Nivolumab, Chemotherapy, and Radiation Therapy in Treating Patients with Locally Advanced Esophageal Squamous Cell Carcinoma

Status: Active

Description

This phase I / II trial studies the side effects of nivolumab and how well it works when given together with chemotherapy and radiation therapy in treating patients with esophagus squamous cell carcinoma that has spread to nearby tissue or lymph nodes. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab with chemotherapy and radiation therapy may kill more cancer cells.

Eligibility Criteria

Inclusion Criteria

  • Histologically or cytologically confirmed, treatment-naive esophageal squamous cell carcinoma
  • Previously obtained archival tumor tissue, or tissue obtained by endoscopically guided core biopsy at screening
  • Tany N1-3 or T3-4 N0 as determined by endoscopic ultrasound (EUS) or PET/CT; all palpable or CT/PET visible lymph nodes outside the usual surgical field must be biopsy-proven negative for cancer
  • All patients must have locoregional staging determined by endoscopic ultrasound (EUS) if technically feasible; endoscopy reports or subsequent gastrointestinal (GI) clinic note should clearly state both the T and N stage
  • All patients must have initial PET/CT scans to document no evidence of metastatic or unresectable squamous cell cancer
  • All patients with tumors involving the thoracic esophagus must undergo bronchoscopy to document the absence of a fistula no known contraindication to the use of taxanes or platinum compounds
  • No history of severe hypersensitivity reaction to Cremophor EL
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • A patient must be capable of giving informed consent or have an acceptable surrogate capable of giving consent on the subject’s behalf
  • Deemed a suitable candidate for esophagectomy by the treating surgeon as documented in a pre-operative assessment visit per standard practice at each participating institution
  • Deemed a suitable candidate for radiation therapy by the treating radiation oncologist as documented in a standard pretreatment visit per standard practice at each participating institution
  • Patient must be non-pregnant and non-nursing; women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to randomization
  • Obtained within 14 days prior to course 1 day 1 (C1D1): White blood cells (WBC) >= 2000/uL
  • Obtained within 14 days prior to C1D1: Neutrophils >= 1500/uL
  • Obtained within 14 days prior to C1D1: Platelets >= 100,000 4/uL
  • Obtained within 14 days prior to C1D1: Hemoglobin > 9.0 g/dL
  • Obtained within 14 days prior to C1D1: Serum creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 40 mL/min calculated using the Cockcroft-Gault formula
  • Obtained within 14 days prior to C1D1: Aspartate aminotransferase (AST) =< 3 x ULN
  • Obtained within 14 days prior to C1D1: Alanine aminotransferase (ALT) =< 3 x ULN
  • Obtained within 14 days prior to C1D1: Total Bilirubin =< 1.5 x ULN, except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL
  • Obtained within 14 days prior to C1D1: Oxygen saturation (O2 Sat.) >= 92% on ambient air
  • Obtained within 14 days prior to C1D1: Hepatitis B virus (HBV) surface antigen negative
  • Obtained within 14 days prior to C1D1: HBV surface antibody positive or negative
  • Obtained within 14 days prior to C1D1: HBV core antibody negative * Subjects whose HBV core antibody is positive must have a negative HBV viral load measurement
  • Obtained within 14 days prior to C1D1: HBV viral load negative
  • Obtained within 14 days prior to C1D1: Anti-hepatitis C virus (HCV) total antibody negative
  • Obtained within 14 days prior to C1D1: HCV NA analysis negative
  • Obtained within 14 days prior to C1D1: Rapid human immunodeficiency virus (HIV) 1/2 antibodies negative
  • Patients with a positive hepatitis B core antibody (HBVcAb) must have negative viral load measurement
  • All patients have to agree to participate in the correlative study of sample collection for immune correlative assays in order to participate in the main study; however, if the sample cannot be obtained due to feasibility issues, the patient will be allowed to continue on treatment

Exclusion Criteria

  • T1-2 N0 as determined by EUS and PET/CT
  • Pregnant or lactating women
  • Active or prior documented autoimmune or inflammatory disorders including but not limited to inflammatory bowel disease; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis) within the past 3 years prior to the start of treatment; the following are exceptions to this criterion: * Subjects with vitiligo or alopecia * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
  • History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
  • The use of immunosuppressive medication within 28 days prior to the first dose of nivolumab; the following are exceptions to this criterion: * Intranasal, topical, inhaled corticosteroids or local steroid injections (e.g. intra-articular injection) * Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent * Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
  • Positive test for human immunodeficiency virus (HIV)
  • Active hepatitis B or hepatitis C (defined as positive-HBV surface antigen or detectable HCV-antibody); patients with a positive Hepatitis B core antibody (HBVcAb) must have negative viral load measurement
  • Prior treatment with any immunotherapy
  • Any other factors, including psychiatric or social, that in the opinion of the treating physician makes the patient an inappropriate candidate for a study
  • Patients are excluded if they have active brain metastases or leptomeningeal metastases; subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for [lowest minimum is 4 weeks or more] after treatment is complete and within 28 days prior to the first dose of nivolumab administration; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
  • Patients should be excluded if they have an active, known or suspected autoimmune disease; subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  • As there is potential for hepatic toxicity with nivolumab or nivolumab non-drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen
  • Patients with a history of allergy to the study drug components are excluded

Locations & Contacts

California

La Jolla
UC San Diego Moores Cancer Center
Status: Temporarily closed to accrual
Contact: Lawrence Leichman
Phone: 858-822-6100
Email: lleichman@ucsd.edu
Los Angeles
USC / Norris Comprehensive Cancer Center
Status: Active
Contact: Syma Iqbal
Phone: 323-865-3900
Email: Iqbal@med.usc.edu

New York

New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: Active
Contact: Jennifer J. Wu
Phone: 212-263-6485
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Geoffrey Yuyat Ku
Phone: 646-888-4588

Oregon

Portland
Oregon Health and Science University
Status: Temporarily closed to accrual
Contact: Gina Maria Vaccaro
Phone: 503-494-6594
Email: vaccarog@ohsu.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Assess the safety of induction nivolumab followed by chemoradiation with nivolumab and adjuvant nivolumab for patients with locally advanced squamous cell cancer of the esophagus. (Phase I)

II. Estimate the clinical complete response (cCR) + pathological complete response (pCR) rate of induction nivolumab followed by chemoradiation with nivolumab. (Phase II)

SECONDARY OBJECTIVES:

I. Describe the progression-free survival (PFS) and overall survival (OS) of nivolumab and chemoradiation, followed by adjuvant nivolumab. (Phase II)

II. Describe the major toxicities encountered in this treatment. (Phase II)

EXPLORATORY OBJECTIVES:

I. Assess whether positron emission tomography (PET)/computed tomography (CT) clinical response to nivolumab can predict the following outcomes: pCR, PFS, and OS.

II. Assess the association between the outcomes pCR, PFS, and OS and immune correlative assays.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 60 minutes on days 1, 15, 29, 43 and 57, carboplatin IV over 30 minutes on days 29, 36, 43, 50, 57 and 64, and paclitaxel IV over 2 hours on days 29, 36, 43, 50, 57 and 64. Patients also undergo radiation therapy on days 29-66.

SURGERY: Patients who did not achieve a complete response undergo esophagectomy.

Patients receive nivolumab IV over 2 hours every 2 weeks for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Laura and Isaac Perlmutter Cancer Center at NYU Langone

Principal Investigator
Jennifer J. Wu

Trial IDs

Primary ID S16-00971
Secondary IDs NCI-2017-01141, s16-00971
Clinicaltrials.gov ID NCT03278626