Esophageal Cancer
Conditions
Keywords
Operable, Based on CHFR Methylation Status, Diagnostic Biopsies
Brief summary
This is a Phase 2 Study of Paclitaxel with Cisplatin versus Fluoropyrimidine with a Platinum Agent for Neoadjuvant Therapy in Operable Esophageal Cancer Based on CHFR Methylation Status in Diagnostic Biopsies.
Detailed description
Primary Objectives • To determine the rate of pathological complete response when the inclusion of paclitaxel in neoadjuvant therapy is based on the presence or absence of CHFR methylation in diagnostic biopsy specimens. Secondary Objectives * To determine the survival outcome with this treatment strategy. * To determine time to disease progression with this treatment strategy. * To determine the agreement between tumor CHFR methylation and detection in plasma.
Interventions
DRUGPaclitaxel
Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29.
DRUGCisplatin
Paclitaxel and cisplatin: * Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29. * Cisplatin 30 mg/m² days 1, 8, 15, 22, 29. Cisplatin and 5-fluorouracil: * 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1- 4 and 29 - 32. * Cisplatin 75 mg/m² days 1, 29.
DRUGOxaliplatin
Oxaliplatin 85 mg/m2 days 1, 15, 29.
DRUG5-Fluorouracil
Oxaliplatin and 5-fluorouracil: * Oxaliplatin 85 mg/m2 days 1, 15, 29. * 5-Fluorouracil 180 mg/m2 prolonged infusion starting day 1 of radiation and completing on the final day of radiation (up to 40 days) Cisplatin and 5-fluorouracil: * 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1-4 and 29-32. * Cisplatin 75 mg/m² days 1, 29.
RADIATIONRadiotherapy
Patients will be treated 5 days/week at 1.8 Gy/day to a total dose of 45Gy.
PROCEDUREEsophagectomy
The type of resection (Ivor-Lewis, Transhiatal, etc.) will be left to the discretion of the operating surgeon. Resection will be completed between 5 and 8 weeks starting from the completion of chemotherapy and radiation (days 36 - 56).
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed adenocarcinoma of the esophagus or GE junction 2. Patient must be untreated with chemotherapy, radiation therapy, or surgery for this diagnosis of esophageal cancer. (Endoscopy with biopsy and dilation is permitted.) 3. Tumor must be located between 20 cm from the teeth endoscopically and 2 cm into the gastric cardia. Cervical esophageal cancers and true gastric cancers are excluded. 4. Stage T2-3/N0-3/M0 as determined by imaging studies and biopsy where appropriate. T4 disease is permitted if defined as resectable by the thoracic surgeon (involvement of the pleura, pericardium or diaphragm). 5. Patients must have had an endoscopic ultrasound 6. Patients must have had a staging PET scan 7. Age ≥ 18 and ≤ 75 8. ECOG performance status 0-1. 9. Surgically resectable tumor 10. Patients with a history of a curatively treated malignancy must be disease-free and have a survival prognosis that exceeds three years. 11. Patients must have adequate organ and marrow function as defined below: * absolute neutrophil count ≥ 1,000/mcL * platelets ≥ 100,000/mcL * total bilirubin ≤ 2 mg/dL * AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional ULN * creatinine \< 1.5 X institutional ULN 12. Female patients must not be pregnant or breast feeding. Radiotherapy is associated with significant birth defects and/or non-viable fetus. Paclitaxel, cisplatin, oxaliplatin, and 5-fluorouracil have teratogenic potential. A negative pregnancy test is required within 14 days of treatment for all women of childbearing potential. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately. 13. Patients must have the ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
1. Patients may not be receiving any investigational agents. 2. Incomplete healing from previous major surgery. 3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents they are assigned to. 4. Concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, or St John's Wort; these drugs induce CYP3A and may decrease levels paclitaxel. 5-FU is a strong CYP2C9 inducer, and concomitant use with carvedilol, celecoxib, fosphenytoin, fluoxetine, phenytoin, warfarin and other CYP2C9 substrates should be used with caution. 5. Uncontrolled, inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 6. HIV-positive patients on combination antiretroviral therapy are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. 7. Patients from whom biopsy tissue cannot be obtained for correlate study analysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response | 3 years | CHFR methylation status correlates with response to taxane containing platinum-based combination therapy and tumor response involving operable Esophageal Cancer. Perform analysis comparing detection of CHFR in tumor and plasma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival | 3 years | Overall survival with given treatment strategy. |
| Time to Disease Progression | 3 years | To determine time to disease progression with this treatment strategy. |
| Esophageal Tumor CHFR Methylation and Detection in Plasma | 3 years | To determine the agreement between tumor CHFR methylation and detection in plasma. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Paclitaxel with Cisplatin along with Radiotherapy and followed by Esophagectomy
Paclitaxel: Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29.
