Preoperative Hypofractionated Radiotherapy With FOLFOX for Esophageal or Gastroesophageal Junction Adenocarcinoma

Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Trial

— PHOX  

Official title:

Preoperative Hypofractionated Radiotherapy With FOLFOX for Esophageal/Gastroesophageal Junction Adenocarcinoma (PHOX)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06078709
• Other study ID #: GMROR2241
• Secondary ID: NCI-2023-07432GM
• Status: Recruiting
• Phase: Phase 2
• Start date: November 20, 2023
• Est. completion date: November 30, 2026

Study information

• Verified date: February 2024
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial tests how well preoperative (prior to surgery) radiation therapy with fluorouracil, oxaliplatin, and leucovorin calcium (FOLFOX) works for the treatment of stage I-III esophageal or gastroesophageal junction adenocarcinoma. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Fluorouracil stops cells from making deoxyribonucleic acid (DNA) and it may kill tumor cells. Leucovorin is not a chemotherapy medication but is given in conjunction with chemotherapy. Leucovorin is used with the chemotherapy medication fluorouracil to enhance the effects of the fluorouracil, in other words, to make the drug work better. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It damages the cell's DNA and may kill tumor cells. Giving preoperative hypofractionated radiation with fluorouracil and oxaliplatin may kill more tumor cells in patients with stage I-III esophageal or gastroesophageal junction adenocarcinoma.

Description:

PRIMARY OBJECTIVE: I. To demonstrate non-inferiority of pathologic complete response (pCR) with hypofractionated radiotherapy and concurrent FOLFOX compared to historical controls. SECONDARY OBJECTIVES: I. Report acute grade ≥ 3 gastrointestinal (GI) toxicity, per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. II. Assess post-operative toxicity for patients undergoing esophagectomy, as determined by the Clavien-Dindo Classification. III. Analyze patient-reported quality of life, per Functional Assessment of Cancer Therapy- Esophageal (FACT-E). IV. Determine the financial toxicity of hypofractionated radiotherapy, using Comprehensive Score for Financial Toxicity (COST-FACIT). V. Report overall survival and progression-free survival. VI. Report long-term toxicity secondary to trimodality therapy. VII. Report event-free survival. VIII. Assess outcomes for patients treated with hypofractionated radiotherapy and FOLFOX but who did not proceed to esophagectomy. IX. Compare toxicity of chemoradiation between patients receiving proton based versus (vs.) photon-based radiotherapy. CORRELATIVE OBJECTIVES: I. Explore the predictive and prognostic role for circulating tumor DNA in esophageal cancer. II. Study the utility of whole exome and germline sequencing to predict chemoradiation treatment response. III. Explore the predictive power of whole exome sequencing regarding chemoradiotherapy toxicity. IV. Implement whole exome and germline sequencing to personalize immunotherapy in esophageal cancer. V. Study the predictive and prognostic role of tumor-derived extracellular vesicles in esophageal cancer. OUTLINE: Patients receive oxaliplatin intravenously (IV) over 2-6 hours on day 1, leucovorin calcium IV over 10-120 minutes on day 1, and and fluorouracil IV over 46-48 hours on days 1 and 2. Treatment repeats every 2 weeks for a total of 3 cycles in the absence of disease progression or unacceptable toxicity. Starting at cycle 2, patients undergo radiation therapy daily on Monday through Friday for a total of 15 treatments. Patients undergo esophagogastroduodenoscopy (EGD) and/or endoscopic ultrasound (EUS) during screening and undergo computed tomography (CT)/position emission tomography (PET) scan and CT scan as well as blood sample collection throughout the study. After completion of study treatment, patients are followed up at 6,12 and 24 months and then up to 5 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 99
• Est. completion date: November 30, 2026
• Est. primary completion date: May 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years
• Histological confirmation of esophageal or gastroesophageal junction adenocarcinoma, American Joint Committee on Cancer (AJCC) 8th edition stage T1-4N0-3M0
• Candidate for trimodality therapy: neoadjuvant chemotherapy, chemoradiation, and esophagectomy
• Surgical consultation has confirmed that patient is an appropriate candidate for esophagectomy
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Negative pregnancy test done = 7 days prior to chemotherapy, for women of childbearing potential only
• Ability to provide written informed consent and complete questionnaire(s) by themselves or with assistance
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• Willing to provide blood samples for correlative research purposes

Exclusion Criteria:

