Brief Title
Brivanib Alaninate in Treating Patients With Recurrent or Persistent Endometrial Cancer
Official Title
A Phase II Evaluation of Brivanib (BMS582664), an Oral, Multitargeted Growth Factor Tyrosine Kinase Inhibitor in the Treatment of Recurrent or Persistent Endometrial Carcinoma
Brief Summary
This phase II trial is studying how well brivanib alaninate works in treating patients with
endometrial cancer that has come back (recurred) or is persistent. Brivanib alaninate may
stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by
blocking blood flow to the tumor.
Detailed Description
PRIMARY OBJECTIVES:
I. To assess the activity of brivanib (brivanib alaninate) for patients with recurrent or
persistent endometrial cancer with the frequency of patients who survive progression-free for
at least 6 months after initiating therapy or have objective tumor response..
SECONDARY OBJECTIVES:
I. To determine the duration of progression-free survival and overall survival. II. To
determine the nature and degree of toxicity of brivanib as assessed by Common Terminology
Criteria for Adverse Events (CTCAE) version (v)3.0 in this cohort of patients.
TERTIARY OBJECTIVES:
I. To determine whether activating mutations in fibroblast growth factor receptor 2 (FGFR2)
are associated with progression-free survival status > 6 months following brivanib treatment,
objective tumor response following brivanib treatment, or endometrioid histology.
II. To explore the associations between select biomarkers and response to brivanib
(progression-free survival status > 6 months and objective tumor response), measures of
clinical outcome (progression-free survival and overall survival) or disease status including
histologic cell type: i) mutations in FGFR2 or phosphatase and tensin homolog (PTEN) in
deoxyribonucleic acid (DNA) from formalin-fixed and paraffin-embedded (FFPE) tumor or normal
blood cells; ii) immunohistochemical (IHC) expression of the FGFR family and ligands, steroid
receptor isoforms or phosphorylated (p) v-akt murine thymoma viral oncogene homolog 1 (AKT)
in FFPE tumor; iii) concentration or the change in the concentration of vascular endothelial
growth factor (VEGF) or type IV collagen in pre-cycle 1, pre-cycle 2 and/or pre-cycle 3
plasma.
III. To explore the relationship among the panel of biomarkers evaluated in this cohort: i)
mutations in FGFR2 or PTEN; ii) IHC expression of the FGFR family and ligands, steroid
receptor isoforms or pAKT; iii) concentration or the change in the concentration of VEGF or
type IV collagen.
OUTLINE:
Patients receive brivanib alaninate orally (PO) once daily (QD) on days 1-28. Courses repeat
every 28 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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Progression-free Survival > 6 Months
Secondary Outcome
Duration of Overall Survival
Condition
Endometrial Adenocarcinoma
Intervention
Brivanib Alaninate
Study Arms / Comparison Groups
Treatment (brivanib alaninate)
Description: Patients receive brivanib alaninate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
45
Start Date
July 6, 2009
Completion Date
July 16, 2016
Primary Completion Date
July 16, 2016
Eligibility Criteria
Inclusion Criteria:
- Patients must have recurrent or persistent endometrial carcinoma, which is refractory
to curative therapy or established treatments; 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, and
transitional cell carcinoma
- All patients must have measurable disease; measurable disease is defined as at least
one lesion that can be accurately measured in at least one dimension (longest
dimension to be recorded); each lesion must be >= 20 mm when measured by conventional
techniques, including palpation, plain x-ray, computed tomography (CT), and magnetic
resonance imaging (MRI), or >= 10 mm when measured by spiral CT
- Patients must have at least one ?target lesion? to be used to assess response on this
protocol as defined by Response Evaluation Criteria in Solid Tumors (RECIST); 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 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 immunologic agents,
must be discontinued at least three weeks prior to registration
- Patients must have had one prior chemotherapeutic regimen for management of
endometrial carcinoma; 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 endometrial disease
according to the following definition:
- Cytotoxic regimens include any agent that targets the genetic and/or mitotic
apparatus of dividing cells, resulting in dose-limiting toxicity to the bone
marrow and/or gastrointestinal mucosa
- Note: Patients on this non-cytotoxic study are allowed to receive one additional
cytotoxic chemotherapy regimen for management of recurrent or persistent
endometrial disease, as defined above; however, patients are encouraged to enroll
on second-line non-cytotoxic studies prior to receiving additional cytotoxic
therapy
- Patients must NOT have received any non-cytotoxic therapy for management of
