Neoplasms

Digestive System Diseases

All Conditions

Rare Diseases

Esophageal Neoplasms

Esophageal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Carboplatin

Albumin-Bound Paclitaxel

Avelumab

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

6 patients enrolled will receive weekly carboplatin (AUC2) and paclitaxel (50 mg/m2) \[intravenous infusion on days 1, 8, 15, 22, \& 29\] while undergoing radiation therapy \[23 fractions, M-F, estimated completion day 35\].

Avelumab combined with Chemoradiation - Avelumab (10 mg/kg IV) every 2 weeks starting on the day of the last chemotherapy infusion (day 29). A total of 3 doses administered during the pre-operative period and an additional 6 doses of avelumab post-operatively.

Trial enrollment will resume after at least 5 patients do not have a DLT during the DLT evaluation period or until all 6 patients are seen for post-operative evaluation. If 2 or more patients experience dose limiting toxicities associated with the proposed treatments, further accrual of the subjects will be halted and trial will be suspended. Trial may be reopened in the future with appropriate schedule and dose modifications of the proposed treatment.

Following a determination of safe and tolerable treatment outcome of the Run-In Phase, Part 2 of the trial will enroll 18 additional patients to evaluate activity of the proposed treatment and to obtain further safety information (carboplatin, paclitaxel, radiation \& Avelumab combined with Chemoradiation).

Co-administration of avelumab with chemoradiation in pre-operative period.

Avelumab combined with Chemoradiation

Weekly Carboplatin (AUC2) \[intravenous infusion on days 1, 8, 15, 22, \& 29\]

Weekly paclitaxel \[intravenous infusion on days 1, 8, 15, 22, \& 29\]

Radiation therapy \[23 fractions, M-F, estimated completion day 35\]

Radiation

Nataliya Uboha

This is a 2 part Phase I/II clinical trial evaluating the safety, tolerability and efficacy of avelumab in combination with chemoradiation in patients with resectable esophageal and gastroesophageal cancer.

Part 1: This is the run-in phase of the trial. This portion will determine the safety and tolerability of avelumab in combination with chemoradiotherapy in 6 patients. The proposed combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.

Part 2: This is a Phase 2 portion of the trial, which will evaluate the efficacy of the proposed treatment regimen in patients with stage II/III resectable esophageal and gastroesophageal cancer

Background:

Neoadjuvant chemoradiation is part of the standard of care for patients with stage II and III resectable esophageal and gastroesophageal cancer. This approach is based on the results of a large randomized clinical trial (CROSS) that demonstrated superior survival in patients receiving neoadjuvant chemoradiotherapy followed by surgical resection compared to patients treated with surgery alone. Pathological complete response at the time of resection is strongly linked to better survival. However, with current strategies pathological complete response is achieved only in a minority (29%) of patients. Remaining patients, especially those with positive lymph nodes at the time of the resection, are at significant risk for recurrences. Five-year survival rate for these patients is only 37%, and overall survival is as low as 9 months for those with persistent lymph node disease. Among patients who develop recurrent disease, most present with distant metastases outside of the radiation field. This is not surprising since the accepted treatment paradigm for this disease does not target possible disseminated microscopic systemic disease. Hence, novel strategies are needed to improve outcomes of these patients. We propose conducting a phase I/II clinical trial evaluating a role of immune checkpoint inhibitor in combination with chemoradiotherapy and post-operatively in the management of resectable esophageal cancer.

Study Rationale:

1. A number of preclinical and clinical studies demonstrated synergism between radiation and immunotherapy, suggesting that combining these approaches can enhance anti-tumor activity and increase treatment efficacy.
2. Immune checkpoint inhibitors have demonstrated promising activity in a subset of patients with metastatic esophageal and gastric cancers. Moving these agents into neoadjuvant setting may increase the cure rate of this disease compared to the standard approach.
3. Current neoadjuvant therapy does not target any potential microscopic disease outside of the radiation field since chemotherapy serves primarily as a radiation sensitizer. Immunotherapy treatment will target both local and systemic disease.

Hypothesis:

We hypothesize that co-administration of avelumab with chemoradiation will be well tolerated and will increase pathological complete response rate in resected tumor specimens. We hypothesize that avelumab treatment will also decrease the rates of disease recurrence.

Study Design:

This is a 2 part Phase I/II clinical trial evaluating the safety, tolerability and efficacy of avelumab in combination with chemoradiation in patients with resectable esophageal and gastroesophageal cancer.

Part 1: This is the run-in phase of the trial. This portion will determine the safety and tolerability of avelumab in combination with chemoradiotherapy in 6 patients. The proposed combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.

Part 2: This is a Phase 2 portion of the trial, which will evaluate the efficacy of the proposed treatment regimen in patients with stage II/III resectable esophageal and gastroesophageal cancer.

Objectives:

Primary: Evaluate the safety of avelumab in combination with chemoradiation in patients with resectable esophageal cancer and gastroesophageal receiving perioperative therapy.

