Immune Checkpoint Therapy With Nivolumab Esophageal Squamous Cell Carcinoma

• Sponsor: NYU Langone Health (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03278626
• Collaborator: (none)
• Enrollment: 12
• Locations: 5
• Arm: 1
• Actual Duration (Months): 47.1
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

In this multi-institution phase I/II trial, the investigators have chosen paclitaxel and carboplatin using a schedule and doses identical to those used in the CROSS trial. Following a run-in with nivolumab alone at 240 mg IVPB every 2 weeks for 2 doses, nivolumab at 240 mg every 2 weeks will be added to paclitaxel and carboplatin, which will be dosed according to the standard of care established by the CROSS trial: paclitaxel 50 mg/m2 weekly for 6 weeks and carboplatin AUC 2 weekly for 6 weeks. Concurrent radiation will be administered with chemotherapy at 1.8 Gy/fraction × 28 fractions to a total dose of 50.4 Gy, the standard radiation dose administered in the United States for trimodality therapy that includes concurrent therapy with carboplatin and paclitaxel. A decrease in dose to 41.4 Gy per the protocol established by van Hagen, et al. will be permitted before discontinuing therapy due to unacceptable toxicity. While the CROSS study administered only 5 weekly doses of chemotherapy during the 5 weeks of radiation, the higher dose of 50.4 Gy (1.8 Gy/fraction ×28 fractions over 5½ weeks) utilized in this study permits for a sixth dose during the additional week of radiation.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Squamous Cell Carcinoma	Drug: Nivolimumab+Carboplatin/paclitaxel+Radiation	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Open Label Multi Center Study of Immune Checkpoint Therapy With Nivolumab for Patients With Locally Advanced Esophageal Squamous Cell Carcinoma
• Actual Study Start Date: Jun 27, 2017
• Actual Primary Completion Date: Nov 7, 2019
• Actual Study Completion Date: May 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Other: Nivolimumab+Carboplatin/paclitaxel+Radiation 240 mg IVPB every 2 weeks for 2 doses, nivolumab at 240 mg every 2 weeks will be added to paclitaxel and carboplatin, which will be dosed according to the standard of care: paclitaxel 50 mg/m2 weekly for 6 weeks and carboplatin AUC 2 weekly for 6 weeks and radiation	Drug: Nivolimumab+Carboplatin/paclitaxel+Radiation; In the phase I portion of the study, up to six patients will be treated (radiation will be 50.4 Gy (1.8 Gy/fraction × 28 fractions)) and then observed for 28 days (following last day of treatment (Day 64)).; Other Names: Opdivo Paraplatin Taxol

Outcome Measures

Primary Outcome Measures

1. Phase 1: Number of Unacceptable Toxicity (UT) Events [92 days (up to 28 days after Day 64)]

   UT is defined as: Recurrent grade 3 or 4 hematologic toxicity (despite 1 prior dose reduction in chemotherapy) any toxicity that results in a > 2-week delay in chemoradiation

2. Phase 2: Number of Subjects Who Achieved cCR (Clinical Complete Response) or pCR (Pathological Complete Response) [5-8 Weeks post radiation treatment (7-8 months after treatment start)]

   Clinical and pathological response after neoadjuvant therapy cCR by endoscopic + PET/CT evaluation; pCR for patients undergoing surgery Clinical Complete Response (cCR), no malignancy is found on clinical examination, imaging, endoscopy, and biopsy; Pathological Complete Response (pCR), no invasive and no in situ residual tumors in tissue

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

• TanyN1-3 or T3-4 N0as determined by EUS and 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 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.

• Patients who are ≥ 18 years old are eligible for this study. Neither specific gender distribution, nor specific racial or ethnic origins are necessary for enrollment in this study.

• 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 HCG) within 72 hours prior to C1D1.

