A Phase 2 Clinical Trial of the Safety and Effects of IRX-2 in Treating Patients With Operable Head and Neck Cancer

• ClinicalTrials.gov Identifier: NCT00210470
• Recruitment Status: Completed
• First Posted: September 21, 2005
• Results First Posted: February 8, 2012
• Last Update Posted: December 11, 2020
• Sponsor: Brooklyn ImmunoTherapeutics, LLC
• Information provided by (Responsible Party): Brooklyn ImmunoTherapeutics, LLC

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Squamous Cell Carcinoma of the Head and Neck
• Interventions: Biological: IRX-2; Drug: Cyclophosphamide; Drug: Indomethacin; Drug: Zinc; Drug: Omeprazole
• Enrollment: 27

Participant Flow

Recruitment Details	The first subject was enrolled July 2005 and the last subject visit was August 2009.
Pre-assignment Details	Pathologically confirmed (by histology) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. No prior surgery, radiation therapy, or chemotherapy of this tumor other than biopsy or emergency procedure required for supportive care. No medical contraindications to surgical resection and reconstruction required.

Arm/Group Title	IRX-2 Regimen
Arm/Group Description	The IRX-2 regimen is the combination of a 2-week course of IRX-2 itself, an initial dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation.
Period Title: Overall Study
Started	27
Completed	27
Not Completed	0

Baseline Characteristics

Arm/Group Title		IRX-2 Regimen
Arm/Group Description		The IRX-2 regimen is the combination of a 2-week course of IRX-2 itself, an initial dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation.
Overall Number of Baseline Participants		27
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	27 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	24 88.9%
	>=65 years	3 11.1%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	27 participants
		57.4 (9.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	27 participants
	Female	7 25.9%
	Male	20 74.1%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	27 participants
United States		26
Mexico		1

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events and Serious Adverse Events
Description	The frequency of all Adverse Events (greater than 5%) is reported. All Serious Adverse Events were described.
Time Frame	Enrollment through 30 days post-surgery

Outcome Measure Data

Analysis Population Description

27 participants were entered into study and treated. All participants were included in the safety analysis.

Arm/Group Title	IRX-2 Regimen
Arm/Group Description:	A 2-week course of IRX-2, an initial low dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation
Overall Number of Participants Analyzed	27
Measure Type: Count of Participants; Unit of Measure: Participants
Adverse Event: Injection Site Pain	6 22.2%
Adverse Event: Headache	8 29.6%
Adverse Event: Nausea	6 22.2%
Adverse Event: Constipation	4 14.8%
Adverse Event: Dizziness	4 14.8%
Adverse Event: Fatigue	3 11.1%
Adverse Event: Pneumonia Aspiration	3 11.1%
Adverse Event: Anaemia	3 11.1%
Adverse Event: Injection Site Discomfort	3 11.1%
Adverse Event: Myalgia	2 7.4%
Adverse Event: Contusion	2 7.4%
Adverse Event: Dry Mouth	2 7.4%
Adverse Event: Vomiting	2 7.4%
Additional AE Categories w lower frequency	4 14.8%
Serious Adverse Events	7 25.9%

2. Secondary Outcome

Title	Clinical and Histological Tumor Responses
Description	Number of participants with the specified percent change in size of target lesion is presented
Time Frame	On approximately Day 21 (last day of treatment) prior to undergoing post-treatment surgery

Outcome Measure Data

Analysis Population Description

A total of 23 subjects who received the IRX-2 regimen were evaluated for tumor response based on the RECIST criteria

Arm/Group Title	IRX-2 Regimen
Arm/Group Description:	A 2-week course of IRX-2, an initial low dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation
Overall Number of Participants Analyzed	23
Measure Type: Count of Participants; Unit of Measure: Participants
-20% to < -10%	4 17.4%
-10% to < 0%	7 30.4%
0% to < 10%	9 39.1%
10% to < 20%	1 4.3%
20% to < 30%	0 0.0%
>= 30%	2 8.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IRX-2 Regimen
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	The correlation of each of the above variables at biopsy/Day 1, surgery/Day 21, and change with percent change in the longest diameter (LD) of the primary tumor was calculated using Spearman rank correlations (183 correlations). Due to outliers in the distribution of percent change in the longest diameter, it was felt that the Spearman rank correlations would be more appropriate than Pearson correlations.
Statistical Test of Hypothesis	P-Value	<0.10
	Comments	[Not Specified]
	Method	Spearman Rank
	Comments	[Not Specified]

