A Phase II Study of the Addition of Nivolumab and Cetuximab to Chemoradiation in Locally Advanced Esophageal Squamous Cell Carcinoma (ESqCC).
Overview
- Phase
- Phase 2
- Intervention
- Cisplatin
- Conditions
- Esophageal Squamous Cell Carcinoma
- Sponsor
- Baruch Brenner
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Progression Free Survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
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.
Investigators
Baruch Brenner
Director of the Oncology Division and the Davidoff Cancer Center
Rabin Medical Center
Eligibility Criteria
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.
Arms & Interventions
Neoadjuvant Treatment
All subjects will receive induction chemotherapy and chemoradiation combined with cetuximab followed by nivolumab and cetuximab as neoadjuvant treatment
Intervention: Cisplatin
Neoadjuvant Treatment
All subjects will receive induction chemotherapy and chemoradiation combined with cetuximab followed by nivolumab and cetuximab as neoadjuvant treatment
Intervention: 5-FU
Neoadjuvant Treatment
All subjects will receive induction chemotherapy and chemoradiation combined with cetuximab followed by nivolumab and cetuximab as neoadjuvant treatment
Intervention: Radiation therapy
Neoadjuvant Treatment
All subjects will receive induction chemotherapy and chemoradiation combined with cetuximab followed by nivolumab and cetuximab as neoadjuvant treatment
Intervention: Cetuximab
Neoadjuvant Treatment
All subjects will receive induction chemotherapy and chemoradiation combined with cetuximab followed by nivolumab and cetuximab as neoadjuvant treatment
Intervention: Nivolumab
Outcomes
Primary Outcomes
Progression Free Survival (PFS)
Time Frame: 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
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
pathological complete response (pCR) rate
Time Frame: Time from start of neoadjuvant treatment until surgical resection, assessed up to 24 months
pCR is defined when no tumor is found on pathology review of the surgical specimen (TRG -0)
Modified pathological complete response
Time Frame: Time from start of neoadjuvant treatment until surgical resection in operated patients (pCR) and long-term (≥12 months) clinical complete response (cCR) in unoperated patients, assessed up to 24 months.
We defined a novel primary endpoint, combining pathological complete response (pCR) rate among operated patients and long-term (≥12 months) clinical complete response (cCR) rate for those electing watchful waiting, into a composite endpoint of modified pCR (mpCR) rate.
Incidence of Treatment-Emergent Adverse Events (Safety)
Time Frame: Time from screening until the end of study drug administration, assessed up to 24 months
Treatment-emergent AEs will be graded according to NCI CTCAE v5.0, vital signs and clinical laboratory
Secondary Outcomes
- Overall survival (OS)(The time interval between the first day of treatment and the date of death from any cause, assessed up to 66 months)