• Screening Laboratory Values must meet the following criteria and should be obtained within 14 days prior to C1D1 (see Table 1 below)

• Patients with a positive Hepatitis B core antibody (HBVcAb) must have negative viral load measurement; Patients with HBV core positive, must have negative viral load measurements

• Screening Laboratory Values must meet the following criteria and should be obtained within 14 days prior to randomization/registration (see Table 1 below) Test Acceptable Result WBC ≥ 2000/µL Neutrophils ≥ 1500/µL Platelets ≥ 100,000 /µL Hemoglobin > 9.0 g/dL Serum Creatinine ≤ 1.5 x ULN OR Creatinine Clearance (CrCl)* ≥ 40 mL/min AST ≤ 3 x ULN ALT ≤ 3 x ULN Total Bilirubin** ≤ 1.5 x ULN

Oxygen Saturation (O2 Sat.) ≥92% on ambient air Hepatitis B status HBV Surface Antigen Negative HBV Surface Antibody Positive or Negative HBV Core Antibody Negative Hepatitis C status Anti-HCV Total Antibody Negative HCV RNA analysis Negative HIV status Rapid HIV 1/2 Antibodies Negative *Creatinine Clearance Calculated using the Cockcroft-Gault formula

Female CrCl = (140- age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL

Male CrCl = (140- age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

**Total Bilirubin ≤ 1.5 x ULN, except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL

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; type I diabetes mellitus; 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) or known acquired immunodeficiency syndrome (AIDS)

• Active Hepatitis B or Hepatitis C (defined as positive-HBV surface antigen or detectable HCV-antibody) indicating acute or chronic infection. 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 ESCC Nivolumab 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, 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.

• No herbal supplements are allowed in this protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Califonia, San Diego	La Jolla	California	United States	92093
2	University of Southern California	Los Angeles	California	United States	90033
3	New York University School of Medicine	New York	New York	United States	10016
4	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
5	Oregon Health Sciences University	Portland	Oregon	United States	97239

Sponsors and Collaborators

• NYU Langone Health

Investigators

• Principal Investigator: Jennifer Wu, MD, NYU Langone Health

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 22, 2020

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT03278626
• Other Study ID Numbers: 16-00971
• First Posted: Sep 11, 2017
• Last Update Posted: Mar 28, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by NYU Langone Health: Locally Advanced Esophageal Squamous Cell Carcinoma
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Paclitaxel; Carboplatin

Study Results

Participant Flow

Arm/Group Title	Nivolimumab+Carboplatin/Paclitaxel+Radiation
Arm/Group Description	240 mg IVPB every 2 weeks for 2 doses, nivolumab at 240 mg every 2 weeks will be added to paclitaxel and carboplatin, which will be dosed according to the standard of care: paclitaxel 50 mg/m2 weekly for 6 weeks and carboplatin AUC 2 weekly for 6 weeks and radiation Nivolimumab+Carboplatin/paclitaxel+Radiation: In the phase I portion of the study, up to six patients will be treated (radiation will be 50.4 Gy (1.8 Gy/fraction × 28 fractions)) and then observed for 28 days (following last day of treatment (Day 64)).
Period Title: Overall Study
STARTED	12
COMPLETED	7
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Nivolimumab+Carboplatin/Paclitaxel+Radiation
Arm/Group Description	240 mg IVPB every 2 weeks for 2 doses, nivolumab at 240 mg every 2 weeks will be added to paclitaxel and carboplatin, which will be dosed according to the standard of care: paclitaxel 50 mg/m2 weekly for 6 weeks and carboplatin AUC 2 weekly for 6 weeks and radiation Nivolimumab+Carboplatin/paclitaxel+Radiation: In the phase I portion of the study, up to six patients will be treated (radiation will be 50.4 Gy (1.8 Gy/fraction × 28 fractions)) and then observed for 28 days (following last day of treatment (Day 64)).
Overall Participants	12
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63.95
Sex: Female, Male (Count of Participants)
Female	5 41.7%
Male	7 58.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	12 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 25%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 16.7%
White	7 58.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	Phase 1: Number of Unacceptable Toxicity (UT) Events
Description	UT is defined as: Recurrent grade 3 or 4 hematologic toxicity (despite 1 prior dose reduction in chemotherapy) any toxicity that results in a > 2-week delay in chemoradiation
Time Frame	92 days (up to 28 days after Day 64)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nivolimumab+Carboplatin/Paclitaxel+Radiation
Arm/Group Description	240 mg IVPB every 2 weeks for 2 doses, nivolumab at 240 mg every 2 weeks will be added to paclitaxel and carboplatin, which will be dosed according to the standard of care: paclitaxel 50 mg/m2 weekly for 6 weeks and carboplatin AUC 2 weekly for 6 weeks and radiation Nivolimumab+Carboplatin/paclitaxel+Radiation: In the phase I portion of the study, up to six patients will be treated (radiation will be 50.4 Gy (1.8 Gy/fraction × 28 fractions)) and then observed for 28 days (following last day of treatment (Day 64)).
Measure Participants	6
Number [Unacceptable Toxicity Events]	0

