Feasibility Study of Intra-Tumoral Lipopolysaccharide Immunotherapy for Intra-Abdominal

Malignancy Clinical Trial

— LPS  

Official title:

Feasibility Study of Intra-Tumoral Lipopolysaccharide Immunotherapy for Intra-Abdominal

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05751837
• Other study ID #: 2022-263
• Status: Recruiting
• Phase: Phase 1
• Start date: March 16, 2023
• Est. completion date: February 28, 2027

Study information

• Verified date: April 2023
• Source: Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)
• Contact: Patrick M Wagner, MD
• Phone: 412-359-3731
• Email: Patrick.Wagner[@]ahn.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this research study is to determine whether a sterile bacteria wall chemical, called lipopolysaccharide (LPS), can be injected safely into abdominal tumors during routine laparoscopic surgery performed as a preliminary procedure in patients who will subsequently undergo a larger planned operation to remove abdominal tumors. The researchers will biopsy the tumor before injection and then again at the time of the larger operation to assess whether any effect of the treatment can be measured.

Description:

Immunotherapy for advanced cancers of the abdomen can be quite effective, but not all tumors are responsive to this type of treatment. There is intense interest in new methods to convert non-responsive tumors into responsive tumors. One such method is to inject chemical constituents of micro-organisms into tumors in order to stimulate the immune system to recognize the tumor as foreign and mount an immune response to treatment. Provide a concise and brief, one-paragraph summary of your research project. Include a summary of the problem, the main objective and rationale of your project; a brief description of the experimental approach and methods; a concise description/summary of the most important results that you hope to obtain; and why think your results will be significant

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 6
• Est. completion date: February 28, 2027
• Est. primary completion date: February 2, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

1. Males or females age 18 to 99 years

2. Pre-menopausal women less than or equal to18 years of age must have a negative urine/serum pregnancy test prior to standard-of-care surgery and investigational treatment.

3. Participants must have an advanced intra-abdominal tumor, including metastatic or recurrent, biopsy-proven, digestive tract tumors.

4. Participants must have at least two index non-visceral intra-abdominal tumors that are grossly visible, >1cm3 in volume, and amenable to biopsy and injection of investigational drug or control solution at the time of laparoscopy.

5. Participants must be planning or scheduled to undergo a standard-of-care abdominal laparoscopic surgical procedure at AGH or WPH and be potentially eligible for a second, definitive operation to remove the tumor(s) pending the findings during laparoscopy.

6. Must be able to read and understand English and consent for themselves

Exclusion Criteria:

1. Pregnant or lactating females

2. Investigational drug use within 30 days prior to enrollment.

3. Immunosuppressive medication including corticosteroids within 30 days prior to enrollment.

4. Active chemotherapy or radiotherapy within 4 weeks of investigational agent injection.

5. Active infection requiring systemic therapy or causing fever >38.1 degree C or unexplained fever >38.1 degree C within seven days prior to investigational agent injection

6. Laboratory abnormalities, drawn according to standard clinical care in anticipation of upcoming surgery outside the following limits: AST/SGOT > 1.5 times the upper limit of normal ALT/SGPT > 1.5 times the upper limit of normal Total bilirubin > 1.5 times the upper limit of normal Creatinine > 1.5 times the upper limit of normal Hemoglobin < 9 gm/dL White blood cell count < 3,000/ mm3 Platelet count < 70,000/mm3 INR >1.5 times the upper limit of normal PTT >1.5 times the upper limit of normal

7. History of allergic reaction to the investigational agent carrier solution.

8. Medical contra-indication or allergic reaction to acetaminophen or NSAIDs.

9. Participants who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

10. Adverse events from prior therapy that have not resolved to CTCAE version 5 grade < and equal to1 prior to enrollment

Related Conditions & MeSH terms

• Abdominal Cancer
• Malignancy
• Neoplasms

Intervention

Biological:
• Lipopolysaccharide
One tumor will be injected with 1 ug LPS (investigational drug) over approximately one minute

Locations

Country	Name	City	State
United States	Allegheny Health Network Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Allegheny Health Network West Penn Hospital	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Patrick Wagner, MD, FACS	List Biological Laboratories, Inc

Country where clinical trial is conducted

United States, 

References & Publications (19)

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Calvano SE, Coyle SM. Experimental human endotoxemia: a model of the systemic inflammatory response syndrome? Surg Infect (Larchmt). 2012 Oct;13(5):293-9. doi: 10.1089/sur.2012.155. Epub 2012 Oct 16. — View Citation

Chicoine MR, Won EK, Zahner MC. Intratumoral injection of lipopolysaccharide causes regression of subcutaneously implanted mouse glioblastoma multiforme. Neurosurgery. 2001 Mar;48(3):607-14; discussion 614-5. doi: 10.1097/00006123-200103000-00032. — View Citation

Coley WB. II. Contribution to the Knowledge of Sarcoma. Ann Surg. 1891 Sep;14(3):199-220. doi: 10.1097/00000658-189112000-00015. No abstract available. — View Citation

Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991 Jan;(262):3-11. No abstract available. — View Citation

