The IAPACA trial

(Immunostimulatory Antibodies for Treatment of Pancreatic Cancer)

Cancer type: Pancreatic ductal adenocarcinoma (PDA)

Treatment concept: administration of agonist anti-CD40 IS-Ab ChiLob7/4, targeting the CD40 receptor on several immune cell subsets, in combination with standard 28-week cycles of gemcitabine

Rationale for trial design:

Standard 28-cycles of gemcitabine, involving i.v. administration of Gemcitabine (1000 mg/m2), are a commonly applied chemotherapy in the treatment of non-resectable PDA and in adjuvant treatment of primary and secondary resectable PDA
This treatment is generally well tolerated;
Experiments in pre-clinical mouse tumor models demonstrated strong synergy between gemcitabine and agonist anti-CD40 IS-Ab. This involves the activation of CD40-positive dendritic cells that present tumor-derived antigens to T-cells. Moreover, anti-CD40 IS-Abs can make the tumor microenvironment more permissive to T-cell immune action by reprogramming CD40-positive immune-inhibitory myeloid cells such as macrophages. Gemcitabine provides synergy by promoting tumor cell death and availability of tumor antigens for immune activation.
Anti-CD40 IS-Ab ChiLob7/4 has been successfully tested in a previous phase I, single agent dose escalation trial conducted by University Hospital Southampton, and was found well tolerated up to a dose of 200 mg when administered as 4 weekly doses.

IAPACA Part 1:

Goal: establishment of a well-tolerated dose of anti-CD40 IS-Ab ChiLob7/4 when administered in conjunction with gemcitabine chemotherapy

Type of study: phase I dose escalation study

Patient cohort: patients with metastatic, non-resectable PDA for which gemcitabine is one of the most commonly applied treatment regimens

Number of patients to be enrolled: 12-21, depending on study findings

Treatment duration: 2 months

Treatment: administration of anti-CD40 IS-Ab ChiLob7/4 in conjunction with two 28-day cycles of gemcitabine, where gemcitabine is given on days 1, 8 and 15 of each cycle, and anti-CD40 Ab on days 8 and 15.

Treatment follow up: patients with continue on standard of care gemcitabine chemotherapy, unless their medical condition would require otherwise.

Primary endpoint: establishment of the maximal tolerated dose (MTD) of anti-CD40 IS-Ab ChiLob7/4 when administered in conjunction with gemcitabine treatment by evaluation of occurrence of treatment-related adverse events.

Main secondary endpoint:

Evaluation of clinical impact of the treatment by means of measurement of tumor burden through tomography and analysis of plasma levels of the tumor markers CA19-9 and circulating tumor DNA.

Starting date: Q3 2016

IAPACA Part 2:

Goal: to obtain biomarker-based evidence that anti-CD40 IS-Ab ChiLob7/4, when dosed in conjunction with gemcitabine, can significantly enhance the anti-tumor immune response in PDA.

Type of study: phase II neo-adjuvant biomarker trial

Patient cohort: patients with primary resectable PDA

Number of patients to be enrolled: 17 fully evaluable patients (total up to 23)

Treatment duration: 15 days (trial-related treatment schedule)

Treatment: administration of anti-CD40 IS-Ab ChiLob7/4 in conjunction with three doses of gemcitabine, where gemcitabine is given on days 1, 8 and 15, and anti-CD40 Ab on days 8 and 15.

Treatment follow up: 3-5 days after administration of the 2nd dose of anti-CD40 Ab, the patients proceed to surgery for tumor resection according to standard practice; after approximately 6 weeks, patients will receive standard of care adjuvant chemotherapy (gemcitabine), unless their medical status would require alternative treatment.

Primary endpoint: analysis of changes in immune cell infiltration in the resected tumor, in particular the number of CD8+ T-cells per mm2, by means of validated computerized image analysis (Immunomap) of whole tissue sections.

Secondary endpoints:

Analysis of additional changes in immune infiltrate and in tumor cell viability by means of Immunomap technology 
Tumor load as determined by plasma levels of CA19-9 and circulating tumor DNA 
Disease-free and overall survival 
Blood-based immune activation markers 
Adverse event rate 

Starting date: Q2 2017