The purpose of this Phase I study is to determine the recommended phase 2 dose (RP2D) and safety profile of NBTXR3 activated by radiation therapy with concurrent chemotherapy for the treatment of patients with esophageal adenocarcinoma. NBTXR3 is a drug that when activated by radiation therapy, may cause targeted destruction of cancer cells. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as oxaliplatin, fluorouracil, capecitabine, docetaxel, 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 NBTXR3 activated by radiation therapy with concurrent chemotherapy may help control the disease.
PRIMARY OBJECTIVE: I. To determine the recommended phase II dose (RP2D) of hafnium oxide-containing nanoparticles NBTXR3 (NBTXR3) activated by radiotherapy with concurrent chemotherapy, per standard of care, for treatment naive patients with adenocarcinoma of the esophagus. SECONDARY OBJECTIVES: I. To evaluate the safety and feasibility of radiation with NBTXR3 in patients with adenocarcinoma of the esophagus. II. To evaluate the anti-tumor response of chemoradiation with NBTXR3 in patients with adenocarcinoma of the esophagus. III. To evaluate time-to-event outcomes after chemoradiation with NBTXR3 in patients with adenocarcinoma of the esophagus. EXPLORATORY OBJECTIVES: I. To evaluate the body kinetic profile of intratumorally/intranodally injected NBTXR3. II. To evaluate time to event outcomes for patients with clinical staging of locally advanced, unresectable disease. III. To evaluate surgical outcomes in patients who undergo surgery after study treatment. IV. To evaluate radiomic measurements with outcomes. V. To assess immune-related biomarkers of response. OUTLINE: This is a dose-escalation study of NBTXR3. Patients receive NBTXR3 intratumorally (IT) or intranodally (IN) on day 1. Beginning day 15, patients undergo intensity-modulated radiation therapy (IMRT) 5 days per week for 6 weeks for a total of 28 fractions in the absence of disease progression or unacceptable toxicity. Beginning on day 15, concurrent with IMRT, patients receive a chemotherapy regimen consisting of either fluorouracil and oxaliplatin with or without leucovorin, oxaliplatin and capecitabine, docetaxel and fluorouracil with or without leucovorin, docetaxel and paclitaxel, or carboplatin and paclitaxel per physician discretion. After completion of study treatment, patients are followed up every 3 months for 1 year.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Not applicable to this study
Not applicable to this study
Not applicable to this study
Not applicable to this study
Given IT or IN
Undergo IMRT
Not applicable to this study
Not applicable to this study
Not applicable to this study
M D Anderson Cancer Center
Houston, Texas, United States
RECRUITINGIncidence of dose limiting toxicities (DLTs)
Will be coded and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5 criteria. Descriptive summary tables will be produced, providing the DLTs by initial planned dose level of NBTXR3, initial planned volume of NBTXR3 to be injected, the injected volume, the radiation therapy dose given and the details of the concurrent chemotherapy given.
Time frame: Up to end of treatment visit (day 85)
Maximum tolerated dose and recommended phase 2 dose (RP2D)
The Bayesian Optimal Interval design, with accelerated titration, will be used to identify RP2D.
Time frame: Up to end of treatment visit (day 85)
Incidence of NBTXR3/radiation therapy related late onset toxicities
Will be defined as any grade \>= 3 adverse event.
Time frame: From end of treatment visit (day 85) until end of study (1 year)
Feasibility of NBTXR3 injection in the esophageal tumor and involved regional lymph nodes
The feasibility features of NBTXR3 local administration by intratumoral injection will be presented relative to the initial planned volume level in every cohort.
Time frame: Up to 1 year
Objective response rate
Will be defined as the rate of complete or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, in target and non-target lesions.
Time frame: Up to 1 year
Major pathological response rate
Will be assessed by the Modified Ryan Scheme for Tumor Regression Score.
Time frame: Up to 1 year
Local progression-free survival
Will be estimated using the method of Kaplan and Meier. Median times and 95% confidence intervals will also be estimated per dose level.
Time frame: From NBTXR3 injection to locoregional (i.e., within the esophagus or regional nodes) disease recurrence, local progression confirmed radiographically (RECIST v1.1), or death from any cause, whichever occurs first, assessed up to 1 year
Distant progression-free survival
Will be estimated using the method of Kaplan and Meier. Median times and 95% confidence intervals will also be estimated per dose level
Time frame: From NBTXR3 injection to the radiographic confirmation (RECIST version 1.1) of a new lesion outside the esophagus and regional nodes, or death from any cause, whichever occurs first, assessed up to 1 year
Progression-free survival
Will be estimated using the method of Kaplan and Meier. Median times and 95% confidence intervals will also be estimated per dose level.
Time frame: From NBTXR3 injection to local recurrence, local progression, distant progression, confirmed radiographically (RECIST version 1.1), or death from any cause, whichever occurs first, assessed up to 1 year
Overall survival
Will be estimated using the method of Kaplan and Meier. Median times and 95% confidence intervals will also be estimated per dose level.
Time frame: From NBTXR3 injection to death from any cause or end of study, whichever occurs first, assessed up to 1 year
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