Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: Vaccine Therapy With or Without Sirolimus in Treating Patients With NY-ESO-1 Expressing Solid Tumors

Summary: This phase I trial studies the side effects and best schedule of vaccine therapy with or without sirolimus in treating patients with cancer-testis antigen (NY-ESO-1) expressing solid tumors. Biological therapies, such as sirolimus, may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines made from a person's white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells that express NY-ESO-1. Infusing the vaccine directly into a lymph node may cause a stronger immune response and kill more tumor cells. It is not yet known whether vaccine therapy works better when given with or without sirolimus in treating solid tumors.

Detailed description: PRIMARY OBJECTIVES:
  I. Determine the safety of DC205-NY-ESO-1 vaccine (DEC-205/NY-ESO-1 fusion protein CDX-1401) with and without sirolimus. Toxicity as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
  SECONDARY OBJECTIVES:
  I. Assess the NY-ESO-1 specific cellular and humoral immunity:
  -  Peripheral blood NY-ESO-1 specific cluster of differentiation (CD)8+ and CD4+ T-cells.
  -  Peripheral blood NY-ESO-1 specific antibodies.
  -  Peripheral blood frequency of CD4+CD25+forkhead box P3 (FOXP3)+ regulatory T-cells.
  TERTIARY OBJECTIVES:
  I. Explore time to disease progression.
  OUTLINE:
  Patients undergo standard collection of peripheral white blood cells via leukapheresis over 90-240 minutes for vaccine preparation. Patients are assigned sequentially to Cohorts 1a-1d.
  COHORT 1a: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 intranodally on days 1, 29, 57, and 113.
  COHORT 1b: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 as in Cohort 1a and sirolimus orally (PO) on days 1-14, 29-42, and 57-70.
  COHORT 1c: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 as in Cohort 1a and sirolimus PO or percutaneous endoscopic gastrostomy (PEG) tube on days 15-28, 43-56, and 71-84.
  COHORT 1d: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 as in Cohort 1a and sirolimus PO or PEG on days 1-84.
  COHORT 2: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 as in the Cohort (1a-1d) that is determined to be safe and produces optimal immunological effects and sirolimus PO on days 1-14 as in Cohort 1b dose.
  After completion of study treatment, patients are followed up at 6 weeks, 6 months and 12 months.

