

24 hr

Anterior Pelvis

Fig. 2 A. whole body images of patient 6 obtained the next day after infusion showed excellent localization in clinically involved nodal sites as well

as prominent skin uptake. B, spot images from patient 1 , who had T-CLL, were obtained near the end of infusion and at -24 h afterwards. The images

show prominent uptake in multiple nodal sites in a markedly enlarged spleen and in liver and bone marrow. No skin uptake is noted. Although lymph

node uptake is present in the early images, it was more prominent in the delayed images. C, spot images from patient 5. who had B-CLL and received

5 mCi of � � ‘In-TIOl and a total of 2 mg. The images show increased tracer uptake in an enlarged spleen. liver, and in the bone marrow. Noaccumulation is noted in nodes in the axilla, and the inguinal area that were palpable on physical exam.

skin uptake. Extensive bone marrow uptake was noted in both

the B-CLL and the CTCL patients, with histopathologic cvi-

dence of bone marrow involvement as well as in two other

CTCL patients with histopathologically uninvolved marrows. In

addition to uptake in nodal sites and bone marrow, uptake in

liver and spleen was consistently observed, and mild uptake in

bowel was seen in some patients receiving the 10-mg dose (Fig.

2, B and C).

Two 90Y dose levels (5 or 10 mCi) were administered

under this protocol along with either 2 or 10 mg of unconjugated

TlOl antibody (Table 2). The first three patients were dosed

with 10 mCi of90Y and 2 mg ofTlOl. Significant bone marrow

toxicity was noted in patient 3; therefore, the 9()y dose was

decreased to 5 mCi for the next six patients and the dose of cold

TlOl was increased to 10 mg in patients with CTCL. The last

CTCL patient received 10 mCi of 9#{176}Y-TlOl with 10 mg of

TlOl.

A skin biopsy was performed in seven patients with CTCL

(Table 3) at 5 to 8 days postinfusion (mean, 6.7 days). The

concentration of ‘ ‘ ‘ In, corrected for the protein-bound fraction,




- Saline Fraction

� SDS Fraction

� � Bone Fraction

0.018 -

0.016 -

0.014

I) 0.012

0 o.oio -

.�0):� 0.008 -C

� 0.006 -

0.004 -

0.002 -

0.000�: �I I

4 5 6 7 8 9

Patient Number

Fig. 3 The activity in the bone marrow was plotted for the patients

indicated in the v-axis. The ‘ ‘ ‘In data (first stacked bar) and ‘�#{176}Ydata

(secotid stacked bar) are plotted for each patient. The amount of activity

in each bar represents that in the saline, SDS, and bone fractions (see

“Material and Methods.”).

2696 Phase I Study of #{176}#{176}YTIOl in CD5� Lymphoma

ranged from 0.00066 to 0.0032 %ID/g, and for 90Y, the con-

centration from 0.00081 to 0.0039 %ID/g. This represented a

mean of 1 .5 ± 0.5-fold higher 90y uptake than ‘ ‘ ‘In uptake

(P = 0.012). No visible skin uptake was seen in patients with

CLL (Fig. 2, B and C). There was no correlation between total

dose of antibody administered or 90Y-TlOl dose and skin up-

take in the CTCL patients.

The localization of radioactivity in bone marrow was meas-

ured in all patients. The %ID/g in the unprocessed bone marrow

ranged from 0.0008 to 0.0136 %ID/g (0.00398 ± 0.0035 %ID/g,

mean ± SD) for “In and from 0.00109 to 0.0115 %ID/g

(0.005542 ± 0.00488 %ID/g, mean ± SD) for 90y, The activity

of ‘ ‘ ‘ In recovered in the treated bone was 98 ± 5% of that of the

nonprocessed bone marrow, indicating that very little loss oc-

curs as the result of processing. The true amount of 90Y in the

unprocessed marrow was underestimated due to geometry of the

sample and quench. The recovery of #{176}#{176}Yfrom treated bone was

133 ± 17% of that of the unprocessed bone marrow and was

significantly higher (P = 0.0027), indicating a greater efficiency

of counting for 9t)y when the bone marrow was processed. The

accumulation of ‘ ‘ � In in the processed bone was always lower

than that of 90y (Fig. 3) with 0.0046 ± 0.0045 %ID/g versus

0.00758 ± 0.00432 %ID/g, respectively (P 0.0078). Overall

there was 1.97 ± 0.75-fold more ‘�#{176}Ythan “In in the bone.

