Neoplasms

Digestive System Diseases

All Conditions

Rare Diseases

Esophageal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Carboplatin

Capecitabine

Everolimus

Oxaliplatin

Antimetabolites

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Patients receive XELOX comprising oxaliplatin intravenously (IV) over 120 minutes on day 1 and capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo radiotherapy (RT) 5 days a week for up to 6 weeks. Patients also receive carboplatin IV over 15 minutes to 24 hours once weekly for 5-6 weeks and RAD001 PO every other day (QOD) or once daily (QD) for 5-6 weeks during radiation therapy (RT). Patients with resectable disease undergo surgery.

Dose escalation for Phase I; dose for Phase II to be determined after Phase I is completed.

RAD001

Patients will receive two cycles of XELOX.

XELOX

Given on a 3 weeks on and 1 week off schedule.

1.8 Gy to 36 Gy; 3 fields or laterals to 50.4 Gy.

Radiation

Nabil F. Saba, MD

The purpose of this study is to test the drug RAD001 in combination with another chemotherapy drug, Carboplatin, as well as radiation therapy in the treatment of esophageal cancer. Because RAD001 has not been used in this combination before, it is not clear which dose will be best when used in combination.

The standard of care for patients who have esophageal cancer that has not moved to other areas of the body (non-metastatic) includes a combination of chemotherapy, radiation therapy and possibly surgery. If the patient chooses to participate in this study, the patient will receive chemotherapy and radiation therapy. The patient will possibly also have surgery to have the cancer removed. This decision will be made by the treating physicians. All of the chemotherapy the patient will receive on the study is considered standard chemotherapy for esophagus cancer. The investigators do not know as of yet if the drug called RAD001 will help improve the treatment for patients with this disease. RAD001 is a pill that has been used in many other types of cancer and has been proven to be effective in other cancers such as kidney cancer.

Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Recent medical advances have led to small improvements in survival, but the overall rate of survival remains low, making new treatment approaches necessary.

Chemotherapy drugs and radiation therapy are often both used in treating esophageal cancer. The combination of oxaliplatin and capecitabine (XELOX) is a commonly used chemotherapy combination. Sometimes chemotherapy is given as an "induction" therapy, before the radiation is given.

The drug RAD001 is a targeted drug that acts specifically on a protein inside cells (called mTOR), which is important for cancer development. The combination of RAD001 and radiation therapy has been shown to improve anti-cancer effects.

This study will look for the ideal dose of RAD001 when given in combination with radiation therapy after induction chemotherapy with XELOX, and test the anticancer effects of this treatment approach in patients with esophageal cancer.

Trial of XELOX Followed by Radiation Combined With Carboplatin and RAD001 for Esophageal Cancer

Phase I/IIB Study of Induction Chemotherapy With XELOX, Followed by Radiation Therapy and Dose Escalation of RAD001 in Patients With Esophageal Cancer

Novartis

Emory University

Principal Investigator

Anti-MUC1 CAR-T cells will be prepared ex vivo using the T cells from the patients and infused back to the patients.

Anti-MUC1 CAR-T cells and PD-1 knockout Engineered T cells will be prepared ex vivo using the T cells from the patients and infused back to the patients.

PD-1 knockout Engineered T cells will be prepared ex vivo using the T cells from the patients and infused back to the patients.

Using the T cells from the patients' blood to produce anti-MUC1 CAR-T Cells and then the cells will be infused back to the patients.

Anti-MUC1 CAR-T cells

Using the T cells from the blood of the patients to prepare PD-1 knockout T cells, then the cells will be infused back to the patients.

PD-1 knockout Engineered T cells

Using the T cells from the blood of the patients to prepare anti-MUC1 CAR-T Cells and PD-1 knockout T cells, then the cells will be infused back to the patients

CAR-T combined with PD-1 Knockout T cells

Size Chen, MD, PhD

Zhizhou Huang, MSc

Guobiao Huang

Size Chen, MD,PhD

Yiguang Lin, MD, PhD

Micheal Yin, PhD

The study is to assess the safety and efficacy of the immunotherapies using anti-MUC1 CAR T cells and /or PD-1 knockout engineered T cells in the treatment of patients with advanced esophageal cancer.

This is a combined phase 1 and 2 clinical study. The aim of the study is to assess the safety and efficacy of the immunotherapies using anti- MUC1 CAR T cells alone, anti- MUC1 CAR T combining PD-1 knockout engineered T cells, and PD-1 knockout engineered T cell only in the treatment of patients with advanced esophageal cancer. The treatment outcomes from each group will be compared.

