Clinical Trials /

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

NCT03490292

Description:

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

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avelumab With Chemoradiation for Stage II/III Resectable Esophageal and Gastroesophageal Cancer
  • Official Title: Phase I/II Trial of Avelumab in Combination With Chemoradiation in the Treatment of Stage II/III Resectable Esophageal and Gastroesophageal Cancer

Clinical Trial IDs

  • ORG STUDY ID: UW17106
  • SECONDARY ID: P30CA014520
  • SECONDARY ID: NCI-2018-00150
  • SECONDARY ID: 2017-1491
  • NCT ID: NCT03490292

Conditions

  • Resectable Esophageal Cancer
  • GastroEsophageal Cancer

Interventions

DrugSynonymsArms
CarboplatinRun-In Phase
PaclitaxelRun-In Phase

Purpose

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

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Run-In PhaseExperimental6 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.
  • Carboplatin
  • Paclitaxel
Expansion CohortExperimentalFollowing 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).
  • Carboplatin
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          1. Patients with histologically confirmed, potentially curable squamous-cell carcinoma,
             adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and
             gastroesopagus (Siewert type 1-3).

          2. Locoregional disease with clinical stage of T1N1 or T2-3N0-2.

          3. No clinical evidence of metastatic spread. Staging should include endoscopic
             ultrasound and PET/CT as recommended by NCCN guidelines. PET/CT should be performed
             within 3 weeks of signing informed consent.

          4. Age 18 years or older.

          5. ECOG performance status 0-2.

          6. Subjects must be deemed to be potential surgical candidates by an evaluating surgeon.

          7. Adequate organ function:

               1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               2. Hemoglobin ≥ 9 g/dL (transfusions allowed)

               3. Platelets ≥ 100 x 109/L

               4. AST/ALT ≤ 2.5 x ULN

               5. Total serum bilirubin of ≤1.5 x institutional upper limit of normal (ULN)

               6. Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault
                  formula

          8. Female patients of childbearing potential must have a negative pregnancy test (urine
             or serum) within 21 days prior to the start of the study drug treatment and must agree
             to use adequate birth control if conception is possible during the study and up to 30
             days after the completion of adjuvant therapy.

          9. Male patients must agree to use adequate birth control during the study and up to 30
             days after the last avelumab dose.

         10. Women who are nursing must discontinue breast-feeding prior to the enrollment in the
             trial.

         11. Patient must be able and willing to comply with study procedures as per protocol.

         12. Patient able to understand and willing to sign and date the written voluntary informed
             consent form (ICF) at screening visit prior to any protocol-specific procedures.

        Exclusion Criteria:

          1. Prior history of radiation to the mediastinum.

          2. Diagnosis of cervical esophageal carcinoma.

          3. Other active malignancy within the last 3 years (except for non-melanoma skin cancer,
             a non-invasive/in situ cancer, or indolent non metastatic Gleason 6 prostate cancer).

          4. Subjects with an active or known autoimmune disease. Subjects with type I diabetes
             mellitus, hypo- or hyperthyroidism only requiring hormone replacement/suppression,
             skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic
             immunosuppressive treatment are eligible.

          5. Current use of immunosuppressive medication, except for the following:

               1. intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
                  intra-articular injection)

               2. systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
                  equivalent

               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          6. Active infection requiring systemic therapy at the time of study treatment initiation.

          7. Prior organ transplantation including allogenic stem-cell transplantation.

          8. Known history of testing positive for HIV or known immunodeficiency syndrome

          9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
             HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

         10. Vaccination within 4 weeks of the first dose of avelumab and while on trials is
             prohibited except for administration of inactivated vaccines..

         11. Major surgery within prior 4 weeks of treatment initiation (the surgical incision
             should be fully healed prior to all neoadjuvant treatment initiation).

         12. Any prior anticancer therapy for esophageal cancer.

         13. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to carboplatin, paclitaxel or avelumab, including known severe
             hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3).

         14. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
             prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
             Association Classification Class II), or serious cardiac arrhythmia requiring
             medication. Patients with stable rate-controlled atrial fibrillation will be allowed
             to participate.

         15. Other severe acute or chronic medical conditions including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior; or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study.

         16. Psychological, familial, or sociological condition potentially hampering compliance
             with the study protocol and follow-up schedule.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Dose Limiting Toxicity.
Time Frame:Up to 4 weeks post-resection of all 6 Part 1 subjects.
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Number of Adverse Events.
Time Frame:Up to 30 days post-avelumab of all 24 Part 2 subjects.
Safety Issue:
Description: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.
Measure:Number of Subjects who Complete Planned Treatment.
Time Frame:Up to 30 days post-avelumab of all 24 Part 2 subjects.
Safety Issue:
Description: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.
Measure:Disease free survival.
Time Frame:Up to 4 years post-resection for all 24 subjects.
Safety Issue:
Description: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.
Measure:Incidence of surgical complications.
Time Frame:Following resection (80-100 days) for all 24 subjects.
Safety Issue:
Description: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.
Measure:Rate of R0 resection.
Time Frame:Following pathology review post-resection (80-100 days) for all 24 subjects.
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Wisconsin, Madison

Last Updated