Phase II Study of Cediranib (AZD2171) in Patients With Alveolar Soft Part Sarcoma

Background:

Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor accounting for less than
1% of soft tissue sarcomas. There is no effective systemic treatment for patients with
metastatic ASPS. Little is known with regards to relevant molecular markers as potential
therapeutic targets. Cediranib (AZD2171), a VEGF/KIT tyrosine kinase inhibitor, has recently
demonstrated antitumor activity in early phase clinical trials, which included 7 adult and 3
pediatric patients with ASPS.

Objectives:

Adult patients:

- To determine the response rate (PR + CR) of AZD2171 in adult patients with ASPS.

- To compare gene expression profiles between pre-treatment and post-treatment biopsy
specimens.

Pediatric patients:

-To determine if pediatric patients with ASPS will experience at least a minimal response
rate when treated with AZD2171

Eligibility:

Patients must have histologically or cytologically confirmed metastatic alveolar soft part
sarcoma.

- Less than 16 years old. BSA must be greater than or equal to 1.04 m2 and subject must be
able to swallow tablets.

- Adequate organ function.

Design:

Adult patients will be treated with AZD2171 at 30 mg by mouth once a day for 28 days (28-day
cycles). Pediatric patients (< 16 years old) will be treated with 12 mg/m2/day once a day for
28 day (28-day cycles).

Blood pressure will be monitored weekly for the first 2 cycles then every 2 weeks for the
remainder of the study (unless patients have experienced elevated blood pressure requiring
drug therapy).

CT scans will be performed at baseline and every 2 cycles for restaging during the first 18

months; after 18 and 36 months, restaging CT scans will be performed every 3 or 4 cycles,
respectively.

The study will be conducted using an optimal two-stage design in both pediatric and adult
patients. The portion in adults will rule out an unacceptably low 5% clinical response rate
(PR+CR) in favor of a modestly high response rate of 25%. In pediatric patients, the study
will rule out an unacceptably low 5% overall clinical response rate (CR + PR) in favor of a
higher response rate of 35%.

Optional biopsies will be performed in adult patients only at baseline and after 3-5 days of
treatment (D3-D5) to evaluate early drug effect. A third optional biopsy after completion of
4 weeks of therapy (between C1D28 and C2D7) may be collected with the intention of providing
further information about disease response to treatment. Depending on results of initial gene
expression profiles, the timing of the biopsies may be adjusted, but without change in total
number of biopsies per patient.

In a retrospective pilot study, CT scans from 20 consecutive off-study patients will be
re-reviewed. RECIST imaging measurements will be compared to volumetric density (Total Volume
of Viable Tumor, TVVT) CT measurements. The objective is to establish whether volumetric
density/percent necrosis algorithms such as TVVT more accurately assess extent of disease and
response to therapy than standard RECIST criteria.

The total accrual ceiling is 73 participants (60 adult and 13 pediatric patients).

- INCLUSION CRITERIA:

Patients must have histologically confirmed alveolar soft part sarcoma. Pathology should be
confirmed at the Laboratory of Pathology, National Institutes of Health.

Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as greater
than or equal to 20 millimeters with conventional techniques or as greater than or equal to
10 millimeters with spiral CT scan.

Patients must have metastatic alveolar soft part sarcoma that is not curable by surgery.
Patients who have surgically resectable tumors with metastasis will be considered on a case
by- case basis.

Any prior therapy must have been completed greater than or equal to 4 weeks prior to
enrollment on protocol and the participant must have recovered to eligibility levels from
prior toxicity. Patients should be at least 6 weeks out from nitrosoureas and mitomycin C.
Prior radiation should have been completed greater than or equal to 4 weeks prior to study
enrollment and all associated toxicities resolved to eligibility levels. Patients must be
greater than or equal to 2 weeks since any investigational agent administered as part of a
Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a
sub-therapeutic dose of drug is administered) at the PI s discretion, and should
haverecovered to eligibility levels from any toxicities.

Any degree of prior treatment is allowed, including other anti-angiogenic treatments (e.g.,
VEGFR2 inhibitors or bevacizumab). Patients with no prior therapy are eligible, provided
they have metastatic disease that is not curable by surgery.

BSA greater than or equal to 1.04 square meter.

ECOG performance status less than or equal to 2 for adults, Karnofsky performance status
greater than or equal to 50% for pediatric patients greater than 10 years of age, and
Lansky performance status greater than or equal to 50 for pediatric patients less than or
equal to 10 years of age.

Life expectancy of greater than 8 weeks.

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

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

- platelets greater than or equal to 100,000/microliter

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

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- creatinine within normal limits based on age as follows:

Age (Years) Maximum Serum Creatinine (milligrams per deciliter)

less than or equal to 5 0.8

5 less than age less than or equal to 10 1.0

10 less than age less than or equal to 15 1.2

greater than 15 1.5

OR

creatinine clearance greater than or equal to 60 milliter/min for adults or greater than or
equal to 60 milliter/min/1.73m2 for children with creatinine levels above institutional
upper

limit of normal.

QTc must be less than 500 msec.

Pediatric patients: Normal left ventricular function with ejection fraction greater than
55% or shortening fraction greater than or equal to 27%.

At present, the potential of AZD2171 for clinically significant drug interactions involving
the CYP isozymes is unknown. However, studies of the agent in rats indicated possible
suppression of CYP1A that may be of biological significance. Eligibility of patients
receiving any medications or substances known to affect or with the potential to affect the
activity of PK of AZD2171 will be determined following review of their case by the
Principal Investigator. Efforts should be made to switch patients with brain metastases who
are taking enzyme-inducing anticonvulsant agents to other medications one week prior to
starting therapy.

AZD2171 has been shown to terminate fetal development in the rat, as expected for a process
dependent on VEGF signaling. For this reason, women of child-bearing potential must have a
negative pregnancy test prior to study entry. Women of child-bearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation. Should a
woman become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately.

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

Patients should not be receiving any other investigational agents.

Prior therapy with anti-angiogenic agents is permitted.

EXCLUSION CRITERIA:

Patients with clinically significant illnesses which would compromise participation in the
study, including, but not limited to: active or uncontrolled infection, uncontrolled
diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina
pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia;
or psychiatric illness/social situations that would limit compliance with study
requirements.

Patients may not be receiving any medication that may markedly affect renal function (e.g.,
vancomycin, amphotericin, ibuprofen, pentamidine).

Patients who are unable to swallow tablets.

Mean QTc greater than 500 msec (with Bazett s correction) in screening electrocardiogram or
history of familial long QT syndrome.

Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart.

Pregnant women are excluded from this study because AZD2171 is a VEGF inhibitor with known
abortifacient effects. Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with AZD2171, breastfeeding should be
discontinued if the mother is treated with AZD2171.

HIV-positive patients on combination antiretroviral therapy are ineligible because of the
potential for PK interactions with AZD2171.

Adult patients with hypertension not controlled by medical therapy (hypertension defined as
systolic blood pressure greater than 150 millimeters of mercury or diastolic pressure
greater than 90 millimeters of mercury despite optimal medical management). Pediatric
patients must have BP WNL for age. NOTE: blood pressure within the upper limit of normal is
defined as: blood pressure less than or equal to the 95th percentile for age, height, and
gender, and measured, and not be receiving medication for treatment of hypertension.