Dalantercept in Treating Patients With Recurrent Ovarian Epithelial, Fallopian Tube, or Primary Peritoneal Cavity Cancer

Study Overview
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Brief Summary
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This phase II trial studies the side effects and how well dalantercept works in treating patients with ovarian epithelial, fallopian tube, or primary peritoneal cavity cancer that has returned. Dalantercept may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Dalantercept may also stop the growth of tumor cells by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the proportion of patients who survive progression-free for at least 6 months and the proportion of patients who have objective tumor response (complete or partial) in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, treated with dalantercept. II. To determine the frequency and severity of adverse events associated with treatment with dalantercept as assessed by the Active Version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). SECONDARY OBJECTIVES: I. To determine the duration of progression-free survival (PFS) and overall survival (OS). 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-B), activin receptor-like kinase 1 (ALK1), cluster of differentiation 105 (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 (BMP)9, BMP10, and ALK1 in pre-cycle 1 plasma using an enzyme-linked immunosorbent assay (ELISA), and clinical response to treatment. OUTLINE: Patients receive dalantercept subcutaneously (SC) on day 1. Courses repeat every 3 weeks 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 (NSC #757172), a Novel Soluble Recombinant Activin Receptor-Like Kinase 1 (ALK-1) Inhibitor Receptor-Fusion Protein, in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma

Conditions
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Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal 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 epithelial ovarian, fallopian tube, or primary peritoneal carcinoma; histologic documentation of the original primary tumor is required via the pathology report All patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measurable disease is defined 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 Patient must have at least one target lesion to be used to assess response on this protocol as defined by RECIST 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; continuation of hormone replacement therapy is permitted Any other prior therapy directed at the malignant tumor, including immunologic agents, must be discontinued at least three weeks prior to registration; therapy with nitrosoureas or mitomycin must be discontinued at least six weeks 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 platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, biologic/targeted (non-cytotoxic) agents (e.g., bevacizumab) or extended therapy administered after surgical or non-surgical assessment Patients are allowed to receive, but are not required to receive, one additional cytotoxic regimen for management of recurrent or persistent disease Patients who have received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease), must have a platinum-free interval of less than 12 months, or have progressed during platinum-based therapy, or have persistent disease after a platinum-based therapy Patients are allowed to receive, but are not required to receive, biologic/targeted (non-cytotoxic) therapy as part of their primary treatment regimen Patients must have NOT received any biologic/targeted (non-cytotoxic) therapy targeting the VEGF pathway for management of recurrent or persistent disease For the purposes of this study, poly (ADP-ribose) polymerase (PARP) inhibitors will be considered ?cytotoxic?; patients are allowed to receive, but are not required to receive, PARP inhibitors for management of primary or recurrent/persistent disease (either alone or in combination with cytotoxic chemotherapy); PARP inhibitors will NOT count as a prior regimen when given alone Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl Platelets greater than or equal to100,000/mcl Hemoglobin greater than or equal to 9 g/dl Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN) Sodium greater than or equal to 130 mEq/L (CTCAE version 4 [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 < 1000 mg (< 1.0 g/24 hrs) for patient enrollment Bilirubin less than or equal to 1.5 x ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 x ULN Alkaline phosphatase less than or equal to 3 x 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 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and partial thromboplastin time (PTT) less than or equal to 1.5 x 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 pregnancy test prior to the study entry and be practicing an effective form of contraception Exclusion Criteria: Patients who have had previous treatment with dalantercept or any other anti-ALK1 (activin receptor-like kinase 1) agent 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 ovarian, fallopian tube, or primary peritoneal 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 ovarian, fallopian tube, or primary peritoneal 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 a past history of primary endometrial cancer are excluded unless all of the following conditions are met: stage not greater than I-B; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serious, clear cell or other International Federation of Gynecology and Obstetrics (FIGO) grade 3 lesions Patients with history or evidence upon physical exam of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy or any brain metastases Serious or non-healing wound, ulcer or bone fracture History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months Patients requiring parenteral hydration or parenteral/total parenteral nutrition Patients with: Active bleeding (e.g., active hemoptysis, defined as bright red blood of greater than or equal to 1/2 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 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 (325mg oral daily), clopidogrel (Plavix) or dabigatran (Pradaxa) Patients with peripheral edema greater than or equal to grade 1, within 4 weeks of registration 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 CHF Serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate Prolonged corrected QT (QTc) interval > 450 ms Prior anthracycline cumulative dose > 450 mg/m^2 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 Tris buffered saline 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 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 3 weeks 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 |
| --- | --- | --- |
| Progression-free for at Least 6 Months Without Non-protocol Therapy From Study Entry | Percentage of participants who survive progression-free for at least 6 months without non-protocol therapy after study entry. Progression is assessed by RECIST 1.1. RECIST 1.1 defines progressive disease as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions or unequivocal progression of non-target lesions is also considered progression. | Every other cycle for first 6 months | 
| Incidence of Adverse Effects as Assessed by Common Terminology Criteria for Adverse Events Version 4.0 | Number of participants with a maximum grade of 3 or higher during the treatment period. | Assessed every cycle while on treatment, 30 days after the last cycle of treatment, and up to 5 years in follow-up | 
| Objective Tumor Response | Complete and Partial Tumor Response by RECIST 1.1. RECIST 1.1 defines complete response as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm and the disappearance of all non-target lesions and normalization of tumor marker level. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated above. Complete and partial responses are included in the objective tumor response rate. | Every other cycle for first 6 months; then every 3 months thereafter until disease progression confirmed; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease, up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the duration of time from study entry to time of death or the date of last contact. | Every cycle during treatment, then every 3 months for the first 2 years, then every six months for the next three years and then annually for the next 5 years. | 
| Progression-free Survival | Progression-free survival is the period of time from study entry to time of disease progression, death or date of last contact, whichever occurs first. Progression is assessed by RECIST 1.1. RECIST 1.1 defines progressive disease as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions or unequivocal progression of non-target lesions is also considered progression. | Every other cycle for first 6 months; then every 3 months thereafter until disease progression confirmed; and at any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease, up to 5 years. |