2. Primary Outcome

Title	Phase 2: Number of Subjects Who Achieved cCR (Clinical Complete Response) or pCR (Pathological Complete Response)
Description	Clinical and pathological response after neoadjuvant therapy cCR by endoscopic + PET/CT evaluation; pCR for patients undergoing surgery Clinical Complete Response (cCR), no malignancy is found on clinical examination, imaging, endoscopy, and biopsy; Pathological Complete Response (pCR), no invasive and no in situ residual tumors in tissue
Time Frame	5-8 Weeks post radiation treatment (7-8 months after treatment start)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nivolimumab+Carboplatin/Paclitaxel+Radiation
Arm/Group Description	240 mg IVPB every 2 weeks for 2 doses, nivolumab at 240 mg every 2 weeks will be added to paclitaxel and carboplatin, which will be dosed according to the standard of care: paclitaxel 50 mg/m2 weekly for 6 weeks and carboplatin AUC 2 weekly for 6 weeks and radiation Nivolimumab+Carboplatin/paclitaxel+Radiation: In the phase I portion of the study, up to six patients will be treated (radiation will be 50.4 Gy (1.8 Gy/fraction × 28 fractions)) and then observed for 28 days (following last day of treatment (Day 64)).
Measure Participants	3
Count of Participants [Participants]	1 8.3%