Cisplatin: Paclitaxel and cisplatin:
* Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29.
* Cisplatin 30 mg/m² days 1, 8, 15, 22, 29.
Cisplatin and 5-fluorouracil:
* 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1- 4 and 29 - 32.
* Cisplatin 75 mg/m² days 1, 29.
Radiotherapy: Patients will be treated 5 days/week at 1.8 Gy/day to a total dose of 45Gy.
Esophagectomy: The type of resection (Ivor-Lewis, Transhiatal, etc.) will be left to the discretion of the operating surgeon. Resection will be completed between 5 and 8 weeks starting from the completion of chemotherapy and radiation (days 36 - 56). | 13 |
| Arm B Oxaliplatin with 5-Fluorouracil along with Radiotherapy and followed by Esophagectomy
Cisplatin: Paclitaxel and cisplatin:
* Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29.
* Cisplatin 30 mg/m² days 1, 8, 15, 22, 29.
Cisplatin and 5-fluorouracil:
* 5-Fluorouracil 1000 mg/m2 per day over 24 hours days 1- 4 and 29 - 32.
* Cisplatin 75 mg/m² days 1, 29.
Oxaliplatin: Oxaliplatin 85 mg/m2 days 1, 15, 29.
5-Fu: Oxaliplatin & 5-fu:
* Oxaliplatin 85 mg/m2 days 1, 15, 29.
* 5-Fu 180 mg/m2 prolonged infusion day 1 of radiation & completing on the final day of radiation
Cisplatin/5-fluorouracil:
* 5-Fu 1000 mg/m2 per day over 24 hours days 1-4 and 29-32.
* Cisplatin 75 mg/m² days 1, 29.
Radiotherapy: Treated 5 days/week at 1.8 Gy/day to a total dose of 45Gy. | 9 |
| Arm C Cisplatin with 5-Fluorouracil along with Radiotherapy and followed by Esophagectomy | 9 |
| Total | 31 |
Baseline characteristics
| Characteristic | Arm B | Arm C | Arm A | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 7 Participants | 9 Participants | 23 Participants |
| Age, Continuous | 67 years | 60 years | 63 years | 62 years |
| Region of Enrollment United States | 9 participants | 9 participants | 13 participants | 31 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 12 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 13 | 4 / 9 | 3 / 9 |
| other Total, other adverse events | 4 / 13 | 1 / 9 | 7 / 9 |
| serious Total, serious adverse events | 4 / 13 | 6 / 9 | 5 / 9 |
Outcome results
Primary
Pathological Complete Response
CHFR methylation status correlates with response to taxane containing platinum-based combination therapy and tumor response involving operable Esophageal Cancer. Perform analysis comparing detection of CHFR in tumor and plasma.
Time frame: 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Pathological Complete Response | 3 Participants |
| Arm B | Pathological Complete Response | 0 Participants |
| Arm C | Pathological Complete Response | 3 Participants |
Secondary
Esophageal Tumor CHFR Methylation and Detection in Plasma
To determine the agreement between tumor CHFR methylation and detection in plasma.
Time frame: 3 years
Population: Study closed due to early stopping rule, therefore data was not collected to assess this outcome measure.
Secondary
Survival
Overall survival with given treatment strategy.
Time frame: 3 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Survival | 6 Participants |
| Arm B | Survival | 5 Participants |
| Arm C | Survival | 6 Participants |
Secondary
Time to Disease Progression
To determine time to disease progression with this treatment strategy.
Time frame: 3 years
Population: Study closed due to early stopping rule, therefore data was not collected to assess this outcome measure.