Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis

Background:

- Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive,
slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated
with severe loss of organ function and significant morbidity.

- Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused
significant tumor shrinkage in patients with unresectable desmoid tumors in an early
phase clinical trial.

- The Notch pathway is a key regulator of cell differentiation, proliferation and
apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis.

Objectives:

- Primary: Determine the response rate (CR+PR) of PF-03084014 in patients with desmoid
tumors/aggressive fibromatosis

- Exploratory: Assess symptom measures at baseline and on study; perform genotyping for
germline and somatic mutations in APC and CTNNB1 genes; correlate clinical response to
therapy with genotyping data; and assess modulation of the Notch pathway by evaluating
notch response genes in tumor biopsies at baseline and after drug administration

Eligibility:

- Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to
curative resection or definitive radiation therapy that has progressed after receiving
at least one line of standard treatment; adequate organ function

- Willingness to provide blood samples and 10 unstained slides or a tumor block for
genetic research studies

Study Design:

- This is an open-label Phase II trial of PF-03084014; study drug will be administered
orally at 150 mg twice a day in 21-day cycles

- Optional tumor biopsies for research purposes will be performed at baseline prior to
study treatment and at the beginning of cycle 7 (+/- one cycle)

- Restaging scans (CT scan of the known site of disease) will be performed at baseline and
then every 6 cycles (+/- one cycle)

- Optional MRI scans may be performed prior to start of study treatment, end of cycle 1,
and every 6 cycles (at the same times as the CT scans)

- Health-related quality of life (HRQOL)/symptom questionnaires will be administered at
baseline and at restaging

- INCLUSION CRITERIA:

2.1.1.1 Patients must have histologically confirmed desmoid tumor confirmed by the
Laboratory of Pathology, NCI, that has progressed after receiving at least one line of
standard treatment and that is not amenable to surgical resection or definitive radiation
therapy.

2.1.1.2 Willingness to provide blood samples and 10 unstained slides or a tumor block for
genetic research studies.

2.1.1.3 Any line of therapy with prior desmoid therapy, including radiotherapy, should have
been completed at least 2 weeks before study entry and all toxicities must have resolved at
least to eligibility levels.

2.1.1.4 Age greater than or equal 18 years; because no dosing or adverse event data are
currently available on the use of PF-03084014 in patients <18 years of age, children are
excluded from this study, but may be eligible for future pediatric trials.

2.1.1.5 ECOG performance status less than or equal 2.

2.1.1.6 Life expectancy > 3 months.

2.1.1.7 Patients must have normal organ and marrow function as defined below:

- -absolute neutrophil count greater than or equal 1,500/mcL

- -platelets greater than or equal 100,000/mcL

- -total bilirubin less than or equal 1.5 times institutional upper limit of normal

- -AST(SGOT)/ALT(SGPT) less than or equal 5 times institutional upper limit of normal

- -creatinine < 1.5 times institutional upper limit of normal

OR

- -creatinine clearance greater than or equal 60 mL/min/1.73 m(2) for patients with
creatinine levels >1.5 mg/dL

- -hemoglobin greater than or equal 9 g/dL

2.1.1.8 Patients must be able to swallow whole tablets or capsules with no GI condition
affecting absorption; nasogastric or G-tube administration is not allowed.

2.1.1.9 The effects of PF-03084014 on the developing human fetus are unknown. For this
reason and because >=-secretase inhibitors are known to be teratogenic, women of
childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) for the duration of study participation and
for at least 6 months after dosing with study drugs ceases. Should a woman become pregnant
or suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately. Men treated or enrolled on this protocol
must also agree to use adequate contraception for the duration of study participation, and
6 months after completion of study drug administration.

2.1.1.10 Ability to understand and the willingness to sign a written informed consent
document.

2.1.1.11 Evidence of measurable disease by CT scan. Measurable lesions are defined as those
that can be accurately measured in at least one dimension (longest diameter to be recorded)
as greater than or equal 20 mm by chest x-ray, as greater than or equal 10 mm with CT scan,
or greater than or equal 10 mm with calipers by clinical exam.

EXCLUSION CRITERIA:

2.1.2.1 Patients who are receiving any other investigational agents. Concurrent mediations
that the patient is taking will be reviewed by the PI to assess safety and eligibility.

2.1.2.2 Prior treatment with Gamma-secretase inhibitors or anti-notch antibody therapy.

2.1.2.3 Uncontrolled intercurrent illness including, but not limited to, serious infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study requirements.

2.1.2.4 QTc interval of >470 msec at study entry; congenital long QT syndrome.

2.1.2.5 Pregnant women are excluded from this study because PF-03084014 is a
Gamma-secretase inhibitor with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with PF-03084014, breastfeeding should be discontinued
if the mother is treated with PF-03084014.

2.1.2.6 Patients with gastrointestinal conditions that might predispose for drug
intolerability or poor drug absorption (e.g., inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption,
malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with
ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel
obstruction are also excluded, as are any patients who cannot swallow the tablet whole.
Tablets must not be crushed or chewed; nasogastric or G-tube administration is not allowed.

2.1.2.7 HIV-positive patients on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with PF-03084014.

2.1.3 Recruitment Strategies

We have had multiple discussions with the Desmoid Tumor Research Foundation, Inc., who have
various outreach efforts including patient meetings and webcasts. Senior executives of the
Foundation have indicated strong interest in this trial and willingness to inform their
members. We also have a network of referring physicians nationally that refers patients
with solid tumors to our clinical program. Given our interest and trials for sarcomas, we
have formed connections with centers that treat patients with mesenchymal malignancies. We
will be informing all of these of the availability of this trial once it is open.