Sunitinib or Cediranib for 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) and sunitinib (SU011248), oral small molecule inhibitors of VEGF
receptor tyrosine kinases, are showing preliminary evidence of activity in patients with
ASPS.

Objectives:

- Part I: Determine the objective response rate (ORR) of single-agent cediranib and
single-agent sunitinib malate in patients with advanced ASPS.

- Part II: Determine the ORR of cediranib in patients who progress on the sunitinib arm,
and determine the ORR of sunitinib in patients who progress on the cediranib arm.

- Determine the progression-free survival (PFS) at 24 weeks for single-agent cediranib and

single-agent sunitinib malate in patients with advanced ASPS.

Eligibility:

Status Update: Patients enrolled after Amendment G (version dated 08/16/2013), will be

evaluated and compared to the first 13 patients by the study statistician and the Principal

Investigator. Patients with newly diagnosed ASPS with clinical evidence of disease
progression will also be assessed separately.

- Patients aged greater than or equal to 16 years with histologically or cytologically
confirmed metastatic ASPS.

- Patients must show evidence of objective disease progression per RECIST 1 on scans
within the 3-month period immediately preceding enrollment. Both scans used to determine
disease progression should have been obtained within this 6-month period.

- Patients with newly diagnosed, unresectable, measurable, metastatic ASPS who show
clinical evidence of disease progression will be eligible.

- Patients must not have received treatment with any VEGF receptor tyrosine kinase
inhibitor (e.g., cediranib, sunitinib, pazopanib, sorafenib); however, prior treatment
with bevacizumab is allowed.

Design:

- Two sets of patients will be enrolled and assessed in separate cohorts: a) patients with
non-newly diagnosed ASPS and b) patients with newly diagnosed ASPS

- Part I: Patients will be randomized to receive cediranib (30 mg) or sunitinib malate
(37.5 mg) orally, once a day in 28-day cycles.

- Part II: At the time of disease progression, patients will cross over to the other
treatment arm after a 2-week wash-out period.

- Appropriate anatomic imaging studies will be performed at baseline and every 2 cycles
for restaging.

- The study will be conducted using an optimal two-stage design to rule out an
unacceptably low 15% clinical response rate (PR+CR) in favor of a modestly high response
rate of 40%.

The study will initially enroll 10 evaluable patients in each arm. If 0 or 1 of the 10
patients has a clinical response, then no further patients will be accrued. If 2 or more the
first 10 patients have a response, then accrual continues to a total of 22 patients in each
arm.

- INCLUSION CRITERIA:

Status Update: Patients enrolled after Amendment G (version dated 08/16/2013), will be
evaluated and compared to the first 13 patients by the study statistician and the Principal
Investigator.

- Patients must have histologically confirmed metastatic alveolar soft part sarcoma that
is not curable by surgery. Diagnosis of malignancy must be confirmed by the department
of pathology at the institution where the patient is enrolled prior to patient
enrollment.

- Patients must show evidence of objective disease progression per RECIST 1 on scans
within the 6 month period immediately preceding enrollment. Both scans used to
determine disease progression should have been obtained within this 6-month period.

- Patients with newly diagnosed, unresectable, metastatic, and measurable ASPS who show
clinical evidence of disease progression (including history and increasing physical
symptoms) will also be eligible. On-study documentation will include a physician s
rationale that supports evidence of clinical disease progression (i.e., increasing
tumor pain).

- 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 mm with conventional techniques or as greater than or
equal to 10 mm with spiral CT scan.

- 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 who have had prior monoclonal antibody therapy must have completed
that therapy at least 3 half-lives of the antibody or 6 weeks ago. Patients who have
received more than a cumulative dose of 350 mg/m(2) of doxorubicin may be enrolled at
the discretion of the Coordinating Center PI after consultation with a cardiologist
and if screening echocardiogram is normal.

- 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
Coordinating Center PI s discretion, and should have recovered to eligibility levels
from any toxicities.

- Patients with no prior therapy are eligible, provided they have metastatic disease
that is not curable by surgery.

- Age greater than or equal to 16 years. Patients age 16-17 years are eligible only if
they have a BSA greater than or equal to 1.7 m(2) or weigh greater than or equal to 60
kg.

- ECOG performance status less than or equal to 2.

