Clinical Trials /

Induction FLOT With CROSS CRT for Esophageal Cancer

NCT04028167

Description:

This study evaluates a novel regimen of induction chemotherapy using a combination of docetaxel, oxaliplatin, and leucovorin, with short term infusional 5-FU (FLOT), given prior to chemoradiotherapy with concurrent carboplatin and paclitaxel, as neoadjuvant therapy prior to definitive surgical resection for patients with adenocarcinoma of the esophagus or gastroesophageal junction

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Induction FLOT With CROSS CRT for Esophageal Cancer
  • Official Title: Phase II Study of Induction FLOT Followed by Neoadjuvant Chemoradiation in Patients With Resectable Adenocarcinoma of the Esophagus or Gastroesophageal Junction

Clinical Trial IDs

  • ORG STUDY ID: 19-0376.cc
  • SECONDARY ID: P30CA046934
  • NCT ID: NCT04028167

Conditions

  • Adenocarcinoma Esophagus
  • Adenocarcinoma of the Gastroesophageal Junction

Interventions

DrugSynonymsArms
Sequential FLOT followed by chemoradiationSequential FLOT followed by chemoradiation

Purpose

This study evaluates a novel regimen of induction chemotherapy using a combination of docetaxel, oxaliplatin, and leucovorin, with short term infusional 5-FU (FLOT), given prior to chemoradiotherapy with concurrent carboplatin and paclitaxel, as neoadjuvant therapy prior to definitive surgical resection for patients with adenocarcinoma of the esophagus or gastroesophageal junction

Detailed Description

      Clinical outcomes following standard of care therapy for resectable esophageal and
      gastroesophageal junction adenocarcinoma are suboptimal, with low rates of pathologic
      complete response (pCR) to current neoadjuvant treatment strategies. Although significant
      progress has been made by incorporation of neoadjuvant chemoradiation or perioperative
      chemotherapy, most patients will ultimately develop disease recurrence, with both
      locoregional and distant recurrence representing a significant component of failure. For
      patients receiving preoperative chemoradiation, a regimen consisting of concurrent
      carboplatin and paclitaxel with radiotherapy has been established as a standard of care based
      on the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study (CROSS). In the long
      term results of CROSS, locoregional progression was noted in 22% of patients receiving
      neoadjuvant therapy, with distant progression in 39%.

      Recent studies have also suggested perioperative chemotherapy as a potential alternative
      strategy for selected patients, based on results of the MAGIC trial, which included a subset
      patients with esophageal/GE junction tumor location, and demonstrated improved survival for
      patients receiving perioperative epirubicin, cisplatin, and infusional 5-fluorouracil (ECF)
      compared to surgery alone. The FLOT4-AIO trial has subsequently demonstrated a further
      overall survival benefit to a perioperative regimen of docetaxel, oxaliplatin, and
      leucovorin, with short term infusional 5-FU (FLOT) compared to ECF. A regimen of
      perioperative FLOT is currently being compared to preoperative chemoradiotherapy using the
      CROSS regimen in the ongoing ESOPEC trial (NCT02509286).

      Given the significant risk of recurrence either with the CROSS preoperative chemoradiation
      regimen, or the perioperative FLOT regimen, it is plausible that selected patients may
      benefit from a combination of intensified systemic therapy using the FLOT backbone, in
      combination with sequential preoperative chemoradiation due to the known risk of locoregional
      recurrence in this population. This study evaluates the proposed neoadjuvant regimen of
      induction FLOT followed by neoadjuvant chemoradiation in patients with resectable cT3/T4 or
      node positive adenocarcinoma of the esophagus or gastroesophageal junction.
    

Trial Arms

NameTypeDescriptionInterventions
Sequential FLOT followed by chemoradiationExperimentalSequential Chemotherapy with Docetaxel, Oxaliplatin, and 5-Fluorouracil/Leucovorin followed by chemoradiation with concurrent carboplatin and paclitaxel
  • Sequential FLOT followed by chemoradiation

Eligibility Criteria

        Inclusion Criteria:

          1. Provision to sign and date the consent form.

          2. Stated willingness to comply with all study procedures and be available for the
             duration of the study.

          3. Be a male or female aged 18-100.

          4. Have newly diagnosed, resectable cT3-T4 or node positive adenocarcinoma of the
             esophagus or gastroesophageal junction as assessed by CT or MRI of the chest, abdomen
             and pelvis and by endoscopic ultrasound, with pathologic diagnosis obtained within 3
             months of signing consent, without delivery of prior chemotherapy or radiation
             therapy.

          5. Subjects must be previously untreated with systemic chemotherapy or radiation therapy.

          6. Subjects must be deemed a candidate for trimodality therapy (radiation, chemotherapy
             and surgery) based upon multidisciplinary evaluation with plan for preoperative
             chemoradiation followed by surgical resection.

