Celecoxib, Recombinant Interferon Alfa-2b, and Rintatolimod in Treating Patients With Colorectal Cancer Metastatic to the Liver

Sponsor
Roswell Park Cancer Institute (Other)
Overall Status
Completed
CT.gov ID
NCT03403634
Collaborator
National Cancer Institute (NCI) (NIH)
19
1
1
40.3
0.5

Study Details

Study Description

Brief Summary

This early phase IIA trial studies how well celecoxib, recombinant interferon alfa-2b, and rintatolimod work in treating patients with colorectal cancer that as spread to the liver. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Recombinant interferon alfa-2b is a substance that can improve the body's natural response and may interfere with the growth of tumor cells. Rintatolimod may stimulate the immune system. Giving celecoxib, recombinant interferon alfa-2b, and rintatolimod may work better at treating colorectal cancer that has spread to the liver.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To determine the impact of a chemokine-modulatory regimen on the immune microenvironment of colorectal liver metastases, specifically the changes in the ratio between cytotoxic T-lymphocyte (CTL) marker (CD8a gene expression) to regulatory T cell (Treg) markers (FoxP3 gene expression).
SECONDARY OBJECTIVES:
  1. Estimate the objective response rate of a chemokine-modulatory regimen in metastatic colorectal cancer (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1).

  2. Examine the safety and tolerability profile of the combination of recombinant interferon alfa-2b (interferon alpha-2b), rintatolimod, and celecoxib when given as chemokine modulation to colorectal cancer patients prior to surgical resection using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 4.0).

TERTIARY OBJECTIVES:
  • Estimate the median progression free survival of a chemokine-modulatory regimen in metastatic colorectal cancer

  • Estimate overall survival in participants with recurrent and/or metastatic unresectable colorectal cancer who received the chemokine-modulatory regimen

  • Comparison (using RT-PCR, immunofluorescence [IF] and immunohistochemistry [IHC] on serial sections) of the metastatic tissue specimen with regard to total numbers of infiltrating T cells, their CD4/CD8 ratios, frequencies of FoxP3 cells, and the expression of chemokine receptors on CD4+ and CD8+ T cells (CXCR3, CCR5, CCR4, CCR6, and CXCR4)

  • Evaluate the local expression of effector T cells (Teff)-attracting chemokines (CCR5, CXCL9, CXCL10 and CXCL11) and Treg-favoring chemokines (CCL22 and CXCL12) using IF and RT-PCR.

OUTLINE:

Patients receive celecoxib orally (PO) twice daily (BID), recombinant interferon alfa-2b intravenously (IV) over 20 minutes, and rintatolimod IV QD on days 1, 2,3,8,9,10,15,16 and 17 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 12 months.

Study Design

Study Type:
Interventional
Actual Enrollment :
19 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase 2a Study Evaluating a Chemokine-Modulatory Regimen in Patients With Colorectal Cancer Metastatic to the Liver
Actual Study Start Date :
Apr 19, 2018
Actual Primary Completion Date :
Dec 23, 2020
Actual Study Completion Date :
Aug 29, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (celecoxib, interferon alfa-2b, rintatolimod)

Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity.

Drug: Celecoxib
Given PO
Other Names:
  • Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
  • Celebrex
  • SC-58635
  • YM 177
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Biological: Recombinant Interferon Alfa-2b
    Given IV
    Other Names:
  • Alfatronol
  • Glucoferon
  • Heberon Alfa
  • IFN alpha-2B
  • Interferon alfa 2b
  • Interferon Alfa-2B
  • Interferon Alpha-2b
  • Intron A
  • Sch 30500
  • Urifron
  • Viraferon
  • Drug: Rintatolimod
    Given IV
    Other Names:
  • Ampligen
  • Atvogen
  • Outcome Measures

    Primary Outcome Measures

    1. Change in Tumor-infiltrating Lymphocytes (TILs) in the Colorectal Cancer Lesions [Baseline up to 12 months]

      The TILs will be summarized by time-point (pre-/post-treatment) using the mean, median, standard deviation; and graphically using dot-plots. The TIL of interest is CD8a expression, which is reported as the mean fold change from pre-treatment (i.e. post treatment / pre treatment).

