A growing number of tumor therapies are being developed where patients are selected based on specific genetic or molecular biomarkers. The enrollment of a biomarker-specified patient population into clinical trials entails some operational challenges, since a notable number of patients will test negative for the required biomarker leading to a high screening failure rate.

immatics biotechnologies GmbH develops several therapeutic multi-peptide cancer vaccines designed for the treatment of a certain cancer entity with a certain human leukocyte antigen (HLA) marker. During clinical trials HLA-typing is conducted at a central laboratory using peripheral blood (EDTA blood) shipped at room temperature and obtaining results takes at least seven working days (about 14 days). Depending on the HLA-restriction of the vaccine, only 45-60 percent of patients with an appropriate tumor type possess a suitable HLA-type.

Due to the high HLA-type screening failure rate of 40-55 percent, investigators and immatics (as the trial sponsor) would like to analyze the HLA-type first before continuing with the remaining screening procedures. Such a staggered screening approach saves time and effort of investigators and prevents additional burden to the patients and thus, facilitates enrollment. Likewise, costs for the sponsor are reduced since tumor assessment, usually based on radiological images and other expensive screening procedures are only conduced in patients with an appropriate HLA-type.

However, the total screening duration adds up to about six weeks (two weeks for HLA-typing and about four weeks for remaining screening procedures), which is quite long for fast growing cancers and sometimes not acceptable, if established therapies are available, which need to be initiated without time delay. In particular, a long screening period is a disadvantage for cancer vaccines, because it takes some time until cancer vaccines exert their clinical effect due to their specific mode of action. Therefore, the start of vaccination should be shortly after diagnosis or failure of prior anti-tumor therapy.

These challenges were addressed in the phase I/II IMA910-101 trial (92 vaccinated patients) in the following way: HLA-A*02 positive, initially untreated, advanced colorectal cancer patients with stable or responding disease following 12 weeks of first-line chemotherapy were enrolled to receive vaccinations with IMA910, a multi-peptide vaccine. Two separate informed consents (ICs) including patient information were established, whereby the HLA-IC (Screening 1) was limited to blood sampling for HLA-typing and the capture of selected demographic data, whereas the main-IC covered all remaining screening procedures (Screening 2) and all study procedures.

As defined in the clinical study protocol, HLA-typing could be conducted after signing of the HLA-IC without any further time restrictions. The main-IC could be signed one week after the last chemotherapy cycle at the earliest and only in HLA-A*02 positive patients. This staggered screening approach was justified by the fact that the HLA-type of a patient does not change throughout a patient's lifetime and thus, HLA-typing at any time reveals the same result without any impact on the interpretation of the IMA910-101 trial data. Furthermore, early knowledge of the HLA-status supports the selection of the right treatment strategy since investigators commonly discuss subsequent treatment options with their patients before the start of palliative chemotherapy and not just after the last cycle of first-line chemotherapy.

This staggered screening approach solves some issues mentioned above, however creates new issues with respect to safety surveillance. According to regulations, safety surveillance (i.e. capture of all adverse events [AEs] independent of relationship to study-specific treatments and procedures) has to start with the signature of the informed consent and includes all AEs occurring during pre-, post- and drug-free treatment periods. In the currently discussed trial, the HLA-IC was signed before, during or after chemotherapy, which means that this could have happened up to five months before signing the main-IC and the start of vaccination subsequently. It is quite obvious, that the collection of AEs during standard chemotherapy is not very meaningful for the assessment of the safety profile of the vaccine, which is only applied as monotherapy after the chemotherapy has been completed.

On the other side, the blood drawing for HLA-typing is clearly a study-specific procedure, which may induce AEs. Therefore, the following procedures were implemented into the clinical study protocol. All AEs and SAEs (serious AEs), whether or not considered causally related to the HLA-typing were captured from signing the HLA-IC until five days after the blood sampling for HLA typing. Thereafter, only AEs and SAEs that were, in the investigator's opinion potentially related to the blood sampling for HLA typing were captured. Full safety surveillance was resumed on the date of signing the main-IC until four weeks after the last application of the investigational product. These safety surveillance procedures were justified by the low safety risk associated with drawing a single blood sample of 3mL and the high likelihood that induced AEs should occur right after or a few days after blood sampling. The IMA910-101 trial applying the described staggered screening approach and reduced safety surveillance between HLA-IC and main-IC was approved in 10 European countries and involved about 50 clinical sites.



Dr. Andrea Mayer-Mokler
Clinical Program Director
immatics biotechnologies GmbH