3. Secondary Outcome

Title	Patient Tolerance of Surgery and Post-operative Adjuvant Therapy;
Description	Patient Tolerance of Surgery and Post-operative Adjuvant Therapy as measured by median days spent in the hospital, intensive care unit, and step down unit.
Time Frame	Following surgery and post-operative therapy (up to 39 days post surgery)

Outcome Measure Data

Analysis Population Description

Following surgery the median days spent in the hospital, intensive care unit and step down unit was determined for 26 subjects

Arm/Group Title	IRX-2 Regimen
Arm/Group Description:	A 2-week course of IRX-2, an initial low dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation
Overall Number of Participants Analyzed	26
Median (Full Range); Unit of Measure: days
Median Days in hospital	8.5; (1 to 39)
Median Days in intensive care unit	0.5; (0 to 17)
Median Days in step-down unit	0.5; (0 to 22)

4. Secondary Outcome

Title	Immune Competence as Measured by Skin Test Reactivity
Description	To assess measures of immune competence following administration of the IRX-2 regimen, including skin test reactivity.
Time Frame	At approx. 21 days, prior to surgery

Outcome Measure Data

Analysis Population Description

Skin response (erythema) was evaluated at Baseline and Day 21 on 26 subjects treated with IRX-2 Regimen

Arm/Group Title	IRX-2 Regimen
Arm/Group Description:	A 2-week course of IRX-2, an initial low dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation
Overall Number of Participants Analyzed	26
Measure Type: Count of Participants; Unit of Measure: Participants
Positive at both Baseline and at Day 21 (%)	12 46.2%
Negative at both Baseline and Day 21 (%)	6 23.1%
Positive at Baseline and Negative Day 21 (%)	6 23.1%
Negative at Baseline and Positive at Day 21	2 7.7%
Induration at Day 21	3 11.5%

5. Secondary Outcome

Title	Disease-free Survival
Description	Estimate disease-free survival (DFS) (time from surgery to death or clinically apparent, biopsy confirmed recurrent or progressive disease after the completion of initial therapy, assessed up to 3 years; margins of resection positive for tumor will not be considered disease recurrence).
Time Frame	Time from surgery to death or clinically apparent, biopsy confirmed recurrent or progressive disease after the completion of initial therapy, assessed up to 3 years; margins of resection positive for tumor will not be considered disease recurrence

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IRX-2 Regimen
Arm/Group Description:	A 2-week course of IRX-2, an initial low dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation
Overall Number of Participants Analyzed	26
Measure Type: Number; Unit of Measure: DFS Probability
1-year disease free survival probability	0.721
2-year disease free survival probability	0.641
3-year disease free survival probability	0.620

6. Secondary Outcome

Title	Overall Survival
Description	Estimate overall survival (OS) in patients receiving the IRX-2 regimen. IRX-2 is currently being studied in an on-going Phase 2b clinical trial in patients with newly diagnosed Stage II, III, and IVA squamous cell carcinoma of the oral cavity (INSPIRE)
Time Frame	Time from surgery to death or confirmed recurrent or progressive disease, assessed up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IRX-2 Regimen
Arm/Group Description:	A 2-week course of IRX-2, an initial low dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation
Overall Number of Participants Analyzed	26
Measure Type: Number; Unit of Measure: percentage of subjects
First Year (%)	92
Second Year (%)	73
Third Year (%)	69

7. Secondary Outcome

Title	Number of Participants With High Lymphocyte Infiltration (LI) According to the Visual Analog Scale (VAS)
Description	Immunologic response features were extracted and quantified using a VAS of 0-100 mm to provide for a more continuous variable than the 0-4+ scale that is often used to assess histological responses. The scoring was such that 100 represented the maximum for any sample and 0 represented the lack of any parameter of interest. See publication of Berinstein, et al., 2012 for complete details.
Time Frame	On approximately Day 21 (last day of treatment) prior to undergoing post-treatment surgery

Outcome Measure Data

Analysis Population Description

Number of patients with high lymphocyte infiltration (LI).

