This is a single-institution, prospective phase II trial with an initial safety run-in to
evaluate the efficacy and safety of neoadjuvant pembrolizumab combined with chemoradiotherapy
and adjuvant pembrolizumab in patients with locally advanced esophageal and gastric cancers
(EGC). Chemoradiation therapy (45Gy in 25 fractions with concurrent, weekly carboplatin [AUC
2] and paclitaxel [50mg/m2 of BSA]) with three cycles of pembrolizumab will be administered
as neoadjuvant therapy. These patients will also receive three cycles of adjuvant
pembrolizumab after surgical resection
Enrolled patients will receive three doses of neoadjuvant pembrolizumab (200 mg administered
as an intravenous infusion over 30 minutes every 3 weeks). The first dose of pembrolizumab
will be administered approximately 14 days prior to initiating radiotherapy. The second dose
will be administered three weeks later (week 1 of chemoradiation). The third dose will be
administered 3 weeks later (week 4 of chemoradiotherapy). Pembrolizumab will be given every 3
weeks and may be given at the same time as systemic therapy. All patients will receive
radiation treatment (45Gy in 25 fractions at 1.8 Gy/fraction) using image-guided radiation
therapy with concurrent, weekly carboplatin (AUC 2) and paclitaxel (50mg/m2 of BSA).
Restaging will be performed per standard of care approximately 4-8 weeks after completing
chemoradiotherapy. Resection will be performed approximately 6-12 weeks after completing
chemoradiotherapy per standard of care. Postoperatively, three additional cycles of
pembrolizumab (200 mg every 3 weeks) will be administered as adjuvant therapy.
Inclusion Criteria:
1. Be willing and able to provide written informed consent for the trial.
2. Be 18 years of age or older on day of signing informed consent.
3. Has a pathologic diagnosis of invasive esophageal, gastroesophageal or gastric
adenocarcinoma.
4. Staging CT CAP or PET/CT shows no evidence of metastatic disease.
5. Have a performance status of 0-2 on the ECOG Performance Scale.
6. Plan for neoadjuvant chemoradiation.
7. Demonstrate adequate organ function as defined in the study protocol, all screening
labs should be performed within 14 days of treatment initiation.
8. Female subject of childbearing potential should have a negative serum pregnancy within
48 hours prior to receiving the first dose of study medication.
9. Female and male subjects of childbearing potential must be willing to use an adequate
method of contraception as outlined in the Duke Contraception Policy.
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. 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 for
the current diagnosis of EGC.
7. Has a known additional malignancy that is progressing or requires active treatment.
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. (all
patients with prior radiotherapy must be reviewed by the PI to determine if patient is
eligible).
8. Has known metastatic disease. Staging CT C/A/P or PET/CT will be mandatory no more
than 45 days prior to enrollment to evaluate for the presence of metastatic disease.
9. Has unresectable disease or is medically inoperable.
10. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with chronic use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment.
11. Has known history of, or any evidence of active, non-infectious pneumonitis.
12. Has an active infection requiring systemic therapy.
13. 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.
14. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
15. 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.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
18. Has known, active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
19. 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.
20. Has a diagnosis of scleroderma.
21. Has a known history of allogenic stem cell transplant
22. Has received a solid organ transplant
