A multi-centre, open-label Phase I/randomised Phase II study of VP-002, a C-C motif chemokine receptor 1 (CCR1) inhibitor, given orally in combination with nab-paclitaxel and gemcitabine (nPG) to patients with advanced pancreatic ductal adenocarcinoma
Advanced pancreatic ductal adenocarcinoma
CRISTAL-APC is split into two (2) phases and the participants will receive the following treatments: Phase I: Dose Escalation Phase CRISTAL-APC will evaluate VP-002 at a total daily dose of 600mg to a maximum of 1,800mg per day in combination with nab-paclitaxel and gemcitabine. Nab-paclitaxel will be administered at the allocated dose level of either 100mg/m2 or 125mg/m2. Gemcitabine will be administered at the allocated dose level of either 800mg/m2 or 1000mg/m2. Cycle 0 is a 14-day monotherapy cycle where patients will self-administer VP-002 only. It will be taken once a day on day 1 and twice daily on days 2-14. Cycles 1-6: Patients will self-administer VP-002 twice daily on days 1-28 of a 28-day cycle. Intravenous (IV) nab-paclitaxel 30-minute infusion followed immediately by IV gemcitabine 30-minute infusion will be administered on days 1, 8 and 15 of a 28-day cycle. Phase II: Dose Expansion Phase Patients will be randomised using a Web-based randomisation system into one of the following arms: Experimental Arm A: The dose levels of VP-002, nab-paclitaxel and gemcitabine will be decided from the phase I dose escalation. Cycles 1-6: Patients will self-administer VP-002 twice daily on days 1-28. Intravenous (IV) nab-paclitaxel 30-minute infusion followed immediately by IV gemcitabine 30-minute infusion will be administered on days 1, 8 and 15 of a 28-day cycle. Control Arm B: Cycles 1-6: Intravenous (IV) nab-paclitaxel 30-minute infusion followed immediately by IV gemcitabine 30-minute infusion will be administered on days 1, 8 and 15 of a 28-day cycle. The trial drugs will continue in both phases until disease progression, unacceptable toxicity that precludes further treatment or patient withdrawal, pregnancy, or choice. Patients may continue treatment in phases I and II for another 6 cycles at the investigator’s discretion after discussing with the sponsor.
1. Histologically or cytologically (based on local assessment and per local guidelines) confirmed PDAC and variants. Either of the following: 1.1. Adenosquamous carcinoma 1.2. Ductal adenocarcinoma 1.3. Intraductal papillary mucinous neoplasm (IPMN) with an associated invasive carcinoma 1.4. Mucinous adenocarcinoma 1.5. Mucinous cystic neoplasm (MCN) with an associated invasive carcinoma 1.6. Undifferentiated carcinoma 2. Aged 18 years and over 3. Radiologically confirmed stage IV disease 4. Measurable disease by RECIST version 1.1 4.1. If the patient has received prior radiotherapy to the lesion, it should have progressed since irradiation to be included as a measurable lesion: 5. ECOG PS 0 or 1 6. Estimated life expectancy ≥12 weeks at screening 7. Adequate bone marrow function: 7.1. Absolute neutrophil count (ANC) ≥1.5 x 10^9 /L 7.2. Haemoglobin (Hb) ≥90 g/L for Phase I; ≥100 g/L for Phase II, with no blood transfusions in the preceding 14 days 7.3. Platelets ≥100 x 10^9 /L 8. Adequate liver function: 8.1. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤2.5 x upper limit of normal range (ULN) (<5 x ULN in presence of liver metastasis) 8.2. Total bilirubin <1.5 x ULN 8.3. Total albumin ≥28 g/L 9. Adequate renal function: 9.1. Calculated creatinine clearance by Cockcroft Gault of ≥50 mL/min 10. 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. Updated 20/04/2026: 10. Women of childbearing potential (WoCBP) (see section 14.1 for the definition of WoCPB) 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 6 months after the completion of the trial treatment. Male participants and their female partner
Phase I and Phase II: 1. Patients with operable or locally advanced PDAC 2. 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 3. 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. Examples include, but are not limited to: 3.1. Patients who have had a venous thromboembolic event who are not appropriately anticoagulated or have had a significant bleeding episode in the 3 weeks prior to randomization 3.2. Patients with symptoms of severe chronic obstructive airways disease or significant shortness of breath at rest AND have an Forced expiratory volume (FEV)1 < 1.0 L within the last 6 months 3.3. Patients with a history of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, cystic fibrosis or bronchiectasis 3.4. Patients with uncontrolled ischaemic heart or other cardiovascular event (myocardial infarction, new angina, stroke transient ischaemic attack (TIA), or new congestive cardiac failure (CCF) within the last 6 months 3.5. Patients with stable but significant cardiovascular disease defined by heart failure (New York Heart Association Functional Classification (NYHF) III or IV) or frequent angina 3.6. Presence of active infection 3.7. Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C 3.8. Known allergy or hypersensitivity to gemcitabine or nab-paclitaxel or CCR1 inhibitors or the components of VP-002. Components of VP-002 are Kollidon SR, lactose monohydrate, fumaric acid, magnesium stearate, Opadry II Yellow 4. Women who are pr