Clinical trial NCT03800953: The Ave-CRT Study for Newly Diagnosed Metastatic Esophageal Squamous Cell Carcinoma
Official title: Chemotherapy/Avelumab Plus Radiotherapy to Primary Esophageal Tumor for Newly Diagnosed Metastatic Esophageal Squamous Cell Carcinoma: The Ave-CRT Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Esophageal Tumor
Metastatic Esophageal Squamous Cell Carcinoma
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
First posted: 2019-01-11
Enrollment: 26
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single institutional, single arm, open labeled phase II study to assess the overall radiographic response of adding Avelumab to chemotherapy and palliative radiotherapy in patients with metastatic advanced esophageal squamous cell carcinoma.

Detailed description: Avelumab belongs to the group of immune checkpoint blockade cancer therapies. Avelumab binds to the programmed death-ligand 1 (PD-L1) and therefore inhibits binding to its receptor programmed cell death 1 (PD-1). In the case of avelumab, the formation of PD-1/PDL1 ligand pairs is blocked and CD8+ T cell immune response should be increased. This study comprises 2 phases, the concurrent immune-chemoradiotherapy (Ave-PF-CRT) phase and the immune-chemotherapy (Ave-PF) phase. In the immune-chemoradiotherapy phase, patients are treated with PF-CRT and concomitant Avelumab. In the immune-chemotherapy phase, patients are treated with PF plus Avelumab. Overall radiological response, time to progression, overall survival and adverse events will be evaluated. Subjects' health-related quality of life will be assessed as well.

Eligibility criteria: Inclusion Criteria:

* To be eligible for inclusion, patients must fulfill the following criteria:

  1. Histologically proved squamous cell carcinoma of esophagus
  2. Metastatic disease, which are defined by TNM system of American Joint Committee on Cancer (AJCC) Cancer Staging System (8th edition) in 2017, involving distant lymph node (para-aortic or cervical) metastasis and/or visceral metastasis (lung, liver) documented by radiological examinations
  3. Age ≥ 20 years
  4. ECOG Performance Status 0 or 1
  5. Adequate bone marrow reserves within 2 weeks prior to registration, defined as:a. absolute neutrophil count (ANC) ≥ 1.5×109/L (1,500/μl)b. platelets ≥ 100×109/L (100,000/µl)c. hemoglobin ≥ 9.0 g/dl (may have been transfused)
  6. Adequate liver function reserves within 2 weeks prior to registration, defined as:

     1. hepatic transaminases (AST and ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN for subjects with documented metastatic disease to liver
     2. serum total bilirubin ≤ 2.5 × upper limit of normal (ULN)
  7. Adequate renal function within 2 weeks prior to registration: Creatinine ≤1.5 mg/dL
  8. Negative serum or urine pregnancy test for women of childbearing potential
  9. Women of childbearing potential and male participants must practice highly effective contraception throughout the study and for at least 30 days after last avelumab treatment administration if the risk of conception exists
  10. Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent

Exclusion Criteria:

* Patients fulfill any of the following criteria will be excluded from this trial

  1. Prior radiotherapy to head and neck, chest, or abdomen
  2. Tumor invasion to adjacent structures (T4 lesion)
  3. Adenocarcinoma of esophagus or gastroesophageal junction.
  4. No measurable metastatic target lesion(s) by RECIST criteria
  5. Synchronously or metachronously diagnosed squamous cell carcinoma of aerodigestive way, other than esophageal cancer
  6. Prior invasive malignancy
  7. Prior organ transplantation including allogenic stem-cell transplantation
  8. 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).
  9. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
  10. Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:

      1. Uncontrolled active infection requiring intravenous antibiotics at the time of registration
      2. Transmural myocardial infarction \< 6 months prior to registration
      3. Unstable angina or congestive heart failure requiring hospitalization \< 6 months prior to registration
      4. Life-threatening uncontrolled clinically significant cardiac arrhythmias
      5. Cerebral vascular accident/stroke (\< 6 months prior to enrollment)
      6. Congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
      7. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
      8. Chronic obstructive pulmonary disease exacerbation or other respiratory illness including pulmonary fibrosis requiring hospitalization or precluding study therapy at the time of registration
      9. Uncontrolled psychiatric disorder including recent (within the past year) or active suicidal ideation or behavior
      10. Laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results
      11. Immune colitis, inflammatory bowel disease, immune pneumonitis
  11. Known history of testing positive for HIV or known acquired immunodeficiency syndrome."
  12. 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)
  13. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines
  14. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)"
  15. Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic

Primary outcomes:
measure: overall radiographic response
timeFrame: 6 months
Secondary outcomes:
measure: Best radiographic response
timeFrame: up to 2 years
measure: Progression-free survival
timeFrame: up to 2 years
measure: Overall survival
timeFrame: up to 2 years
measure: Frequency of adverse events
timeFrame: up to 2 years
measure: Heath-related quality of life
timeFrame: up to 2 years
measure: New metastasis-free survival
timeFrame: up to 2 years
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital, Taiwan
Study officials:
affiliation: National Taiwan University Hospital
name: Chia-Hsien Cheng
role: PRINCIPAL_INVESTIGATOR
References: