Clinical trial NCT01642082: Dalantercept in Treating Patients With Recurrent or Persistent Endometrial Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: GOG Foundation
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2012-07-17
Enrollment: 28
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Response
timeFrame: 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.
measure: Treatment and Progression-free Survival at 6 Months
timeFrame: 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 outcomes:
measure: Progression-free Survival at 6 Months
timeFrame: : 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.
measure: Duration of Progression-free Survival
timeFrame: 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.
measure: Duration of Survival
timeFrame: Patients are followed every three months for the first two years and then every six months for the next three years.
measure: Adverse Events (Primary Serious and All Other AEs)
timeFrame: Every cycle of study treatment and after treatment for a maximum of 5 years from study entry
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Medical Center-Mount Zion
state: California
city: Lewes
country: United States
facility: Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Orlando
country: United States
facility: Florida Hospital Orlando
state: Florida
city: Sarasota
country: United States
facility: Sarasota Memorial Hospital
state: Florida
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Saint Vincent Hospital and Health Care Center
state: Indiana
city: Portland
country: United States
facility: Maine Medical Center-Bramhall Campus
state: Maine
city: Elkton
country: United States
facility: Union Hospital of Cecil County
state: Maryland
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Cancer Center/Fairview Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Mayfield Heights
country: United States
facility: Hillcrest Hospital Cancer Center
state: Ohio
city: Mentor
country: United States
facility: Lake University Ireland Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Providence
country: United States
facility: Women and Infants Hospital
state: Rhode Island
city: Sioux Falls
country: United States
facility: Sanford Cancer Center-Oncology Clinic
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford NCI Community Oncology Research Program of the North Central Plains
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Seattle
country: United States
facility: Pacific Gynecology Specialists
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Seattle
country: United States
facility: Northwest Hospital
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
affiliation: NRG Oncology
name: Vicky Makker
role: PRINCIPAL_INVESTIGATOR
References: