APX005M With Concurrent Chemoradiation for Resectable Esophageal and Gastroesophageal Junction Cancers

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

This pilot phase II trial studies the therapeutic effects and side effects of CD40 agonistic monoclonal antibody APX005M when combined with chemotherapy and radiation therapy, and to see how well they work to reduce or remove esophageal or gastroesophageal (GE) cancers when given before surgery in treating patients with esophageal cancer or GE cancer than 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.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer; GastroEsophageal Cancer
• Intervention / Treatment: Drug: Carboplatin; Radiation: Radiation Therapy; Drug: Paclitaxel; Drug: APX005M; Procedure: Surgical resection of tumor

Detailed Description

Primary Objective:

To assess the efficacy of this novel combination, as measured by the pathologic complete response (pCR) rate.

Secondary Objectives:

1. 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.
2. 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:

1. To identify possible predictive molecular or immune-based efficacy biomarkers for this novel combination.
2. To characterize and assess overall survival.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • University of Arizona
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • District of Columbia
    • Washington, District of Columbia, United States, 20007-2113
      • MedStar Georgetown University Hospital (MGUH)
  • New York
    • New York, New York, United States, 10016
      • New York University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305
      • The University of North Carolina at Chapel Hill
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
  • Texas
    • The Woodlands, Texas, United States, 77380
      • Renovatio Clinical
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years of age.
2. Histologically proven squamous cell carcinoma, adenocarcinoma or undifferentiated carcinoma of the esophagus or GE junction.
3. 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).
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
5. Adequate hematological, renal, and hepatic parameters.

Exclusion Criteria:

1. Any history of or current hematologic malignancy.
2. 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.
3. Major surgery within 4 weeks of first dose of investigational product.
4. Prior or concurrent treatment with any anticancer agent for the same cancer diagnosis.
5. 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).
6. History of bone marrow transplantation.
7. History of autoimmune disorders with the exception of vitiligo or autoimmune thyroid disorders.
8. Chronic steroid dependency (prednisone equivalent > 10 mg/day). Any steroid use should be discontinued at least 2 weeks prior to initiation of study treatment.
9. 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.
10. Known human immunodeficiency virus (HIV) infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: APX005M With Standard of Care Chemoradiation; Participants will receive standard of care chemoradiation, consisting of: External beam radiation in daily fractions (28 fractions) from Weeks 1-6, administered once per day up to 5 days/week.; Carboplatin (area under the carboplatin plasma concentration versus time curve = 2) and paclitaxel (50 mg/m^2) chemotherapy intravenously (IV) over 1 hour, once weekly, from Weeks 1-5. The participants also will receive concurrent 0.3 mg/kg APX005M IV over 1 hour, once weekly, on Weeks 1, 2, 4, and 6 (2-3 days after chemoradiation). Surgical resection of the tumor will be planned from Week 10 up to approximately Week 17, as indicated in the protocol amendment under which each participant is enrolled.