Although the number of biopsies was small, there was no

correlation between histopathologic evidence of bone marrow

involvement by tumor and bone marrow radioisotope uptake.

The distribution of activity in the saline fraction represented

mainly plasma, that in the SDS fraction was mainly in the cells,

and that in the perchloric acid represented bone-bound activity.

A comparison of the uptake between the nonprocessed bone

marrow from the right and left iliac crest showed a difference of

64 ± 20% from the highest to the lowest side for ‘ ‘ ‘In and 69 ±

23% for #{176}#{176}Y,indicating variability due to sampling.

- The blood and plasma clearance varied from patient to

patient (Fig. 1 , and Table 4). Nevertheless, the differences

between ‘ ‘ ‘ In and 90Y retention in blood and plasma were very

small, and overall there were no statistical differences between

the pharmacokinetic parameters obtained from ‘ ‘ ‘ In versus 9#{176}y

in blood or in plasma (P > 0.05, paired t test). A comparison of

the ‘ ‘ ‘In versus 90Y radioactivity remaining in the blood at the

end of infusion showed no statistical differences, with 66.7 ±

27.8 %ID/g for ‘ ‘ ‘In-TlOl and 68.7 ± 26.7 %ID/g for 9#{176}y�

TIOl remaining in the blood (P = 0.356, paired t test). Simi-

larly, the amount of ‘ ‘ ‘In and 90y remaining in the blood at 24 h

was 24.3 ± 15.8 %ID/g for “In-TlOl and 25.6 ± 14.6 %ID/g

for #{176}#{176}Y-TlOl(P = 0.488, paired t test). In addition, the cone-

sponding radioactivity remaining in the plasma at the end of

- infusion was 65.4 ± 36.8 %ID/g for ‘ ‘ ‘In-TlOl and 68.5 ± 36.9

1 0 %ID/g for 90Y-TlO 1 (P = 0. 1 1 8, paired t test). A larger amount

of ‘ ‘ ‘ In than 90y was excreted in the urine at all time points

examined (Table 5).

Antigenic Modulation on Peripheral Lymphocyte Pop-

ulations. Flow cytometric analysis demonstrated a rapid drop

in T and B cells within 24 h after Tl0l therapy was initiated

(Table 6). The mean drop in CD3 + cells was 62. 1%. In five of

seven patients, this persisted for 3 weeks. The CD5 fluorescence

intensity was less in the individual remaining T cells, suggesting

antigenic modulation related to antibody exposure. A decrease

in B cells was also observed, with a mean drop of 77.5% at 24 h.

However, the number of circulating B cells declined slightly

more during the 2-3 weeks posttherapy, reaching a mean de-

crease of 83.4% at 3 weeks posttherapy. The depression in B

cells persisted at 5 weeks posttherapy in all patients studied

(seven of seven).

The expression of TlOl in all lymphocyte populations was

altered in all patients with cutaneous lymphoma but not in the

one patient with T-CLL. The alteration consisted of a decrease

in mean fluorescence of 90.6% in the seven patients studied.

The mean channel of all patients prior to therapy ranged from

406 to 699, whereas 24 h after therapy the range was 2 1-74.

Conversely, the mean CDS+ channel fluorescence on all lym-

phocytes from the patient with T-CLL increased from 620 to

1 148 after therapy, and this increase persisted for S weeks.

Because pharmacokinetic studies showed rapid elimination of

radioisotope at short time points, it may be that the large number

of circulating CD5+ tumor cells adsorbed most of the infused

antibody, thereby diminishing the effect of antigenic modulation

on the normal lymphocytes.

