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)
• Enrollment: 19
• Location: 1
• Arm: 1
• Actual Duration (Months): 40.3
• Patients Per Site Per Month: 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
Metastatic Carcinoma in the Liver; Recurrent Colorectal Carcinoma; Stage IV Colorectal Cancer AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7	Drug: Celecoxib; Other: Laboratory Biomarker Analysis; Biological: Recombinant Interferon Alfa-2b; Drug: Rintatolimod	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)

• Study Protocol and Statistical Analysis Plan - Oct 29, 2020

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: Carcinoma; Colorectal Neoplasms; Interferons; Interferon-alpha; Interferon alpha-2; poly(I).poly(c12,U); Celecoxib; Benzenesulfonamide

Study Results

Participant Flow

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.
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.