Dasatinib, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV or Recurrent Endometrial Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01440998
First received: September 24, 2011
Last updated: August 12, 2014
Last verified: August 2014
  Purpose

This pilot clinical trial studies how well dasatinib works together with paclitaxel and carboplatin in treating patients with stage III, stage IV or recurrent endometrial cancer. 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 or by stopping them from dividing. Giving dasatinib together with paclitaxel and carboplatin may kill more tumor cells.


Condition Intervention
Endometrial Adenocarcinoma
Endometrial Adenosquamous Cell Carcinoma
Endometrial Clear Cell Carcinoma
Endometrial Papillary Serous Carcinoma
Recurrent Endometrial Carcinoma
Stage IIIA Endometrial Carcinoma
Stage IIIB Endometrial Carcinoma
Stage IIIC Endometrial Carcinoma
Stage IVA Endometrial Carcinoma
Stage IVB Endometrial Carcinoma
Drug: dasatinib
Drug: paclitaxel
Drug: carboplatin
Other: laboratory biomarker analysis

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot and Translational Study of Dasatinib (NSC#732517) Paclitaxel and Carboplatin in Women With Advanced Stage and Recurrent Endometrial Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Change in EphA2 expression [ Time Frame: From baseline to up to day 14 ] [ Designated as safety issue: No ]
    Summary statistics and box plots will be used to describe the distributions of expression of EphA2 and its downstream signaling effectors.


Secondary Outcome Measures:
  • Response rate (complete [CR] or partial response [PR]) according to RECIST v. 1.1 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Estimate the proportion of patients with CR and with (CR+PR) with 95% confidence intervals.

  • PFS [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year ] [ Designated as safety issue: No ]
    Estimated with the product-limit estimator of Kaplan and Meier and illustrated with Kaplan-Meier plots.

  • OS [ Time Frame: From start of treatment to time of death, assessed up to 1 year ] [ Designated as safety issue: No ]
    Estimated with the product-limit estimator of Kaplan and Meier and illustrated with Kaplan-Meier plots.

  • Numbers of CTCs [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Descriptive statistics will be used to summarize the number of CTCs for patients with each type of response. Estimate the mean number of CTCs for each of these groups with 95% confidence intervals.

  • Incidence of adverse events as assessed by CTCAE v. 4 [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
    Tabulated by grade and relationship to study drug, stratified by whether or not patients had prior pelvic radiation.


Estimated Enrollment: 15
Study Start Date: September 2011
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (dasatinib, paclitaxel, carboplatin)
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.
Drug: dasatinib
Given PO
Other Names:
  • BMS-354825
  • Sprycel
Drug: paclitaxel
Given IV
Other Names:
  • Anzatax
  • Asotax
  • TAX
  • Taxol
Drug: carboplatin
Given IV
Other Names:
  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the impact of dasatinib on ephrin type-A receptor 2 (EphA2) expression in tissue biopsies from patients with previously untreated, 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 (PFS) and overall survival (OS).

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 Focal adhesion kinase (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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  • Recovered 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 v4) grade 1
  • Platelets greater than or equal to 100,000/mcL
  • Creatinine less than or equal to 1.5 times institutional upper limit normal (ULN)
  • Bilirubin less than or equal to 1.5 times ULN (CTCAE v4 grade 1)
  • Serum glutamic oxaloacetic transaminase (SGOT) less than or equal to 2.5 times ULN
  • Alkaline phosphatase less than or equal to 2.5 times ULN
  • 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 v.4 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01440998

Locations
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Robert L. Coleman    713-745-3357    rcoleman@mdanderson.org   
Principal Investigator: Robert L. Coleman         
Sponsors and Collaborators
Investigators
Principal Investigator: Robert Coleman M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01440998     History of Changes
Other Study ID Numbers: NCI-2011-03275, NCI-2011-03275, CDR0000712251, MDA-2011-0252, 2011-0252, 8836, P30CA016672, P50CA098258
Study First Received: September 24, 2011
Last Updated: August 12, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma
Endometrial Neoplasms
Carcinoma, Adenosquamous
Adenocarcinoma, Clear Cell
Adenomyoepithelioma
Cystadenocarcinoma, Serous
Uterine Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Genital Diseases, Female
Neoplasms, Complex and Mixed
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Carboplatin
Paclitaxel
Dasatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 28, 2014