The HARE-40 trial

(HPV Anti-CD40 RNA vaccine)

Cancer Type: human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC)

Treatment concept: administration of agonist anti-CD40 IS-Ab ChiLob7/4, targeting the CD40 receptor on several immune cell subsets, in combination with an mRNA-based vaccine against HPV16-derived tumor antigens.

Rationale of trial design:

Pre-clinical experiments have demonstrated that application of agonist anti-CD40 IS-Ab can greatly enhance the magnitude of vaccine-induced T-cell immune responses through the activation of CD40-positive dendritic cells that present vaccine antigen 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. 
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.
mRNA vaccines were found to be well tolerated and highly capable of inducing antigen-specific T-cell immunity in phase I clinical studies conducted by SME-partner BioNTech
T-cell responses against HPV-derived tumor antigens, when applied in the context of HPV16-positive cancers, are truly tumor specific, limiting the risk that strong T-cell responses against these antigens will create a risk for immune pathology in normal somatic tissues in the patient.

HARE-40 Arm 1A:

Goal: establishment of a safe and tolerable dose of HPV16 mRNA vaccine capable of inducing strong HPV16-specific T-cell responses.

Type of study: phase I dose-escalation study; adjuvant setting

Patient cohort: previously treated, clinically disease-free HPV16+ HNSCC

Primary endpoint: establishment of a safe and tolerable dose of HPV16 mRNA vaccine

Secondary endpoint: evaluation of the capacity of the vaccine to elicit HPV16 antigen-specific immune responses in blood and tumor

Starting date: Q1/2016

HARE-40 Arms 1B and 1C:

Goal: evaluation of the immunogenicity and clinical impact of the HPV16 mRNA vaccine dose as established in study Arm 1A.

Type of study: phase II neo-adjuvant study

Patient cohort: HPV16+ HNSCC, newly diagnosed (arm 1B) or recurrent disease (arm 1C)

Primary endpoint: detailed evaluation of the impact of the HPV16 mRNA vaccine on the systemic and intra-tumoral HPV16-specific T-cell response on basis of extensive biomarker analyses.

Secondary endpoint: evaluation of the clinical impact of the vaccine on basis of RECIST criteria

Starting date: Q3/2016

HARE-40 Arm 2A:

Goal: establishment of a safe and tolerable dose of anti-CD40 IS-Ab ChiLob7/4 when dosed in conjunction with the HPV16 mRNA vaccine dose as established in study Arm 1A.

Type of study: phase I dose-escalation study; adjuvant setting

Patient cohort: previously treated, clinically disease-free HPV16+ HNSCC

Primary endpoint: establishment of a safe and tolerable dose of anti-CD40 IS-Ab ChiLob7/4 when dosed in conjunction with the HPV16 mRNA vaccine

Secondary endpoint: evaluation of the capacity of the combination of anti-CD40 Ab and mRNA vaccine to elicit HPV16 antigen-specific immune responses in blood and tumor; comparison with the impact of mRNA vaccine alone (Arm 1A)

Starting date: Q4/2016

HARE-40 Arms 2B and 2C:

Goal: evaluation of the immunogenicity and clinical impact of the combination of HPV16 mRNA vaccine and anti-CD40 IS-Ab ChiLob when dosed as established through study Arm 2A.

Type of study: phase II neo-adjuvant study

Patient cohort: HPV16+ HNSCC, newly diagnosed (arm 2B) or recurrent disease (arm 2C)

Primary endpoint: detailed evaluation of the impact of the combination of HPV16 mRNA vaccine and anti-CD40 Ab on the systemic and intra-tumoral HPV16-specific T-cell response on basis of extensive biomarker analyses; comparison with the impact of mRNA vaccine alone (Arm 1B)

Secondary endpoint: evaluation of the clinical impact of the combination treatment on basis of RECIST criteria; comparison with the clinical outcome of study 1B

Starting date: Q2/2017