• Clinical or biopsy-proven distant metastatic disease (AJCC 8th edition stage TanyNanyM1)
• Cervical or upper esophageal tumor
• Prior chemotherapy or radiotherapy for esophageal cancer or history of radiotherapy to the thorax
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with proper assessment of adverse events
• Receiving any investigational agent which would be considered as a treatment for the primary neoplasm or other active malignancy = 1 year prior to registration that is considered by the investigator to interfere with the current treatment or measurement of outcomes
• Any of the following:
• Pregnant women
• Nursing women
• Men or women of childbearing potential who are unwilling to employ adequate contraception

Related Conditions & MeSH terms

• Adenocarcinoma
• Clinical Stage I Esophageal Adenocarcinoma AJCC v8
• Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8
• Clinical Stage II Esophageal Adenocarcinoma AJCC v8
• Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8
• Clinical Stage III Esophageal Adenocarcinoma AJCC v8
• Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
• Esophageal Neoplasms

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT and PET/CT scan
• Endoscopic Ultrasound
Undergo EUS
• Esophagogastroduodenoscopy
Undergo EGD

Drug:
• Fluorouracil
Given IV

Radiation:
• Hypofractionated Radiation Therapy
Undergo hypofractionated radiation therapy

Drug:
• Leucovorin Calcium
Given IV
• Oxaliplatin
Given IV

Procedure:
• Positron Emission Tomography
Undergo PET and PET/CT scan

Other:
• Survey Administration
Ancillary studies

Locations

Country	Name	City	State
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Mayo Clinic in Arizona	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Mayo Clinic

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathologic complete response	A single-group design will be used to test whether the proportion is potentially non-inferior, with a non-inferiority proportion (P0) of 0.13 (H0: P = 0.13 versus H1: P > 0.13).	Up to 5 years after completion of chemoradiation
Secondary	Incidence of acute = gastrointestinal (GI) adverse events (AEs)	Report acute grade = 3 GI AEs per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Will be summarized descriptively.	Up to 6 weeks after completion of chemoradiation
Secondary	Incidence of post operative AEs	Determined by the Clavien-Dindo Classification. Will be summarized descriptively.	From surgery up to 6 months after completion of chemoradiation
Secondary	Patient-reported quality of life (QOL)	Per Functional Assessment of Cancer Therapy- Esophageal. Will be assessed over time. Wilcoxon signed-rank tests will be used to calculate p-values. Descriptive statistics and graphical methods will also be used to summarize the data.	Up to 24 months after completion of chemoradiation
Secondary	Financial toxicity	Financial toxicity will be measured using the COmprehensive Score for financial Toxicity (COST), a patient-reported outcome measure that describes the financial distress experienced by cancer patients. The survey consists of 12 questions, each answered with a 0-4 scale where 0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, and 4=Very much. Results will be reported descriptively and include separate consideration of individual item scores.	Up to 24 months after completion of chemoradiation
Secondary	Overall survival (OS)	Will be assessed graphically using the Kaplan-Meier method. Summary statistics will be reported, including medians, 95% confidence intervals, etc.	From study entry to death from any cause, up to 5 years after completion of chemoradiation
Secondary	Progression-free survival (PFS)	Will be assessed graphically using the Kaplan-Meier method. Summary statistics will be reported, including medians, 95% confidence intervals, etc.	From study entry to the first of either disease progression or death, up to 5 years after completion chemoradiation
Secondary	Long-term toxicity secondary to trimodality therapy	Will be reported descriptively using CTCAE version 5.0 criteria.	Up to 5 years after completion of chemoradiation
Secondary	Event free survival	Will be assessed graphically using the Kaplan-Meier method. Summary statistics will be reported, including medians, 95% confidence intervals, etc.	From study entry to the first of either disease progression or recurrence or relapse or death, up to 5 years after completion of chemoradiation
Secondary	Outcomes for patients treated with hypofractionated radiotherapy and FOLFOX but who did not proceed to esophagectomy	OS and PFS will be assess using Kaplan-Meier methodology. Summary statistics will be reported, including medians, 95% confidence intervals, etc. AEs and QOL data will be reported with summary statistics and graphical methods, as appropriate.	Up to 5 years after completion of chemoradiation
Secondary	Toxicity of chemoradiation between patients receiving proton based versus photon-based radiotherapy	Will be done descriptively, reporting frequencies and percentages between patients.	Up to 5 years after completion of chemoradiation
Secondary	Toxicity of chemoradiation between groups receiving proton based versus photon-based radiotherapy	Will be done descriptively, reporting toxicity rates between groups using the chi-square test.	Up to 5 years after completion of chemoradiation