Brief Title
Dasatinib, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV or Recurrent Endometrial Cancer
Official Title
Pilot and Translational Study of Dasatinib (NSC#732517) Paclitaxel and Carboplatin in Women With Advanced Stage and Recurrent Endometrial Cancer
Brief Summary
This pilot phase I trial studies how well dasatinib works together with paclitaxel and
carboplatin in treating patients with stage III, stage IV, or endometrial cancer that has
come back after a period of improvement. Dasatinib may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either
by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Giving dasatinib together with paclitaxel and carboplatin may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES:
I. To evaluate pMEK and EphA2 signaling effectors in pre- and post- treatment biopsy tissues
from patients with advanced staged measurable primary or recurrent endometrial cancer.
SECONDARY OBJECTIVES:
I. To determine the frequency and severity of adverse events as assessed by Common
Terminology Criteria for Adverse Events version 4 (CTCAE v. 4) of dasatinib administered in
combination with paclitaxel and carboplatin in patients with advanced staged measurable
primary or recurrent endometrial cancer.
II. To record the objective response rate by Response Evaluation Criteria in Solid Tumors
(RECIST) v.1.1.
III. To describe the progression-free survival and overall survival.
TERTIARY OBJECTIVES:
I. To explore the relationship of micro ribonucleic acid (RNA) 520d-3p (miR520d-3p) and EphA2
in pretreatment biopsies.
II. To evaluate downstream EphA2 signaling effectors, such as CAV-1, pAKT, FAK, paxillin, and
p130cas in pre- and post-tissue treatment biopsies.
III. To explore the effect of dasatinib on the expression of other Eph family members such as
EphB2 and EphB4.
IV. To quantify circulating tumor cells (CTCs) before and during the individual treatment
phases.
OUTLINE:
Patients receive induction therapy comprising dasatinib orally (PO) once daily (QD) for 14
days. *Beginning 7 days later, patients receive paclitaxel intravenously (IV) over 3 hours
and carboplatin IV on day 1, and dasatinib PO QD on days 1-21. Treatment repeats every 21
days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
NOTE: * Patients who have had prior external-beam pelvic or extended-field pelvic/para-aortic
radiation therapy must receive treatment at a reduced dose.
After completion of study treatment, patients are followed up every 3 months for 1 year.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Change in pMEK expression
Secondary Outcome
Response rate (complete [CR] or partial response [PR]) according to Response Evaluation Criteria in Solid Tumors version 1.1
Condition
Endometrial Adenocarcinoma
Intervention
Carboplatin
Study Arms / Comparison Groups
Treatment (dasatinib, paclitaxel, carboplatin)
Description: Patients receive induction therapy comprising dasatinib PO QD for 14 days. *Beginning 7 days later, patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1, and dasatinib PO QD on days 1-21. Treatment repeats every 21 days for up to 6 courses 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
18
Start Date
September 20, 2011
Completion Date
December 31, 2015
Primary Completion Date
December 31, 2015
Eligibility Criteria
Inclusion Criteria:
- Patients must have measurable stage III, stage IV, or recurrent endometrial carcinoma
whose potential for cure by surgery or radiation therapy alone is poor
- 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, transitional cell
carcinoma, and mesonephric carcinoma; uterine carcinosarcoma are not eligible for
either COHORT
- 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; measurable disease
lesions must be amenable to pre- and post- treatment biopsy
- Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by 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 have a Gynecologic Oncology Group (GOG) performance status of 0 to 2
- 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 should have had NO prior chemotherapy agents for advanced or recurrent
endometrial cancer; prior chemotherapy administration in conjunction with primary
radiation therapy as a radiosensitizer would not exclude a patient from participation
in this trial
- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcL, equivalent to
Common Terminology Criteria (CTCAE version [v]4) grade 1
- Platelets greater than or equal to 100,000/mcL
- Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN), CTCAE
v4 grade 1
- Bilirubin less than or equal to 1.5 x ULN (CTCAE v4 grade 1)
- Serum glutamic oxaloacetic transaminase (SGOT) less than or equal to 2.5 x ULN (CTCAE
v4 grade 1)
- Alkaline phosphatase less than or equal to 2.5 x ULN (CTCAE v4 grade 1)
- Neuropathy (sensory and motor) less than or equal to CTCAE v4 grade 1
- Therapeutic anticoagulation is not contraindicated, but for those patients on
therapeutic anticoagulation, alteration in coagulation parameters is expected
following initiation of dasatinib; for patients on therapeutic anticoagulation,
coagulation parameters should be assessed weekly for the first cycle following
initiation of dasatinib, weekly for the first cycle following a dose reduction, and
weekly for a minimum of two weeks after stopping dasatinib
- Warfarin is permitted for prophylaxis or treatment of thrombosis; Note: low-molecular
weight heparin is permitted provided the patient's prothrombin time (PT)/international
normalized ratio (INR) is =< 1.5; for patients on anticoagulation, coagulation
parameters should be assessed weekly for the first cycle following initiation of
dasatinib, weekly for the first cycle following a dose reduction, and weekly for a
minimum of two weeks after stopping dasatinib
- PT such that INR is =< 1.5 (or an in-range INR, usually between 2 and 3, if a patient
is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT)
=< 1.5 times the institutional upper limit of normal; patients receiving low-molecular
weight heparin for the prevention or treatment of venous thromboembolic disease are
eligible if considered clinically stable on their regimen
- Oxygen saturation greater than or equal to 88% on room air (CTCAE 4 < grade 2)
- Patients must have a baseline electrocardiogram (EKG) performed prior to enrolling on
study; the EKG must have corrected QT interval (QTc) < 450 msec and must not show
evidence of serious ventricular arrhythmia (ventricular tachycardia or ventricular
fibrillation must be less than 3 beats in a row)