Arm/Group Title	IRX-2 Regimen
Arm/Group Description:	The IRX-2 regimen is the combination of a 2-week course of IRX-2 itself, an initial dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation.
Overall Number of Participants Analyzed	25
Measure Type: Number; Unit of Measure: participants with high LI (>34 mm) VAS
	18

8. Secondary Outcome

Title	Relationship Between Overall Survival (OS) and Immune Competence (Lymphocyte Infiltration, LI) in Participants With High LI and Low LI
Description	After participants completed the IRX-2 regimen and the tumor resection was performed, tumor pathology was evaluated from tissue specimens obtained at tumor resection. Formalin-fixed, paraffin-embedded blocks, or unstained slides from the primary tumor were submitted to an independent pathology laboratory for hematoxylin and eosin staining, and evaluation of lymphocyte infiltration (LI). Participants were grouped into a "low LI" and "high LI" group based on the change in lymphocyte infiltration from the pretreatment tumor biopsy to the post-treatment tumor surgical resection. 5-year overall survival probabilities were then estimated (Kaplan-Meier) between the "low LI" and "high LI" groups
Time Frame	At time of surgery, after treatment with IRX-2 Regimen, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Lymphocyte Infiltration (LI)	Low Lymphocyte Infiltration
Arm/Group Description:	Participants with high lymphocyte infiltration after treatment with the IRX-2 regimen	Participants with low lymphocyte infiltration after treatment with the IRX-2 regimen
Overall Number of Participants Analyzed	13	12
Measure Type: Number; Unit of Measure: 5-Year OS Probability
	0.80	0.50

Adverse Events

Time Frame	Primarily from the administration of cyclophosphamide to the time of surgery, except for Serious Adverse Events (reported up to 30 days after last dose of study medication)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	IRX-2 Regimen
Arm/Group Description	The IRX-2 regimen is the combination of a 2-week course of IRX-2 itself, an initial dose of cyclophosphamide, and a 3-week course of indomethacin and zinc supplementation.
All-Cause Mortality
	IRX-2 Regimen
	Affected / at Risk (%)
Total	10/27 (37.04%)
Serious Adverse Events
	IRX-2 Regimen
	Affected / at Risk (%)	# Events
Total	7/27 (25.93%)
General disorders
ALCOHOL WITHDRAWAL * 1	1/27 (3.70%)	1
Infections and infestations
ASPIRATION PNEUMONIA * 1	3/27 (11.11%)	3
NECK ABSCESS * 1	1/27 (3.70%)	1
POSTOPERATIVE INFECTION * 1	1/27 (3.70%)	1
Respiratory, thoracic and mediastinal disorders
RESPIRATORY INFECTION * 1 [1]	1/27 (3.70%)	2
1 Term from vocabulary, MedDRA (8.0); * Indicates events were collected by non-systematic assessment; [1] Respiratory Infection with Asthma
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	IRX-2 Regimen
	Affected / at Risk (%)	# Events
Total	23/27 (85.19%)
Blood and lymphatic system disorders
ANAEMIA † 1	3/27 (11.11%)	3
Gastrointestinal disorders
CONSTIPATION † 1	4/27 (14.81%)	4
DRY MOUTH † 2	2/27 (7.41%)	2
VOMITING † 2	2/27 (7.41%)	2
General disorders
DIZZINESS † 1	4/27 (14.81%)	4
FATIGUE † 1	3/27 (11.11%)	3
HEADACHE † 1	8/27 (29.63%)	8
INJECTION SITE PAIN † 1	6/27 (22.22%)	6
NAUSEA † 1	6/27 (22.22%)	6
INJECTION SITE DISCOMFORT † 1	2/27 (7.41%)	2
Injury, poisoning and procedural complications
CONTUSION † 2	2/27 (7.41%)	2
Musculoskeletal and connective tissue disorders
MYALGIA † 2	2/27 (7.41%)	2
Respiratory, thoracic and mediastinal disorders
PNEUMONIA ASPIRATION † 1	3/27 (11.11%)	3
1 Term from vocabulary, MedDRA (8.0); 2 Term from vocabulary, MedDRA (Unspecified); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS 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: Gregory T. Wolf
• Organization: University of Michigan Hospital
• EMail: gregwolf@umich.edu

Publications of Results:

Freeman SM, Franco JL, Kenady DE, Baltzer L, Roth Z, Brandwein HJ, Hadden JW. A phase 1 safety study of an IRX-2 regimen in patients with squamous cell carcinoma of the head and neck. Am J Clin Oncol. 2011 Apr;34(2):173-8. doi: 10.1097/COC.0b013e3181dbb9d8.

Wolf GT, Fee WE Jr, Dolan RW, Moyer JS, Kaplan MJ, Spring PM, Suen J, Kenady DE, Newman JG, Carroll WR, Gillespie MB, Freeman SM, Baltzer L, Kirkley TD, Brandwein HJ, Hadden JW. Novel neoadjuvant immunotherapy regimen safety and survival in head and neck squamous cell cancer. Head Neck. 2011 Dec;33(12):1666-74. doi: 10.1002/hed.21660. Epub 2011 Jan 31.

