APX005M With Concurrent Chemoradiation for Resectable Esophageal and Gastroesophageal Junction Cancers

Study Overview
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Brief Summary
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This pilot phase II trial studies the side effects of CD40 agonistic monoclonal antibody APX005M (APX005M), chemotherapy, and radiation therapy, and to see how well they work when given before surgery in treating patients with esophageal cancer or gastroesophageal cancer that can be removed by surgery. APX005M is intended to stimulate the body's own immune system so that the immune cells can more effectively invade and destroy the tumor, adding to the benefits of the chemotherapy and radiation therapy. 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 APX005M, chemotherapy, and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description
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Primary Objective: To assess the efficacy of this novel combination, as measured by the pathologic complete response (pCR) rate. Secondary Objectives: To further characterize the safety and feasibility of combining APX005M with SOC chemoradiation (external beam radiation in daily fractions, with concurrent weekly low-dose carboplatin/paclitaxel) in the neoadjuvant setting for patients with resectable esophageal and GE junction cancers. To assess the efficacy of combining APX005M with SOC chemoradiation as measured by rates of R0 resection (microscopically negative margins, i.e., no tumor remains following surgery); and radiographic/metabolic response to neoadjuvant treatment on CT-PET. Exploratory Objectives: To identify possible predictive molecular or immune-based efficacy biomarkers for this novel combination. To characterize and assess overall survival.

Official Title
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A Phase 2 Study of APX005M in Combination With Concurrent Chemoradiation as Neoadjuvant Therapy for Resectable Esophageal and Gastroesophageal Junction Cancers

Conditions
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Esophageal Cancer, GastroEsophageal Cancer

Intervention / Treatment
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* Drug: APX005M
* Radiation: Radiation Therapy
* Drug: Paclitaxel
* Drug: Carboplatin
* Procedure: Surgical resection of tumor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years of age Histologically proven squamous cell carcinoma, adenocarcinoma or undifferentiated carcinoma of the esophagus or GE junction Surgically resectable (T1-3 Nx preferably by endoscopic ultrasound [EUS]). (Excluded: T1N0 tumors, cervical esophageal location, tumors invading the tracheobronchial tree or with fistula, distant disease that cannot be included in the radiation field or be resected at the time of esophagectomy) Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Adequate hematological, renal, and hepatic parameters Exclusion Criteria: Any history of or current hematologic malignancy History of a second primary cancer is allowed in the event the cancer is curatively resected and there is no evidence of recurrence/metastatic disease x 1 year. Subjects who have a history of cervical or breast carcinoma in situ, localized prostate cancer, adequately treated basal cell or squamous cell carcinoma of the skin, or superficial bladder tumors [Ta, Tis & T1] are also allowed. Major surgery within 4 weeks of first dose of investigational product Prior or concurrent treatment with any anticancer agent for the same cancer diagnosis Prior exposure to any immuno-oncology agents, including CD40/PD-1/PD-L1/CTLA-4 inhibitors (if any ambiguity, should be discussed with study principal investigator) History of bone marrow transplantation History of autoimmune disorders with the exception of vitiligo or autoimmune thyroid disorders Chronic steroid dependency (prednisone equivalent > 10 mg/day). Any steroid use should be discontinued at least 2 weeks prior to initiation of study treatment. Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months before first dose Known human immunodeficiency virus (HIV) infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Non-comparative, open-label pilot study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APX005M with chemoradiation<br>APX005M: 0.3mg/kg dose intravenously over 1 hour, every 3 weeks x 3 doses (weeks 1, 4, and 7). Treatment begins 2 weeks prior to concurrent chemoradiation (chemoRT); continues during weeks 2 and 5 of chemoRT. Daily radiation therapy (RT): 28 fractions (28 days) Chemotherapy: Carboplatin and paclitaxel will be given intravenously over 1 hour, once weekly, for 5 weeks (days 1, 8, 15 22, and 29 of RT). Carboplatin dose will be area under curve (AUC) 2. Paclitaxel dose will be 50mg/m2. Surgical resection of tumor: between weeks 10-16 | Drug: APX005M<br>* APX005M intravenous (IV) infusion<br>* Other names: CD40 Agonistic Monoclonal Antibody);Radiation: Radiation Therapy<br>* Radiation therapy, total dose 5040cGy in 180cGy fractions<br>* Other names: Radiotherapy;Drug: Paclitaxel<br>* Paclitaxel IV infusion<br>* Other names: Taxol;Drug: Carboplatin<br>* Carboplatin IV infusion<br>* Other names: Paraplatin;Procedure: Surgical resection of tumor<br>* Surgical removal of the tumor will occur between weeks 10-16<br>* Other names: Operation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response (pCR) rate |  | At time of surgery (at 10-16 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of R0 resection (microscopically negative margins, i.e., no tumor remains following surgery) |  | At time of surgery | 
| Pathologic stage at time of surgery |  | At time of surgery | 
| Radiographic/metabolic response to neoadjuvant treatment on Computed Tomography (CT) / CT-Positron Emission Tomography (PET) (CT-PET) |  | Baseline, then at time of surgery, and 3 and 6 months post-operatively | 
| Frequency of adverse events |  | Up to 5 months for each patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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esophagus, gastroesophageal (GE) junction, T1-3N0-1