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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8; Clinical Stage I Esophageal Adenocarcinoma AJCC v8; Clinical Stage II Esophageal Adenocarcinoma AJCC v8; Clinical Stage III Esophageal Adenocarcinoma AJCC v8; Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8; Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8
• Intervention / Treatment: Procedure: Biospecimen Collection; Other: Survey Administration; Drug: Fluorouracil; Drug: Oxaliplatin; Drug: Leucovorin Calcium; Radiation: Hypofractionated Radiation Therapy; Procedure: Endoscopic Ultrasound; Procedure: Esophagogastroduodenoscopy; Procedure: Computed Tomography; Procedure: Positron Emission Tomography

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 99
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Not yet recruiting
      • Mayo Clinic in Arizona
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Principal Investigator: Jonathan B. Ashman, M.D., Ph.D.
  • Florida
    • Jacksonville, Florida, United States, 32224-9980
      • Recruiting
      • Mayo Clinic in Florida
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu
      • Principal Investigator: Michael S. Rutenberg, M.D., Ph.D.
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic in Rochester
      • Principal Investigator: Christopher L. Hallemeier, M.D.
      • Contact: Clinical Trials Referral Office; Phone Number: 855-776-0015; Email: mayocliniccancerstudies@mayo.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (Radiation and FOLFOX); Patients receive oxaliplatin 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 EGD and/or EUS during screening and undergo CT/PET scan and CT scan as well as blood sample collection throughout the study.

Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Other: Survey Administration; Ancillary studies; Drug: Fluorouracil; Given IV; Other Names: 5-Fluracil; Fluracil; 5 Fluorouracil; 5 Fluorouracilum; 5 FU; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; 5-Fu; 5FU; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluracedyl; Fluril; Fluroblastin; Ribofluor; Ro 2-9757; Ro-2-9757; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Ai Heng; Aiheng; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Drug: Leucovorin Calcium; Given IV; Other Names: Wellcovorin; folinic acid; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Citrovorum Factor; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Factor, Citrovorum; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; Radiation: Hypofractionated Radiation Therapy; Undergo hypofractionated radiation therapy; Other Names: Hypofractionated Radiotherapy; hypofractionation; Radiation, Hypofractionated; Hypofractionated; Procedure: Endoscopic Ultrasound; Undergo EUS; Other Names: endosonography; EUS; Procedure: Esophagogastroduodenoscopy; Undergo EGD; Other Names: EGD; Procedure: Computed Tomography; Undergo CT and PET/CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Procedure: Positron Emission Tomography; Undergo PET and PET/CT scan; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; PT; Positron emission tomography (procedure)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Christopher L. Hallemeier, M.D., Mayo Clinic in Rochester

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2023
• Primary Completion (Estimated): May 30, 2026
• Study Completion (Estimated): November 30, 2026

Study Registration Dates

• First Submitted: October 3, 2023
• First Submitted That Met QC Criteria: October 9, 2023
• First Posted (Actual): October 12, 2023

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Adenocarcinoma; Esophageal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin; Folic Acid; Calcium, Dietary
• Other Study ID Numbers: GMROR2241 (Other Identifier: Mayo Clinic Radiation Oncology); 23-001689 (Other Identifier: Mayo Clinic Institutional Review Board); NCI-2023-07432 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No