Drug: Carboplatin; Carboplatin IV infusion; Other Names: Paraplatin; Radiation: Radiation Therapy; Radiation therapy, total dose 5040cGy in 180cGy fractions; Other Names: Radiotherapy; Drug: Paclitaxel; Paclitaxel IV infusion; Other Names: Taxol; Drug: APX005M; APX005M IV infusion; Other Names: CD40 Agonistic Monoclonal Antibody; PYX-107; Sotigalimab; Procedure: Surgical resection of tumor; Surgical removal of the tumor will occur between weeks 10-17; Other Names: Operation; Surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response (pCR) Rate (%) Overall	The pCR was defined as post-neoadjuvant pathologic tumour, node, metastasis (ypTNM) (after chemoRT; after surgery) with T0, N0 stages. pCR rate was defined as the percentage of participants who achieved a pCR at surgery, as assessed by the Investigator.; T0: No evidence of primary tumor.; N0: Cancer has not spread to nearby lymph nodes. An exact Clopper-Pearson lower 95% confidence limit was used to test the null hypothesis that the pCR rate is ≤30%.	At time of surgery, up to a maximum of 261 days
pCR Rate (%) by Baseline Histologic Subgroup	The pCR was defined as ypTNM (after chemoRT; after surgery) with T0, N0 stages. pCR rate was defined as the percentage of participants who achieved a pCR at surgery, as assessed by the Investigator. An exact Clopper-Pearson lower 95% confidence limit was used to test the null hypothesis that the pCR rate is ≤30%.	At time of surgery, up to a maximum of 261 days
pCR Rate (%) by Baseline Tumor Location Subgroup	The pCR was defined as ypTNM (after chemoRT; after surgery) with T0, N0 stages. pCR rate was defined as the percentage of participants who achieved a pCR at surgery, as assessed by the Investigator. An exact Clopper-Pearson lower 95% confidence limit was used to test the null hypothesis that the pCR rate is ≤30%.	At time of surgery, up to a maximum of 261 days
pCR Rate (%) by Steroid Use Subgroup	The pCR was defined as ypTNM (after chemoRT; after surgery) with T0, N0 stages. pCR rate was defined as the percentage of participants who achieved a pCR at surgery, as assessed by the Investigator. Steroids use: Yes was defined as participants with any steroid (ATC2 class corticosteroids for systemic use) from within 30 days of the first dose of sotigalimab to up to 7 days after the first dose and participants not fulfilling previous requirements are defined as Steroids use: No. An exact Clopper-Pearson lower 95% confidence limit was used to test the null hypothesis that the pCR rate is ≤30%.	At time of surgery, up to a maximum of 261 days
pCR Rate (%) by Surgery Subgroup	The pCR was defined as ypTNM (after chemoRT; after surgery) with T0, N0 stages. pCR rate was defined as the percentage of participants who achieved a pCR at surgery, as assessed by the Investigator. The subgroup of participants who had surgery before or at 16/17 weeks were defined as start of study treatment to surgery date from the surgical resection form, less than or equal to 17 weeks (119 days = 17 weeks * 7 days) or participants who were scheduled to have surgery but had their procedure aborted due to progressive disease at the time of the procedure or immediately before and did not have surgery because of metastasis. The subgroup of participants who had surgery after Week 17 were defined as start of study treatment to surgery date from the surgical resection form, greater than 17 weeks. An exact Clopper-Pearson lower 95% confidence limit was used to test the null hypothesis that the pCR rate is ≤30%.	At time of surgery, up to a maximum of 261 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate (%) of R0 Resection Overall	R0 was defined as the absence of gross and microscopic tumor involvement in the surgical margins i.e., no tumor remains following surgery. Rate of R0 resection was defined as the percentage of participants who achieved R0 following surgical resection.	At time of surgery, up to a maximum of 261 days
Rate (%) of R0 Resection by Baseline Histologic Subgroup	R0 was defined as the absence of gross and microscopic tumor involvement in the surgical margins i.e., no tumor remains following surgery. Rate of R0 resection was defined as the percentage of participants who achieved R0 following surgical resection.	At time of surgery, up to a maximum of 261 days
Pathologic Stage at Time of Surgery	Pathologic staging was assessed via ypTNM (after chemoRT and surgery): Tumor Stage (TX, T0, T1, T1a, T1b, T2, T3, T4, T4a, T4b) refers to the size and/or extent of the main tumor. The higher the number after the T, the larger the tumor or the more it had grown into the wall of the esophagus.; Node Stage (NX, N0, N1, N2, N3) refers to the number and location of lymph nodes that cancer has spread to. The higher the number after the N, the more lymph nodes that contained cancer cells.; Metastasis Stage (M0, M1) refers to whether the cancer had not spread (M0) or spread (M1) to other parts of the body.; Stage group (0, I, IA, IB, II, IIA, IIB, III, IIIA, IIIB, IV, IVA, IVB) are based on the TNM stages detailed above. The higher the number, the more advanced the cancer was. For each category, a lower stage/group represents a better outcome.	At time of surgery, up to a maximum of 261 days
Radiographic/Metabolic Response to Neoadjuvant Treatment on Computed Tomography (CT)/CT-Positron Emission Tomography (PET) (CT-PET) Overall	Response was adjudicated by the investigator; based on combination of change in wall thickening; size of regional lymph nodes; and metabolic activity of involved areas. As the population does not typically have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), radiographic/metabolic response was described in qualitative terms (responding/ stable, unchanged/ progressing/ not evaluable).	At time of surgery, up to a maximum of 261 days, 3 and 6 months post-operatively, and End of Study Visit (maximum of 6 months post-operatively)
Radiographic/Metabolic Response to Neoadjuvant Treatment on CT-PET by Baseline Histologic Subgroup	Response was adjudicated by the investigator; based on combination of change in wall thickening; size of regional lymph nodes; and metabolic activity of involved areas. As the population does not typically have measurable disease by RECIST, radiographic/metabolic response was described in qualitative terms (responding/ stable, unchanged/ progressing/ not evaluable).	At time of surgery, up to a maximum of 261 days, 3 and 6 months post-operatively, and End of Study Visit (maximum of 6 months post-operatively)
Radiographic/Metabolic Response to Neoadjuvant Treatment on CT-PET by Baseline Tumor Location Subgroup	Response was adjudicated by the investigator; based on combination of change in wall thickening; size of regional lymph nodes; and metabolic activity of involved areas. As the population does not typically have measurable disease by RECIST, radiographic/metabolic response was described in qualitative terms (responding/ stable, unchanged/ progressing/ not evaluable).	At time of surgery, up to a maximum of 261 days, 3 and 6 months post-operatively, and End of Study Visit (maximum of 6 months post-operatively)
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	TEAEs were defined as adverse events which started on or after the first infusion of study treatment (Carboplatin/Paclitaxel/Sotigalimab/Radiotherapy) until 100 days after receiving the last dose of study treatment, death, or initiation of new anticancer therapy, whichever occurs first. Laboratory values that were considered clinically significant were reported as adverse events.	Up to approximately 20 weeks

Collaborators and Investigators

• Sponsor: Apexigen America, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2017
• Primary Completion (Actual): November 10, 2022
• Study Completion (Actual): February 21, 2023

Study Registration Dates

• First Submitted: May 23, 2017
• First Submitted That Met QC Criteria: May 23, 2017
• First Posted (Actual): May 24, 2017

Study Record Updates

• Last Update Posted (Estimated): May 2, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: GE junction; gastroesophageal junction; esophagus; T1-3N0-1
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel
• Other Study ID Numbers: APX005M-006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No