Activity of PF-03084014 in Adults with Desmoid Tumors ......Best tumor responses (percent change...
Transcript of Activity of PF-03084014 in Adults with Desmoid Tumors ......Best tumor responses (percent change...
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.