This is a Phase IB study assessing the safety of 2 cycles of induction (Arm A) nivolumab or
(Arm B) 1 cycle of induction nivolumab plus ipilimumab prior to concurrent chemoradiation
plus nivolumab before surgical resection in operable stage II/III
esophageal/gastroesophageal junction cancer.
Approximately 32 patients will be enrolled on study with 16 enrolled on Arm A and if no
unexpected toxicities then an additional 16 patients will be enrolled on Arm B.
- Men and women aged ≥ 18 years old
- Histologically proven (squamous cell or adenocarcinoma) esophageal or gastro-
esophageal junction cancer (core biopsy required).
- Stage II/III disease as per AJCC staging 7.0
- Baseline imaging with FDG-PET scan and endoscopic ultrasound within 28 days prior to
- ECOG performance status 0-1 (see Appendix B).
- Adequate oral intake/nutritional status without the need for enteral or parenteral
feeding during chemoradiation or preoperative period
- Adequate organ function as follows:
- Leukocytes ≥ 2,000/mm3
- Absolute neutrophil count (ANC) ≥ 1000/mm3
- Platelet count ≥ 100,000/mm3
- Hemoglobin ≥ 9 g/dL
- Creatinine ≤ 2.0 mg/dL
- Bilirubin (total) within normal institutional limits (except subjects with
Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL)
- AST(SGOT), ALT(SGPT), and alkaline phosphatase ≤ 2.5 times the upper limit of
- PT such that international normalized ratio (INR) is ≤ 1.5 (or an in-range INR,
usually between 2 and 3, if a patient is on a stable dose of therapeutic
warfarin and a PTT ≤ upper limit of normal
- Adequate cardiac function as defined by: no evidence of PR prolongation or AV block
on baseline electrocardiogram (ECG).
- Radiation oncology consultation within 28 days to confirm that disease can be
encompassed in the radiotherapy field and that normal tissue constraints can be met.
- Subjects must have adequate lung function to permit surgical resection determined by
pre-enrollment pulmonary function tests to include DLCO as follows:
- DLCO≥70% predicted OR DLCO<70% but ≥55% with a VO2 max ≥10L/min/kg (assessed by
cardiopulmonary exercise testing) or 6 minute walk test ≥500 meters
- Subjects with a DLCO<55% are excluded from this study.
- Subjects must have a baseline O2 saturation by pulse oximetry that is ≥ 92% both
at rest and while walking, off supplemental oxygen
- Esophagogastrectomies will be performed via a laparotomy and a right thoracotomy with
en-bloc removal of perigastric, celiac, periesophageal and subcarinal lymph nodes.
Esophagogastric reconstruction will be performed above the level of the azygo-caval
junction using an EEA stapling device.
- Either a formalin fixed paraffin block or a minimum of ten 5-micron tissue section's
(slides) of tumor biopsy sample must be available for biomarker evaluation from
baseline and repeat EGD.
- The effects of nivolumab, on the developing human fetus are unknown. For this reason
women of child-bearing potential (WOCBP) 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 and for 5 months after the
last dose of nivolumab. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately. Sexually active fertile men must use effective
barrier birth control if their partners are WOCBP for 7 months after the last dose of
nivolumab. WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within two weeks of registration.
- Patient understands the study regimen, its requirements, risks and discomforts and is
able and willing to sign the informed consent form. Voluntary signed and dated
IRB/IEC approved written informed consent form in accordance with regulatory and
institutional guidelines must be obtained before the performance of any protocol
related procedures that are not part of normal patient care. Subjects must be
competent to report AEs, understand the drug dosing schedule and use of medications
to control AEs.
- Patient has active, known or suspected autoimmune disease. Subjects with vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement, or conditions not expected to recur in the absence of
an external trigger are permitted to enroll.
- Esophageal tumors that are located in the mid esophagus or higher i.e. not involving
distal esophagus or GE junction.
- Tumors whose proximal end are higher that the level of the carina
- Biopsy proven involvement of supraclavicular lymph nodes
- Tumors must not extend 5cm or more into the stomach
- Patient has a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
days of first dose. Inhaled or topical steroids and adrenal replacement steroid doses
are permitted in the absence of active autoimmune disease.
- Subjects with previous malignancies (except non-melanoma skin cancers, in situ
bladder, gastric, breast, colon or cervical cancers/dysplasia) are excluded unless a
complete remission was achieved at least 1 years prior to study entry and no
additional therapy (other than adjuvant hormonal therapy for breast cancer) is
required or anticipated to be required during the study period.
- Subjects with brain metastasis are excluded from this study and all patients should
have brain imaging (either MRI brain or CT brain with contrast) prior to enrollment.
- Subjects with a history of interstitial lung disease.
- Active systemic infection requiring therapy, positive tests for Hepatitis B surface
antigen or Hepatitis C ribonucleic acid (RNA).
- Known positive history or positive test for Human Immunodeficiency Virus or Acquired
ImmunoDeficiency Syndrome (AIDS).
- History of allergy to study drug components.
- Women who are pregnant or nursing.
- WOBP and Men with female partners (WOCBP) that are not willing to use contraception.
- Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or
any other antibody targeting T cell co-regulatory pathways).
- Underlying medical conditions that, in the Investigator's opinion, will make the
administration of study drug hazardous or obscure the interpretation of toxicity or
- Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for
treatment of either a psychiatric or physical (e.g. infectious disease) illness.