- Life expectancy of greater than 3 months.

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

- leukocytes greater than or equal to 3,000/mcL

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

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

- hemoglobin greater than or equal to 9 g/dL

- total serum bilirubin within normal institutional limits

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

- creatinine within normal institutional limits

OR

- creatinine clearance greater than or equal to 60 mL/min for patients with creatinine
levels above institutional normal

- QTc <480 msec (with Bazett s correction) in screening electrocardiogram.

- The following groups of patients are eligible after consultation with a
cardiologist and at the Coordinating Center PI s discretion, provided they have
New York Heart Association Class II (NYHA) cardiac function on baseline
ECHO/MUGA:

- those with a history of Class II heart failure who are asymptomatic on treatment

- those with prior anthracycline exposure greater than a cumulative dose of 350 mg/m(2)

- those who have received central thoracic radiation that included the heart in the
radiotherapy port.

- Patients must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90
mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is
permitted prior to study entry provided that the BP reading prior to enrollment
is no greater than 140/90 mmHg.

- Left ventricular ejection fraction (LVEF) greater than or equal to institutional
lower limit of normal.

- Because sunitinib is metabolized primarily by the CYP3A4 liver enzyme, strong
CYP3A4 inhibitors are not permitted within 7 days before and during the study,
and strong CYP3A4 inducers are not permitted within 12 days before and during the
study. A list of drugs that may interact with the cytochrome P450 system is
included in Appendix C. Every effort should be made to switch patients taking
such agents or substances to other medications 1 week prior to starting therapy,
particularly patients with brain metastases who are taking enzyme-inducing
anticonvulsant agents (Appendix D). Patients who require potent CYP3A4 inducers
or inhibitors and cannot switch medications must have their case reviewed by the
Coordinating Center PI and may be enrolled only after discussion with and
agreement from the Coordinating Center PI. Current clinical studies with
cediranib have not found clinically significant effects on cediranib PK with
co-administration of CYP3A4 inducers or inhibitors. Eligibility of patients
receiving any medications or substances known to affect or with the potential to
affect the activity or pharmacokinetics (PK) of cediranib will be determined
following review of their case by the Coordinating Center PI.

- Both study agents have been shown to terminate fetal development in the rat, as
expected for a process dependent on VEGF signaling. For this reason, women of
childbearing potential must have a negative pregnancy test prior to study entry.
Women of child-bearing potential and men must agree to use two reliable forms of
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry, for the duration of study participation, and for 2 months following
study drug discontinuation. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating
physician immediately.

- Patients who are nursing infants: because there is an unknown but potential risk
for AEs in nursing infants secondary to treatment of the mother with study
agents, breastfeeding should be discontinued if the mother is treated with the
study agents.

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

- Patients must be able to swallow whole tablets and capsules.

EXCLUSION CRITERIA:

- Patients must not have received prior treatment with any VEGF receptor tyrosine kinase
inhibitor (e.g., cediranib, sunitinib, pazopanib, sorafenib); however, prior treatment
with bevacizumab is allowed.

- Patients may not be receiving any other investigational agents.

- Major surgery within 4 weeks prior to entry into the study, or a surgical incision
that is not fully healed.

- History of familial long QT syndrome, or use of medications that may cause QTc
interval prolongation.

- Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid
function in the normal range with medication are ineligible.

- Warfarin and its derivatives are not allowed. Patient can be receiving low molecular
weight heparin if clinically indicated.

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

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior surgical
procedures affecting absorption, or active peptic ulcer disease) that impairs their
ability to swallow, retain, and/or absorb the drug are excluded.

- Patients with any of the following conditions are excluded: serious or non-healing
wound, ulcer; history of abdominal fistula, gastrointestinal perforation, or intra
-abdominal abscess within 28 days of treatment; coronary/peripheral artery bypass
graft or stenting within the past 12 months; or cerebrovascular accident (CVA) or
transient ischemic attack within the past 12 months.

- Greater than 2+ proteinuria on two consecutive dipsticks taken no less than 1 week
apart or 24-hour urine protein of > 1 g. Patients with < 2+ proteinuria are eligible
following initial determination by urinalysis within 1 week prior to enrollment and do
not need the urinalysis repeated.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for PK interactions with cediranib or sunitinib. Appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when
indicated.