Esophageal Adenocarcinoma
Conditions
Brief summary
This is a randomized, multicenter phase II study of pembrolizumab in combination with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma to examine the safety and efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma as assessed by 1 year disease free survival rate.
Detailed description
This is a randomized, multicenter phase II study of pembrolizumab in combination with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma to examine the safety and efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation in locally advanced esophageal adenocarcinoma as assessed by 1 year disease free survival rate. The investigators primary aim is to examine the safety and efficacy of pembrolizumab in both pre-operative treatment paradigms for esophageal/GEJ carcinoma. The specific rationale for the investigators study design is rooted in three unanswered questions: 1. does the addition of an immune check-point inhibitor (pembrolizumab) enhance the efficacy of cytotoxic therapy (chemotherapy with chemoradiation) as determined by response rates, nodal down-staging and 1 year disease free survival in comparison to historical controls, 2. what are the pathological effects of combining pembrolizumab with chemotherapy alone, and 3. what are the molecular (PD-L1 expression), immunological (TILs extent) and gene-expression signatures associated with the efficacy of pembrolizumab in the neoadjuvant setting.
Interventions
DRUGPembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
DRUGTaxol
Taxol is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.
DRUGCarboplatin
Carboplatin is a platinum coordination compound that is used as a cancer chemotherapeutic agent. Carboplatin produces predominantly interstrand DNA cross-links rather than DNA -protein cross-links.
Sponsors
Weill Medical College of Cornell University
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Patients must have histologically or cytologically confirmed esophageal or GEJ adenocarcinoma 2. Clinical tumor stage should be T2 Npositive M0 or T3--T4, Nany, M0 3. Be willing and able to provide written informed consent/assent for the trial 4. Be 18 years of age or older on day of signing informed consent. 5. Be a candidate for surgical resection. 6. Be willing to provide tissue during endoscopic assessment of their tumor. 7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 8. Demonstrate adequate organ function as defined below, all screening labs should be performed within 14 days of treatment initiation. * Absolute neutrophil count (ANC) ≥1,500 /mcL * Platelets≥100,000 / mcL * Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion within 7 days of assessment * Serum creatinine OR Measured or calculated creatinine clearance ≤1.5 X upper limit of normal (ULN) OR * ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN (Creatinine clearance should be calculated per institutional standard) (GFR can also be used in place of creatinine or CrCl) * Serum total bilirubin ≤ 1.5 X ULN OR * Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN * AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN * Albumin \>2.5 mg/dL * International Normalized Ratio (INR) OR Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants 9. Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days 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 should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year. 11. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Exclusion criteria
1. Is 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. Evidence of metastatic disease. 3. 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. 4. Has active TB or a history of active TB within 10 years of registration (Bacillus Tuberculosis) 5. Hypersensitivity to pembrolizumab or any of its excipients. 6. Has had a prior anti-cancer treatment, including chemotherapy, radiation, or monoclonal antibody (mAb) for their current diagnosis of esophageal adenocarcinoma. 7. Has a known additional malignancy that is active. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 8. Has a previous invasive malignancy treated with curative intent less than 3 years from time of registration. Exceptions include prostate cancer, basal cell squamous skin cancer, and cervical cancer. 9. 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. 10. Has known history of, or any evidence of active, non-infectious pneumonitis. 11. Has an active infection requiring systemic therapy. 12. 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. 13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 14. 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. 15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). 18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Major Pathological Response | Between approximately week 15 to 19 | Tumor tissue will be assessed for major pathological response as defined as complete response or near complete response. Pathologic response was assessed by tumor regression grade. This is a pathologic assessment of the amount of residual cancer cells in the specimen and the degree of fibrosis in the sample specimen. A completer response is 0% residual cancer cells. A partial response is 10-50% residual cancer cells, and no response is \>50% residual cancer cells within the tumor specimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| R0 Resection Rate. | 1 year | To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by R0 resection rate, which is reported as the number of participants achieving R0 resection. |
| Overall Survival Rates | Until death from any cause or for a maximum of 5 years | To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by overall survival rates |
| Number of Participants That Remained Progression Free as of 1 Year | 1 year | Number of participants that remained progression free (per RECIST v1.1) and alive as of 1 year |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORManish Shah, MD
Weill Medical College of Cornell University
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Subjects in Cohort 1 receive conventional induction chemotherapy with taxol/ carboplatin followed by weekly chemoradiation (taxol/ carboplatin) with pembrolizumab. Following surgery, pembrolizumab is administered every 3 weeks for 1 year.