          7. ECOG performance status score of 0-1 (See Appendix).

          8. Adequate bone marrow function (WBC > 3 x 109/L; hemoglobin > 9 g/dl; platelets > 100 x
             109/L)

          9. Adequate liver function (total bilirubin < 1.5 x upper limit of normal, AST < 3 x
             upper limit of normal, and ALT < 3 x upper limit of normal)

         10. Serum creatinine < 1.5 x ULN or calculated creatinine clearance > 50 mL/min (using the
             Cockcroft-Gault formula)

             Males:

             Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

             Females:

             Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine
             (mg/dL)

         11. Women of child-bearing potential (WOCBP) must have a negative serum or urine pregnancy
             test within 2 weeks prior to study enrollment and must agree to follow instructions
             for method(s) of contraception for the duration of the study period and at least 3
             months after the last dose of chemotherapy is administered. For the purpose of this
             study, a woman is considered of childbearing potential following menarche and until
             becoming post-menopausal unless permanently sterile. Permanent sterilisation methods
             include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

             For the purpose of this study, methods that can achieve a failure rate of less than 1%
             per year when used consistently and correctly are considered as highly effective birth
             control methods and acceptable contraception. Such methods include:

               -  combined (estrogen and progestogen containing) hormonal contraception associated
                  with inhibition of ovulation:

               -  oral

               -  intravaginal

               -  transdermal

               -  progestogen-only hormonal contraception associated with inhibition of ovulation:

               -  oral

               -  injectable

               -  implantable

               -  intrauterine device (IUD)

               -  intrauterine hormone-releasing system (IUS)

               -  bilateral tubal ligation

               -  vasectomized partner

               -  sexual abstinence

         12. WOCBP who are continuously not heterosexually active are exempt from contraceptive
             requirements but still must undergo pregnancy testing as described in this section.

         13. Males who are sexually active with WOCBP must agree to follow instructions for methods
             of contraception for the duration of the study period and for at least 3 months
             (duration of sperm turnover) after the last dose of chemotherapy is administered. In
             addition, males must be willing to refrain from sperm donation during this time.

        Azoospermic males are exempt from contraceptive requirements.

        Exclusion Criteria:

          1. Subjects with metastatic or inoperable esophageal or gastroesophageal junction
             adenocarcinoma.

          2. Subjects with esophageal or gastroesophageal junction squamous cell carcinoma or
             adenosquamous carcinoma.

          3. Prior treatment with chemotherapy or radiation therapy for esophageal or
             gastroesophageal adenocarcinoma.

          4. Prior malignancy active within the previous 3 years, except for early stage cancers
             treated with curative intent, including basal or squamous cell carcinoma of the skin,
             superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast.

          5. Prior history of thoracic or abdominal radiotherapy that would overlap with the
             planned treatment volume.

          6. Active collagen vascular disease.

          7. Subjects with > Grade 1 peripheral neuropathy.

          8. Any serious or uncontrolled medical disorder or active infection, that in the opinion
             of the investigator may increase the risk associated with study participation, study
             treatment administration or would impair the ability of the subject to receive study
             treatment.

          9. Known history of hepatitis B or hepatitis C.

         10. Clinically unstable cardiac disease including unstable angina, congestive heart
             failure, ventricular arrhythmia or known prior QTc > 450msec.

         11. History of allergy or hypersensitivity to any of the study drugs or study drug
             components.

         12. Any contraindications to any of the study drugs of the chemotherapy regimens (FLOT or
             carboplatin/paclitaxel) selected by the investigator. Investigators should refer to
             the local package insert of the chemotherapy drugs.

         13. Prisoners or subjects who are involuntarily incarcerated.

         14. History of psychiatric illness that precludes completion of informed consent process,
             or which is deemed by the investigators as potentially influencing study compliance.

         15. Known dihydropyrimidine dehydrogenase (DPD) deficiency.

         16. Pregnant or breast-feeding women.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate the rate of pathologic complete response (pCR) to the study regimen.
Time Frame:5 years
Safety Issue:
Description:The percentage of pathologic complete response at resection for patients who has completed the study regimen of induction FLOT, CROSS regimen chemoradiation, and surgical resection

Secondary Outcome Measures

Measure:To determine estimates of the 1-year overall survival and disease-free survival among patients treated with the study regimen.
Time Frame:5 years
Safety Issue:
Description:The endpoint of overall survival will be defined by the proportion of evaluable patients that are living at a 1-year time interval from initial pathologic diagnosis. The endpoint of disease-free survival will be defined by the proportion of evaluable patients that are living and free of cancer recurrence at a 1-year time interval from initial pathologic diagnosis
Measure:To describe toxicity of the study regimen as a component of neoadjuvant therapy for the study population.
Time Frame:5 years
Safety Issue:
Description:The proportion of patients experiencing any ≥grade 3 and ≥grade 4 toxicity as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be recorded.
Measure:Patient reported quality of life
Time Frame:5 years
Safety Issue:
Description:Patient reported quality of life outcomes using the validated European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)
Measure:Measurement of change in the SUVmax on FDG-PET following induction FLOT, compared to initial diagnosis, and describe change in SUVmax among patients with and without a pCR to neoadjuvant therapy.
Time Frame:5 years
Safety Issue:
Description:Percentage reduction in SUVmax from the baseline to the post-chemotherapy PET.
Measure:Measurement of ctDNA to generate initial descriptive data regarding ctDNA kinetics as a potential measure of treatment response
Time Frame:5 years
Safety Issue:
Description:The sensitivity and specificity of detectable ctDNA postoperatively to predict 1 year disease-free survival within the study cohort.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Colorado, Denver

Trial Keywords

  • Resectable

Last Updated

February 21, 2021