Clinical Trials /

VSV-hIFNbeta-NIS With or Without Ruxolitinib Phosphate in Treating Patients With Stage IV or Recurrent Endometrial Cancer

NCT03120624

Description:

This phase I trial studies the side effects and best dose of vesicular stomatitis virus-human interferon beta-sodium iodide symporter (VSV-hIFNbeta-NIS) with or without ruxolitinib phosphate 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. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving VSV-hIFNbeta-NIS with ruxolitinib phosphate may work better in treating patients with endometrial cancer compared to VSV-hIFNbeta-NIS alone.

Related Conditions:
  • Endometrial Adenocarcinoma
  • Endometrial Undifferentiated Carcinoma
  • Uterine Corpus Carcinosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: VSV-hIFNbeta-NIS With or Without Ruxolitinib Phosphate in Treating Patients With Stage IV or Recurrent Endometrial Cancer
  • Official Title: Phase I Trial of Intravenous Administration of Vesicular Stomatitis Virus Genetically Engineered to Express Thyroidal Sodium Iodide Symporter (NIS) and Human Interferon Beta (hIFNb), in Patients With Metastatic or Recurrent Endometrial Cancer

Clinical Trial IDs

  • ORG STUDY ID: MC1562
  • SECONDARY ID: NCI-2017-00615
  • SECONDARY ID: MC1562
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03120624

Conditions

  • Metastatic Endometrial Carcinoma
  • Recurrent Endometrial Adenocarcinoma
  • Recurrent Endometrial Carcinoma
  • Recurrent Endometrial Clear Cell Adenocarcinoma
  • Recurrent Endometrial Endometrioid Adenocarcinoma
  • Recurrent Endometrial Mixed Cell Adenocarcinoma
  • Recurrent Endometrial Serous Adenocarcinoma
  • Recurrent Endometrial Undifferentiated Carcinoma
  • Recurrent Uterine Corpus Carcinosarcoma
  • Stage IV Uterine Corpus Cancer AJCC v7
  • Stage IVA Uterine Corpus Cancer AJCC v7
  • Stage IVB Uterine Corpus Cancer AJCC v7

Interventions

DrugSynonymsArms
Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide SymporterOncolytic VSV-hIFNbeta-NIS, Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter, Voyager-V1, VSV-expressing hIFNb and NIS, VSV-hIFNb-NIS, VSV-hIFNbeta-NIS, VV1Arm A (VSV-hIFNbeta-NIS, SPECT/CT, TFB-PET, biopsy)
RuxolitinibINCB-18424, INCB18424, Jakafi, Oral JAK Inhibitor INCB18424Arm B (ruxolitinib, VSV-hIFNbeta-NIS, SPECT/CT,TFB-PET,biopsy)
Ruxolitinib PhosphateINCB-18424 Phosphate, JakafiArm B (ruxolitinib, VSV-hIFNbeta-NIS, SPECT/CT,TFB-PET,biopsy)
Technetium Tc-99m Sodium PertechnetatePertscan-99m, Sodium Pertechnetate (Na99mtco4), Tc 99m Generator, Ultra-Technekow FMArm A (VSV-hIFNbeta-NIS, SPECT/CT, TFB-PET, biopsy)

Purpose

This phase I trial studies the side effects and best dose of vesicular stomatitis virus-human interferon beta-sodium iodide symporter (VSV-hIFNbeta-NIS) with or without ruxolitinib phosphate 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. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving VSV-hIFNbeta-NIS with ruxolitinib phosphate may work better in treating patients with endometrial cancer compared to VSV-hIFNbeta-NIS alone.

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 (alone and in combination with
      ruxolitinib phosphate [ruxolitinib]).

      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 (alone and in combination with ruxolitinib) using Tc-99m pertechnetate
      planar and single photon emission computed tomography (SPECT)/computed tomography (CT) or
      fluorine F18 tetrafluoroborate (TFB)-positron emission tomography (PET) 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
      (alone and in combination with ruxolitinib).

      IV. To monitor humoral responses to the injected virus. V. To estimate the tumor response
      rate and overall survival.

      CORRELATIVE 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 are randomized to 1 of
      2 arms.

      ARM A: Patients receive VSV-hIFNbeta-NIS IV over 60-90 minutes on day 1. After 2 days,
      patients receive technetium Tc-99m sodium pertechnetate IV, and about 30 minutes later,
      undergo whole body planar imaging and SPECT/CT imaging or receive fluorine F18
      tetrafluoroborate IV and undergo TFB-PET imaging. If previous imaging data are positive,
      patients receive technetium Tc-99m sodium pertechnetate IV and undergo another planar and
      SPECT/CT imaging or fluorine F18 tetrafluoroborate IV and undergo another TFB-PET imaging
      between 7-10 days and on 15 days if needed 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.