endometrial cancer with the exception of hormonal therapy
- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl, equivalent to
Common Terminology Criteria (CTCAE v3.0) grade 1
- Platelets greater than or equal to 100,000/mcl
- Hemoglobin > 9 g/dl
- Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN), CTCAE
v3.0 grade 1
- Urinalysis needs to be assessed at baseline and proteinuria must be less than or equal
to 3+ by dipstick (CTCAE v3.0 grade 2 or less); if the urine dipstick is > 3+, a
24-hour protein level can be done, as clinically indicated by the investigator; the
24-hour protein level must be less than or equal to 3.5 g/24 hours (CTCAE v3.0 grade 2
or less)
- Bilirubin less than or equal to 1.5 x ULN (CTCAE v3.0 grade 1)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) less
than or equal to 2.5 x ULN (CTCAE v3.0 grade 1)
- Alkaline phosphatase less than or equal to 2.5 x ULN (CTCAE v3.0 grade 1)
- Albumin greater than or equal to 2.5 g/dl
- Neuropathy (sensory and motor) less than or equal to CTCAE v3.0 grade 1
- Prothrombin time (PT) such that international normalized ratio (INR) is < 1.5 x ULN;
patients on therapeutic warfarin are excluded from trial, anticoagulation with low
molecular weight heparin is allowed
- 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 performed
48 hours prior to study entry and be practicing an effective form of contraception
during the study and for at least 3 months after receiving the final treatment of
brivanib
- All patients must have a baseline electrocardiogram completed prior to study entry;
baseline electrocardiogram (ECG) should be repeated if corrected QT interval (QTc) is
found to be > 450 msec; QTc must NOT be > 450 msec on both ECGs performed during the
same visit
Exclusion Criteria:
- Patients who have had prior therapy with brivanib or anti-vascular, anti-PDGFR
(platelet-derived growth factor receptor) or anti-FGFR (fibroblast growth factor
receptor) therapy
- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer and other specific malignancies as noted below, are excluded
if there is any evidence of the 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 that are on required chronic anti-platelet therapy (aspirin > 300 mg/day, or
clopidogrel greater than or equal to 75 mg/day)
- Patients with gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE
grade >= 3 within 30 days prior to study entry
- Patients with a history of poor wound healing, non healing ulcers or bone fractures
within the last 3 months
- Patients with uncontrolled or significant cardiovascular disease including:
- Myocardial infarction within 12 months
- Uncontrolled angina within 12 months
- Class III-IV New York Heart Association (NYHA) congestive heart failure
- Uncontrolled hypertension (systolic blood pressure [BP] > 150 or diastolic BP >
100 mmHg for 24 hours) despite optimized anti-hypertensive therapy; BP must be
below 150/100 mmHg at screening; subjects with a history of hypertension who are
receiving treatment with calcium channel blockers that are cytochrome P450 family
3, subfamily A, polypeptide 4 (CYP3A4) inhibitors should be changed to an
alternative antihypertensive medication before study entry
- History of stroke, transient ischemic attack (TIA), or other central nervous
system (CNS) ischemic event
- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
digoxin
- Patients must have pre-therapy left ventricle ejection fraction (LVEF) testing
and have an ejection fraction > 50%
- Patients with valvular heart disease >= CTCAE grade2
- Patients with a serious uncontrolled medical disorder or active infection which would
impair the ability of the subject to receive protocol therapy or whose control may be
jeopardized by the complications of this therapy
- Pre-existing thyroid abnormality with thyroid function that can not be maintained in
the normal range with medication
- Patients with hyponatremia (sodium < 130 mEq/L)
- Patients with active/known human immunodeficiency virus (HIV), hepatitis B, or
hepatitis C
- Patients with known brain metastases
- Patients who are pregnant or nursing
- Patients with inability to swallow tablets or untreated malabsorption syndrome
- Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to
restore the serum potassium above this level prior to entry study)
- Patients on therapeutic warfarin anticoagulation will be excluded; patients converted
to anticoagulation with a heparin compound will be allowed provided the patient?s PT
is such that international normalized ratio (INR) is =< 1.5 x ULN
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Matthew Powell, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00888173
Organization ID
GOG-0229I
Secondary IDs
NCI-2011-01918
Responsible Party
Sponsor
Study Sponsor
Gynecologic Oncology Group
Collaborators
National Cancer Institute (NCI)
Study Sponsor
Matthew Powell, Principal Investigator, NRG Oncology
Verification Date
August 2017