CRISTAL-APC

• Histologically or cytologically (based on local assessment and per local guidelines) confirmed PDAC and variants. Either of the following: 
  • Adenosquamous carcinoma 
  • Ductal adenocarcinoma 
  • Intraductal papillary mucinous neoplasm (IPMN) with an associated invasive carcinoma 
  • Mucinous adenocarcinoma, 
  • Mucinous cystic neoplasm (MCN) with an associated invasive carcinoma, 
  • Undifferentiated carcinoma 
• Aged 18 years and over 
• Radiologically confirmed stage IV disease 
• Measurable disease by RECIST version 1.1
• If patient has received prior radiotherapy to the lesion, it should have progressed since irradiation to be included as a measurable lesion 
• ECOG PS 0 or 1 
• Estimated life expectancy ≥12 weeks at screening 
• Adequate bone marrow function
• Adequate liver function
• Adequate renal function
• Women of childbearing potential (WoCBP), male participants and their partners are required, and must be willing, to use 1 highly effective form PLUS 1 effective form of contraception for the duration of the trial and for six (6) months after the completion of the trial treatment. Patient is willing and able to comply with the visit schedule outlined in the protocol for the duration of the trial 
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial 
• Have given written informed consent 
• Be enrolled/registered in the Precision-Panc Master Protocol study 

Inclusion Criteria – Phase I Specific 

In addition to the inclusion criteria for Phase I and Phase II in Section 8.1 above: 

• Tumour site amenable to biopsy 
• Gemcitabine and Nab-Paclitaxel deemed reasonable treatment or re-treatment options: 
• have not received it previously OR 
• have received it previously and tolerated treatment without significant dose reductions 
• Confirmation of adequate tumour tissue sample: Archival tissue if taken within 8 weeks with no intervening therapy and the site must confirm if >100 cells are present in the sample, or a baseline tumour biopsy. 

Inclusion Criteria – Phase II Specific 

• Received no prior systemic therapy for stage IV disease; or received prior systemic anti-cancer therapy as neo-adjuvant or adjuvant therapy AND such treatment was completed at least 6 months previously. 
• Confirmation of adequate tumour tissue sample: Archival tissue within 2 years of study entry. This can include a primary resection specimen, or consented for baseline tumour biopsy, or a baseline tumour biopsy. 

• Patients with operable or locally advanced PDAC.
• Other invasive malignancies with the exception of adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer. Cancer survivors who have undergone potentially curative treatment for a prior malignancy, have no recurrence within the last 2 years and are deemed at negligible risk for recurrence are eligible for trial.
• Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk or interfere with the trial. Women who are pregnant, plan to become pregnant or are lactating during the trial period. 
• Resting ECG with mean QTc interval of >480ms msec (confirmation of any prolongation to be used based on the average QT interval by Fridericia (QTcF) value of 3 reads within a 30-minute time period). Concomitant use of medications known to prolong QT interval, or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome), or unexplained sudden death under 40 years of age. Inability to discontinue medication with agents designated as having a risk of Torsades de Pointes due to QT prolongation (see Appendix 4) 
• Concurrent treatment in an interventional clinical trial (observational studies and follow up on CTIMPs are allowed) 
• Patients that have not been enrolled onto the Precision Panc Master Protocol 

Exclusion Criteria – Phase I Specific 

• Any unresolved toxic effects Grade ≥2 according to NCI CTCAE v 5.0 from prior chemotherapy administered for locally advanced or metastatic disease (with the exception of alopecia, Gr 2 peripheral neuropathy and haemoglobin ≥90g/L with no blood transfusions in the preceding 28 days 

Exclusion Criteria – Phase II Specific 

• Prior chemotherapy for locally advanced or metastatic pancreatic adenocarcinoma. 
• Any unresolved toxic effects Grade ≥2 according to NCI CTCAE v 5.0 from previous treatment for cancer (adjuvant or neoadjuvant) before randomization, except for alopecia, grade 2 peripheral neuropathy, and haemoglobin level ≥100 g/L, with no blood transfusions in the preceding 28 days.

This is not an exhaustive list. Please refer to CRISTAL-APC protocol for more details.