      ARM B: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on days -3 to 9.
      Patients also receive VSV-hIFNbeta-NIS IV over 60-90 minutes on day 1. After 2 days, patients
      receive technetium Tc-99m sodium pertechnetate IV, and about 30 minutes later, undergo whole
      body planar imaging and SPECT/CT imaging or receive fluorine F18 tetrafluoroborate IV and
      undergo TFB-PET imaging. If previous imaging data are positive, patients receive technetium
      Tc-99m sodium pertechnetate IV and undergo another planar and SPECT/CT imaging or fluorine
      F18 tetrafluoroborate IV and undergo another TFB-PET imaging between 7-10 days and on 15 days
      if needed 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 at day 29, every 3 months until
      disease progression and then every 6 months for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (VSV-hIFNbeta-NIS, SPECT/CT, TFB-PET, biopsy)ExperimentalPatients receive VSV-hIFNbeta-NIS IV over 60-90 minutes on day 1. After 2 days, patients receive technetium Tc-99m sodium pertechnetate IV, and about 30 minutes later, undergo whole body planar imaging and SPECT/CT imaging or receive fluorine F18 tetrafluoroborate IV and undergo TFB-PET imaging. If previous imaging data are positive, patients receive technetium Tc-99m sodium pertechnetate IV and undergo another planar and SPECT/CT imaging or fluorine F18 tetrafluoroborate IV and undergo another TFB-PET imaging between 7-10 days and on 15 days if needed 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.
  • Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
  • Technetium Tc-99m Sodium Pertechnetate
Arm B (ruxolitinib, VSV-hIFNbeta-NIS, SPECT/CT,TFB-PET,biopsy)ExperimentalPatients receive ruxolitinib phosphate PO BID on days -3 to 9. Patients also receive VSV-hIFNbeta-NIS IV over 60-90 minutes on day 1. After 2 days, patients receive technetium Tc-99m sodium pertechnetate IV, and about 30 minutes later, undergo whole body planar imaging and SPECT/CT imaging or receive fluorine F18 tetrafluoroborate IV and undergo TFB-PET imaging. If previous imaging data are positive, patients receive technetium Tc-99m sodium pertechnetate IV and undergo another planar and SPECT/CT imaging or fluorine F18 tetrafluoroborate IV and undergo another TFB-PET imaging between 7-10 days and on 15 days if needed 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.
  • Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
  • Ruxolitinib
  • Ruxolitinib Phosphate
  • Technetium Tc-99m Sodium Pertechnetate

Eligibility Criteria

        Inclusion Criteria:

          -  Measurable stage IVA, stage IVB (with or without measurable disease) or recurrent
             (with or without measurable disease) endometrial carcinoma

               -  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, carcinosarcoma, adenocarcinoma not
                  otherwise specified (NOS)

               -  NOTE: measurable disease is defined by Response Evaluation Criteria in Solid
                  Tumors (RECIST) (version 1.1)

          -  Group A only: Largest tumor diameter =< 5 cm

               -  NOTE: Group B patients have no maximum tumor size

          -  Absolute neutrophil count (ANC) >= 1500/uL (obtained =< 14 days prior to registration)

          -  Platelet count (PLT) >= 100,000/uL (obtained =< 14 days prior to registration)

          -  Hemoglobin >= 10 g/dL (obtained =< 14 days prior to registration)

          -  Creatinine =< 2.0 mg/dL (obtained =< 14 days prior to registration)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2 x upper limit
             of normal (ULN) (obtained =< 14 days prior to registration)

               -  NOTE: if baseline liver disease, Child Pugh score not exceeding class A

          -  Total bilirubin =< 1.5 x ULN (obtained =< 14 days prior to registration)

          -  International normalized ratio (INR)/prothrombin time (PT), activated partial
             thromboplastin time (aPTT) =< 1.4 x ULN (obtained =< 14 days prior to registration)
             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 because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown:

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of VSV-hIFNbeta-NIS (alone and in combination with ruxolitinib phosphate)
Time Frame:Up to 28 days
Safety Issue:
Description:Graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4. Defined as the highest safely-tolerated dose level where at most one patient out of six experiences dose limiting toxicities (DLT) with the next higher dose level having at least 2 of 6 patients who have experienced DLT.

Secondary Outcome Measures

Measure:Number of clinical responses
Time Frame:Up to 1 year
Safety Issue:
Description:Defined as complete response, partial response, or stable disease assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Will be summarized by simple descriptive summary statistics across all patients in each group as well as by dose level and primary type of cancer (EC).
Measure:Viral replication and shedding in blood, throat washings, urine, and buccal swabs assessed via quantitative reverse transcriptase polymerase chain reaction
Time Frame:Up to 1 year
Safety Issue:
Description:Descriptive statistics and scatterplots will form the basis of presentation of these variables. Correlations with other outcome measures will be carried out by standard parametric and non-parametric tests (e.g. Pearson's and Spearman's rho).
Measure:Biodistribution and kinetics of virus spread and NIS gene expression in vivo
Time Frame:Up to day 10
Safety Issue:
Description:Assessed via single-photon emission computed tomography/computed tomography. Will be correlated with tumor distribution.
Measure:Time until treatment related grade 3+ toxicity
Time Frame:Up to 1 year
Safety Issue:
Description:Graded according to the NCI CTCAE version 4. Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and related confidence intervals. The effect of dose and ancillary dichotomized covariates such as age will be explored using logrank testing involving one covariate at a time.
Measure:Time until hematologic nadirs (white blood cells, absolute neutrophil count, platelets)
Time Frame:Up to 1 year
Safety Issue:
Description:Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and related confidence intervals. The effect of dose and ancillary dichotomized covariates such as age will be explored using logrank testing involving one covariate at a time.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

August 6, 2020