Dalantercept in Treating Patients With Recurrent or Persistent Endometrial Cancer

PRIMARY OBJECTIVES:

I. To estimate the proportion of patients with persistent or recurrent endometrial cancer who
survive progression-free for at least 6 months and the proportion of patients who have
objective tumor response (complete or partial), treated with dalantercept (ACE-041).

II. To determine the nature and degree of toxicity of dalantercept in this cohort of
patients.

SECONDARY OBJECTIVES:

I. To estimate progression-free survival (PFS) and overall survival (OS) of patients with
persistent or recurrent endometrial cancer treated with dalantercept.

TERTIARY OBJECTIVES:

I. To measure the expression of vascular endothelial growth factor (VEGF), fibroblast growth
factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β),
activin receptor-like kinase 1 (ALK1), endoglin (CD105), and other markers via
immunohistochemistry (IHC) and determine if there is correlation between expression and
clinical response to treatment.

II. To determine the correlation between ALK1 gene expression, other markers, and clinical
response to treatment.

III. To determine the correlation between concentration of VEGF, bone morphogenetic protein 9
(BMP9), bone morphogenetic protein 10 (BMP10), and ALK1 in pre-cycle 1 plasma using an
enzyme-linked immunosorbent assay (ELISA), and clinical response to treatment.

IV. To correlate somatic mutations in candidate genes with response to therapy.

OUTLINE:

Patients receive dalantercept subcutaneously (SC) on day 1. Courses repeat every 21 days in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- Patients must have recurrent or persistent endometrial carcinoma; histologic
confirmation of the original primary tumor is required

- Patients with the following histologic epithelial cell types are eligible:
Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma,
clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not
otherwise specified (N.O.S.), mucinous adenocarcinoma, squamous cell carcinoma,
and transitional cell carcinoma

- All patients must have measurable disease; measurable disease is defined by Response
Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) as at least one lesion that
can be accurately measured in at least one dimension (longest diameter to be
recorded); each lesion must be >= 10 mm when measured by computed tomography (CT),
magnetic resonance imaging (MRI), or caliper measurement by clinical exam; or >= 20 mm
when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when measured
by CT or MRI

- Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST version 1.1; tumors within a previously irradiated field
will be designated as "non-target" lesions unless progression is documented or a
biopsy is obtained to confirm persistence at least 90 days following completion of
radiation therapy

- Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG)
protocol, if one exists; in general, this would refer to any active GOG phase III
protocol or rare tumor protocol for the same patient population

- Patients who have received one prior regimen must have a GOG performance status of 0,
1, or 2; patients who have received two prior regimens must have a GOG performance
status of 0 or 1

- Recovery from effects of recent surgery, radiotherapy, or chemotherapy

- Patients should be free of active infection requiring antibiotics (with the
exception of uncomplicated urinary tract infection [UTI])

- Any hormonal therapy directed at the malignant tumor must be discontinued at
least one week prior to registration

- Any other prior therapy directed at the malignant tumor, including chemotherapy
and immunologic agents, must be discontinued at least three weeks prior to
registration; any investigational drug must be discontinued at least 30 days
prior to registration

- Any prior radiation therapy must be discontinued at least four weeks prior to
registration

- At least 4 weeks must have elapsed since the patient underwent any major surgery
(e.g., major: laparotomy, laparoscopy); there is no delay in treatment for minor
procedures (e.g., central venous access catheter placement)

- Prior therapy

- Patients must have had one prior chemotherapeutic regimen for management of
endometrial carcinoma. Initial treatment may include chemotherapy, chemotherapy
and radiation therapy, and/or consolidation/maintenance therapy; chemotherapy
administered in conjunction with primary radiation as a radio-sensitizer WILL be
counted as a systemic chemotherapy regimen

- Patients are allowed to receive, but are not required to receive, one additional
cytotoxic regimen for management of recurrent or persistent disease

- Patients must have NOT received any non-cytotoxic (biologic or targeted) agent(s)
for management of recurrent or persistent disease; prior non-cytotoxic (biologic
or targeted) agent(s) is allowed as part of initial treatment; prior hormonal
therapy is allowed, but must be discontinued at least one week prior to
registration

- Absolute neutrophil count (ANC) 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

- Creatinine less than or equal to 1.5 times institutional upper limit normal (ULN)

- Sodium greater than or equal to 130 mEq/L (Common Terminology Criteria for Adverse
Events [CTCAE] v. 4, grade 0 or 1)

