Dalantercept in Treating Patients With Recurrent or Persistent Endometrial Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well dalantercept works in treating patients with endometrial cancer that has come back or is persistent. Dalantercept may stop the growth of endometrial cancer by blocking blood flow to the tumor.

Detailed Description
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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.

Official Title
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A Phase II Evaluation of Dalantercept, a Novel Soluble Recombinant Activin Receptor-Like Kinase 1 (ALK-1) Inhibitor Receptor-Fusion Protein, in the Treatment of Recurrent or Persistent Endometrial Carcinoma

Conditions
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Endometrial Adenocarcinoma, Endometrial Clear Cell Adenocarcinoma, Endometrial Mixed Adenocarcinoma, Endometrial Mucinous Adenocarcinoma, Endometrial Serous Adenocarcinoma, Endometrial Squamous Cell Carcinoma, Endometrial Transitional Cell Carcinoma, Endometrial Undifferentiated Carcinoma, Recurrent Uterine Corpus Carcinoma

Intervention / Treatment
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* Biological: Dalantercept
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (dalantercept)<br>Patients receive dalantercept SC on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Biological: Dalantercept<br>* Given SC<br>* Other names: ALK1-Fc Fusion Protein ACE-041;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response | Response was defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and based on imaging done every other cycle. Responses can be either partial or complete. Per RECIST v1.1 target and non-target lesions are assessed by MRI or CT scan: Complete Response (CR), Disappearance of all target and non-target lesions and all lymph nodes must be < 10 mm in short axis; Partial Response (PR), >=30% decrease in the sum of the longest dimensions (LD) of all target measurable lesions taking as reference the baseline sum of LD. | Scans to assess response were done every other cycle for the first 6 months; every three months thereafter; and any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease. Responses must be confirmed. | 
| Treatment and Progression-free Survival at 6 Months | Treatment and Progression-free Survival is defined as the duration alive from study entry until progression is documented, death or non-protocol treatment is initiated; whichever comes sooner. Progressive disease is defined as at least a 5 mm absolute increase and a 20% relative increase in the sum of measurable target lesions' longest dimensions relative to the smallest sum at baseline or on study or the appearance of new lesions or unequivocal progression of existing non-target lesions. Non-protocol treatment initiation prior to disease progression and prior to 6 months from study entry was counted as an event for treatment and progression-free survival at 6 months. Disease progression within 6 months of study entry or death within 6 months of study entry and prior to disease progression counts as an event for treatment and progression-free survival at 6 months. | CT scan or MRI were to assess progression every other cycle for the first 6 months; every three months thereafter; and any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 6 Months | Progression-free survival is defined as the duration alive from study entry until progression is documented or death, whichever comes sooner. Progressive disease is defined as at least a 5 mm absolute increase and a 20% relative increase in the sum of measurable target lesions' longest dimensions relative to the smallest sum at baseline or on study or the appearance of new lesions or unequivocal progression of existing non-target lesions. Disease progression within 6 months of study entry or death within 6 months of study entry and prior to disease progression counts as an event for progression-free survival at 6 months. | : CT scan or MRI were to assess progression every other cycle for the first 6 months; every three months thereafter; and any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease. | 
| Duration of Progression-free Survival | Progression-free survival is defined as the duration alive from study entry until progression is documented or death, whichever comes sooner. Progressive disease is defined as at least a 5 mm absolute increase and a 20% relative increase in the sum of measurable target lesions' longest dimensions relative to the smallest sum at baseline or on study or the appearance of new lesions or unequivocal progression of existing non-target lesions. | CT scan or MRI were to assess progression every other cycle for the first 6 months; every three months thereafter; and any time if clinically indicated based on symptoms or physical signs suggestive of progressive disease. | 
| Duration of Survival | Duration of survival is defined as the duration alive from study entry until death or last contact. | Patients are followed every three months for the first two years and then every six months for the next three years. | 
| Adverse Events (Primary Serious and All Other AEs) | The frequencies of the maximum grade of any acute adverse event, regardless of attribution are reported during treatment and up to 30 days after stopping the study treatment are reported. | Every cycle of study treatment and after treatment for a maximum of 5 years from study entry |