JCO-2013-Dickson-2024-8

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Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients

With Advanced CDK4-Ampliﬁed Well-Differentiated or

Dedifferentiated Liposarcoma

Mark A. Dickson, William D. Tap, Mary Louise Keohan, Sandra P. D’Angelo, Mrinal M. Gounder,

Cristina R. Antonescu, Jonathan Landa, Li-Xuan Qin, Dustin D. Rathbone, Mercedes M. Condy,

Yelena Ustoyev, Aimee M. Crago, Samuel Singer, and Gary K. Schwartz

All authors: Memorial Sloan-Kettering

Cancer Center, New York, NY.

Published online ahead of print at

www.jco.org on April 8, 2013.

Supported by Pﬁzer and in part by

National Cancer Institute, National Insti-

tutes of Health, Soft Tissue Sarcoma

Program Project Grant No. P01

CA047179 (C.R.A., S.S, G.K.S.).

Presented in part at the 48th Annual

Meeting of the American Society for

Clinical Oncology, Chicago, IL, June

1-5, 2012.

Authors’ disclosures of potential con-

ﬂicts of interest and author contribu-

tions are found at the end of this

article.

Clinical trial information: NCT01209598.

Corresponding author: Mark A. Dickson,

MD, 300 E 66th St, New York, NY

10065; e-mail: dicksonm@mskcc.org.

Oncology

0732-183X/13/3116w-2024w/$20.00

DOI: 10.1200/JCO.2012.46.5476

ABSTRACT

Purpose

CDK4 is ampliﬁed in ⬎90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS).

The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and

induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with

WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to

determine the safety and efﬁcacy of PD0332991 in patients with advanced WDLS/DDLS.

Patients and Methods

Patients age ⱖ18 years experiencing disease progression while receiving systemic therapy before

enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day

cycles. All were required to have CDK4 ampliﬁcation by ﬂuorescence in situ hybridization and

retinoblastoma protein (RB) expression by immunohistochemistry (ⱖ1⫹). The primary end point

was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ⱖ40% considered

promising and ⱕ20% not promising. If ⱖnine of 28 patients were progression free at 12 weeks,

PD0332991 would be considered active.

Results

We screened 48 patients (44 of 48 had CDK4 ampliﬁcation; 41 of 44 were RB positive). Of those,

30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included

anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12

weeks, PFS was 66% (90% CI, 51% to 100%), signiﬁcantly exceeding the primary end point. The

median PFS was 18 weeks. There was one partial response.

Conclusion

Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free

rate in patients with CDK4-ampliﬁed and RB-expressing WDLS/DDLS who had progressive

disease despite systemic therapy.

INTRODUCTION

Liposarcomas are malignant mesenchymal tumors

that are classiﬁed into three main biologic groups:

well-differentiated (WDLS) and dedifferentiated li-

posarcomas (DDLS), myxoid/round-cell liposar-

coma, and pleiomorphic liposarcoma.

WDLS/

DDLS are considered a biphasic disease. The

dedifferentiated component, which can be rapidly

growing, aggressive, and metastatic, is thought to

arise from the well-differentiated component, which

can grow slowly.

Both WDLS and DDLS are rela-

tively resistant to chemotherapy, and few viable

treatments exist for patients with locally advanced or

metastatic disease.

The oncogene cyclin-dependent kinase 4

(CDK4) is ampliﬁed in ⬎90% of WDLS/DDLS,

4,5

and it is also highly ampliﬁed.

Gene expression

array studies have shown that that CDK4 expression

is ⬎10⫻as high in WDLS/DDLS as in normal fat

tissue.

Inhibition of CDK4 expression with short

hairpin RNA inhibits growth of WDLS/DDLS cells

in vitro.

PD0332991 is a potent oral inhibitor of CDK4

and CDK6 that prevents downstream phosphoryla-

tion of the retinoblastoma (RB) protein.

9,10

The

drug inhibits the growth of WDLS/DDLS cells in

vitro and in xenograft models.

In a phase I study of

PD0332991, two patients with RB-positive WDLS/

DDLS had prolonged stable disease lasting several

JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT

VOLUME 31 䡠NUMBER 16 䡠JUNE 1 2013

from 128.122.114.215

Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on July 22, 2013

years.

We performed a single-arm phase II clinical trial of

PD0332991 in patients with progressive advanced WDLS/DDLS.

PATIENTS AND METHODS

To be eligible, patients had to be adults (age ⱖ18 years) with locally advanced or

metastatic WDLS/DDLS. In addition, patients had to have CDK4 ampliﬁcation, as

detected by ﬂuorescence in situ hybridization (FISH), and RB expression by im-

munohistochemistry, both determined on an archival tumor specimen.

Main inclusion criteria were histologically conﬁrmed WDLS/DDLS, ad-

equate organ and marrow function, Eastern Oncology Cooperative Group

(ECOG) performance status of 0 or 1, and measurable disease by RECIST

(version 1.1).

Patients must have received at least one other systemic treat-

ment for advanced disease. All patients had evidence of clinical disease pro-

gression before enrolling onto this trial. The protocol was approved by the

institutional review board of Memorial Sloan-Kettering Cancer Center, and all

patients provided written informed consent.

Study Design and Statistical Analysis

This was a single-institution nonrandomized open-label phase II study.

The primary end point was progression-free survival (PFS) at 12 weeks. On the

basis of historical controls, PFS ⬎40% at 3 months was considered promising

for second-line therapy, and PFS ⬍20% was considered not promising.

one-stage design was used.