Toxicity. Grade 3 or 4 hematologic toxicity occurred in

two patients with CTCL and one with CLL, as shown in Table

2. One of these was a CTCL patient with extensive tumor stage

disease, heavily pretreated with combination chemotherapy,

who received the initial dosing of 10 mCi and developed grade

4 thrombocytopenia, neutropenia, and sepsis on day 34 after

therapy. The blood counts did not recover until day 54. Al-

though the patient’s day 7 bone marrow demonstrated signifi-

cant 90Y uptake, the prolonged bone marrow suppression was

likely secondary to poor marrow reserve from prior chemother-

apy as well as from accumulation of 90Y. Another CTCL patient

(patient 9) who had been heavily pretreated with cytotoxic




Table 2 Dosing and toxicity

Dose �#{176}Y Dose TlOl BM” uptake Toxicity Toxicity(mCi) (mg) (p.Ci/g) WBC (Neut) PItPatient Disease/stage

1 CLL IV 5, 10 2 0.683 0 2

2 CTCLIVA 10 2 0.66 2(3) 1

3 CTCL IVA 10 2 1.36 4 (4) 4

4 CTCL IVB 5 10 0.314 3 (1) 0

5 CLL IV 5 2 0.5 2 (3) 1

6 CTCL IVA 5 10 0.66 0 0

7 CTCL/SS IVA 5 10 0.223 0 0

8 CTCL IVA 5 10 0. 139 0 0

9 CTCLIVA 5 10 0.344 3(4) 0

10 CTCL IVB 10 10 1.55 1 (1)

“ BM, Bone marrow uptake (determined as outlined in “Materials and Methods.”)

Table 3 Concentration of radiolabeled TlOl in skin biopsy

Patient no. Skin “‘In (%ID/g) Skin ‘�#{176}Y(%ID/g)

2 0.003241 0.003862

3 0.000656 0.001579

4 0.001121 0.001446

6 0.002375 0.004656

7 0.001727 0.002967

8 0.000703 0.000806

9 0.0039 0.005322

Mean ± SD 0.0020 ± 0.0013 0.0029 ± 0.0017


chemotherapy, fludarabine, and interferon-a, and who had a

total leukocyte count of 2.9/ul prior to therapy, developed grade

4 granulocytopenia 89 days after a dose of S mCi of 9#{176}y,The

patient’s pretreatment bone marrow biopsy was notable for

hypocellularity, with normal maturation of all lineages and no

evidence of involvement by CTCL. Patient 8 with B-CLL who

was also treated with 5 mCi of �#{176}Ydeveloped grade 3 neutro-

penia on day 58 and recovered by day 60. Pretreatment bone

marrow biopsy showed diffuse replacement by atypical lympho-

cytes consistent with CLL. Three of six patients dosed at 5 mCi

of ‘�#{176}Yand two of four dosed at 10 mCi experienced grade 3 or

4 hematologic toxicity. The median time to nadir was 4.5 weeks

for all patients (range, 1-13 weeks), and median time to hema-

tologic recovery from nadir was 2 weeks (range < 1-4 weeks).

Four of five patients who received 10 mg of cold TlOl

experienced transient allergic-like manifestations, consisting of

chest tightness in three, hives in two, hypotension in one, and

chills and fever in one. None of the four patients who received

2 n�g of cold TIO1 had a hypersensitivity-type reaction. All

reactions were immediate and were controlled by slowing of the

infusion and administration of benadryl.

HAMA Production. All CTCL patients produced

HAMAs after the first course of therapy, precluding further

administration of the antibody. In contrast, neither of the CLL

patients produced HAMAs, and the patient with T-CLL was

re-treated with a second dose of antibody without any alterations

in pharmacokinetics.

Clinical Response. All 10 treated patients were evalu-

able for response and toxicity. Five of 10 patients (50%) had a

PR after one cycle of therapy, including both CLL patients and

3 of 8 CTCL patients (Table 7). The B-CLL patient had a

marked decrease in splenomegaly after therapy, and the T-CLL

patient had a decrease in spleen size as well as disappearance of

palpable nodes and a decrease in the number of circulating CLL

cells. This patient was initially treated at a dose of 10 mCi of

90y but then received a second cycle of therapy at 5 mCi after

it was determined that he did not have significant titers of

HAMA; he continued to demonstrate clinical improvement after

the second dose of antibody. Two of the CTCL responders had

improvement in cutaneous plaques and tumors, and one of these

who had circulating atypical lymphocytes (Sezary cells) had a

decrease in the absolute number of circulating cells from 1400

to 574 by day 9. Another CTCL responder with minimal skin

disease but significant adenopathy had a >50% decrease in the

size of his nodes. One CTCL patient with diffuse patch and

plaque disease had a minor improvement in skin disease, which

did not meet the criteria for a PR, and the remaining four

patients had no response. None of the other responders were

retreated due to elevated HAMA titers. The median duration of

response for the five partial responders was 23 weeks (range,

16-33 weeks). One of the CTCL patients (patient 4) had ma-

diation of a nonresponding tumor on his extremity after com-

pleting one cycle of therapy with 9#{176}Y-T101 and has had no

disease recurrence at a follow-up of 6 years.

