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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03490292
Recruitment Status : Recruiting
First Posted : April 6, 2018
Last Update Posted : December 6, 2019
Sponsor:
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Resectable Esophageal Cancer GastroEsophageal Cancer Combination Product: Avelumab combined with Chemoradiation Drug: Carboplatin Drug: Paclitaxel Radiation: Radiation Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Avelumab in Combination With Chemoradiation in the Treatment of Stage II/III Resectable Esophageal and Gastroesophageal Cancer
Actual Study Start Date : May 29, 2018
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: Run-In Phase

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.

Combination Product: Avelumab combined with Chemoradiation
Co-administration of avelumab with chemoradiation in pre-operative period.

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

Drug: Paclitaxel
Weekly paclitaxel [intravenous infusion on days 1, 8, 15, 22, & 29]

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

Experimental: Expansion Cohort
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).
Combination Product: Avelumab combined with Chemoradiation
Co-administration of avelumab with chemoradiation in pre-operative period.

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

Drug: Paclitaxel
Weekly paclitaxel [intravenous infusion on days 1, 8, 15, 22, & 29]

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




Primary Outcome Measures :
  1. Part 1: Dose Limiting Toxicity [ Time Frame: Up to 4 weeks post-resection of all 6 Part 1 subjects. ]
    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.

  2. Part 2: Pathological complete response rate. [ Time Frame: Post-resection (80-100 days) pathology review for all 24 Part 2 subjects. ]
    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.


Secondary Outcome Measures :
  1. Number of Adverse Events [ Time Frame: Up to 30 days post-avelumab of all 24 Part 2 subjects. ]

    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.


  2. Number of Subjects who Complete Planned Treatment [ Time Frame: Up to 30 days post-avelumab of all 24 Part 2 subjects. ]

    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.


  3. Disease free survival [ Time Frame: Up to 4 years post-resection for all 24 subjects. ]
    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.

  4. Incidence of surgical complications [ Time Frame: Following resection (80-100 days) for all 24 subjects. ]
    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.

  5. Rate of R0 resection [ Time Frame: Following pathology review post-resection (80-100 days) for all 24 subjects. ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03490292


Contacts
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Contact: Cancer Connect 8006228922 clinicaltrials@cancer.wisc.edu

Locations
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United States, Wisconsin
University of Wisconsin Carbone Cancer Center Recruiting
Madison, Wisconsin, United States, 53792
Contact: Cancer Connect    800-622-8922    clinicaltrials@cancer.wisc.edu   
Principal Investigator: Nataliya Uboha         
Sponsors and Collaborators
University of Wisconsin, Madison
Investigators
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Principal Investigator: Nataliya Uboha University of Wisconsin, Madison

Additional Information:
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Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT03490292    
Other Study ID Numbers: UW17106
NCI-2018-00150 ( Registry Identifier: NCI Trial ID )
2017-1491 ( Other Identifier: Institutional Review Board )
A534260 ( Other Identifier: UW Madison )
SMPH\MEDICINE\HEM-ONC ( Other Identifier: UW Madison )
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: December 6, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Paclitaxel
Albumin-Bound Paclitaxel
Carboplatin
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs