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

• ClinicalTrials.gov Identifier: NCT03120624
• Recruitment Status: Recruiting
• First Posted: April 19, 2017
• Last Update Posted: August 7, 2020
• Sponsor: Mayo Clinic
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Mayo Clinic

Tracking Information

• First Submitted Date: April 14, 2017
• First Posted Date: April 19, 2017
• Last Update Posted Date: August 7, 2020
• Actual Study Start Date: September 15, 2017
• Estimated Primary Completion Date: June 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 6, 2020)

• Maximum tolerated dose of VSV-hIFNbeta-NIS (alone and in combination with ruxolitinib phosphate) [ Time Frame: Up to 28 days ]
  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.
• Incidence of adverse events [ Time Frame: Up to 1 year ]
  Graded according to the NCI CTCAE version 4. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables. Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and related confidence intervals.

Original Primary Outcome Measures (submitted: April 14, 2017)

• Incidence of adverse events graded according to the NCI CTCAE version 4 [ Time Frame: Up to 1 year ]
  Frequency distributions and other descriptive measures will form the basis of the analysis of these variables. Simple summary statistics will be supplemented with Kaplan-Meier survival estimates and related confidence intervals.
• Maximum tolerated dose of VSV-hIFNbeta-NIS graded according to the National Cancer Institute (NCI) CTCAE version 4 [ Time Frame: Up to 5 weeks ]
  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.

Current Secondary Outcome Measures (submitted: August 6, 2020)

• Number of clinical responses [ Time Frame: Up to 1 year ]
  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).
• 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 ]
  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).
• Biodistribution and kinetics of virus spread and NIS gene expression in vivo [ Time Frame: Up to day 10 ]
  Assessed via single-photon emission computed tomography/computed tomography. Will be correlated with tumor distribution.
• Time until treatment related grade 3+ toxicity [ Time Frame: Up to 1 year ]
  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.
• Time until hematologic nadirs (white blood cells, absolute neutrophil count, platelets) [ Time Frame: Up to 1 year ]
  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.

Original Secondary Outcome Measures (submitted: April 14, 2017)

• Biodistribution and kinetics of virus spread and NIS gene expression in vivo assessed via SPECT/CT [ Time Frame: Up to day 10 ]
  Will be correlated with tumor distribution.
• Number of clinical responses defined as complete response, partial response, or stable disease assessed by RECIST 1.1 criteria [ Time Frame: Up to 1 year ]
  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).
• Time until hematologic nadirs (white blood cells, ANC, platelets) [ Time Frame: Up to 1 year ]
  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.
• Time until treatment related grade 3+ toxicity graded according to the NCI CTCAE version 4 [ Time Frame: Up to 1 year ]
  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.
• Viral replication and shedding in blood, throat washings, urine, and buccal swabs assessed via quantitative RT-PCR [ Time Frame: Up to 1 year ]
  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).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief 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) 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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

Intervention

• Procedure: Biopsy
  Undergo image-guided biopsy
  Other Name: Bx
• Procedure: Computed Tomography
  Undergo SPECT/CT
  Other Names:

  • CAT
  • CAT Scan
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography
• Other: Fluorine F 18 Tetrafluoroborate
  Given IV
  Other Names:

  • 18F-Tetrafluoroborate
  • 18F-TFB
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Pharmacological Study
  Correlative studies
• Procedure: Planar Imaging
  Undergo whole body planar imaging
• Procedure: Positron Emission Tomography
  Undergo TFB-PET
  Other Names:

  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging
• Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
  Given IV
  Other Names:

  • Oncolytic 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
  • VV1
• Drug: Ruxolitinib
  Given PO
  Other Names:

  • INCB-18424
  • INCB18424
  • Jakafi
  • Oral JAK Inhibitor INCB18424
• Drug: Ruxolitinib Phosphate
  Given PO
  Other Names:

  • INCB-18424 Phosphate
  • Jakafi
• Procedure: Single Photon Emission Computed Tomography
  Undergo SPECT/CT
  Other Names:

  • Medical Imaging, Single Photon Emission Computed Tomography
  • Single Photon Emission Tomography
  • single-photon emission computed tomography
  • SPECT
  • SPECT imaging
  • SPECT SCAN
  • SPET
  • tomography, emission computed, single photon
  • Tomography, Emission-Computed, Single-Photon
• Drug: Technetium Tc-99m Sodium Pertechnetate
  Given IV
  Other Names:

  • Pertscan-99m
  • Sodium Pertechnetate (Na99mtco4)
  • Tc 99m Generator
  • Ultra-Technekow FM

Study Arms

• Experimental: Arm A (VSV-hIFNbeta-NIS, SPECT/CT, TFB-PET, biopsy)
  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.
  Interventions:

  • Procedure: Biopsy
  • Procedure: Computed Tomography
  • Other: Fluorine F 18 Tetrafluoroborate
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Procedure: Planar Imaging
  • Procedure: Positron Emission Tomography
  • Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
  • Procedure: Single Photon Emission Computed Tomography
  • Drug: Technetium Tc-99m Sodium Pertechnetate
• Experimental: Arm B (ruxolitinib, VSV-hIFNbeta-NIS, SPECT/CT,TFB-PET,biopsy)
  Patients 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.
  Interventions:

  • Procedure: Biopsy
  • Procedure: Computed Tomography
  • Other: Fluorine F 18 Tetrafluoroborate
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Procedure: Planar Imaging
  • Procedure: Positron Emission Tomography
  • Biological: Recombinant Vesicular Stomatitis Virus-expressing Human Interferon Beta and Sodium-Iodide Symporter
  • Drug: Ruxolitinib
  • Drug: Ruxolitinib Phosphate
  • Procedure: Single Photon Emission Computed Tomography
  • Drug: Technetium Tc-99m Sodium Pertechnetate

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 6, 2020): 77
• Original Estimated Enrollment (submitted: April 14, 2017): 33
• Estimated Study Completion Date: July 15, 2023
• Estimated Primary Completion Date: June 1, 2023 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03120624
• Other Study ID Numbers: MC1562; NCI-2017-00615 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); MC1562 ( Other Identifier: Mayo Clinic in Rochester ); P30CA015083 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Mayo Clinic
• Study Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jamie N Bakkum-Gamez; Mayo Clinic

• PRS Account: Mayo Clinic
• Verification Date: June 2020