Trial of Nivolumab and Cetuximab After Chemoradiation in Esophageal Squamous Cell Carcinoma Patients.

Study Overview
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Brief Summary
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This is a phase II, open label, two-centered study for evaluation of the addition of nivolumab and cetuximab after chemoradiation as a neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma patients. Subjects must have received no prior treatment for esophageal cancer (chemotherapy, radiotherapy or surgery) and no prior treatment with checkpoint inhibitors. Eligible subjects will receive induction chemotherapy with cetuximab for a period of 4 weeks, chemoradiation with cetuximab for a period of 6 weeks, 3 cycles of immunotherapy (nivolumab + cetuximab) for a period of 6 weeks, and will undergo surgery at the end of the treatment.

Official Title
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A Phase II Study of the Addition of Nivolumab and Cetuximab to Chemoradiation in Locally Advanced Esophageal Squamous Cell Carcinoma (ESqCC).

Conditions
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Esophageal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Cisplatin
* Drug: 5-FU
* Radiation: Radiation therapy
* Drug: Cetuximab
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written IRB approved informed consent. Age > 18 years. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 Subjects with histologically confirmed operable, primary (non-recurrent) locally advanced (T3NxM0, TxN1M0) middle (distal to the thoracic inlet) or distal (up to the gastroesophageal junction) ESqCC according to endoscopic ultrasound (EUS) and PET-CT. No prior systemic or radiation therapy for esophageal cancer. Presence of adequate contraception in fertile patients. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. Women must not be breastfeeding. No previous (within the last 5 years) or concurrent malignancies, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix or basal cell carcinoma of the skin. Exclusion Criteria: Cervical esophageal tumors or tumors < 5 cm from the cricopharyngeal cartilage. Gastric cancers with minor involvement of the GEJ or distal esophagus, or an esophageal tumor extending beyond 2 cm into the stomach. Prior chest or upper abdomen radiotherapy, prior systemic chemotherapy within the past 5 years or prior esophageal or gastric surgery. Patients with evidence of metastatic disease. Biopsy proven tumor invasion of the tracheobronchial tree or presence of tracheo-esophageal (TE) fistula or recurrent laryngeal nerve or phrenic nerve paralysis. New York Heart Association Class III or IV heart disease. Angina or myocardial infarction within the last 12 months, history of significant ventricular arrhythmia requiring medication with antiarrhythmics, or a history of a clinically significant conduction system abnormality. Clinically significant hearing loss. Patients with a history of seizure disorder who are receiving phenytoin, phenobarbital, or other antiepileptic medication. Any positive test for hepatitis B virus or hepatitis C virus indicating active infection. Ongoing immunosuppressive therapy. Active autoimmune disease. [Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll]. Prior organ transplant. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant Treatment<br>All subjects will receive induction chemotherapy and chemoradiation combined with cetuximab followed by nivolumab and cetuximab as neoadjuvant treatment | Drug: Cisplatin<br>* Cisplatin 100mg/m2 IV on day 1 of induction chemotherapy, 75mg/m2 IV on day 1 and 29 of chemoradiation<br>Drug: 5-FU<br>* 5-FU 1000mg/m2/d IV on days 1-5 of induction chemotherapy, 1000mg/m2/d IV on days 1-4 and days 29-32 of chemoradiation<br>Radiation: Radiation therapy<br>* 1.8 Gy/fraction, 5 days a week for a total of 28 days<br>Drug: Cetuximab<br>* Cetuximab 400mg/m2 IV on day 1 followed by 250mg/m2 IV weekly on induction chemotherapy, 250mg/m2 IV weekly on chemoradiation, 500mg/m2 IV on day 1 of each treatment cycle, every two weeks during immunotherapy<br>* Other names: Erbitux;Drug: Nivolumab<br>* Nivolumab 3mg/kg IV on day 1 of each treatment cycle, every two weeks during immunotherapy<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pathological complete response (pCR) rate | pCR is defined when no tumor is found on pathology review of the surgical specimen (TRG -0) | Time from start of neoadjuvant treatment until surgical resection, assessed up to 36 months | 
| Progression Free Survival (PFS) | PFS will be censored in patients without loco-regional failure, metastatic recurrence or death, at the last date known to be alive or at the start of a new anti-cancer treatment, whatever occurs first. PFS rate will be estimated using the Kaplan-Meier method | The time interval from the first day of treatment to the first event of loco-regional failure, metastatic recurrence or death from any cause, assessed up to 66 months | 
| Incidence of Treatment-Emergent Adverse Events (Safety) | Treatment-emergent AEs will be graded according to NCI CTCAE v5.0, vital signs and clinical laboratory | Time from screening until the end of study drug administration, assessed up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Patients who are still alive when last traced will be censored at the date of last follow-up. OS rate will be estimated using the Kaplan-Meier method | The time interval between the first day of treatment and the date of death from any cause, assessed up to 96 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophageal Cancer, Esophageal Squamous Cell Carcinoma, Cetuximab, Nivolumab