Esophageal Squamous Cell Carcinoma
Conditions
Keywords
Esophageal Squamous Cell Carcinoma, pembrolizumab, PD-1, neoadjuvant, chemoradiation
Brief summary
In this study, participants with esophageal squamous cell carcinoma will receive preoperative chemoradiotherapy with paclitaxel,carboplatin and pembrolizumab then undergo surgery. The primary study hypothesis is that adding pembrolizumab will increase complete pathologic response rate at surgery.
Interventions
DRUGMK-3475(pembrolizumab)
Neo-adjuvant chemoradiation period:The treatment consisted of taxol, carboplatin, pembrolizumab and radiation. The radiation treatment comprises 44.1Gy (2.1Gy/Fr, total 21Fr) and that will be about 5 weeks. Intensity modulated RT (IMRT) or 3D CRT (three-dimensional conformal radiotherapy) will be allowed. Surgery:Before surgery, abdomen/chest CT scan, endoscopic ultrasound (EUS), and gastroscopy with biopsy will be done. Surgery should be done within 12 weeks after last neo-adjuvant treatment. Adjuvant period:Adjuvant treatment with pembrolizumab 200mg every 2week (maximum 2 years) should be performed within 8 weeks after surgery (recommended period : 3-6 weeks after surgery). Gastroscopy and abdomen/chest CT scan will be performed at 6 month after surgery.
Sponsors
Yonsei University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed ESCC 2. Clinical stage T1N1-2 or T2-34aN0-12 (AJCC 7 TNM classification) 3. No evidence of metastasis 4. Be willing and able to provide written informed consent/assent for the trial. 5. Be 20 years of age on day of signing informed consent. 6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion through repeated biopsies. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor. 7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 8. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation. 9. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication. \- Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 11. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Exclusion criteria
1. Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 3. Has a known history of active TB (Bacillus Tuberculosis) 4. Hypersensitivity to pembrolizumab or any of its excipients. 5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. * Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 7. Has another malignancy within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative surgery, or in situ cervical cancer. 8. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 9. Has known history of, or any evidence of active, non-infectious pneumonitis. 10. Has an active infection requiring systemic therapy. 11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). 17. Has received a live vaccine within 30 days of planned start of study therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Pathologic Response Rate | Up to 3 years | The primary endpoint of phase II study is to assess complete pathologic response rate. Definition of complete pathologic response is no cancer cell, including lympho nodes which corresponds with tumor regression score 0. Definition of pathologic response is as follows. Tumor regression score Grade 0 and 1 will be defined as responder and 2 and 3 will be considered as non-responders |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Free Survival | Up to 3 years | Disease free survival is defined from the time of surgery to initial replace or death. |
| Overall Survival | Up to 3 years | Overall survival is defined from the time of enrollment to death or last follow-up date. |
| Pathologic Response Rate | Up to 3 years | Pathologic response rate is defined as tumor regression score. A score of '0' means 'No cancer cell, including lymph nodes'. A score of '1' means 'Single cells or small groups of cancer cells'. A score of '2' means 'Residual cancer cells outgrown by fibrosis'. A score of '3' means 'Minimum or no treatment effect'. |
| Safety According to Common Terminology Criteria for Adverse Events (CTCAE) 4.03 | Up to 3 years | Grade 3-4 adverse events occurring during the neoadjuvant period (no death) |
| Event Free Survival | Up to 3 years | Event free survival is defined from the time of enrollment to 'event' included disease recurrence. |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab MK-3475(pembrolizumab): Neo-adjuvant chemoradiation period:The treatment consisted of taxol, carboplatin, pembrolizumab and radiation. The radiation treatment comprises 44.1Gy (2.1Gy/Fr, total 21Fr) and that will be about 5 weeks. Intensity modulated RT (IMRT) or 3D CRT (three-dimensional conformal radiotherapy) will be allowed.
Surgery:Before surgery, abdomen/chest CT scan, endoscopic ultrasound (EUS), and gastroscopy with biopsy will be done. Surgery should be done within 12 weeks after last neo-adjuvant treatment.
Adjuvant period:Adjuvant treatment with pembrolizumab 200mg every 2week (maximum 2 years) should be performed within 8 weeks after surgery (recommended period : 3-6 weeks after surgery). Gastroscopy and abdomen/chest CT scan will be performed at 6 month after surgery. | 28 |
| Total | 28 |
Baseline characteristics
| Characteristic | Pembrolizumab | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 10 Participants | — |
| Age, Categorical Between 18 and 65 years | 18 Participants | — |
| Age, Continuous | 60 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment South Korea | 28 participants | — |
| Sex: Female, Male Female | 3 Participants | — |
| Sex: Female, Male Male | 25 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 28 |
| other Total, other adverse events | 28 / 28 |
| serious Total, serious adverse events | 10 / 28 |
Outcome results
Primary
Complete Pathologic Response Rate
The primary endpoint of phase II study is to assess complete pathologic response rate. Definition of complete pathologic response is no cancer cell, including lympho nodes which corresponds with tumor regression score 0. Definition of pathologic response is as follows. Tumor regression score Grade 0 and 1 will be defined as responder and 2 and 3 will be considered as non-responders
Time frame: Up to 3 years
Population: Underwent surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Complete Pathologic Response Rate | 6 Participants |
Secondary
Disease Free Survival
Disease free survival is defined from the time of surgery to initial replace or death.
Time frame: Up to 3 years
Population: Underwent surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Disease Free Survival | 17.9 months |
Secondary
Event Free Survival
Event free survival is defined from the time of enrollment to 'event' included disease recurrence.
Time frame: Up to 3 years
Population: Enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Event Free Survival | 11.0 months |
Secondary
Overall Survival
Overall survival is defined from the time of enrollment to death or last follow-up date.
Time frame: Up to 3 years
Population: Enrollment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Overall Survival | 33.6 months |
Secondary
Pathologic Response Rate
Pathologic response rate is defined as tumor regression score. A score of '0' means 'No cancer cell, including lymph nodes'. A score of '1' means 'Single cells or small groups of cancer cells'. A score of '2' means 'Residual cancer cells outgrown by fibrosis'. A score of '3' means 'Minimum or no treatment effect'.
Time frame: Up to 3 years
Population: Underwent surgery
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pembrolizumab | Pathologic Response Rate | Score '0' | 6 participants |
| Pembrolizumab | Pathologic Response Rate | Score '1' | 10 participants |
| Pembrolizumab | Pathologic Response Rate | Score '2' | 10 participants |
| Pembrolizumab | Pathologic Response Rate | Score '3' | 0 participants |
Secondary
Safety According to Common Terminology Criteria for Adverse Events (CTCAE) 4.03
Grade 3-4 adverse events occurring during the neoadjuvant period (no death)
Time frame: Up to 3 years
Population: Enrollment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Safety According to Common Terminology Criteria for Adverse Events (CTCAE) 4.03 | 25 percentage of participants |