Predictive Value of Transcriptome-based OncoTreat/Oncotarget and Organoid Testing in Metastatic Pancreatic Cancer.

HIPANC-002 - Observational Performance Study of Transcriptome-Based OncoTreat/OncoTarget Testing With Patient-Derived Organoids in Metastatic Pancreatic Cancer

Pancreatic cancer is burdened by a survival of barely 10% at 5 years. About 80% of new cases do not qualify for surgery due to either locally-advanced or metastatic disease. In patients with good performance status (PS), palliative first-line treatments mainly consist of combination regimens, such as FOLFIRINOX, modified FOLFIRINOX or Gemcitabine-Abraxane. For subjects with a poor PS, instead, guidelines recommend single-agent infusions (e.g. Gemcitabine, Capecitabine or 5-FU alone). Nevertheless, upon disease progression therapeutic options are still scarce and with limited sustained efficacy.

Overall survival in metastatic pancreatic cancer ranges between 9.1 and 13.5 months, while progression-free survival under either FOLFIRINOX or Gemcitabine-Abraxane spans between 5.5 and 6.4 months. This timespan reduces even further when standard second-line regimens must be initiated upon disease progression.

Nowadays, genomic and transcriptomic analysis are crucial tools in cancer research that enable the identification of genetic mutations and alterations that drive the development and progression of cancer. By studying the changes in the DNA and RNA sequences of cancer cells, researchers can gain insights into the underlying molecular mechanisms of cancer and identify potential therapeutic targets. Genomic analysis can identify specific mutations or alterations that are present in cancer cells, while transcriptomic analysis can reveal changes in gene expression that may be linked to disease progression or response to treatment. These analyses are an essential component for the development of precision medicine approaches, which aim to tailor cancer treatment to the individual genetic profile of each patient.

PDOs can replicate in vitro the biological, genetic and molecular aspects of the primary tumour. Some of their advantages include their rapid growth compared to xenografts, the possibility to perform high-throughput drug screening, and their direct application to precision oncology by predicting best therapies. In this study they will be used as an in vitro comparator of the molecular tests to the clinical course of the patient.

Overall, combining genomic and transcriptomic analysis with PDO technology in cancer research might lead to exponential capacity to provide oncologic patients with extremely tailored and effective cancer treatments in the future.

For HIPANC-002 these tests are being evaluated as non-interventional investigational IVD's. Test results are not to be used for protocol mandated therapy decisions.

Primary objective.

The study seeks primarily to demonstrate whether a significant correlation between the IVD based predicted drug sensitivity and the patient's progression-free survival (PFS) in metastatic pancreatic adenocarcinoma after administered standard therapies (which are not chosen based on the test) exist.

Secondary objectives. The study seeks further to

1. Explore the correlation between Darwin-test predicted drug sensitivity and patient-derived PDO sensitivity to clinically used drug regimens.
2. Explore the correlation between the measured PDO sensitivity to the administered standard therapies and the clinical course of the patient, i.e. PFS (in vivo and in vitro comparison).
3. Collect samples for biobanking and future identification of potential new markers associated with tumor response.

Safety objectives.

The study aims to assess:

The rate and severity of 30-days post-operative surgical complications related to laparoscopic surgical biopsy required to retrieve tumoral tissue for IVD-based testing and PDO generation.

The primary outcome is achieved if a significant correlation between IVD based predictions of drug sensitivity and clinically observed patient outcome (progression-free survival after administered standard therapy) exist.

The secondary outcomes are achieved if

1. There is a significant correlation between Darwin-test predicted drug sensitivity and patient-derived PDO sensitivity to clinically used drug regimens.
2. There is a significant correlation between the measured PDO sensitivity to the administered standard therapies and the clinical course of the patient, i.e. PFS (in vivo and in vitro comparison).

Biobanked samples will be retrospectively analysed to highlight potential biochemical markers of tumour response to therapy if attributable.

The safety outcome will assess descriptively the rate of severe surgical post-operative complication related to laparoscopic surgical biopsy required to retrieve tumoral tissue for IVD-testing and PDO generation and occurring within 30 postoperative days.

Non-Interventional, single arm, observational study

Inclusion criteria:

• Informed Consent as documented by signature
• Patients older than 18 years
• Patients with metastatic pancreatic ductal adenocarcinoma
• At least one lesion amenable for surgical excisional biopsy
• ECOG Performance status 0-2
• Radiologically measurable disease
• Life expectancy > 3 months
• Absolute leucocyte count >1.5 G/l, platelets >100 G/l
• Serum creatinine <1.5 times of the upper limit of normal or Clearance >50ml/min (according to the CKD-EPI formula)

Exclusion criteria:

• Known allergies or intolerance to one or more compounds present in one of the first line or second line regimens
• Concomitant need for full anticoagulation that cannot be interrupted or bridged prior to tissue biopsy
• ECOG PS >2
• Heart failure (NYHA class III-IV)
• Severe or uncontrolled concurrent illness
• Active viral infection from HIV, HBV or HCV, even if under antiretroviral treatment
• Myocardial infarction within the previous 6 months
• Patients who are pregnant or breastfeeding

Inclusion criteria:

• Informed Consent as documented by signature
• Patients older than 18 years
• Patients with metastatic pancreatic ductal adenocarcinoma
• At least one lesion amenable for surgical excisional biopsy
• ECOG Performance status 0-2
• Radiologically measurable disease
• Life expectancy > 3 months
• Absolute leucocyte count >1.5 G/l, platelets >100 G/l
• Serum creatinine <1.5 times of the upper limit of normal or Clearance >50ml/min (according to the CKD-EPI formula)

Exclusion criteria:

• Known allergies or intolerance to one or more compounds present in one of the first line or second line regimens
• Concomitant need for full anticoagulation that cannot be interrupted or bridged prior to tissue biopsy
• ECOG PS >2
• Heart failure (NYHA class III-IV)
• Severe or uncontrolled concurrent illness
• Active viral infection from HIV, HBV or HCV, even if under antiretroviral treatment
• Myocardial infarction within the previous 6 months
• Patients who are pregnant or breastfeeding