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


Phase 2
18 Years
N/A
Open (Enrolling)
Female
Endometrial Cancer

Thank you

Trial Information

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


OBJECTIVES:

Primary

- 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) when treated with dalantercept.

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

Secondary

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

Tertiary

- 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.

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

- 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.

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

OUTLINE: This is a multicenter study.

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

Blood and tumor tissue samples are collected for VEGF, FGF, PDGF, TGF-β, ALK1, CD105, ALK1,
BMP9, and BMP10 protein analysis and gene expression by IHC, ELISA, and reverse
transcriptase polymerase chain reaction (RT-PCR).

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


DISEASE CHARACTERISTICS:

- 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 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 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

- No 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

- No 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

PATIENT CHARACTERISTICS:

- 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

- 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 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

- No patients who are pregnant or nursing

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

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

- No serious or non-healing wound, ulcer, or bone fracture

- No history of abdominal fistula or anastomotic leak, gastrointestinal perforation, or
intra-abdominal abscess within 6 months of registration

- No 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

- No 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

- No history of syndrome of inappropriate antidiuretic hormone secretion (SIADH)

- No 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

- No 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

- No clinically significant active pulmonary risk including pulmonary hypertension,
pulmonary embolism, or history of pulmonary edema

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

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

- 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)

- 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 anthracycline cumulative dose > 450 mg/m²

- Patients are excluded if their previous cancer treatment contraindicates this
protocol therapy

- No patients who have had prior therapy with dalantercept or other inhibitor of the
ALK1 pathway

- 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

- No patients receiving treatment with full-dose aspirin (325 mg oral daily),
clopidogrel (Plavix), or dabigatran (Pradaxa)

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

PFS until subsequent therapy for at least 6 months as measured by RECIST

Safety Issue:

No

Principal Investigator

Vicky Makker, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

Unspecified

Study ID:

CDR0000736764

NCT ID:

NCT01642082

Start Date:

September 2012

Completion Date:

Related Keywords:

  • Endometrial Cancer
  • endometrial adenocarcinoma
  • endometrial adenosquamous cell carcinoma
  • endometrial clear cell carcinoma
  • recurrent endometrial carcinoma
  • endometrial papillary serous carcinoma
  • Endometrial Neoplasms
  • Sarcoma, Endometrial Stromal
  • Adenoma

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
University of Chicago Cancer Research CenterChicago, Illinois  60637
Harrington Cancer CenterAmarillo, Texas  79106
Florida Hospital Cancer Institute at Florida Hospital OrlandoOrlando, Florida  32803-1273
Presbyterian Cancer Center at Presbyterian HospitalCharlotte, North Carolina  28233-3549
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115
Oklahoma University Cancer InstituteOklahoma City, Oklahoma  73104
Maine Medical Center - Bramhall CampusPortland, Maine  04102
Rosenfeld Cancer Center at Abington Memorial HospitalAbington, Pennsylvania  19001
St. Vincent Oncology CenterIndianapolis, Indiana  46260