Engelhardt R, Mackensen A, Galanos C. Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients. Cancer Res. 1991 May 15;51(10):2524-30. — View Citation

Fong YM, Marano MA, Moldawer LL, Wei H, Calvano SE, Kenney JS, Allison AC, Cerami A, Shires GT, Lowry SF. The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. J Clin Invest. 1990 Jun;85(6):1896-904. doi: 10.1172/JCI114651. — View Citation

Goto S, Sakai S, Kera J, Suma Y, Soma GI, Takeuchi S. Intradermal administration of lipopolysaccharide in treatment of human cancer. Cancer Immunol Immunother. 1996 May;42(4):255-61. doi: 10.1007/s002620050279. — View Citation

Hudgins LC, Parker TS, Levine DM, Gordon BR, Saal SD, Jiang XC, Seidman CE, Tremaroli JD, Lai J, Rubin AL. A single intravenous dose of endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal volunteers. J Lipid Res. 2003 Aug;44(8):1489-98. doi: 10.1194/jlr.M200440-JLR200. Epub 2003 May 16. — View Citation

Humeau J, Le Naour J, Galluzzi L, Kroemer G, Pol JG. Trial watch: intratumoral immunotherapy. Oncoimmunology. 2021 Oct 15;10(1):1984677. doi: 10.1080/2162402X.2021.1984677. eCollection 2021. — View Citation

Kiers D, Leijte GP, Gerretsen J, Zwaag J, Kox M, Pickkers P. Comparison of different lots of endotoxin and evaluation of in vivo potency over time in the experimental human endotoxemia model. Innate Immun. 2019 Jan;25(1):34-45. doi: 10.1177/1753425918819754. — View Citation

Mariani CL, Rajon D, Bova FJ, Streit WJ. Nonspecific immunotherapy with intratumoral lipopolysaccharide and zymosan A but not GM-CSF leads to an effective anti-tumor response in subcutaneous RG-2 gliomas. J Neurooncol. 2007 Dec;85(3):231-40. doi: 10.1007/s11060-007-9415-2. Epub 2007 Jun 14. — View Citation

Mehta RS, Nishihara R, Cao Y, Song M, Mima K, Qian ZR, Nowak JA, Kosumi K, Hamada T, Masugi Y, Bullman S, Drew DA, Kostic AD, Fung TT, Garrett WS, Huttenhower C, Wu K, Meyerhardt JA, Zhang X, Willett WC, Giovannucci EL, Fuchs CS, Chan AT, Ogino S. Association of Dietary Patterns With Risk of Colorectal Cancer Subtypes Classified by Fusobacterium nucleatum in Tumor Tissue. JAMA Oncol. 2017 Jul 1;3(7):921-927. doi: 10.1001/jamaoncol.2016.6374. Erratum In: JAMA Oncol. 2019 Apr 1;5(4):579. — View Citation

Millischer V, Heinzl M, Faka A, Resl M, Trepci A, Klammer C, Egger M, Dieplinger B, Clodi M, Schwieler L. Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial. J Neuroinflammation. 2021 Jul 17;18(1):158. doi: 10.1186/s12974-021-02196-x. — View Citation

Oblak A, Jerala R. Toll-like receptor 4 activation in cancer progression and therapy. Clin Dev Immunol. 2011;2011:609579. doi: 10.1155/2011/609579. Epub 2011 Nov 3. — View Citation

Otto F, Schmid P, Mackensen A, Wehr U, Seiz A, Braun M, Galanos C, Mertelsmann R, Engelhardt R. Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer. Eur J Cancer. 1996 Sep;32A(10):1712-8. doi: 10.1016/0959-8049(96)00186-4. — View Citation

Shetab Boushehri MA, Lamprecht A. TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings. Mol Pharm. 2018 Nov 5;15(11):4777-4800. doi: 10.1021/acs.molpharmaceut.8b00691. Epub 2018 Oct 3. — View Citation

van Lier D, Geven C, Leijte GP, Pickkers P. Experimental human endotoxemia as a model of systemic inflammation. Biochimie. 2019 Apr;159:99-106. doi: 10.1016/j.biochi.2018.06.014. Epub 2018 Jun 22. — View Citation

Vila G, Riedl M, Resl M, van der Lely AJ, Hofland LJ, Clodi M, Luger A. Systemic administration of oxytocin reduces basal and lipopolysaccharide-induced ghrelin levels in healthy men. J Endocrinol. 2009 Oct;203(1):175-9. doi: 10.1677/JOE-09-0227. Epub 2009 Jul 8. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	The number, nature and severity of adverse events as assessed by CTCAE v 4.0 will be determined in a series of six patients undergoing injection of bacterial-derived immunotherapeutic toll receptor agonist (LPS) instilled via direct injection into intra-abdominal tumors during laparoscopic surgery.	30 Days
Secondary	Alteration in Cellular and Soluble Immune Biomarkers in Injected Tumors	Changes in intra-tumoral leukocyte subgroup densities and soluble immune biomarker concentrations will be assessed in injected tumors and compared against non-injected tumors.	30 days