Clinical Trials /

APX005M With Concurrent Chemoradiation for Resectable Esophageal and Gastroesophageal Junction Cancers

NCT03165994

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
  • Esophageal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: APX005M With Concurrent Chemoradiation for Resectable Esophageal and Gastroesophageal Junction Cancers
  • Official Title: A Pilot Study of APX005M in Combination With Concurrent Chemoradiation as Neoadjuvant Therapy for Resectable Esophageal and Gastroesophageal Junction Cancers

Clinical Trial IDs

  • ORG STUDY ID: CC# 17701
  • SECONDARY ID: NCI-2017-02197
  • NCT ID: NCT03165994

Conditions

  • Esophageal Cancer
  • GastroEsophageal Cancer

Interventions

DrugSynonymsArms
APX005MCD40 Agonistic Monoclonal Antibody)APX005M with chemoradiation
PaclitaxelTaxolAPX005M with chemoradiation
CarboplatinParaplatinAPX005M with chemoradiation

Purpose

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

      PRIMARY OBJECTIVES:

      I. To establish the safety and feasibility of combining APX005M with standard-of-care
      chemoradiation (external beam radiation in daily fractions, with concurrent weekly low-dose
      carboplatin/paclitaxel) in the neoadjuvant setting for patients with resectable esophageal
      and gastroesophageal junction (GEJ) cancers.

      SECONDARY OBJECTIVES:

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

      OUTLINE:

      Patients receive APX005M intravenously (IV) over 60 minutes during weeks 1, 4, and 7,
      radiation therapy once daily (QD) for 5 days per week during weeks 3-8, and paclitaxel IV
      over 60 minutes and carboplatin IV over 60 minutes once weekly (days 1, 8, 15, 22, and 29)
      during weeks 3-8 in the absence of disease progression or unacceptable toxicity. Patients
      then undergo surgery 4 - 10 weeks after last dose of APX005M.

      After completion of study treatment, patients are followed up at 1, 3, and 6 months.
    

Trial Arms

NameTypeDescriptionInterventions
APX005M with chemoradiationExperimentalAPX005M: 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 AUC 2. Paclitaxel dose will be 50mg/m2. Surgical resection of tumor: between weeks 11-17
  • APX005M
  • Paclitaxel
  • Carboplatin

Eligibility Criteria

        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 by endoscopic ultrasound). Excluded are:

               1. Very early stage tumors (T1N0)

               2. Cervical esophageal tumors

               3. Tumors invading the tracheobronchial tree or associated with tracheoesophageal
                  fistula

               4. Any evidence of distant metastases (as determined by endoscopic ultrasound (EUS)
                  or CT/PET)

               5. Cervical, supraclavicular, or other nodal disease that is either not included in
                  the radiation field or is not able to be resected at the time of esophagectomy

          4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          5. Adequate hematological, renal, and hepatic parameters defined as follows:

               1. Absolute Neutrophil Count (ANC) ≥1.5 × 109/L in absence of growth factor support

               2. Platelet count ≥150 × 109/L

               3. Hemoglobin >9 g/dL

               4. Serum creatinine ≤1.5 mg/dL, or calculated (using the formula of Cockcroft and
                  Gault) or measured creatinine clearance ≥30 mL/min

               5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper
                  limit of normal (ULN)

               6. Total bilirubin ≤1.5x ULN

          6. Women of child bearing potential (WOCBP) must have a negative serum pregnancy test
             within the 7 days prior to investigational product administration and a negative urine
             pregnancy test within the 3 days prior to the first investigational product
             administration, or a negative serum pregnancy test within the 3 days prior to the
             first investigational product administration

          7. WOCBP and male subjects who are sexually active with WOCBP must agree to use 2 highly
             effective methods of contraception (including a physical barrier) during the study and
             for 30 days following the last dose of investigational product

          8. Ability to understand a written informed consent document, and the willingness to sign
             it

        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. Uncontrolled diabetes or hypertension

          8. History of autoimmune disorders with the exception of vitiligo or autoimmune thyroid
             disorders

          9. Chronic steroid dependency (prednisone equivalent > 10 mg/day). Any steroid use should
             be discontinued at least 2 weeks prior to initiation of study treatment.

         10. History of sensitivity or allergy to monoclonal antibodies (mAbs) or immunoglobulin G
             (IgG)

         11. History of severe hypersensitivity reaction to Cremaphor EL.

         12. Pre-existing > grade 2 peripheral sensory neuropathy.

         13. 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

         14. History of any arterial thromboembolic event within 3 months prior to first dose of
             investigational product

         15. Active coagulopathy

         16. Active known clinically serious infections (> Grade 2 National Cancer Institute (NCI)-
             CTCAE version 4.03)

         17. Known human immunodeficiency virus (HIV) infection

         18. Subjects of reproductive potential who do not use effective methods of birth control

         19. Pregnant or actively breastfeeding women

         20. Any clinically significant psychiatric, social, or medical condition that, in the
             opinion of the Investigator, could increase subject's risk, interfere with protocol
             adherence, or affect a subject's ability to give informed consent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Frequency of adverse events based on the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03
Time Frame:Over the period from baseline up to 6 months following the operation (up to 11 months in total)
Safety Issue:
Description:Adverse events will be summarized by presenting, at each dose level, the number and percentage of patients having any adverse event, having an adverse event in each body system and having each individual adverse event. If no patients require a delay in their planned surgery for reasons of toxicity, the study will be considered feasible.

Secondary Outcome Measures

Measure:Pathologic complete response (pCR) rate
Time Frame:At time of surgery (at 11-17 weeks)
Safety Issue:
Description:The proportion of patients who achieve a pathologic complete remission. The point estimate and its 95% confidence interval will be obtained.
Measure:Rates of R0 resection
Time Frame:At time of surgery
Safety Issue:
Description:Will be reported both for the entire study cohort and for each histologic subgroup.
Measure:Pathologic stage at time of surgery
Time Frame:At time of surgery
Safety Issue:
Description:Will be reported both for the entire study cohort and for each histologic subgroup.
Measure:Radiographic/metabolic response to neoadjuvant treatment on Computed Tomography (CT) - Positron Emission Tomography (PET) (CT-PET)
Time Frame:Baseline, then at time of surgery, and 1, 3 and 6 months post-operatively
Safety Issue:
Description:The radiographic/metabolic response will be described in qualitative terms (i.e., improved/stable/worse). Response will be adjudicated by the treating provider, based on combination of change in wall thickening, size of regional lymph nodes, and metabolic activity of involved areas, and will be categorized as either responding, stable/unchanged, progressing, or not evaluable.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

Trial Keywords

  • esophagus
  • gastroesoophageal (GE) junction
  • T1-3N0-1

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