DISCUSSIONBecause our prior imaging trials using ‘3’I-TlOl had dem-

onstrated excellent localization of the TlOl radioimmunocon-

jugate to skin and involved lymph nodes in patients with CTCL,

we sought to further explore the therapeutic utility of this

antibody conjugated to a high energy emitting isotope, �y, in

patients with CD5-expressing hematopoietic malignancies. Be-

cause this was one of the first clinical uses of �#{176}Yimmunocon-

jugates, we report the effect of this treatment not only on the

tumor sites but also on the most vulnerable normal tissue com-

partment, the bone marrow. In this Phase I study of a small

cohort of refractory CTCL and CLL patients, S of 10 demon-

strated a meaningful clinical response to therapeutic doses of

9#{176}Y-Tlol. Toxicities were modest, and the major dose-limiting

toxicity was bone marrow suppression, although dose-limiting

toxicity was not achieved. The response durations observed here

compare favorably with those reported in other radioimmuno-

conjugate studies and other newer therapies in CTCL (13-18).

The clinical efficacy of radioimmunoconjugates depends

on several factors, including the stability of the conjugation,




‘X)y�� (%ID)

8.77 ± 1.61

4.09 ± 1.80

3.37 ± 1.97

3.23 ± 1.38

Paired t test

P < 0.0195

P < 0.0001P < 0.0001P < 0.0001

Table 7 Clinical response

2698 Phase I Study of 90Y ilOl in CD5� Lymphoma

Table 4 Ph armacokinetic parameters

, , ‘In blood 9()y bloodStatistics ‘‘‘In

vs. �#{176}Yblood ‘In plasma �#{176}YplasmaStatistics ‘‘‘In vs.

‘�#{176}Yplasma

AUC (%ID X

Cl(ml/min)

T,,2alpha(h)

T,1,beta(h)

MRT(h)V�(ml)

� (ml)

mUtt) 0.425617 ± 0.245468

314.196± 174.9044

5.348261 ± 11.01101

30.30254± 16.10121

28.718± 11.287938529.9±5204.123

15.889 ± 12,967.31

0.46659 ± 0.23291

263.826± 114.1775

2.37622± 1.386384

34.2564± 11.56528

30.692t9.2857537998.7 ±4298.22

14,306.1 ± 9,469.152

P = 0.0722

P=0.ll89

P=0.3863

P=0.l984

P=0.2057P0.524

P 0.5517

0.645852 ± 0.421803

225.231 ± 133.5115

3.288314± 1.649647

34.80919± 19.03211

31.2± 14.97327189.6±6647.78

13,181.3 ± 13,749.72

0.658428 ± 0.382082

212.965± 141.1577

3.222644± 1.343101

35.46442± 13.63709

31.027± 10.372126810.7±6014.113

11,360.9 ± 10,764.34

P - 0.8301

P=0.6785

P=0.8405

P=0.769

P=0.933P’0.6162

P 0.2545

-- Table 5 Cumulative urinary excretion

Time(day) ‘‘‘In”(%ID) _________

1 16.28 ± 8.91

2 8.32 ± 2.29

3 7.81 ± 2.40

4 8.58 ± 2.54

(1 Data are mean %ID � SD.

Table 6 Effect of 90Yil�l on peripheral blood lymphocyte subsets

Fluorescence-activated cell-sorting analysis was performed on pe-

ripheral blood mononuclear cells at 2 h, 1 , 2, 3, 4, and 5 days: and 1 , 2,

3. and 5 weeks after treatment with ‘�#{176}Y-T10l. Values represent %

change in fluorescence from baseline to nadir as measured by direct

immunofluorescence using conjugated antibodies for CD2O, CD3, CD4.

and CD8. TIO1 unconjugated antibody and goat antimouse-FITC were

used as described in “Materials and Methods.” Data are not available for

patients 4-6.