Secondary: Obtain efficacy data and further safety data of the proposed drug combination in this patient population.

Exploratory objectives: The translational focus of the study will evaluate changes in tumor microenvironment that occur in response to radiation and immunotherapy.

Endpoints:

Part 1 - Primary endpoint: Establish safety and tolerability of the proposed treatment.

Part 2 - Primary Endpoint: Pathological complete response rate.

Part 2 - Secondary Endpoints:

1. Safety and tolerability.
2. Disease free survival.
3. Incidence of surgical complications.
4. Rate of R0 resection.

Number of centers \& patients: One center.

Part 1: total of 6 eligible patients will be accrued to evaluate the safety and tolerability of the proposed combination.

Part 2: 18 patients will be enrolled in the phase 2 portion of the trial.

Population:

Patients with histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and gastroesophagus who are candidates for neoadjuvant therapy and surgical resection.

Investigational drugs:

Avelumab (Provided by EMD Serono). IND information to be added as needed.

The study is a two-part phase 1/2 clinical trial conducted in one center.

Part 1. Run-in phase to assess the safety and tolerability of avelumab in combination with chemoradiation. Will enroll 6 patients, after which accrual will be stopped temporarily while safety data is being obtained.

Part 2. An open-label phase 2 study. Part 2 will obtain further safety data of the proposed drug combination and will evaluate the anti-tumor efficacy of perioperative avelumab and chemoradiation in this patient population. Will enroll 18 additional patients.

Each phase of the study will have a 21-day screening period, treatment procedures (neoadjuvant therapy, resection and adjuvant therapy), and active surveillance for a year after the completion of adjuvant therapy.

After active surveillance visit at 12 months post treatment completion, survival data and disease status will be collected via phone calls or medical record review every 6 months during the following 3 years.

Avelumab With Chemoradiation for Stage II/III Resectable Esophageal and Gastroesophageal Cancer

Phase I/II Trial of Avelumab in Combination With Chemoradiation in the Treatment of Stage II/III Resectable Esophageal and Gastroesophageal Cancer

A total number of 6 subjects will be enrolled during the run-in phase of the trial. A sample size of 6 is sufficient to estimate the true dose limiting toxicity rate of the proposed avelumab/chemoradiation therapy with adequate accuracy. Specifically, the true dose limiting toxicity rate will be estimated with a standard error of 20%. The proposed treatment combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.

Pathologic compete response (pCR) is defined as an absence of any viable tumor at microscopic examination of the primary tumor and any lymph nodes sampled after surgery following neoadjuvant therapy. Participants with invalid/missing pCR assessments will be defined as non-responders. The number and frequency of patients with a pCR will be summarized in tabular format. The pCR rate will be reported along with the corresponding 90% confidence interval which will be constructed using the Wilson score method.

Part 2 will further evaluate the safety of the studied drug combination, building on the observations from Part 1.

All patients who receive at least one dose of avelumab will be evaluated for toxicity. Toxicities observed will be summarized in terms of types and severities by Common Terminology Criteria for Adverse Events (CTCAE) v 5.0. The number and severity of toxicity incidents will be analyzed descriptively in tabular format. The 90% confidence interval for the dose limiting toxicity rate (DLT) will be constructed using the Wilson score method.

Part 2 will further evaluate the tolerability of the studied drug combination, building on the observations from Part 1.

Tolerability will be reported as the number of subjects who did or did not complete the planned treatment, including the reason they ended treatment early.

Disease free survival (DFS) will be defined as the number of days from the day of resection to the day a subject experiences an event of disease recurrence or death, whichever comes first. If a subject has not experienced an event of disease recurrence progression or death at the time of analysis, then the subject's data will be censored at the date of the last available evaluation. DFS will be summarized using point estimates of the median time to progression and the associated 95% confidence interval. The data will be presented graphically using Kaplan-Meier plots.

Incidence of surgical complications will be calculated and reported along with the corresponding 95% confidence intervals which will be constructed using the Wilson score method.

Rate of R0 resection will be calculated and reported along with the corresponding 95% confidence intervals which will be constructed using the Wilson score method.

University of Wisconsin, Madison

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Cetuximab

cetuximab initial dose 400 mg/m2 iv 1 week before start radiotherapy and subsequent weekly doses of 250 mg/m2 iv for the duration of the radiation treatment

cetuximab

45 Gy delivered in 25 fractions of 1.8 Gy 5d/wk

radiotherapy to oesophageal tumour

M. P. Lolkema, MD/PhD

The purpose of this study is to determine whether the addition of the combination between cetuximab and radiotherapy to the standard chemotherapy for resectable oesophageal cancer is safe and adds efficacy.