The initial study design called for a sample size of

28. The study would meet its primary end point if at least nine patients were

progression free at 12 weeks. This design has a type I error rate of 0.09 and a

type II error rate of 0.15.

CDK4 and RB Assessment

CDK4 ampliﬁcation testing by FISH was performed using a probe com-

prising BAC clones RP11-571M6 (Wellcome Trust Sanger Institute, Hinxton,

United Kingdom) and RP11-970A5 (BACPAC Resources, Oakland, CA)

spanning CDK4, labeled with red deoxyuridine triphosphate, together with

chromosome 12 centromeric clone p

␣

12H8, labeled with green deoxyuridine

triphosphate (Enzo Life Sciences, Farmingdale, NY; supplied by Abbott Mo-

lecular, Chicago, IL).

FISH was performed on formalin-ﬁxed, parafﬁn-embedded sections

according to standard procedures. Brieﬂy, parafﬁn sections were dewaxed in

xylenes, microwaved in 10 mmol/L sodium citrate (pH, 6.0) solution for

approximately 10 minutes, cooled to room temperature, rinsed, and treated

with approximately 150 units/mL pepsin– hydrochloric acid for approxi-

mately 5 minutes at 37°C before being rinsed and dehydrated. Prewarmed

probe mixture was applied to the slides, and a coverslip was sealed in place with

rubber cement. The slides were then denatured at 80°C for 8 minutes on a

HYBrite automated hybridizer (Vysis, Des Plaines, IL) and incubated over-

night at 37°C. After standard nonformamide posthybridization washes, the

slides were stained with 4⬘,6-diamidino-2-phenylindole and mounted in anti-

fade (Vectashield; Vector Laboratories, Burlingame, CA).

Analysis was performed using a Zeiss Axioplan epiﬂuorescence micro-

scope (Carl Zeiss Microscopy, Thornwood, NY) with motorized stage and Isis

5 imaging software (MetaSystems Group, Waltham, MA). Image records

consisted of collapsed stacks captured at 0.5-micron intervals through the

depth of the tissue. Ampliﬁcation was deﬁned as CDK4-to-centromere

ratio ⬎2.5, with a ratio ⬎10 representing high-level ampliﬁcation.

RB expression by immunohistochemistry was determined using stan-

dard methods (RB [4H1] mouse monoclonal antibody; Cell Signaling Tech-

nology, Danvers, MA). Tumor samples were required to express RB at a

level ⱖ1⫹(above background).

Treatment

Patients were treated with 200 mg of PD0332991 once per day for 14 days,

followed by 7 days of rest. This was the maximum-tolerated dose determined in the

phase I study.

Cycles were repeated every 3 weeks, provided the following criteria

were met on the ﬁrst day of the next cycle: platelet count ⱖ50,000/

␮

L, absolute

neutrophil count ⱖ1000/

␮

L, and hemoglobin ⱖ8.0 g/dL. If these criteria were

not met, the start of the cycle was delayed up to 7 days to allow for hematologic

recovery. If the start of the next cycle had to be delayed ⬎7 days, the dose was

reduced to 150 mg. In addition, the dose was reduced to 150 mg for grade 4

hematologic toxicity occurring at any time. If a second dose reduction was required

for the same reasons, the dose was reduced to 100 mg.

Response Assessment

Clinical examinations and laboratory testing were performed at a screening

visit, at the start of treatment, and at the start of each cycle of therapy for the ﬁrst 12

cycles and thereafter at every other cycle. In addition, a complete blood count was

performed once per week during the ﬁrst cycle. Tumor response was assessed by a

reference radiologist by computed tomography (CT) scan once every 6 weeks

(regardless of dose delays) for 36 weeks and once every 12 weeks thereafter. Toxic-

ities were assessed and graded according to the National Cancer Institute Com-

mon Terminology Criteria for Adverse Events (version 4.0).

RESULTS

Between October 2010 and November 2011, 51 patients gave consent

to the protocol. The ﬂow of patients and tumor testing is described

Consent obtained

(n = 51)

Tested for CDK4

(n = 48)

Tested for RB

(n = 44)

CDK4 amplified and RB expressed

(n = 41)

Treated on study

(n = 30)

Analyzed for the primary end point

(n = 29)

Patients excluded (n = 3)

)1 = n( sedils oN

Ineligible (n = 2; patients with disease

other than WD/DD LPS)

No CDK4 amplification detected

(n = 4)

RB not detected (n = 3)

)1 = n( eruliaf tseT

Test not completed (n = 2)

Patients not treated (n = 11)

No prior systemic therapy (n = 6)

No disease progression (n = 2)

)3 = n( eciohc tneitaP

Excluded from analysis of (n = 1)

primary end point

Withdrew consent before (n = 1)

completing one cycle of

treatment

Fig 1. Diagram showing ﬂow of patients and testing for CDK4 and retinoblastoma

protein (RB). DD, dedifferentiated; LPS, liposarcoma; WD, well differentiated.

Phase II Trial of the CDK4 Inhibitor PD0332991 for Liposarcoma

from 128.122.114.215

Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on July 22, 2013

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摘要：

PhaseIITrialoftheCDK4InhibitorPD0332991inPatientsWithAdvancedCDK4-AmpliﬁedWell-DifferentiatedorDedifferentiatedLiposarcomaMarkA.Dickson,WilliamD.Tap,MaryLouiseKeohan,SandraP.D’Angelo,MrinalM.Gounder,CristinaR.Antonescu,JonathanLanda,Li-XuanQin,DustinD.Rathbone,MercedesM.Condy,YelenaUstoyev,AimeeM.Cr...

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