Adverse Events

Time Frame	100 days post-treatment
Arm/Group Title	Nivolimumab+Carboplatin/Paclitaxel+Radiation
Arm/Group Description	240 mg IVPB every 2 weeks for 2 doses, nivolumab at 240 mg every 2 weeks will be added to paclitaxel and carboplatin, which will be dosed according to the standard of care: paclitaxel 50 mg/m2 weekly for 6 weeks and carboplatin AUC 2 weekly for 6 weeks and radiation Nivolimumab+Carboplatin/paclitaxel+Radiation: In the phase I portion of the study, up to six patients will be treated (radiation will be 50.4 Gy (1.8 Gy/fraction × 28 fractions)) and then observed for 28 days (following last day of treatment (Day 64)).
All Cause Mortality
	Nivolimumab+Carboplatin/Paclitaxel+Radiation
	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)
Serious Adverse Events
	Nivolimumab+Carboplatin/Paclitaxel+Radiation
	Affected / at Risk (%)	# Events
Total	6/12 (50%)
Cardiac disorders
Myocardial Infarction	1/12 (8.3%)
Gastrointestinal disorders
Abdominal Pain	1/12 (8.3%)
Colitis	1/12 (8.3%)
Dysphagia	1/12 (8.3%)
Esophagitis	1/12 (8.3%)
General disorders
Death	1/12 (8.3%)
Fever	1/12 (8.3%)
Infections and infestations
Lung Infection	1/12 (8.3%)
Psychiatric disorders
Confusion	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Rash-Morbiliform	1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	Nivolimumab+Carboplatin/Paclitaxel+Radiation
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Anemia	11/12 (91.7%)
Cardiac disorders
Chest Pain After Stent	1/12 (8.3%)
Tachycardia	1/12 (8.3%)
Ear and labyrinth disorders
Tinnitus	1/12 (8.3%)
Gastrointestinal disorders
Abdominal Pain	3/12 (25%)
Bloating	1/12 (8.3%)
Colitis	1/12 (8.3%)
Constipation	6/12 (50%)
Diarrhea	3/12 (25%)
Dry Mouth	3/12 (25%)
Dyspepsia	1/12 (8.3%)
Dysphagia	8/12 (66.7%)
Dyspnea	3/12 (25%)
Esophageal Discomfort	1/12 (8.3%)
Esophageal Pain	5/12 (41.7%)
Esophagitis	5/12 (41.7%)
Flatulence	6/12 (50%)
Gastrointestinal Pain	1/12 (8.3%)
Mucositis Oral	1/12 (8.3%)
Nausea	7/12 (58.3%)
Oral Pain	1/12 (8.3%)
Vomiting	4/12 (33.3%)
Vomiting After Stent	1/12 (8.3%)
General disorders
Fatigue	6/12 (50%)
Fever	1/12 (8.3%)
Hyponatremia	4/12 (33.3%)
Infusion Related Reaction	1/12 (8.3%)
Intermittent Non Cardiac Chest Pain	1/12 (8.3%)
Night Sweats	1/12 (8.3%)
Nose Bleed	1/12 (8.3%)
Odynophagia	1/12 (8.3%)
Pain	2/12 (16.7%)
Post Operation Pain	1/12 (8.3%)
Rectal Bleeding	1/12 (8.3%)
Infections and infestations
Upper Respiratory Infection	1/12 (8.3%)
Upper Respiratory Tract Infection	1/12 (8.3%)
Injury, poisoning and procedural complications
Bruising	1/12 (8.3%)
Investigations
Activated Partial Thromboplastin Time Prolonged	1/12 (8.3%)
Alanine Aminotransferase Increased	3/12 (25%)
Aspartate Aminotransferase Increased	4/12 (33.3%)
Decreased Lymphocyte Count	10/12 (83.3%)
Decreased Neutrophil Count	7/12 (58.3%)
Decreased Platelet Count	9/12 (75%)
Decreased Wbc Count	9/12 (75%)
Increased Blood Bilirubin	4/12 (33.3%)
Increased Wbc	1/12 (8.3%)
INR Increased	2/12 (16.7%)
Low Tsh	1/12 (8.3%)
Weight Loss	3/12 (25%)
Alt Increased	3/12 (25%)
Ast Increased	3/12 (25%)
Increased Alk Phos	2/12 (16.7%)
Metabolism and nutrition disorders
Anorexia	5/12 (41.7%)
Dehydration	3/12 (25%)
Hypercalcemia	1/12 (8.3%)
Hyperglycemia	5/12 (41.7%)
Hyperkalemia	3/12 (25%)
Hypernatremia	3/12 (25%)
Hypoalbuminemia	6/12 (50%)
Hypocalcemia	3/12 (25%)
Hypoglycemia	3/12 (25%)
Hypokalemia	7/12 (58.3%)
Hypomagnesemia	4/12 (33.3%)
Hypophosphatemia	3/12 (25%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/12 (16.7%)
Arthralgia Knee Pain	1/12 (8.3%)
Back Pain	1/12 (8.3%)
Generalized Muscle Weakness	1/12 (8.3%)
Left Hip Pain	1/12 (8.3%)
Leg Cramps	1/12 (8.3%)
Myositis	1/12 (8.3%)
Upper Back Pain	1/12 (8.3%)
Nervous system disorders
Ataxia	1/12 (8.3%)
Dizziness	1/12 (8.3%)
Dysgeusia	2/12 (16.7%)
Peripheral Sensory Neuropathy	1/12 (8.3%)
Presyncope	1/12 (8.3%)
Syncope	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Aspiration	5/12 (41.7%)
Cough	5/12 (41.7%)
Hoarseness	2/12 (16.7%)
Nasal Congestion	1/12 (8.3%)
Pharyngolaryngeal Pain	1/12 (8.3%)
Productive Cough	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/12 (8.3%)
Dermatitis	1/12 (8.3%)
Dermatitis Radiation	2/12 (16.7%)
Dry Skin	1/12 (8.3%)
Pruritus	2/12 (16.7%)
Rash Maculo-Papular	4/12 (33.3%)
Rash-Morbiliform	4/12 (33.3%)
Vascular disorders
Hypertension	1/12 (8.3%)
Hypotension	2/12 (16.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.