CAR T and PD-1 Knockout Engineered T Cells for Esophageal Cancer

Combination Therapy of Anti-MUC1 CAR T Cells and PD-1 Knockout Engineered T Cells for Advanced Esophageal Cancer

Safety and tolerability of dose of CART-cells and PD-1 Knockout T cells will be assessed using CTCAE v4.0.

Will be assessed according to the revised RECIST guideline v1.1

Measure the time from enrollment to death

Time from enrollment to date of first documented progression or date of death.

Guangzhou Anjie Biomedical Technology Co., Ltd.

The First Affiliated Hospital of Guangdong Pharmaceutical University

Associate Professor

Nivolumab

Vaccines

Immunomodulating Agents

Monatide (IMS 3015)

Entinostat

Adjuvants, Vaccine

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Adjuvants, Immunologic

Histone Deacetylase Inhibitors

H1299 cell lysate vaccine with Montanide(R) ISA-51 VG, entinostat, and nivolumab (Phase I component to determine lysate dose)

H1299 cell lysate vaccine with Montanide(R) ISA-51 VG, entinostat, and nivolumab (lysate at dose determined in Phase I)

Nivolumab 480 mg flat dose via intravenous infusion on Day 3 of every cycle starting at Cycle 2, for intended duration of 1 year.

Entinostat (5 mg) self-administered on Days -14 and -7 prior to the first vaccination cycle, then entinostat (3 mg) self-administered on Days 1, 8, 15, and 22 of each vaccine cycle (Cycles 1-6). Entinostat continuation for subjects with immunologic response and NED during additional 2 vaccine injections.

H1299 cell lysate with Montanide(R) ISA-51 VG adjuvant vaccine via subcutaneous injections once every cycle (1 cycle=28 days) for 6 cycles (i.e., 6 vaccinations). Dose Level 1 (DL1) starting dose is 20 mg lysate protein in 2-2.5 mL Montanide(R) ISA-51 VG adjuvant; lysate concentration will be 8-10 mg/mL. Additional 2 vaccine injections for subjects with immunologic response and NED.

Montanide(R) ISA-51 VG Adjuvant

H1299 Cell Lysates

Deneise Francis, R.N.

David S Schrump, M.D.

National Cancer Institute Referral Office

This is a Phase I/II study to determine the safety and immune response of the H1299 cell lysate vaccine mixed with Montanide(R) ISA-51 VG adjuvant, to be administered on the study in combination with Entinostat and Nivolumab in eligible participants with locally advanced esophageal cancers (EsC) following either neoadjuvant chemoradiation therapy (nCRT) or nCRT and surgery. Phase I of the protocol aims to determine the safe dose of the H1299 lung cancer cell lysate vaccine mixed with Montanide(R) ISA-51 VG adjuvant when it is administered in combination with Entinostat and Nivolumab. Phase II of the protocol will focus on assessing the level of immune response in participants receiving the study intervention when the H1299 cell lysate vaccine with Montanide(R) ISA-51 VG adjuvant is administered at the dose level determined in Phase I.

Background:

* Esophageal cancers (EsC) are highly lethal malignancies with strong predilections for local and systemic recurrences despite aggressive multimodality interventions.
* Currently the standard of care for locally advanced (stage II/III) EsC is neoadjuvant chemoradiation therapy (nCRT) and surgery.
* Nearly 50% of patients with esophageal squamous cell cancers (ESCC) and 25% of patients with esophageal adenocarcinomas (EAC) have pathologic complete responses (pCR) following nCRT.
* Current staging modalities cannot reliably detect all residual EsC following nCRT, and the benefit of surgery in patients with pCR is unclear.
* Recently nivolumab was approved as adjuvant therapy for patients who have undergone complete (R0) resections of locally advanced esophageal or gastro-esophageal junction (GEJ) carcinomas with pathologic incomplete responses (pIR) following nCRT.
* Preclinical studies and early phase clinical studies suggest that immune checkpoint inhibitors can improve the efficacy of vaccines targeting tumor associated antigens.
* Cancer-testis (CT) antigens (CTA), particularly those encoded by genes on the X chromosome (CT-X antigens) have emerged as attractive targets for cancer immunotherapy given their highly restricted expression in cancers but not normal tissues and oncogenic activities.
* Recent studies suggest that CT antigens are preferentially expressed in pluripotent stem/tumor initiating cells that mediate treatment resistance and metastasis of human cancers.
* Treatment interventions that inhibit activity of immunosuppressive Treg cells significantly increase efficacy of cancer vaccines and immune checkpoint inhibitors; the triple combination therapy cures nearly all mice with established, highly aggressive cancers.
* The class I histone deacetylase (HDAC) inhibitor, entinostat which inhibits Treg activity appears to favorably modulate immune cell subsets in patients with advanced cancers receiving nivolumab.
* Conceivably, vaccination of EsC patients with tumor cell lysates containing high levels of CT antigens in combination with entinostat will facilitate eradication of dormant EsC cells following immune checkpoint blockade.

Primary Objectives:

* Phase I: To determine the safe dose of adjuvant H1299 lung cancer cell lysate vaccines with Montanide(R) ISA-51 VG administered in conjunction with entinostat and nivolumab in participants with locally advanced esophageal cancers (EsC) with pathologic incomplete responses (pIR) following neoadjuvant chemoradiation therapy (nCRT).
* Phase II: To assess the frequency of immunologic responses to purified CT antigens in EsC participants following vaccinations with H1299 cancer cell lysates and Montanide(R) ISA- 51 VG in combination with entinostat and nivolumab.

Eligibility:

* Participants with clinical Stage II or Stage III EsC with pIR following nCRT within the past 16 weeks
* Participants must be 18 years or older with an ECOG performance status of 0 1
* Adequate bone marrow, kidney, liver, lung, and cardiac function
* No prior anti-PD-1/PD-L1 therapy for their EsC
* Participants receiving steroids at supraphysiologic doses will be excluded.
* Participants with HIV or any active infections will be excluded.

Design:

* After recovery from nCRT or nCRT and surgery, eligible participants will commence oral entinostat (5 mg q week).
* Following a two-week entinostat run-in, participants will commence monthly deep subcutaneous vaccinations with H1299 cell lysates and Montanide (r) ISA-51 VG until six vaccinations have been given (each cycle=28 days).
* Following the two-week entinostat (5 mg q week) run-in, entinostat will be administered at a dose of 3 mg q week during nivolumab therapy.
* Four weeks after the first vaccination, participants will commence nivolumab (480 mg IV infusion) monthly for 1 year.
* Each cycle of vaccine therapy is 4 weeks (28 days).
* Participants will be scanned every 12 weeks while on treatment or continued treatment, and during follow up every 3 months for 3 years, every 6 months for another 2 years or through disease progression.
* Leukapheresis will be performed at baseline and at treatment evaluation one month following completion of the six vaccinations.
* Systemic toxicities and immunologic responses to therapy will be recorded.
* Pre- and post-vaccination serologic and cell mediated responses to a panel of CT antigens will be assessed before and one month following completion of the six vaccinations.
* Individuals deemed to have responded to the vaccine regimen and exhibit no evidence of disease recurrence or secondary malignancy will be eligible for two additional vaccinations administered q3 months with weekly entinostat and monthly nivolumab.
* Numbers and percentages of immune subsets, soluble factors, and cytokines in peripheral blood will be assessed before and after the six vaccinations.
* Immunologic responses to autologous tumor cells (if available) as well as lysates from H1299 cells and EsC stem cells vs normal esophageal-induced pluripotent stem cells (Eso-iPSC) will be evaluated in an exploratory manner.
* Accrual ceiling will be set at 50 participants.

Phase I/II Evaluation of a Cancer Lysate Vaccine and Montanide(R) ISA-51 VG With Entinostat and Nivolumab as Adjuvant Therapy Following Chemoradiation Therapy With or Without Surgery for Locally Advanced Esophageal Cancer

.All IPD recorded will be shared upon request.

Assessment of safety and tolerability as determined by the frequency and severity of adverse events

Assessment of immune response to CT antigens (new serologic reactivity or increase in existing antibody response to CT antigens, evidenced by IgM/IgG class switch or antibody titer)

Analyses which investigate immunologic response (i.e., immune response to CT antigens); response to vaccine will be the appearance of new serologic reactivity or an increase in existing antibody response to CT antigens, evidenced by IgM/IgG class switch or antibody titer.

Progression free survival (PFS) determined by RECIST using the Kaplan-Meier method

National Cancer Institute (NCI)

Respiratory Tract (Lung and Bronchial) Diseases

Symptoms and General Pathology

Respiratory Aspiration

Respiration Disorders

Respiratory Tract Diseases

Patients will start the IMT-R, following their consent and within 2 weeks of their scheduled surgery: 10 sessions lasting about 90 minutes. Participants who completed their initial IMT greater than 2 weeks prior to surgery will have an additional visit prior to surgery. Participants will receive a Participant Manual demonstrating and explaining the rehabilitation process. Participants will also receive a log for recording their efforts and notes. A DVD of the rehabilitation is available to the participant. Participants will complete questionnaires at baseline and 3 months.

The training will include the following components:

1. Breathing Awareness
2. Upper and Lower Extremity Exercise.
3. Instructions for Inspiratory Muscle Training (IMT) performed using the PFlex valve
4. Practice at home

Inspiratory Muscle Training-Rehabilitation

Patient quality of life will be measured using patient-reported outcomes measurement information system (PROMIS) global items. Patients will also complete the Chronic Respiratory Questionnaire (CRQ) and the Medical Research Council Dyspnea Scale (MCR).

Questionnaires

Roberto P Benzo

To obtain definitive evidence for the effectiveness of a short preoperative inspiratory muscle training (IMT) protocol on the morbidity and recovery from an esophageal surgical resection.

Study of Inspiratory Muscle Training for Patients Undergoing Esophageal Surgery

A Pilot Study of Inspiratory Muscle Training for Patients Undergoing Esophageal Surgery

Length of hospital stay will be measured by participant monitoring while hospitalized until hospital discharge.

Quality of life will be assessed at baseline and at 3 months after hospital discharge by participant completion of the PROMIS Global 10.

To prospectively determine the effect of a customized preoperative inspiratory muscle training (IMT) and brief pulmonary rehabilitation program on the incidence of postoperative pneumonia in patients that undergo an esophageal surgical resection. The investigators will consider the following as pneumonia: new infiltrate + either fever (\>38.5 C) and white cell count \>11,000 or fever and purulent secretions.

To prospectively determine the effect of a customized preoperative inspiratory muscle training (IMT) and brief pulmonary rehabilitation program on the incidence of postoperative pulmonary complications in patients that undergo an esophageal surgical resection.The investigators will consider the following events as post-operative pulmonary complications: severe atelectasis (requiring bronchoscopy) and respiratory failure (intubation or prolonged mechanical ventilation (\>24hours).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Trial of XELOX Followed by Radiation Combined With Carboplatin and RAD001 for Esophageal Cancer	NCT01490749	Esophageal Canc... Neoplasms, Esop...	RAD001 XELOX Carboplatin Radiation	18 Years -	Emory University
CAR T and PD-1 Knockout Engineered T Cells for Esophageal Cancer	NCT03706326	Advanced Esopha...	Anti-MUC1 CAR-T... PD-1 knockout E... CAR-T combined ...	18 Years - 80 Years	The First Affiliated Hospital of Guangdong Pharmaceutical University
Phase I/II Evaluation of a Cancer Lysate Vaccine and Montanide(R) ISA-51 VG With Entinostat and Nivolumab as Adjuvant Therapy Following Chemoradiation Therapy With or Without Surgery for Locally Advanced Esophageal Cancer	NCT05898828	Neoplasms Esophageal Neop... Esophagus Neopl... Esophagus Cance... Neoplasms, Esop... Esophageal Canc...	Nivolumab Entinostat Montanide(R) IS... H1299 Cell Lysa...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Trial of XELOX Followed by Radiation Combined With Carboplatin and RAD001 for Esophageal Cancer	NCT01490749	Esophageal Canc... Neoplasms, Esop...	RAD001 XELOX Carboplatin Radiation	18 Years -	Emory University
Study of Inspiratory Muscle Training for Patients Undergoing Esophageal Surgery	NCT02843750	Cancer of Esoph... Cancer of the E... Esophageal Canc... Esophagus Cance... Esophagus Neopl... Neoplasms, Esop...	Inspiratory Mus... Questionnaires	40 Years - 99 Years	Mayo Clinic
Phase I/II Evaluation of a Cancer Lysate Vaccine and Montanide(R) ISA-51 VG With Entinostat and Nivolumab as Adjuvant Therapy Following Chemoradiation Therapy With or Without Surgery for Locally Advanced Esophageal Cancer	NCT05898828	Neoplasms Esophageal Neop... Esophagus Neopl... Esophagus Cance... Neoplasms, Esop... Esophageal Canc...	Nivolumab Entinostat Montanide(R) IS... H1299 Cell Lysa...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for neoplasms, esophageal