    Secondary Outcome Measures

    1. Number of Participants With Indicated Grade Adverse Event [Up to 12 months]

      Safety profile will be characterized by type, frequency, severity, timing, seriousness and relationship to study treatment. The highest grade treatment related AE is provided (per Common Terminology Criteria for Adverse Events version 4.0).

    2. Objective Response Rate (ORR) Assessed by Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 [Up to 12 months]

      Will be treated as binary data and summarized using frequencies and relative frequencies; with the ORR estimated using a 90% confidence interval obtained using Jeffrey's prior method.

    Other Outcome Measures

    1. Progression Free Survival [From the start of treatment until disease progression (defined by RECIST 1.1) or last-follow-up, assessed up to 12 months]

      Will be treated as bivariate time-to-event data and will be summarized using standard Kaplan-Meier methods.

    2. Overall Survival [From the start of treatment until death due to any cause or last follow-up, assessed up to 12 months]

      Will be treated as bivariate time-to-event data and will be summarized using standard Kaplan-Meier methods.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Recurrent and/or metastatic unresectable colorectal cancer with hepatic metastases

    • Hepatic metastases present which are amenable to biopsy

    • Prior treatment with, contra-indication to or refusal of a fluoropyrimidine, irinotecan, oxaliplatin and an anti-EGFR targeted therapy (if RAS wild-type [wt]) as well as a PD-1 or PD-L1 targeted drug if MSI-H/dMMR

    • No chemotherapy, radiotherapy, major surgery, or biologic therapy within 3 weeks of protocol treatment

    • An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

    • Have measurable disease per RECIST 1.1 criteria present

    • Ability to swallow and retain oral medication

    • Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

    • Platelet >= 75,000/uL

    • Hemoglobin >= 9 g/dL

    • Hematocrit >= 27%

    • Absolute neutrophil count (ANC) >= 1500/uL

    • Creatinine < = institutional upper limit of normal (ULN) OR

    • Creatinine clearance >= 50 mL/min for patients with creatinine levels greater than ULN

    • Total bilirubin =< 1.5 X institutional ULN or for patients with known Gilbert's Syndrome total bilirubin <= 3 x ULN

    • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN

    • Plasma amylase =< 1.5 X institutional ULN

    • Lipase =< 1.5 X institutional ULN

    • Participant 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

    Exclusion Criteria:
    • Patients currently treated with systemic immunosuppressive agents, including steroids, are ineligible until 3 weeks after removal from immunosuppressive treatment

    • Patients with active autoimmune disease, requiring ongoing immunosuppressive therapy or history of transplantation

    • Patients who are pregnant or nursing; women of childbearing potential (WOCBP) will have to undergo a urine pregnancy test as part of screening

    • Untreated central nervous system (CNS) metastases

    • Cardiac risk factors including:

    • Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial infarction, or ischemia) within 3 months of signing consent

    • Patients with a New York Heart Association classification of III or IV

    • History of upper gastrointestinal ulceration, upper gastrointestinal bleeding, or upper gastrointestinal perforation within the past 3 years; patients with ulceration, bleeding or perforation in the lower bowel are not excluded

    • Prior allergic reaction or hypersensitivity to celecoxib, or non-steroidal antiinflammatory drugs (NSAIDs) or any study agents which would prevent completion of protocol therapy

    • Patients are ineligible if they plan on regular use of NSAIDs at any dose more than 2 times per week (on average) or aspirin at more than 325 mg at least three times per week, on average; low-dose aspirin not exceeding 100 mg/day is permitted; patients who agree to stop regular NSAIDs or higher dose aspirin are eligible and no wash out period is required

    • Received an investigational agent within 30 days prior to enrollment

    • Unwilling or unable to follow protocol requirements

    • Patients with known serious mood disorders

    • Any additional condition which in the investigator?s opinion deems the participant an unsuitable candidate to receive the study drugs

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Roswell Park Cancer Institute Buffalo New York United States 14263

    Sponsors and Collaborators

    • Roswell Park Cancer Institute
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Sarbajit Mukherjee, MD, Roswell Park Cancer Institute

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Roswell Park Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT03403634
    Other Study ID Numbers:
    • I 52917
    • NCI-2017-02471
    • I 52917
    • P01CA234212
    First Posted:
    Jan 18, 2018
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Arm/Group Description Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Celecoxib: Given PO Laboratory Biomarker Analysis: Correlative studies Recombinant Interferon Alfa-2b: Given IV Rintatolimod: Given IV
    Period Title: Overall Study
    STARTED 19
    Treated 15
    COMPLETED 12
    NOT COMPLETED 7

