Organoids to Predict Treatment response In mCRC (OPTIC)

Large randomized clinical trials demonstrate that in the general population
systemic treatment offers survival advantage to patients with metastatic
cancer. Unfortunately, a significant percentage of patients does not benefit
from this treatment but will suffer from the significant side-effects. Being
able to identify those patients that will benefit from palliative treatment
will be a major advance in personalized treatment of patients with metastatic
cancer. At present we are not able to determine tumour drug sensitivity of
individual patients on pre- emptive basis. In order to prevent the unnecessary
exposure of patients to cytotoxic agents, it is imperative to develop a method
that predicts drug sensitivity, optimally guiding therapeutic decision making.

A recent discovery by Sato et al. (2009) and van de Wetering et al., (2015)
might offer this opportunity (1,2). They established a culture system (so
called: *Organoids*) which allows the unlimited expansion of adult stem cells
of various organs which can subsequently be used for functional assays.
Importantly, they showed that the Organoids are genetically and phenotypically
stable over time (3a, b). The Organoid technology allows the expansion of both
healthy and tumor tissue, giving us an array of opportunities to improve health
care. One of these opportunities is to use these in vitro expanded tumors
(tumor organoids) for ex-vivo drug sensitivity screening.

The OPTIC study in patients with mCRC will assess the value of tumor organoids
in therapy response prediction. The study will provide the data to assess the
threshold of the screening test to determine a negative predictive value. In
addition, the data will provide preliminary data to predict positive treatment
response in patients. The study aims to assess the potential value of
incorporating organoid technology in the stratification of patients for
treatment with anti-neoplastic agents. In addition thereto patients will be
offered whole genome sequencing, to be performed by Hartwig. Hartwig is a
national non-profit data sequencing centre conducting large scale DNA analysis
and combining genomic and clinical data with the aim of stimulating
personalised cancer treatment. Furthermore, patients will be asked to
contribute the Organoid to the Organoid biobank that is being generated by HUB
and UMCU. This Organoid biobank and the data collection associated with it is
of great importance to the study of cancer and will benefit from each
additional Organoid study and associated data collection.

Primary objectives:

To validate the concept that ex vivo organoid response correlates to in vivo
response to standard treatment in mCRC patients on a metastasis level.

Secondary objectives:

• Relate organoid results to response to treatment on a patient level.
• Relate organoid results to progression free survival.
• Examine the predictive value of organoid results within subgroups for
response to treatment on a patient level and for progression-free survival.
1. per treatment line (e.g. 1st, 2nd or 3rd)
2. per type of treatment given (e.g. irinotecan,
oxaliplatin-containing))
• Assess the discriminative value of the organoid test for patient outcome.
• Explore potential thresholds for the organoid test to yield clinically
relevant accuracy for treatment response (sensitivity/specificity/positive and
negative predictive value).
• Investigate the feasibility of introducing the organoid test to clinical
practice
• To link drug treatment results, both in vitro and in vivo, to genetic
characteristics of the tumor. Organoid drug screening and clinical data will be
correlated with comprehensive DNA and RNA sequencing results.
• To perform additional organoid screens with potentially non-standard of care
drugs based on specific genetic alterations identified by WGS and potentially
RNA-sequencing and evaluate the correlation between the genomic information,
the drug screen results, and, if available, the patient response.
• To relate blood-derived biomarkers (such as ctDNA, and DNA mutation profiles)
to organoid and in vivo metastasis measurements
• Generation of and addition to the Organoid Biobank and distribution from this
biobank for future research purposes

Multicenter observational cohort study. This feasibility study is the first
step in the evaluation of tumor organoids as a screening tool to predict
treatment response to standard of care drugs in patients with metastatic
colorectal cancer. If trial results are promising we will use the data to
expand the use of the technology for positive selection/prediction of
treatment.

Outcome evaluation for in vivo response to treatment will be performed blinded
from in vitro data. The UMCU will collect the clinical data from the
participating clinical centers. The HUB will generate the organoid response
data from coded patients. At set point HUB will provide this data to the UMCU.

The HUB data will consist of dose response curves that show the response of
patient-derived the organoids at specific time points (5 days after seeding) to
the SOC standard-of-care (SOC) drugs received by each individual of the
specific patient, other SOC options and other experimental compounds.

Hartwig will perform DNA and potentially RNA sequencing on the patient
material. Hartwig will generate whole genome sequencing (WGS) data within
approximately 10-14 days after blood and biopsy are delivered to Hartwig and
provide a patient report and optionally the underlying result files/data to the
treating physician to allow use for clinical decision making. Additionally the
patient report and underlying result files/data will be shared with UMCU and
HUB to correlate with organoid response data and to guide organoid drug
screening.

For all included patient*s biopsies of the metastatic lesion(s) in the liver,
lymph node or subcutaneous lesion will be performed taken in order to obtain
material for organoid cultures. Ample experience exists with performing
biopsies in patients with metastatic lesions and the procedure is considered to
be safe. Alongside the tumor biopsies, up to four blood samples will be
obtained, one for screening and up to three to determine germline DNA and for
biomarker research. Patients will be treated according to standard of care and
clinical management of patients will be performed according to daily practice
in participating institutions.