Berinstein NL, Wolf GT, Naylor PH, Baltzer L, Egan JE, Brandwein HJ, Whiteside TL, Goldstein LC, El-Naggar A, Badoual C, Fridman WH, White JM, Hadden JW. Increased lymphocyte infiltration in patients with head and neck cancer treated with the IRX-2 immunotherapy regimen. Cancer Immunol Immunother. 2012 Jun;61(6):771-82. doi: 10.1007/s00262-011-1134-z. Epub 2011 Nov 6.

Whiteside TL, Butterfield LH, Naylor PH, Egan JE, Hadden JW, Baltzer L, Wolf GT, Berinstein NL. A short course of neoadjuvant IRX-2 induces changes in peripheral blood lymphocyte subsets of patients with head and neck squamous cell carcinoma. Cancer Immunol Immunother. 2012 Jun;61(6):783-8. doi: 10.1007/s00262-011-1136-x. Epub 2011 Nov 23.

Other Publications:

Schilling B, Harasymczuk M, Schuler P, Egan JE, Whiteside TL. IRX-2, a novel biologic, favors the expansion of T effector over T regulatory cells in a human tumor microenvironment model. J Mol Med (Berl). 2012 Feb;90(2):139-47. doi: 10.1007/s00109-011-0813-8. Epub 2011 Sep 14.

Czystowska M, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, Hadden JW, Whiteside TL. Mechanisms of T-cell protection from death by IRX-2: a new immunotherapeutic. Cancer Immunol Immunother. 2011 Apr;60(4):495-506. doi: 10.1007/s00262-010-0951-9. Epub 2010 Dec 23.

Naylor PH, Hernandez KE, Nixon AE, Brandwein HJ, Haas GP, Wang CY, Hadden JW. IRX-2 increases the T cell-specific immune response to protein/peptide vaccines. Vaccine. 2010 Oct 8;28(43):7054-62. doi: 10.1016/j.vaccine.2010.08.014. Epub 2010 Aug 13.

Naylor PH, Hadden JW. Preclinical studies with IRX-2 and thymosin alpha1 in combination therapy. Ann N Y Acad Sci. 2010 Apr;1194:162-8. doi: 10.1111/j.1749-6632.2010.05475.x.

Rapidis AD, Wolf GT. Immunotherapy of head and neck cancer: current and future considerations. J Oncol. 2009;2009:346345. doi: 10.1155/2009/346345. Epub 2009 Aug 9.

Czystowska M, Han J, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, Hadden JW, Signorelli K, Whiteside TL. IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death. Cell Death Differ. 2009 May;16(5):708-18. doi: 10.1038/cdd.2008.197. Epub 2009 Jan 30.

Bright J, Al-Shamahi A. BioPartnering Europe--15th Annual Conference. Highlights from open house and emerging company presentations--Part 1. IDrugs. 2007 Dec;10(12):855-7. No abstract available.

Egan JE, Quadrini KJ, Santiago-Schwarz F, Hadden JW, Brandwein HJ, Signorelli KL. IRX-2, a novel in vivo immunotherapeutic, induces maturation and activation of human dendritic cells in vitro. J Immunother. 2007 Sep;30(6):624-33. doi: 10.1097/CJI.0b013e3180691593.

Hadden JW, Verastegui E, Hadden E. IRX-2 and thymosin alpha1 (Zadaxin) increase T lymphocytes in T lymphocytopenic mice and humans. Ann N Y Acad Sci. 2007 Sep;1112:245-55. doi: 10.1196/annals.1415.032. Epub 2007 Jun 28.

Naylor PH, Quadrini K, Garaci E, Rasi G, Hadden JW. Immunopharmacology of thymosin alpha1 and cytokine synergy. Ann N Y Acad Sci. 2007 Sep;1112:235-44. doi: 10.1196/annals.1415.036. Epub 2007 Jun 13.

Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2004 Sep;26(7):587-612.

Hadden JW. Immunodeficiency and cancer: prospects for correction. Int Immunopharmacol. 2003 Aug;3(8):1061-71. doi: 10.1016/S1567-5769(03)00060-2.

• Responsible Party: Brooklyn ImmunoTherapeutics, LLC
• ClinicalTrials.gov Identifier: NCT00210470
• Other Study ID Numbers: IRX-2 2005-A
• First Submitted: September 13, 2005
• First Posted: September 21, 2005
• Results First Submitted: January 6, 2012
• Results First Posted: February 8, 2012
• Last Update Posted: December 11, 2020