- Urine protein should be screened by urinalysis; if protein is 2+ or higher, 24-hour
urine protein should be obtained and the level should be < 1,000 mg (< 1.0 g/24 hrs)
for patient enrollment

- Bilirubin less than or equal to 1.5 times ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal
to 3 times ULN

- Alkaline phosphatase less than or equal to 3 times ULN

- Albumin greater than or equal to 3 (CTCAE v. 4, grade 0 or 1)

- Prothrombin time (PT) such that international normalized ratio (INR) is less than or
equal to 1.5 times ULN (or an in-range INR, usually between 2 and 3, if a patient is
on a stable dose of therapeutic warfarin)

- Partial thromboplastin time (PTT) less than or equal to 1.5 times ULN

- Left ventricular ejection fraction (LVEF) greater than 50% (measured by echocardiogram
or MUGA [multi-gated acquisition] scan)

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

- Patients must meet pre-entry requirements

- Patients of childbearing potential must have a negative serum pregnancy test prior to
the study entry and be practicing an effective form of contraception

Exclusion Criteria:

- Patients who have had prior therapy with dalantercept or other inhibitor of the ALK1
pathway

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies, are excluded if there is any
evidence of other malignancy being present within the last three years; patients are
also excluded if their previous cancer treatment contraindicates this protocol therapy

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis OTHER THAN for the treatment of endometrial cancer within the last three
years are excluded; prior radiation for localized cancer of the breast, head and neck,
or skin is permitted, provided that it was completed more than three years prior to
registration, and the patient remains free of recurrent or metastatic disease

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER
THAN for the treatment of endometrial cancer within the last three years are excluded;
patients may have received prior adjuvant chemotherapy for localized breast cancer,
provided that it was completed more than three years prior to registration, and that
the patient remains free of recurrent or metastatic disease

- Patients with history or evidence upon physical exam of central nervous system disease
(CNS) disease, including primary brain tumor, seizures not controlled with standard
medical therapy, or any brain metastases or leptomeningeal disease

- Serious or non-healing wound, ulcer, or bone fracture

- History of abdominal fistula or anastomotic leak, gastrointestinal perforation, or
intra-abdominal abscess within 6 months of registration

- Patients requiring parenteral hydration or parenteral/total parenteral nutrition

- No patients with:

- Active bleeding (e.g., active hemoptysis, defined as bright red blood of greater
than or equal to ½ teaspoon [2.5 ml] in any 24-hour period) within 2 weeks prior
to registration or gastrointestinal bleeding within 3 months prior to
registration

- Hereditary hemorrhagic telangiectasia (HHT)

- Platelet function abnormality

- Autoimmune or hereditary hemolysis

- Coagulopathy, or

- Tumor involving major vessels (defined as any lesion invading or abutting the
wall [i.e., no fat plane evident] of major blood vessels as assessed by CT or
MRI)

- Patients receiving treatment with full-dose aspirin (325 mg oral daily), clopidogrel
(Plavix), or dabigatran (Pradaxa)

- Patients with peripheral edema greater than or equal to grade 1 within 4 weeks of
registration

- No patients with clinically significant cardiovascular disease:

- Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm
Hg despite antihypertensive medications

- Evidence of hypertrophic cardiomyopathy

- New York Heart Association (NYHA) class II or greater congestive heart failure
(CHF)

- Any of the following within 6 months prior to study registration:

- Bypass surgery

- Stent placement

- Myocardial infarction

- Acute coronary syndrome/unstable angina

- Hospitalization for congestive heart failure (CHF)

- Serious cardiac arrhythmia requiring medication; this does not include
asymptomatic atrial fibrillation with controlled ventricular rate

- Prolonged QTc interval > 450 ms

- Prior anthracycline cumulative dose > 450 mg/m^2

- Patients who are pregnant or nursing

- History of syndrome of inappropriate antidiuretic hormone secretion (SIADH)

- Patients who have undergone a therapeutic paracentesis within 4 weeks of registration

- Known history of positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV)
surface antigen (HBsAg), or HBV core antibody, or human immunodeficiency virus (HIV)
antibody results

- History of severe (National Cancer Institute-Common Terminology Criteria for Adverse
Events [NCI-CTCAE] v.4.0 >= grade 3) allergic or anaphylactic reaction or
hypersensitivity to recombinant proteins or excipients (10 mM Tris buffered saline) in
the investigational agent

- Clinically significant active pulmonary risk including pulmonary hypertension,
pulmonary embolism, or history of pulmonary edema