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
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
Drug | Synonyms | Arms |
---|
Sequential FLOT followed by chemoradiation | | Sequential 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
Name | Type | Description | Interventions |
---|
Sequential FLOT followed by chemoradiation | Experimental | Sequential 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
Last Updated
February 21, 2021