    Baseline Characteristics

    Arm/Group Title Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Arm/Group Description Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Celecoxib: Given PO Laboratory Biomarker Analysis: Correlative studies Recombinant Interferon Alfa-2b: Given IV Rintatolimod: Given IV
    Overall Participants 15
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    60.5
    (9.9)
    Sex: Female, Male (Count of Participants)
    Female
    3
    20%
    Male
    12
    80%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    1
    6.7%
    White
    14
    93.3%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    15
    100%
    Line of Treatment (Count of Participants)
    Third Line
    5
    33.3%
    Fourth Line
    6
    40%
    Fifth or More Line
    4
    26.7%
    Clinical Stage (Count of Participants)
    Stage I
    0
    0%
    Stage II
    0
    0%
    Stage III
    0
    0%
    Stage IV
    15
    100%
    Not Reported
    0
    0%
    Location of Disease (Count of Participants)
    Cecum
    1
    6.7%
    Colon, NOS
    7
    46.7%
    Rectum, NOS
    6
    40%
    Sigmoid Colon
    1
    6.7%
    Prior Radiation (Count of Participants)
    Count of Participants [Participants]
    6
    40%
    Prior Surgery (Count of Participants)
    Count of Participants [Participants]
    10
    66.7%
    RAS Type (Count of Participants)
    KRAS
    5
    33.3%
    NRAS
    3
    20%
    Wild-type
    7
    46.7%

    Outcome Measures

    1. Primary Outcome
    Title Change in Tumor-infiltrating Lymphocytes (TILs) in the Colorectal Cancer Lesions
    Description The TILs will be summarized by time-point (pre-/post-treatment) using the mean, median, standard deviation; and graphically using dot-plots. The TIL of interest is CD8a expression, which is reported as the mean fold change from pre-treatment (i.e. post treatment / pre treatment).
    Time Frame Baseline up to 12 months

    Outcome Measure Data

    Analysis Population Description
    3 patients did not have post treatment biopsies, and were considered unevaluable for the primary endpoint.
    Arm/Group Title Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Arm/Group Description Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Celecoxib: Given PO Laboratory Biomarker Analysis: Correlative studies Recombinant Interferon Alfa-2b: Given IV Rintatolimod: Given IV
    Measure Participants 12
    Mean (Standard Deviation) [fold change]
    7.25
    (13.79)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.046
    Comments significance level = 0.05
    Method t-test, 1 sided
    Comments df = 11. one-sided as post treatment increases were of interest. the fold changes were log-transformed prior to inferences.
    2. Secondary Outcome
    Title Number of Participants With Indicated Grade Adverse Event
    Description Safety profile will be characterized by type, frequency, severity, timing, seriousness and relationship to study treatment. The highest grade treatment related AE is provided (per Common Terminology Criteria for Adverse Events version 4.0).
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    All patients that received study treatment.
    Arm/Group Title Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Arm/Group Description Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Celecoxib: Given PO Laboratory Biomarker Analysis: Correlative studies Recombinant Interferon Alfa-2b: Given IV Rintatolimod: Given IV
    Measure Participants 15
    No Treatment Related AE Reported
    1
    6.7%
    Grade I
    6
    40%
    Grade II
    7
    46.7%
    Grade III
    1
    6.7%
    Grade IV
    0
    0%
    Grade V
    0
    0%
    3. Secondary Outcome
    Title Objective Response Rate (ORR) Assessed by Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1
    Description Will be treated as binary data and summarized using frequencies and relative frequencies; with the ORR estimated using a 90% confidence interval obtained using Jeffrey's prior method.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    Evaluated in subjects evaluable for the primary end-point.
    Arm/Group Title Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Arm/Group Description Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Celecoxib: Given PO Laboratory Biomarker Analysis: Correlative studies Recombinant Interferon Alfa-2b: Given IV Rintatolimod: Given IV
    Measure Participants 12
    Count of Participants [Participants]
    0
    0%
    4. Other Pre-specified Outcome
    Title Progression Free Survival
    Description Will be treated as bivariate time-to-event data and will be summarized using standard Kaplan-Meier methods.
    Time Frame From the start of treatment until disease progression (defined by RECIST 1.1) or last-follow-up, assessed up to 12 months

