Patient case: 58-year-old female with endometrial cancer; genetic feature: PIK3R1

Clinical trial: VSV-hIFNbeta-NIS in Treating Patients With Stage IV or Recurrent Endometrial Cancer

Summary: This phase I trial studies the side effects and best dose of vesicular stomatitis virus-human interferon beta-sodium iodide symporter (VSV-hIFNbeta-NIS) in treating patients with stage IV endometrial cancer or endometrial cancer that has come back. The study virus, VSV-hIFNbeta-NIS, has been changed so that it has restricted ability to spread to tumor cells and not to healthy cells. It also contains a gene for a protein, NIS, which helps the body concentrate iodine making it possible to track where the virus goes. VSV-hIFNbeta-NIS may be able to kill tumor cells without damaging normal cells.

Detailed description: PRIMARY OBJECTIVES:
  I. To evaluate the optimal dose schedule, safety and tolerability as measured by the incidence of significant toxicity of VSV-hIFNbeta-NIS in immunocompetent patients with metastatic and/or recurrent endometrial cancer (EC).
  SECONDARY OBJECTIVES:
  I. To determine the toxicity profile of VSV-hIFNbeta-NIS. II. To determine the time course of viral gene expression and virus elimination, and the biodistribution of virally infected cells at various times points after infection with VSV-hIFNbeta-NIS using Tc-99m pertechnetate planar and single photon emission computed tomography (SPECT)/computed tomography (CT) imaging.
  III. To assess virus replication, viremia; viral shedding in urine and respiratory secretions; and virus persistence after intravenous (IV) administration of VSV-hIFNbeta-NIS.
  IV. To monitor humoral responses to the injected virus. V. To estimate the tumor response rate and overall survival.
  TERTIARY OBJECTIVES:
  I. To determine the pharmacokinetic (PK) profile of VSV-IFNbeta-NIS in patients with EC by measurement of VSV-IFNbeta-NIS in blood by reverse transcriptase polymerase chain reaction (RT-PCR).
  II. To characterize the pharmacodynamics (PD) of VSV-IFNbeta-NIS by way of measuring serum interferon-beta and also VSV-RT-PCR of VSV-IFNbeta-NIS listed above.
  III. Assess CD8+ T cell (both general and VSV-IFNbeta-NIS specific) and natural killer (NK) cell responses.
  IV. Gene expression analysis pre- and post-virotherapy. V. Evaluate transcription of interferon mediated genes (protein kinase R, the death receptor-TRAIL, 2'-5' oligoadenylate/RNAse L proteins, heat shock proteins [Hsp 60/70/90], major histocompatibility class antigens and IRF-7).
  VI. Assess presence of VSV in tumor and normal tissues subsequent to administration of IV VSV-IFNbeta-NIS.
  OUTLINE: This is a dose-escalation study of VSV-hIFNbeta-NIS.
  Patients receive VSV-hIFNbeta-NIS IV over 30-60 minutes on day 1. After 3-5 days, patients receive technetium Tc-99m sodium pertechnetate IV, and about 30 minutes later, undergo whole body planar imaging and SPECT/CT imaging. If previous imaging data are positive, patients receive technetium Tc-99m sodium pertechnetate IV and undergo another planar and SPECT/CT scan 7-10 days after VSV-hIFNbeta-NIS infusion. Biopsy of accessible NIS image-positive tumors may occur after any imaging. Patients also undergo image-guided biopsy of accessible tumor on day 29.
  After completion of study treatment, patients are followed up every 3 months until disease progression and then every 6 months for up to 5 years.

Eligibility: Inclusion Criteria:
  -  Patients must have measurable stage IVA, stage IVB (with or without measurable disease) or recurrent (with or without measurable disease) endometrial carcinoma; largest tumor diameter =< 5cm
  -  NOTE: Histologic confirmation of the original primary tumor is required; patients with the following histologic epithelial cell types are eligible: Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (NOS)
  -  NOTE: Measurable disease is defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1)
  -  Absolute neutrophil count (ANC) >= 1500/uL
  -  Platelet count (PLT) >= 100,000/uL
  -  Hemoglobin >= 10 g/dL
  -  Creatinine =< 2.0 mg/dL
  -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2 x upper limit of normal (ULN)
  -  NOTE: If baseline liver disease, Child Pugh score not exceeding class A
  -  Total bilirubin =< 1.5 x ULN
  -  International normalized ratio (INR)/prothrombin time (PT), activated partial thromboplastin time (aPTT) =< 1.4 x ULN unless on therapeutic warfarin then INR/PT =< 3.5
  -  Ability to provide written informed consent
  -  Willingness to return to Mayo Clinic in Rochester, Minnesota for follow-up
  -  Life expectancy >= 12 weeks
  -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
  -  Willingness to provide mandatory biological specimens for research purposes
  -  Prior therapy:
  -  Any number of prior chemotherapy regimens and/or targeted therapies and/or prior external beam radiation therapy and/or prior hormonal therapy for endometrial cancer are allowed provided the last treatment was > 4 weeks prior to registration
  -  Vaginal brachytherapy may have been administered at any time prior to registration
  Exclusion Criteria:
  -  Availability of and patient acceptance of curative therapy
  -  Active infection, including any active viral infection, =< 5 days prior to registration
  -  Active or latent tuberculosis or hepatitis
  -  Known untreated or symptomatic brain metastases
  -  Any of the following prior therapies:
  -  Chemotherapy =< 4 weeks prior to registration
  -  Targeted biologic therapy =< 4 weeks prior to registration
  -  Immunotherapy =< 4 weeks prior to registration
  -  Any viral or gene therapy prior to registration
  -  External beam radiotherapy =< 4 weeks prior to registration
  -  NOTE: Vaginal brachytherapy may be performed at any time prior to registration
  -  New York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or uncontrolled current cardiac arrhythmias (atrial fibrillation or supraventricular tachycardia [SVT])
  -  Active central nervous system (CNS) disorder or seizure disorder or known CNS disease or neurologic symptomatology
  -  Human immunodeficiency virus (HIV) positive test result or other immunodeficiency or immunosuppression
  -  History of hepatitis B or C or chronic hepatitis
  -  Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (used for a non-Food and Drug Administration [FDA] approved indication and in the context of a research investigation)
  -  Treatment with oral/systemic corticosteroids, with the exception of topical or inhaled steroids
  -  Exposure to household contacts =< 15 months old or household contact with known immunodeficiency
  -  Any of the following:
  -  Pregnant persons or persons of reproductive ability who are unwilling to use effective contraception
  -  Nursing persons
  -  Any other pathology or condition that the principal investigator deems to negatively impact treatment safety
  -  Any immunotherapy-related adverse events Common Terminology Criteria for Adverse Events (CTCAE) > grade 1 at the time of registration
  -  Receipt of a live virus vaccine =< 2 months prior to registration

Relevance to patient case: not relevant