Safety and Efficacy of Avelumab in Small Intestinal Adenocarcinoma

This is a single-agent, open label, one-arm phase 2 pilot study of avelumab in patients with advanced or metastatic adenocarcinoma of the small intestine.

Primary Objectives

* To describe any antitumor activity of avelumab monotherapy, as measured by the response rate in patients with advanced or metastatic small intestinal adenocarcinoma.
* To describe the safety profile of avelumab monotherapy in patients with advanced or metastatic small intestinal adenocarcinoma.

Secondary Objectives

* To determine overall survival, progression-free survival, and duration of response of avelumab monotherapy in patients with advanced small intestinal adenocarcinoma.
* To evaluate the association of tumor PD-L1 and PD-1 expression, MSI status, lymphocytic infiltration, and somatic mutation burden with response.

Eligibility Criteria:
Inclusion Criteria:

* Signed and dated written informed consent.
* Male or female ≥ 18 years of age.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
* Histologically confirmed adenocarcinoma of the small intestine that is advanced (not amenable to surgery) or metastatic (clinical stage IV). For the purposes of this study, ampullary tumors are considered a part of the duodenum and are classified as adenocarcinomas of the small intestine.
* At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria that has not been previously irradiated and which can be followed by CT or MRI.
* Adequate organ function including:

  * Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
  * Platelets ≥ 100 × 109/L
  * Hemoglobin ≥ 9/g/dL (may have been transfused)
  * Total serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
  * Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present)
  * Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault (CG) equation
* Archival tissue \[paraffin block(s) or unstained slides from paraffin block(s)\] from the primary tumor and/or a metastatic site judged reasonably available prior to initiating treatment, or willingness to undergo fresh pre-treatment tumor biopsy. (Prior to initiating treatment, the screening team must have documentation that an archival or fresh tumor specimen has been requested from a local or outside facility. However, physical possession of requested tissue or waiting for histological analysis or confirmation that an acquired specimen contains tumor tissue sufficient for analysis is not a requirement prior to initiating treatment.) If no archival tissue is available and patient consents to a fresh biopsy, but the patient's lesion is deemed inaccessible to safe biopsy, the patient will be allowed to enroll if otherwise eligible.
* Female patients of childbearing potential and male patients able to father children who have female partners of childbearing potential must agree to use one highly effective method (defined as less than 1% failure rate per year) and one additional effective method of contraception (Appendix 4) from 15 days prior to first trial treatment administration until at least 60 days after study participant's final dose of avelumab.

  * Females of childbearing potential are defined as those who are not surgically sterile or post-menopausal (i.e. patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 12 months without an alternative medical cause). Post-menopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women.
  * Male patients able to father children are defined as those who are not surgically sterile (i.e. patient has not had a vasectomy).
* Serum pregnancy test (for females of childbearing potential) negative at screening.
* Re-enrollment of a subject that has discontinued the study as a pre-treatment screen failure (i.e. a consented patient who did not receive avelumab) is permitted. If re-enrolled, the subject must be re-consented. Only the screening procedures performed outside of protocol-specified timing must be repeated.

Exclusion Criteria:

* There is no restriction on the number of prior therapies. However, prior therapy with antibody or drug specifically targeting T cell regulatory proteins, including but not limited to the following is not allowed: Prior immunotherapy with IL-2 or IFN-α, or an anti-PD-1 (including nivolumab), anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
* Within 28 days before first dose of avelumab: Anti-cancer treatment, major surgery requiring general anesthesia, or the use of any investigational agent.
* Within 14 days before first dose of avelumab: Therapeutic or palliative radiation therapy. (Subjects receiving bisphosphonate or denosumab are eligible provided treatment was initiated at least 14 days before the first dose of avelumab.)
* Current use of immunosuppressive medication, except the following:

  * Subjects are permitted the use of corticosteroids with minimal systemic absorption (e.g. topical, ocular, intra-articular, intranasal, and inhaled);
  * Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent are permitted;
  * A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT scan premedication against contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
* Previous malignant disease other than adenocarcinoma of the small intestine within the last 5 years, with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ considered curatively treated (i.e. complete remission achieved at least 2 years prior to first dose of avelumab AND additional therapy not required while receiving study treatment).
* All subjects with brain metastases, expect those meeting the following criteria:

  * Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment
  * No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable.
  * Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent)
* Receipt of any organ transplantation including allogeneic stem-cell transplantation.
* Significant acute or chronic infections requiring systemic therapy.

  * Known history of testing positive for human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS).
  * 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).
* Active autoimmune disease with reasonable possibility of clinically significant deterioration when receiving an immunostimulatory agent:

  * Subjects with Type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
* Interstitial lung disease that is symptomatic or which may interfere with the detection or management of suspected drug-related pulmonary toxicity.
* Uncontrolled asthma \[defined as having 3 or more of the following features of partially controlled asthma within 28 days prior to starting study treatment: Daytime symptoms more than twice per week, any limitation of activities, any nocturnal symptoms/awaking, need for reliever/rescue inhaler more than twice per week, or known lung function (PEF or FEV1) without administration of a bronchodilator that is \< 80% predicted or personal best (if known)\].
* Current symptomatic congestive heart failure (New York Heart Association \> class II), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension (systolic \> 160 mmHg or diastolic \> 100mmHg). Or any of the following occurring within 6 months (180 days) prior to first dose of avelumab: Myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, or serious cardiac arrhythmia requiring medication. (Use of antihypertensive medication to control blood pressure is allowed.)
* Concurrent treatment with a non-permitted drug.
* Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin (warfarin). Low-dose anticoagulants for the maintenance of patency in a central venous access device or the prevention of deep vein thrombosis or pulmonary embolism is allowed. Therapeutic use of low molecular weight heparin is allowed.
* Persisting toxicity related to prior therapy that has not reduced to Grade 1 \[National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.03; however, alopecia and sensory neuropathy Grade ≤ 2 is acceptable.
* Known severe (Grade ≥ 3 NCI-CTCAE v4.03) hypersensitivity reactions to monoclonal antibodies, including hypersensitivity to the investigational agent or any component in its formulations, or history of anaphylaxis.
* Vaccination within 28 days of the first dose of avelumab and while on trial is prohibited, except for administration of inactivated vaccines (for example, inactivated influenza vaccine).
* Pregnant or breastfeeding females.
* Known alcohol or drug abuse.
* Prisoners or subjects who are involuntarily incarcerated.
* Other severe acute or chronic medical condition, including colitis, inflammatory bowl disease, pneumonitis, pulmonary fibrosis, or psychiatric condition 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.