This study aims at developing a novel strategy to optimize the treatment of oesophageal adenocarcinoma and gastro-oesophageal junctional tumors with curative intent. Surgery in combination with peri-operative chemotherapy, using the combination epirubicin, cisplatin and 5-FU, as defined by the recent MAGIC trial, results in 13% increase in 5-yr survival. To improve the outcome of patients with this disease we hypothesize that the addition of pre-operative combined cetuximab-radiotherapy (cetux-RT) treatment could improve the outcome of this patient category through better local control.

Study of Combination of Cetuximab and Radiotherapy Added to the Standard Treatment for Oesophageal Adenocarcinoma

Multi-Modality Treatment of Resectable Oesophageal Adenocarcinoma Using Peri-operative Chemotherapy With Additional Pre-operative Combined Radiotherapy and Cetuximab

determination of tumor residual cell content in surgical specimen

Merck KGaA, Darmstadt, Germany

P.O. Witteveen

Head of Department

Symptoms and General Pathology

Neoplastic Cells, Circulating

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Neoplasm Metastasis

Neoplastic Processes

This prospective, single-institution study conducted at the University Hospital Hamburg-Eppendorf (Hamburg, Germany) enrolled 123 patients with ECs that were initially considered resectable. Only patients with histologically proven EC were included. Peripheral blood samples for CTC analysis were collected immediately before surgery.

esophagectomy

Despite the availability of several preoperative diagnostic techniques, accurate pretreatment staging of esophageal cancer (EC) remains challenging. Therefore, The investigators evaluated the prognostic significance of circulating tumor cells (CTCs) in patients with EC.

Circulating Tumor Cells as a Biomarker for Preoperative Prognostic Staging in Patients With Esophageal Cancer

Universitätsklinikum Hamburg-Eppendorf

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Irinotecan

Cisplatin

Celecoxib

Topoisomerase I Inhibitors

Enzyme Inhibitors

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Cisplatin, CPT-11 and Celecoxib With Radiation Therapy and Surgery for Operable Esophageal Cancer

Given weekly on weeks 1, 2, 4 and 5 during radiation therapy.

Given weekly on weeks 1, 2, 4 and 5 during radiation therapy

Given twice daily 3 days prior to radiation and up until one week prior to surgery. It will then be started again once the participant is released from the hospital following surgery for 26 weeks.

Radiation Therapy

Within 4-8 weeks of chemoradiation therapy

Esophagectomy

Peter C. Enzinger, MD

This is a study for patients with resectable, locally advanced esophageal cancer. There is evidence to suggest that celecoxib in combination with cisplatin and irinotecan (CPT-11) may work well with radiation therapy to kill cancer cells. The primary goal is to develop a well-tolerated cancer treatment that has an acceptable response rate.

Patients will take celecoxib orally twice daily 3 days prior to radiation therapy and until one week prior to surgery. Celecoxib will then be restarted when the patient is discharged from the hospital following surgery and continued for 26 weeks.

Patients will receive chemotherapy (cisplatin and irinotecan) weekly on weeks 1, 2, 4 and 5 during radiation therapy. Chemotherapy must occur on or before the fifth day of radiation therapy.

Radiation therapy will be performed 5 days a week over a 5.6 week period.

Patients will undergo an esophagectomy within 4-8 weeks of chemotherapy/radiation therapy. Technically accessible lymph nodes will also be removed.

During chemotherapy/radiation therapy, a physical exam and bloodwork will be conducted weekly.

Between chemotherapy/radiation therapy and surgery a physical exam, bloodwork and CT of chest, abdomen, and pelvis should be performed.

After the completion of treatment and surgery, a physical exam and bloodwork should be done every 6 weeks for 6 months, then every 3 months for 1 1/2 years, then every 6 months for 3 years.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Avelumab With Chemoradiation for Stage II/III Resectable Esophageal and Gastroesophageal Cancer	NCT03490292	Resectable Esop... GastroEsophagea...	Avelumab combin... Carboplatin Paclitaxel Radiation	18 Years -	University of Wisconsin, Madison
Study of Combination of Cetuximab and Radiotherapy Added to the Standard Treatment for Oesophageal Adenocarcinoma	NCT00827671	Resectable Esop...	cetuximab radiotherapy to...	18 Years -	UMC Utrecht
Circulating Tumor Cells as a Biomarker for Preoperative Prognostic Staging in Patients With Esophageal Cancer	NCT01858805	Resectable Esop...	esophagectomy	18 Years -	Universitätsklinikum Hamburg-Eppendorf
Cisplatin, CPT-11 and Celecoxib With Radiation Therapy and Surgery for Operable Esophageal Cancer	NCT00137852	Esophageal Canc...	Cisplatin Irinotecan Celecoxib Radiation Thera... Esophagectomy	18 Years -	Dana-Farber Cancer Institute
Circulating Tumor Cells as a Biomarker for Preoperative Prognostic Staging in Patients With Esophageal Cancer	NCT01858805	Resectable Esop...	esophagectomy	18 Years -	Universitätsklinikum Hamburg-Eppendorf

Spots Global Cancer Trial Database for resectable esophageal cancer