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

PRIMARY OBJECTIVES:

I. 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:

I. Estimate the objective response rate of a chemokine-modulatory regimen in metastatic colorectal cancer (per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1).

II. 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.

• Celecoxib (Drug), also known as Benzenesulfonamide, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-, Celebrex, SC-58635, YM 177: Given PO
• Laboratory Biomarker Analysis (Other): Correlative studies
• Recombinant Interferon Alfa-2b (Biological), also known as Alfatronol, Glucoferon, Heberon Alfa, IFN alpha-2B, Interferon alfa 2b, Interferon Alfa-2B, Interferon Alpha-2b, Intron A, Sch 30500, Urifron, Viraferon: Given IV
• Rintatolimod (Drug), also known as Ampligen, Atvogen: Given IV

Primary outcomes

• 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 outcomes

• 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).
• 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 outcomes

• 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.
• 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.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• Change in Tumor-infiltrating Lymphocytes (TILs) in the Colorectal Cancer Lesions (Primary), Mean, fold change: Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod) 7.25 +/- 13.79 (p 0.046)
• Number of Participants With Indicated Grade Adverse Event (Secondary), Count of participants, Participants: Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod) 1
• Objective Response Rate (ORR) Assessed by Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1 (Secondary), Count of participants, Participants: Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod) 0
• Progression Free Survival (Other pre specified), Median, Months: Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod) 1.5 (1.4 to 1.8)
• Overall Survival (Other pre specified), Median, Months: Treatment (Celecoxib, Interferon Alfa-2b, Rintatolimod) 10.5 (2.2 to 15.2)

Adverse events

Time frame: Adverse event data was collected up to 30 days after end of treatment, up to 1 year.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2020-10-29)

• Sarbajit Mukherjee, MD, Principal investigator, Roswell Park Cancer Institute

NIH grants: P01CA234212