Selecting cancer patients for treatment using Tumor Organoids, the SENSOR study

One of the most promising developments in oncology for the past two decades has
been the introduction of targeted anti-cancer drugs. The main purpose of
targeted therapy is to improve treatment efficacy and limit toxicity. Great
results have been obtained by biomarker assisted patient selection, examples of
which are trastuzumab in Her2 positive breast or gastric cancer and vemurafenib
in BRAF V600E mutant melanoma. Nonetheless, actionable mutations and biomarkers
for resistance have yet to be identified for the majority of targeted drugs and
the process of drug development is still hampered by inadequate patient
selection. Biomarker identification is a protracted and costly process and the
complexity of genomic data generally prohibits a full understanding of drug
sensitivity. Additional functional information of individual tumors would
greatly improve our selection criteria in personalized cancer treatment. This
could result in improved patient outcomes but will also greatly benefit the
process of drug development. Although tumor cell lines have been evaluated as
in vitro predictive models, they have a limited success rate. A recent
discovery by Sato et al. and Barker et al. offers an outlook on a new
functional in vitro assay. They have established a culture system in which stem
cells of various organs can be expanded and subsequently used for functional
assays. Furthermore, it was demonstrated that these cultured cells are
genetically stable over long periods of time and can regenerate the organ of
origin when transplanted in mice. The in vitro expansion of stem cells is now
possible for both normal and, importantly in this study, tumor tissue, giving
us a potential in vitro model to screen for individual drug sensitivity.
By using tumor organoids for a comprehensive drug screen including a variety of
targeted agents we have established a discovery pipeline that allows us to
stratify patients for treatment with a (combination of) targeted agent(s). With
the cooperation of the pharmaceutical industry we will have at our disposal a
dynamic collection of targeted agents that will allow us to directly allocate
patients to compound(s) best fit for their response profile. Pre-treatment
stratification using this novel discovery pipeline holds the promise to not
only improve patient outcomes, decrease the number of patients unnecessarily
exposed to toxic agents and to promote cost-effectiveness but to also increase
the number of potentially active targeted agents that become available.

Primary:
Evaluate the efficacy of patient-derived tumor organoids to successfully
allocate patients for treatment with specific targeted agents.

Secondary:
Characterize safety and tolerability per experimental treatment regimen.

This is a single center, interventional, open-label, clinical feasibility trial
for patients with locally advanced (incurable) or metastatic colorectal cancer
or NSCLC that have only one line of standard of care treatment left, or will
start a study treatment. The primary aim of this study is to evaluate the
efficacy of stratifying patients with locally advanced (incurable) or
metastatic colorectal cancer or NSCLC for treatment with anticancer agents.
This will be achieved by performing a comprehensive drug screen on every
patient*s individual tumor organoids using a selected number of targeted agents
supplied by the pharmaceutical industry. According to their individual organoid
response profiles patients will be allocated to a particular treatment with an
early phase (phase 1B or higher) or a currently registered compound that is
consorted in this collective protocol.
Organoid response assays are currently estimated to take about 2-3 months. To
bridge the analysis period, patients will receive standard of care treatment or
another study treatment after inclusion and the subsequent biopsy procedure.
When progressive disease is observed on this treatment, our treatment
stratification will be complete and patients will be allocated to a
(combination of) targeted agent(s). Patients for whom it was not possible to
identify an active agent or combination of agents will be referred back to
standard of care treatment or another experimental treatment. Patients are
asked to undergo a post-treatment biopsy after progressing on the intermittent
treatment, this will allow us to evaluate if the intermittent treatment has
conferred resistance to the allocated agent if a patient does not respond to
the experimental treatment. The post-treatment biopsy will only be performed if
the patient has signed consent for treatment with the selected experimental
agent and has passed baseline screening.

A dynamic number of compounds is available. For each compound a separate
supplemental will be constructed with information about sponsorship, data on
the investigational product (including SPC, RP2D, dosage modification
recommendations, method of administration, known preclinical and clinical
data), agent specific inclusion and exclusion criteria and a compound specific
additional patient information leaflet and informed consent form. Addition of
each individual treatment regimen in this trial will be submitted to the ethics
committee as an amendment.

Treatment with one of the following compounds (if an active agent has been
identified using organoid drug screens):
- Axitinib (VEGFR inhibitor)
- Palbociclib (CDK 4/6 inhibitor)
- PF-04449913 (SMO inhibitor)
- PF-05212384 (PI3K/mTOR inhibitor)
- Iressa (EGFR inhibitor)
- Selumetinib (MEK1/2 inhibitor)
- AZD2014 (mTOR inhibitor)
- AZD5363 (Akt inhibitor)

Patients will undergo a histological tumor biopsy and will subsequently be
treated with standard of care until progression. Ample experience exists with
performing biopsies in patients with locally advanced or metastatic lesions and
the procedure is considered to be safe. At progression patients will undergo a
second biopsy (in order to determine if the intermittent treatment has altered
the drug sensitivity profile of the tumor) and are offered treatment based on
tumor organoid drug sensitivity. Importantly, we will only treat patients with
the recommended phase II or registered phase III dose, which limits the chance
of unexpected toxicities. Safety data will be specified per treatment
regimen.