- Cardiac ejection fraction must be within the institutional range of normal as measured
by left ventricular ejection fraction (LVEF) testing; note that baseline and on
treatment scans should be performed using the same modality and preferably at the same
institution
- Patients must have signed an approved informed consent
- Patients of childbearing potential must have a negative serum pregnancy test prior to
study entry and be practicing an effective form of contraception during the study and
for at least 6 months after receiving the final treatment of dasatinib
- Patients must be able to swallow whole tablets
- Patients may not have any clinically significant cardiovascular disease including the
following:
- Myocardial infarction or ventricular tachyarrhythmia within 6 months
- Prolonged QTc >= 480 msec (Fridericia correction)
- Ejection fraction less than institutional normal
- Major conduction abnormality (unless a cardiac pacemaker is present)
- Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of
breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with
or without stress test as needed in addition to electrocardiogram (EKG) to rule
out QTc prolongation; the patient may be referred to a cardiologist at the
discretion of the principal investigator; patients with underlying
cardiopulmonary dysfunction should be excluded from the study
Exclusion Criteria:
- Patients who have isolated recurrences (vaginal, pelvic, or para-aortic) that are
amenable to potentially curative treatment with radiation therapy or surgery
- Patients who have had a prior chemotherapy regimen for advanced or metastatic disease
are excluded; patients who received adjuvant chemotherapy must be disease-free for at
least 6 months
- Patients may have received prior radiation therapy for treatment of endometrial
carcinoma; prior radiation therapy may have included pelvic radiation therapy,
extended field pelvic/para-aortic radiation therapy, and/or intravaginal
brachytherapy, alone or with chemotherapy as a radiation sensitizer; all radiation
therapy must be completed at least 4 weeks prior to the first date of study therapy;
the prior radiation field, radiation dose, number of fractions and prior radiation
start and stop dates must be provided at registration
- Patients who have previously received dasatinib; additionally, patients may not be
receiving any other investigational agents; patients may have received prior hormonal
therapy for treatment of endometrial carcinoma; all hormonal therapy must be
discontinued at least one week prior to the first date of study therapy; patients with
known brain metastases should be excluded from this clinical trial
- Patients with serious, non-healing wound, ulcer, or bone fracture; this includes
history of abdominal fistula or gastrointestinal perforation; patients with an
intra-abdominal abscess within 28 days prior to the first date of dasatinib therapy
are ineligible
- Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels; patients who have a history of significant bleeding disorder unrelated to
cancer including:
- Bleeding diathesis, congenital or acquired within one year prior to initiating
protocol therapy (e.g. von Willebrand's disease, acquired anti-factor VIII
antibodies); significant gastrointestinal (GI) bleeding within three months prior
to initiating protocol therapy
- Patients with history or evidence upon physical examination of central nervous system
(CNS) disease (treated or untreated), including primary brain tumor, seizures not
controlled with standard medical therapy, or any brain metastases
- Patients who have had radiotherapy within 4 weeks prior to entering the study or those
who have not recovered from adverse events (CTCAE v4 grade 2 or greater, excluding
alopecia) due to agents administered more than 4 weeks earlier
- Patients cannot take St. John's wort or drink grapefruit juice while on study
treatment (discontinue St. John wort at least five days before starting dasatinib)
- Patients who have an active pleural or pericardial effusion of any grade
- Patients receiving IV bisphosphonates agree that IV bisphosphonates will be withheld
for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia, and may be
restarted only if any hypocalcemia has been corrected
- Patients with clinically significant cardiovascular disease; this includes:
- Uncontrolled hypertension, defined as systolic > 140 mmHg or diastolic > 90 mm Hg
- Myocardial infarction or unstable angina within 6 months of the first date of
dasatinib therapy
- New York Heart Association (NYHA) class II or greater congestive heart failure or
serious cardiac arrhythmia requiring medication; this would include women with
atrial fibrillation, who require rate-controlling medication
- CTCAE v4 grade 2 or greater peripheral vascular disease
- History of cerebrovascular accident (CVA, stroke), transient ischemic attack
(TIA), or subarachnoid hemorrhage within six months of the first date of
dasatinib therapy
- Patients with hypokalemia or hypomagnesemia if it cannot be corrected to within
normal limits prior to dasatinib treatment
- Required use of a concomitant medication that can prolong the QT interval
- Patients may not be receiving any prohibited potent cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4) inhibitors; for these drugs, a washout period of
greater than or equal to 7 days is required prior to starting dasatinib treatment
- The concomitant use of histamine (H2) blockers and proton pump inhibitors (PPI's) with
dasatinib is not recommended (e.g., famotidine, omeprazole); the use of antacids
should be considered in place of H2 blockers or PPIs in patients receiving dasatinib
therapy; if antacid therapy is needed, the antacid dose should be administered two
hours before or after the dose of dasatinib
- Patients may not be receiving any other investigational agents
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible
- Patients who are pregnant or nursing; women of child-bearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation; should a
woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately
- Uterine carcinosarcoma and other sarcomas of the uterus will be excluded
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Robert Coleman, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01440998
Organization ID
NCI-2011-03275
Secondary IDs
NCI-2011-03275
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
Robert Coleman, Principal Investigator, M.D. Anderson Cancer Center
Verification Date
April 2018