A Phase II Trial In Which Patients With Metastatic Alveolar Soft Part Sarcoma Are Randomized to Either Sunitinib or Cediranib Monotherapy, With Cross-Over at Disease Progression
- INCLUSION CRITERIA:
- 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
- Patients must show evidence of objective disease progression per RECIST 1 on scans at
least 6 weeks apart within the 3-month period immediately preceding enrollment.
- 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
- 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
- creatinine within normal institutional limits
- 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
- 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
- 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. 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. 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 coadministration 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
- 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
- Ability to understand and the willingness to sign a written informed consent
- Patients must be able to swallow whole tablets and capsules.
- 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
- 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