Pilot study to determine the intraTUMORal OsImertinib concentration in patients with peritoneal metastasizeD colorectal cancer (TUMOROID study)

Patients with peritoneal metastasis (PM) from colorectal cancer (CRC) have
reduced benefit from systemic chemotherapy compared with metastases to other
sites. The mechanism underlying this site-dependent variation is unknown, but
it is often explained as reduced drug exposure due to the peritoneal plasma
barrier. The poorly permeable peritoneal plasma barrier is the rational for
local administration of chemotherapy, which is routinely applied as
hyperthermic intraperitoneal chemotherapy (HIPEC) immediately after
cytoreductive surgery (CRS). However, the clinical evidence for this complex
procedure is lacking. A recent randomized controlled trial failed to show an
effect of CRS+HIPEC over CRS alone which further questions the role of HIPEC in
routine clinical practice. Although HIPEC is performed with curative intent,
two third of patients show recurrent disease of whom 50% have recurrence within
1 year after surgery. Recent findings demonstrate an enrichment of consensus
molecular subtype 4 (CMS4) in peritoneal metastasis. This could be an
alternative explanation for reduced efficacy of chemotherapy in patients with
peritoneal metastasis. Since HIPEC is a complex, invasive and costly
application, being performed without convincing clinical evidence, there is an
urgent need for new treatment strategies for patients with PM of CRC. One
promising strategy is the use of targeted drugs in alternative dosing
schedules, e.g. intermittent high-dose. Although preclinical studies with
tyrosine kinase inhibitors (TKIs) are promising, the efficacy in patients with
CRC is disappointing so far. It is unknown if this is a result of intrinsic
resistance or suboptimal tumor tissue exposure which in the case of PM can be a
result of the peritoneal plasma barrier. Patient-derived tumor organoids
(PDTOs) can be used to select the most promising TKIs for further
investigation. Drug experiments in organoid models can be used for translation
from the preclinic to the clinical setting. Preclinical experiments showed
promising efficacy for the TKI osimertinib in PDTOs from CRC. With the
development of an LC/MS-MS assay we are able to determine the drug
concentrations that inhibit proliferation or induce cell death in organoid
tissue. However, to determine whether these preclinical findings can be
translated to the clinical setting, it is of importance to gain knowledge about
osimertinib exposure at the target site in patients with metastasis from
colorectal cancer.

The main objective of this pilot study is to determine the intratumoral
concentrations of osimertinib upon 1 week of treatment in peritoneal metastasis
of patients who are candidate for CRS-HIPEC treatment (group 1) and in liver
metastasis of patients undergoing primary liver resection surgery (group 2).

Multi-center, non-randomized, interventional pilot study

Patients of both groups will be treated with osimertinib in the registered
dosing schedule (80mg OD) for a period of 1 week prior to CRC-HIPEC (group 1)
or liver resection (group 2). Five patients will be included in both groups.
Intratumoral osimertinib concentrations will be measured from tumor resection
material that is removed as part of routine clinical care. Since the tumor
material is resected with tumor-free margins, it is also possible to measure
osimertinib concentrations in this tumor-free healthy tissue. If ascites is
present a sample is collected during surgery to determine osimertinib
concentration in ascites. Finally, a blood sample will be collected prior to
surgery to determine the osimertinib concentration in plasma.

Enrolment in this study will require 1 week of treatment with osimertinib prior
to cytoreductive surgery or liver surgery (depending on study group).
Osimertinib is registered for the treatment of non-small cell lung cancer.
Adverse events as a result of the use of osimertinib may occur, but are
expected to be limited upon only one week of treatment. Resection of tumor
tissue is part of routine clinical care and no additional intervention is
required to obtain tumor samples. The collection of ascites during surgery and
blood is considered risk-free. A burden for the patient is the extra visit
including physical examination and laboratory analysis one week after the start
of osimertinib to evaluate the treatment. There is no benefit for individual
patients who participate in this pilot study. The benefit is mainly of
scientific value. Preclinical studies investigating osimertinib antitumor
efficacy in CRC cell lines demonstrate a possible enhancement of the effect of
chemotherapy. However, it cannot be expected that osimertinib will
significantly induce antitumor activity in only one week of treatment.