Pembrolizumab dosing is 200 mg administered as a 30 minute IV infusion.
Pembrolizumab: Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Taxol: Taxol is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.
Carboplatin: Carboplatin is a platinum coordination compound that is used as a cancer chemotherapeutic agent. Carboplatin produces predominantly interstrand DNA cross-links rather than DNA -protein cross-links. | 20 |
| Cohort 2 Subjects in Cohort 2 receive pembrolizumab along with induction chemotherapy with taxol/ carboplatin followed by weekly chemoradiation (taxol/ carboplatin) with pembrolizumab. Following surgery, pembrolizumab is administered every 3 weeks for 1 year.
Pembrolizumab dosing is 200 mg administered as a 30 minute IV infusion.
Pembrolizumab: Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Taxol: Taxol is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.
Carboplatin: Carboplatin is a platinum coordination compound that is used as a cancer chemotherapeutic agent. Carboplatin produces predominantly interstrand DNA cross-links rather than DNA -protein cross-links. | 22 |
| Total | 42 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort 2 |
|---|---|---|---|
| Age, Continuous | 61.87 years | 65.06 years | 67.38 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 38 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 18 Participants | 39 Participants | 21 Participants |
| Region of Enrollment United States | 20 participants | 42 participants | 22 participants |
| Sex: Female, Male Female | 5 Participants | 9 Participants | 4 Participants |
| Sex: Female, Male Male | 15 Participants | 33 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 20 | 9 / 22 |
| other Total, other adverse events | 20 / 20 | 22 / 22 |
| serious Total, serious adverse events | 8 / 20 | 13 / 22 |
Outcome results
Primary
Number of Participants With Major Pathological Response
Tumor tissue will be assessed for major pathological response as defined as complete response or near complete response. Pathologic response was assessed by tumor regression grade. This is a pathologic assessment of the amount of residual cancer cells in the specimen and the degree of fibrosis in the sample specimen. A completer response is 0% residual cancer cells. A partial response is 10-50% residual cancer cells, and no response is \>50% residual cancer cells within the tumor specimen.
Time frame: Between approximately week 15 to 19
Population: 3 participants in Cohort 2 did not have surgery and were therefore ineligible.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants With Major Pathological Response | 9 Participants |
| Cohort 2 | Number of Participants With Major Pathological Response | 10 Participants |
Secondary
Number of Participants That Remained Progression Free as of 1 Year
Number of participants that remained progression free (per RECIST v1.1) and alive as of 1 year
Time frame: 1 year
Population: 3 participants in Cohort 2 were unevaluable
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants That Remained Progression Free as of 1 Year | 15 Participants |
| Cohort 2 | Number of Participants That Remained Progression Free as of 1 Year | 12 Participants |
Secondary
Overall Survival Rates
To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by overall survival rates
Time frame: Until death from any cause or for a maximum of 5 years
Secondary
R0 Resection Rate.
To examine the efficacy of the combination of pembrolizumab with chemotherapy and chemoradiation as assessed by R0 resection rate, which is reported as the number of participants achieving R0 resection.
Time frame: 1 year
Population: 1 participant in Cohort 1 and 3 participants in Cohort 2 were unevaluable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | R0 Resection Rate. | 17 Participants |
| Cohort 2 | R0 Resection Rate. | 16 Participants |
Other Pre-specified
Association of Anti-PD1 Therapy With Increased Intra-tumoral Immune Cell Infiltration.
To examine whether anti PD1 therapy is associated with increased intra-tumoral immune cell infiltration.
Time frame: Up to 1 year post-surgery.
Other Pre-specified
Improved 1 Year Survival
To examine whether anti PD1 therapy is associated with a transcriptomic signature of intra-tumoral immune activation predictive of improved 1 year survival.
Time frame: 1 year
Other Pre-specified
Induction of PD-L1 Expression or Induction of an Inflammatory Signature in Tumors.
To examine whether chemotherapy is associated with induction of PD-L1 expression or induction of an inflammatory signature in tumors
Time frame: Up to 1 year post-surgery.
Other Pre-specified
Prediction of Tumor Response.
To examine whether anti PD1 therapy is associated with a transcriptomic signature of intra-tumoral immune activation predictive of response.
Time frame: Up to 1 year post-surgery
Other Pre-specified
Reduction of Local Immune Infiltration.
To explore the effect of the combination of pembrolizumab with chemotherapy as assessed by the local immune infiltration in each treatment group.
Time frame: Up to 1 year post-surgery