Histamine Dihydrochloride and Interleukin-2 in Primary Resectable Pancreatic Cancer (PANCEP-1)

A Phase I/II Trial of Peri- and Postoperative Treatment With Histamine Dihydrochloride and Low-dose Interleukin-2 in Patients With Primary Resectable Pancreatic Cancer

A key aspect of the trial is that functions of anti-neoplastic T cells and natural killer (NK) cells, may be inhibited by immunosuppressive signals from myeloid cells, in particular reactive oxygen species (ROS) produced by several subsets of myeloid cells. In cancer, such immunosuppressive cells are commonly denoted myeloid-derived suppressor cells (MDSCs), which are immature monocytes and granulocytes that impede immune-mediated clearance of malignant cells by multiple mechanisms, including the formation of immunosuppressive ROS via myeloid cell NADPH oxidase (NOX2). The presence of MDSCs within or adjacent to tumor tissue is assumed to facilitate the growth and spread of tumors and may also dampen the efficacy of cancer immunotherapies. The underlying hypothesis for this clinical trial is the administration of HDC/IL-2 will reduce surgery-induced inflammation and reduce metastasis. A phase I/II open label, single-center study of the safety, tolerability, and efficacy of peri- and postoperative therapy with histamine dihydrochloride and low-dose interleukin-2 treatment in subjects with primary pancreatic cancer.To assess the frequency and extent of adverse events associated with low dose interleukin-2 and histamine dihydrochloride when used as perioperative therapy.To determine progression free survival and overall survival following surgery, and compare with matched historical controls from the Swedish Cancer Registry.

Study Overview

• Status: Not yet recruiting
• Conditions: Pancreatic Cancer; Surgery; Metastasis; Immunosuppression
• Intervention / Treatment: Drug: Histamine Dihydrochloride (HDC); Drug: Interleukin-2 (IL-2)

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Svein Olav Bratlie; Phone Number: +46313428218; Email: svein.olav.bratlie@vgregion.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects must give written informed consent prior to initiation of therapy, in keeping with the policies of the institution.
2. Subject is a male or female age >18
3. By the surgeon´s evaluation fit for pancreatic surgery
4. Subjects must have radiologic, and or cytologic confirmation of primary pancreatic cancer

Exclusion Criteria (any of the following):

1. Class III or IV cardiac disease, hypotension or severe hypertension, vasomotor instability, serious or uncontrolled cardiac dysrhythmias (including ventricular arrhythmias) at any time, acute myocardial infarction within the past 6 months, active uncontrolled angina pectoris or symptomatic arteriosclerotic peripheral blood vessel disease.
2. History of uncontrolled seizures, severe central nervous system disorders, or psychiatric disability thought to be clinically significant in the opinion of the Investigator and adversely affecting compliance to protocol.
3. Any other condition or symptoms preventing the patient from entering the study, according to the PI's judgement.
4. A woman of childbearing potential (WOCBP) must agree to comply with using an effective contraceptive method for the duration of the treatment (a WOCBP is a sexually mature woman who is not surgically sterile or has not been naturally postmenopausal for at least 12 consecutive months). Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. Local laws and regulations may require use of alternative and/or additional contraception methods. One of the highly effective methods of contraception listed below is required during study duration and until the end of relevant systemic exposure, defined as 5 months after the end of study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Patients receiving immunomodulating treatment

Drug: Histamine Dihydrochloride (HDC); HDC is administrated in combination with IL-2 as peri- and post-operative treatment in patients undergoing surgery. 0.5 mg HDC is administered twice daily by subcutaneous injections 1 to 3 minutes after each IL-2 injection during three 3 week cycles, with 3-week resting periods inbetween. The first treatment cycle is initated 2 weeks prior to surgery, with an additional 2-3 days rest period during the surgical procedure, before the third treatment week is initiated.; Drug: Interleukin-2 (IL-2); IL-2 is administrated in combination with HDC during three 3 week cycles as peri- and post-operative treatment in patients undergoing surgery. IL-2 is administered twice daily as a subcutaneous injection 1 to 3 minutes prior to the administration of histamine dihydrochloride; each dose of IL-2 is 16,400 IU/kg (1µg/kg).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of Treatment-Emergent Adverse Events as assessed by NCI-CTCAE	Incidence and severity grade of adverse events occuring during and after treatment will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0.	When the first 14 patients have undergone one full 3-week cycle with HDC/IL-2 (approximately 18 months after trial start)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Comparing matched historical controls from national registry	24 months
Disease free survival	Comparing matched historical controls from national registry	24 months
Changes in Natural killer cell subsets in blood	Changes in NK cell number and expression of activation markers during surgery	Change from pre-surgical levels to levels during the post-surgical week
Changes in T cell subsets in blood	Changes in T cell number and expression of activation markers during surgery	Change from pre-surgical levels to levels during the post-surgical week
Changes in Myeloid cell populations	Changes in myeloid cell number and markers of activation and inhibition	Change from pre-surgical levels to levels during the post-surgical week
Tumor infiltrating lymphocytes and tumor infiltrating myeloid cells	Tumor pieces removed during surgery will be assessed for immune populations	immediately after the surgery
Carbohydrate antigen 19-9	Serum CA 19-9 levels are monitored as a biomarker for disease recurrance	12 months

Collaborators and Investigators

• Sponsor: Sahlgrenska University Hospital, Sweden
• Investigators: Study Director: Andreas Muth, Västra Götalandsregionen, Sahlgrenska University Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: March 7, 2023
• First Submitted That Met QC Criteria: March 31, 2023
• First Posted (Actual): April 12, 2023

Study Record Updates

• Last Update Posted (Actual): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Histamine Agents; Histamine Agonists; Interleukin-2; Histamine; Histamine phosphate
• Other Study ID Numbers: PANCEP-1, April 1 2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No