Eligibility: Inclusion Criteria:
  -  Patients with any solid tumors at high risk of recurrence or with minimal residual disease; there may or may not be measurable or symptomatic disease (i.e., patients with bladder, brain, breast, esophageal, gastrointestinal, hepatocellular, kidney, lungs, melanoma, ovarian, prostate, sarcomas, and uterine)
  -  Cancer types:
  -  Prostate cancer: patients with metastatic, castrate refractory prostate cancer; the use of luteinizing hormone-releasing hormone (LHRH) agonist is allowed
  -  Kidney cancer: patients with metastatic kidney cancer; prior therapies with cytokines, vascular endothelial growth factor (VEGF) and mechanistic target of rapamycin (serine/threonine kinase) (mTOR) inhibitors are allowed
  -  Bladder cancer: patients with metastatic urothelial carcinoma; prior cisplatin-based therapies are allowed
  -  Ovarian cancer: eligible patients may have asymptomatic residual measurable disease on physical examination and/or computed tomography (CT) scan, and/or may have an elevated cancer antigen (CA)-125; or may be in complete clinical remission after treatment for primary or recurrent disease
  -  Brain tumors: histologic proof of one of the following: glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma or anaplastic mixed glioma or anaplastic oligoastrocytoma; patients who have had recent cranial surgery are eligible for inclusion, but the vaccine may not be administered prior to postoperative day 14
  -  Uterine cancer: patients with advanced (stages II-IV) or recurrent disease who have completed standard therapy, currently no evidence of disease (NED) or with minimal residual disease; patients with stage I uterine serous carcinomas or sarcomas are also eligible after completion of standard therapy
  -  Breast cancer: patients can enter study after completion of all chemotherapy (including trastuzumab), radiation, and breast/axillary surgery; patients may participate while on endocrine therapy; stages I-III patients with the following characteristics:
  -  Estrogen-receptor (ER) negative with positive lymph nodes; ER negative with negative nodes if tumor > 2 cm; ER positive with positive lymph nodes; and ER positive with negative lymph nodes and tumor > 5 cm
  -  Sarcomas: patients with sarcomas of any site, who have completed standard therapy, and are in remission, or have minimal disease burden
  -  Lungs: resected patients with hilar or ipsilateral mediastinal nodal disease (i.e., a subset of patients with stage II and IIIA disease); and patients with residual disease on imaging after definitive radiation or chemoradiation therapy
  -  Esophageal: resected patients with any nodal (i.e., thoracic or abdominal) disease; and patients with residual disease on imaging after definitive chemoradiation therapy
  -  Melanoma: stage IIB, stage IIC, and stage III who have completed planned definitive therapy for their disease including radiotherapy and/or interferon; patients declining interferon or with contra-indications to interferon will also be eligible provided they meet requisite criteria for this study (i.e., non-measurable disease); stage IV melanoma of M1a sub-type only, who are not candidates for additional therapy of curative potential (i.e., small volume disease; may be measurable or evaluable); and stage IV melanoma, NED, status post (s/p) complete resection of known sites of disease (i.e., non-measurable disease)
  -  Hepatocellular carcinoma (HCC): patients who have been treated with surgical resection for HCC; and following chemoembolization as adjuvant therapy for HCC
  -  Gastrointestinal: patients who have completed standard therapies for gastric and colorectal cancers, and deemed to be at high-risk of relapse
  -  Any human leukocyte antigen (HLA) type; historic HLA typing is permitted
  -  Tumor expression of NY-ESO-1 or LAGE-1 by immunohistochemistry (IHC) and/or reverse transcription polymerase chain reaction (RTPCR)
  -  Life expectancy > 6 months
  -  Absolute neutrophil count (ANC) >= 1,000/uL
  -  Platelets (PLT) >= 75,000/uL
  -  Hemoglobin (Hgb) >= 8 g/dL
  -  Total bilirubin =< 1.5 x upper limit of normal (ULN)
  -  Serum aspartate aminotransferase (serum glutamic oxaloacetic transaminase [SGOT]/aspartate aminotransferase [AST]) or serum alanine aminotransferase (serum glutamate pyruvate transaminase [SGPT]/alanine aminotransferase [ALT]) =< 3 x ULN
  -  Serum creatinine =< 2 x ULN
  -  Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN; patients receiving anticoagulation therapy, PT/INR =< 3
  -  Pulmonary function tests: forced expiratory volume in one second (FEV1) > 50% and diffusion capacity of the lungs for carbon monoxide (DLCO) > 50%
  -  Pulse oximetry: oxygen (O2) saturation >= 90% on room air
  -  Electrocardiogram, showing no clinical significant or acute abnormality
  -  Have been informed of other treatment options
  -  Patient or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
  -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  -  Patients of child-bearing potential must agree to use acceptable contraceptive methods (e.g., double barrier) during treatment
  Exclusion Criteria:
  -  Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, may be available
  -  Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders)
  -  History of severe autoimmune disorders requiring use of steroids or other immunosuppressives
  -  Concomitant systemic treatment with corticosteroids, anti-histamine or non-steroidal anti-inflammatory drugs, aspirin > 325 mg; specific cyclooxygenase (COX)-2 inhibitors are permitted
  -  Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to first dosing of study agent (6 weeks for nitrosoureas); concomitant hormonal therapies for breast and prostate cancers are allowed
  -  Clinically significant heart disease (New York Heart Association [NYHA] class III or IV) within 6 months
  -  Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study
  -  Lack of availability of a patient for immunological and clinical follow-up assessment
  -  Known pulmonary hypertension
  -  Known hypersensitivity to sirolimus
  -  Evidence of current drug or alcohol abuse or psychiatric impairment, which in the investigator's opinion will prevent completion of the protocol therapy or follow-up
  -  Pregnant or nursing female patients
  -  Unwilling or unable to follow protocol requirements
  -  Any condition which in the investigator's opinion deems the patient an unsuitable candidate to receive study drug; (i.e., any significant medical illness or abnormal laboratory finding that would, in the investigator's judgment, increase the subject's risk by participating in this study)
  -  Received an investigational agent within 30 days prior to enrollment
  -  Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)

Relevance to patient case: not relevant