    Outcome Measure Data

    Analysis Population Description
    Evaluated in subjects evaluable for the primary end-point.
    Arm/Group Title Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Arm/Group Description Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Celecoxib: Given PO Laboratory Biomarker Analysis: Correlative studies Recombinant Interferon Alfa-2b: Given IV Rintatolimod: Given IV
    Measure Participants 12
    Median (90% Confidence Interval) [Months]
    1.5
    5. Other Pre-specified Outcome
    Title Overall Survival
    Description Will be treated as bivariate time-to-event data and will be summarized using standard Kaplan-Meier methods.
    Time Frame From the start of treatment until death due to any cause or last follow-up, assessed up to 12 months

    Outcome Measure Data

    Analysis Population Description
    Evaluated in subjects evaluable for the primary end-point.
    Arm/Group Title Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Arm/Group Description Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Celecoxib: Given PO Laboratory Biomarker Analysis: Correlative studies Recombinant Interferon Alfa-2b: Given IV Rintatolimod: Given IV
    Measure Participants 12
    Median (90% Confidence Interval) [Months]
    10.5

    Adverse Events

    Time Frame Adverse event data was collected up to 30 days after end of treatment, up to 1 year.
    Adverse Event Reporting Description
    Arm/Group Title Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Arm/Group Description Patients receive celecoxib orally PO BID, recombinant interferon alfa-2b IV QD over 20 minutes, and rintatolimod IV QD on days 1, 2, 3, 8, 9, 10, 15, 16 and 17 in the absence of disease progression or unacceptable toxicity. Celecoxib: Given PO Laboratory Biomarker Analysis: Correlative studies Recombinant Interferon Alfa-2b: Given IV Rintatolimod: Given IV
    All Cause Mortality
    Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Affected / at Risk (%) # Events
    Total 8/15 (53.3%)
    Serious Adverse Events
    Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Affected / at Risk (%) # Events
    Total 3/15 (20%)
    General disorders
    Death 1/15 (6.7%) 1
    Hepatobiliary disorders
    Hyperbilirubinemia 1/15 (6.7%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm (NOS) 1/15 (6.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion 1/15 (6.7%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod)
    Affected / at Risk (%) # Events
    Total 14/15 (93.3%)
    Gastrointestinal disorders
    Gastrointestinal disorders **Any AE - Maximum Grade Seen Diarrhoea 3/15 (20%) 3
    Dyspepsia 1/15 (6.7%) 1
    Nausea 4/15 (26.7%) 4
    Vomiting 2/15 (13.3%) 2
    Pyrexia 5/15 (33.3%) 5
    General disorders
    Asthenia 1/15 (6.7%) 1
    Chills 11/15 (73.3%) 11
    Fatigue 11/15 (73.3%) 11
    Influenza like illness 1/15 (6.7%) 1
    Infections and infestations
    Mucosal infection 1/15 (6.7%) 1
    Injury, poisoning and procedural complications
    Infusion related reaction 1/15 (6.7%) 1
    Investigations
    Aspartate aminotransferase increased 1/15 (6.7%) 1
    Blood alkaline phosphatase increased 2/15 (13.3%) 2
    Platelet count decreased 1/15 (6.7%) 1
    Weight decreased 2/15 (13.3%) 2
    Metabolism and nutrition disorders
    Decreased appetite 5/15 (33.3%) 5
    Dehydration 1/15 (6.7%) 1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain 1/15 (6.7%) 1
    Myalgia 2/15 (13.3%) 2
    Nervous system disorders
    Dizziness 1/15 (6.7%) 1
    Headache 3/15 (20%) 3
    Psychiatric disorders
    Insomnia 1/15 (6.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 1/15 (6.7%) 1
    Productive cough 1/15 (6.7%) 1
    Sinus congestion 1/15 (6.7%) 1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis 1/15 (6.7%) 1
    Vascular disorders
    Hot flush 6/15 (40%) 6
    Hypotension 1/15 (6.7%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Kris Attwood
    Organization Roswell Park Comprehensive Cancer Center
    Phone 716-845-1300
    Email Kristopher.Attwood@Roswellpark.org
    Responsible Party:
    Roswell Park Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT03403634
    Other Study ID Numbers:
    • I 52917
    • NCI-2017-02471
    • I 52917
    • P01CA234212
    First Posted:
    Jan 18, 2018
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022