Conclusions

Introduction

Objectives

Activity of PF-03084014 in Adults with Desmoid Tumors/Aggressive FibromatosisGeraldine Helen O'Sullivan Coyne1, Shivaani Kummar1, Khanh Tu Do1, Peter L. Choyke2, Baris Turkbey2, Eric Polley1, Yvonne Horneffer1,

Lamin Juwara4, Rasa Vilimas4, Robert S. Meehan1, Lee J. Helman2, James H. Doroshow1,2 , Alice Chen1

1Division of Cancer Treatment and Diagnosis, and 2Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 208924Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702

Responses

Study Design

Outcomes and adverse events

This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract

HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does

mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Desmoids are rare, invasive, slow growing soft tissue tumors that are sporadic or associated with

familial genetic syndromes, such as familial adenomatous polyposis (FAP) and Gardner Syndrome.

Desmoids are characterized by abnormal nuclear localization of β-catenin. Mutations in the CTNNB1

gene are found in 85-90% of desmoid tumors.

Gamma-secretase cleaves intracellular Notch, resulting in Notch signaling. PF-030844014 is an oral,

reversible γ-secretase inhibitor (GSI) that has been well tolerated in studies to date. Based on

encouraging data from a phase I trial, we conducted a phase II study of PF-030844014 in patients with

symptomatic desmoid tumors that had progressed following at least one line of therapy.

• Primary: Determine the response rate (complete response + partial response) of PF-03084014 in

patients with desmoid tumors/aggressive fibromatosis

• Secondary: Perform genotyping for germline/somatic mutations in APC and CTNNB1 genes; assess

change in symptom measures.

• Open label phase II trial of PF-03084014 in patients with symptomatic, progressive desmoids. CT

scans were performed at baseline and then every 6 cycles (+/- cycle) , and optional DCE-MRIs with

diffusion weighting were performed prior to start of treatment, end of cycle 1, and every 6 cycles.

• The psychometrically-validated MD Anderson Symptom Inventory (MDASI) was used to assess

patient-reported outcomes (PRO) at baseline and at restaging

• The study was conducted as a single stage trial to rule out an unacceptably low 10% clinical

response rate (PR+CR; p0=0.10) in favor of a modestly high response rate of 35% (p1=0.35).

Patient Characteristics n=17

Median age 34 (range 19-69)

Gender

Male

Female

3

14

Primary tumor site

Thorax

Abdomen

Extremity

Spine + spinal girdles

1

4

6

6

Performance Status

One

Zero

0

16

Identified Mutation 15

Median No. of prior therapies 4 (range 1-9)

• This trial has met its primary endpoint. This study opened in November of 2014 and

quickly completed accrual of all 17 patients by May 2015. F/U study is under discussion.

• PF-030844014 is active at the selected dose, with a manageable side effect profile. There

were no episodes of grade 3 or 4 diarrhea; grade 1-2 diarrhea was well controlled by

administration of loperamide. Detailed skin adverse event analysis is underway.

• RECIST and MDASI (data not shown) may not be the appropriate tools to assess response

in a slow growing tumor with single site and symptoms related to the specific area being

affected. Volumetric assessment is being additionally explored.

Patient Characteristics and Genetic Analysis

Baseline MRI Post cycle 12 MRI

AE show represent those occurring in >20% of the patient population. Dose reduction to level -1

(100 mg BID daily) occurred in 2 patients, secondary to persistent grade 2 nausea and diarrhea

which occurred during the entire cycle (cycles 3 and 11, respectively). Symptoms resolved

completely following dose reduction.

Figure 3.

Patient 1010016: 30 year-old female

who presented with a left axillary

desmoid at the side of a prior breast

augmentation. Following resection, the

mass recurred in the axilla, resulting in

significant pain and limitation of range

of motion. This patient required triple

opioid analgesics for pain management

along with anti-neuropathic

agents She started therapy with PF-

030844014 in April 2014. By cycle 6,

this patient had discontinued all of her

opioid medication with improvement

in symptoms and increased range of

motion. She currently remains on

study (cycle 36) and has complete

range of motion in her left arm.

Figure 5. Best tumor

responses (percent change

from baseline) for each

patient based on CT data.

Colors represent somatic

variants in CTNNB1 or APC

genes.

# 11028

D1 D21

PF-03084014 150mg BID Day 1-21, PO

Tumor Biopsy (optional)

Germline sequencing APC and CTNNB1

Cycle SchemaC7D1

Patient No. Somatic Mutation Bld. Mutation

1010001 CTNNB1 S45F

1010002 CTNNB1 T41A

1010003 - -

1010004 CTNNB1 T41A

1010005 - -

1010006 CTNNB1 T41A

1010007 CTNNB1 T41A

1010008 CTNNB1 T41A

1010009 CTNNB1 T41A

1010010 CTNNB1 T41A

1010011 APC

1010012 APC A972G

1010013 CTNNB1 T41A

1010014 APC.Q1062fs*1

1010015 CTNNB1 S45F

1010016 CTNNB1 T41A

1010017 CTNNB1 S45F

Figure 2. Time on study per patient.

@geosullivanc@NCItreatment

http://dtc.cancer.gov

Figure 4.

Patient 1010012: 19 year-old female

who presented with a right

subscaspular desmoid with marked

decreased ROM. Following resection

(which improved ROM), the mass

recurred, and was resistant to various

therapies. After 9 cycles she reported

complete resolution of her symptoms,

now will full ROM.

Baseline CT Post cycle 12 CT

Adverse Event (n=17) Grade 1 Grade 2 Grade 3

No. % No. % No. %

Investigations

AST raised 10 (59) 1 (6) -

lymphocyte count decreased 9 (53) 1 (6) -

ALT raised 6 (35) 1 (6) -

platelet count decreased 4 (24) - -

white cell count decreased 4 (24) - -

Gastrointestinal disorders

diarrhea 12 (71) 3 (17) -

nausea 9 (53) - -

mucositis 5 (29) 1 (6) -

dry mouth 5 (29) - -

Metabolism disorders+Nutrition

hypophosphatemia 1 (6) 13 (76) 8 (47)

hypocalcemia 5 (29) - -

hypokalemia 4 (24) - -

Skin and Subcutaneous

rash maculopapular 8 (47) - -

Folliculitis* - 5 (29) -

SCC - 1 (6) -

General Disorders

fatigue 7 (41) - -

Blood and Lymphatics

anemia 5 (29) - -

Vascular disorders

hot flashes 5 (29) - -

Reproductive and Breast

irregular menstruation 4 (24) - -

Skin disorder (any kind or grade)

Total No. of patients

CTNNB1 S45F 2

CTNNB1 T41A 4

APC somatic 1

APC germline 1

None 1

Patient outcomes (n=17)

Median follow up time 23 months (2-27)

Median No. of cycles 28 (4-36)

Remain on study

On study >1 year

10 (59%)

12 (71%)

Off study

Patient choice

Adverse Event

7 (41%)

6 (35%)

1 (6%)

Response Rates

Complete Response

Partial Response

Stable Disease

Disease Progression

0

5 (30%)

12 (71%)

0

* milia, hidradenitis suppurativa, epidermoid cyst.

Figure 1. Representative images of varying skin AEs.