This phase IB/II trial studies the side effects of taladegib, paclitaxel, carboplatin, and external beam radiation therapy and to see how well they work in treating patients with esophageal or gastroesophageal junction cancer found only in the tissue or organ where it began, and has not spread to nearby lymph nodes or to other parts of the body (localized). Taladegib 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. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving taladegib, paclitaxel, carboplatin, and radiation therapy may kill more tumor cells.
PRIMARY OBJECTIVES: I. To evaluate the toxicity of taladegib administered orally daily concurrently with weekly paclitaxel, carboplatin and radiation therapy in patients with localized nuclear glioma-associated oncogene homolog (Gli-1) expressing adenocarcinoma of the esophagus or gastroesophageal junction. (Phase IB) II. To assess the rate of pathologic complete response (pathCR) when taladegib is administered orally daily concurrently with weekly paclitaxel, carboplatin, and radiation therapy in patients with localized nuclear Gli-1 expressing adenocarcinoma of the esophagus or gastroesophageal junction. (Phase II) SECONDARY OBJECTIVES: I. To evaluate the toxicity of biochemoradiation in the phase II study. II. To assess additional biomarkers (hedgehog \[Hh\] related and Hh unrelated) in sequentially procured tissues (biopsies and resected specimens). III. Assess if taladegib down modulates its target (Gli-1) in the first cohort (where taladegib will be administered alone for the first 7 days) of the phase II study. IV. Assess relapse-free survival and overall survival. OUTLINE: PHASE IB: Patients receive taladegib orally (PO) once daily (QD) on days 1-38, paclitaxel intravenously (IV) over 3 hours on the first radiation day of each week for 5 doses, carboplatin IV over 2 hours on the first radiation day of each week for 5 doses, and undergo external beam radiation therapy 5 days weekly on 28 consecutive weekdays for 5.5 weeks. PHASE II: Patients are assigned to 1 of 2 steps. STEP I: Patients receive taladegib PO for 7 days, followed by taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB. STEP II: Patients receive taladegib, paclitaxel, carboplatin, and external beam radiation therapy as in Phase IB. After completion of study treatment, patients are followed up at 3 months, every 3-6 months for 1 year, every 6 months for 2 years, and at years 4 and 5.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
7
Given IV
Undergo external beam radiation therapy
Correlative studies
Given IV
Given PO
M D Anderson Cancer Center
Houston, Texas, United States
Safety of Taladegib When Given in Combination With Paclitaxel, Carboplatin, and Radiation Therapy Defined by Dose-limiting Toxicities (Phase IB)
The safety data will be summarized using frequencies and percentages by adverse event category, grade and attributions.
Time frame: Up to 5 weeks
Pathologic Complete Response Rate (Phase II)
A pathologic complete response (pathCR) rate of at least 35% (\>= 40% is desirable) will be of interest. The pathCR rate in each of the treatment step will be estimated, along with the 95% confidence interval.
Time frame: Up to 4 years and 10 months
Change in Biomarker Expression Levels of Primary and Secondary Resistance
A linear mixed effect model will be used to assess the change of biomarkers over time. The outcome variable will be biomarker expression level and the covariates will include time, treatment step and time by treatment interaction. The biomarker expression may be log-transformed prior to fit the model in order to satisfy the normality assumption. Also, a logistic regression model will be used for the binary outcome of pathCR, using treatment step, baseline biomarker and the change of biomarker between baseline and at surgery as covariates.
Time frame: Baseline to the time of surgery
Relapse-free Survival
Kaplan-Meier method will be used to estimate the probabilities of relapse-free survival.
Time frame: Up to 4 years and 10 months
Overall Survival
Kaplan-Meier method will be used to estimate the probabilities of overall survival.
Time frame: Up to 4 years and 10 months
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