Patient CD2O CD4 CD8 ilOl

I -80% -93% -57% 182%

2 -95% -53% -58% -95%

3 -96% -78% -76% -85%

7 -75% -42% -50% -43%

8 -87% -63% -70% -91%

9 -89% -63% -66% -87%10 -96% -56% -77% -94%

immunoreactivity of the monoclonal, the distribution of the

antigen on the target cells, metabolic fate of the antigen-anti-

body-radioisotope complex and biodistribution of the radioim-

munoconjugate to tumor sites. The design of 9#{176}Y-Tl0l has

evolved from prior studies demonstrating the favorable charac-

teristics of CD5 as a targeting ligand and the unique biological

features of certain hematologic malignancies, which lend to the

successful clinical implementation of this approach (I, 2. 1 1).

Although CD5 antigen is expressed on normal lymphocytes, a

significantly greater receptor density has been demonstrated on

neoplastic cells, and high levels of expression are fairly uniform

among patients with CTCL and CLL. Antigenic modulation or

internalization of the bound radioligand-antibody-CD5 antigen

complex has been demonstrated jn vitro and in prior studies

using ‘ ‘ ‘In-TlOl (2, 1 1). Furthermore, our prior radiolabeling

studies showed that trafficking of CTCL cells occurs between

blood, skin, lymph nodes. and other visceral sites. thus provid-

ing for excellent biodistribution of radioimmunoconjugate-bear-

ing cells to disease sites and perhaps explaining the unexpect-

edly high clinical response rate.

Patient

Dose 9#{176}Y(mCi) Disease/stage Response

Duration(weeks)

1 10 CLLIV PR 22

2 10 CTCLIVA NR

3 10 CTCLIVA NR

4 5 CTCL IVB PR 33

5 5 CLLIV PR 27

6 5 CTCL IVA NR

7 5 CTCL/SS IVA NR

8 5 CTCL IVA NR

9 5 CTCL IVA PR 2310 10 CTCLIVB PR 16

Neither the total quantity of antibody infused nor the total

90y dose administered appear to affect the concentration of

radioactivity in biopsied skin or tumor, as we had observed

previously with ‘ ‘ ‘In-TIOl (2). Furthermore, the biodistribution

and tumor targeting seen with ‘ ‘ ‘In-TiOl in this study was

comparable to that reported with ‘ ‘ ‘ In in our prior studies and

was superior to that reported by Rosen et a!. (3), who used

‘3’I-TlOl in CTCL patients. In that study, there was no clear

delineation of skin lesions by gamma scintigraphy, but rather a

diffuse uptake by liver, spleen, palpable and nonpalpable nodes

thyroid gland, and the gastrointestinal tract. These imaging

findings are consistent with dehalogenation of the ‘ � ‘ I conju-

gate. In contrast, little release from tumor or catabolic sites was

seen with the ‘ ‘ � In conjugate used for imaging in the current

study.

The clinical response rate observed in this study is similar

to that reported by Rosen et a!. (3) using ‘3’I-TlOl. In that

study, two of five evaluable patients had a PR, with response

duration ranging from 3 to 1 2 weeks. Three of five patients were

re-treated with a second dose of radiolabeled antibody after

plasmapheresis was performed to remove HAMAs, and two

demonstrated a second significant disease response. We report

longer response durations, ranging from 16 to 33 weeks, with

one patient in durable response for more than 6 years after

irradiation of a residual lesion. Due to the small study size, it

cannot be established whether the longer response durations

observed here compared to the � ‘ � I immunoconjugate represent

improved biodistribution and targeting of tumor lesions and

disease sites or may be due to prolonged exposure to the

‘�#{176}Y-conjugated isotope due to trafficking of intracellularly

bound isotope.

The two predominant toxicities observed in this study were





hypersensitivity reactions, as seen in other studies with murine

monoclonal antibodies, and hematologic toxicity, most likely

related to the biodistribution of 90Y into bone. In another study

using a 90Y radioimmunoconjugate, Waldmann et a!. ( 17) re-

ported grade 3 thrombocytopenia in one of three patient receiv-

ing 10 mCi of 90Y-anti-Tac and grade 4 neutropenia in one of

three at the 15 mCi dose. In our study, there was no correlation

between the drop in WBC count and dose; however, there was

a correlation between dose and percentage of drop in platelet

count (P = 0.0065). The differences in the degree of hemato-

logic toxicity observed among patients may be related to differ-

ences in bone marrow accumulation of 90Y or to differences in

baseline hematopoietic reserve among patients, perhaps related

to prior chemotherapy.

The rapid decline in circulating T cells observed following

TlOl therapy was expected because prior studies have demon-

strated rapid lymphocyte clearance following in vivo adminis-

tration of unconjugated TlOl antibody. This appeared to involve

both the CD4 and CD8 subpopulations, with relatively equal

distribution (data not shown). However, the suppression of

normal T cells lasted 2-3 weeks, compared to days in prior

studies using naked antibody, suggesting a significant cytotoxic

effect of the radioconjugate, perhaps in bone marrow.

The profound and persistent decrease in B cells using this

antibody conjugate was unexpected. The small subset of circu-

lating mature CD5 + B cells were likely targeted by the conju-

gate. Because most circulating mature B cells do not express

CD5, the prolonged decrease in CD2O populations seen here

may reflect targeting of a CD5 + normal bone marrow precursor

compartment, either directly by the antibody or indirectly

through the bone-seeking effects of the radionuclide.

The marked decrease in Tl0l fluorescent staining was

consistent among the cutaneous lymphoma patients (n = 6) and

parallels the decrease in overall T-cell populations. This sug-

gests that the normal T cells that predominated in the former

group were subject to significant antigenic modulation of CDS

in the presence of the antibody. In contrast, the leukemic cells

from the T-CLL patient showed an increase in immunofluores-

cent intensity for CDS, suggesting that antigenic modulation did

not occur in the tumor cells. These results are similar to those of

Dillman et al. (5), who demonstrated rapid clearance of CLL

cells with an anti-CD5 antibody but no antigenic modulation on

the cells. However, the effects of the antibody on B cells was

similar to that observed in the other patients.

Although our results showed significant differences in bio-

distribution between ‘ ‘ ‘In and �#{176}Y,these differences do not

prevent us from obtaining useful information regarding 9#{176}y

when we used � � � In as a surrogate. Our studies showed that no

significant differences in clearance were seen in the circulation

between the ‘ ‘ ‘In- and 90Y-radiolabeled Tl0l . This suggested

that the differences in retention between both isotopes in the

chelate of the circulating antibody were very small. Neverthe-

less, some differences were seen at the tissue level. We docu-

mented significant differences between the two isotopes in

involved skin, with a mean of 1 .58-fold greater retention of 90Y

than ‘ ‘ ‘ In. This would suggest that, in tumors the ‘ ‘ ‘ In distri-

bution image represents a lower limit of the accumulated activ-

ity. Although there is no reason to suspect that accumulation in

nodal sites would be different than in skin, this was not directly

examined because of the greater difficulties in obtaining nodal

biopsies. In bone marrow, the target organ for toxicity, the

accumulation of 90y also was higher than that of � � � In. Similar

differences between ‘ ‘ ‘In and 90Y distribution in bone have

been observed with other chelates because the strength of asso-

ciation of the chelate for both isotopes is different (19). When

the conjugated antibody is metabolized, the rate of release for

the isotope may vary in different tissues. The free isotope may

also have distinct biodistribution. The differences between ‘ ‘ ‘In

and 90Y in bone marrow were expected because 9#{176}yis rapidly

incorporated into bone matrix (20).

The ‘ ‘ ‘In biodistribution studies for the CTCL and CLL

patients showed some similarities in terms of high splenic, liver,

and bone marrow uptake and frequent lymph node accumula-

tion. The greatest difference was the lack of skin uptake in

noninvolved CLL skin. Although comparisons between the

CTCL and CLL patients need to be made cautiously in terms of

the small study size, skin infiltration is thought to be a more

characteristic feature. Another difference between the two pop-

ulations was in the rate of antibody localization. As seen in one

previous patient with T-CLL (unreported result) the targeting of

involved lymph nodes occurred promptly (within 2 h), at a time

when no accumulation was seen in lymph node areas of CTCL

patients, suggesting a difference in T-cell trafficking between

the two diseases. Further evaluation of this observation is war-

ranted to determine the degree to which trafficking affects the

biodistribution and therapeutic efficacy of these and other ra-

dioimmunoconjugates.

ACKNOWLEDGMENTSWe thank Pat Maloney and Margarita Lora for technical assistance

with binding assays, Millie Whatley for technical assistance. and Mark

Rotman for preparation of the radiolabeled antibodies.

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phase i study of the pharmacokinetics of a radioimmunoconjugate, 90y-t101, in patients with...

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