A Study to Assess RXC004 Efficacy in Advanced Solid Tumours After Progression on Standard of Care (SoC) Therapy (PORCUPINE2)

Core Inclusion Criteria: * At least one lesion that is measurable by RECIST 1.1 at baseline (within 6 weeks prior to start of study treatment). * Mandatory paired biopsies; Patients must have at least one lesion suitable for biopsy at screening * Adequate organ and marrow function * Female patients of childbearing potential must have a negative pregnancy test prior to start of dosing * Female patients of childbearing potential and male patients with female partners of childbearing potential must agree to use a highly effective method of contraception during the study from the time of treatment initiation, and for at least 5 months after the last dose of study drug. Module 1 (PDAC) Specific Inclusion Criteria * Histological documentation of advanced (unresectable)/metastatic (Stage III/IV) PDAC, with documented loss of function tumour mutation in RNF43 * Patients must have received one prior systemic treatment for advanced (unresectable)/metastatic PDAC (Stage III/IV), with clear evidence of radiological disease progression * Patients must be enrolled and receive first dose of study treatment within 6 weeks of radiologically confirmed progression * Karnofsky performance status ≥70. Module 2 and Module 3 (BTC) Specific Inclusion Criteria * Histological documentation of advanced (unresectable)/metastatic (Stage III/IV) BTC (intrahepatic or extrahepatic cholangiocarcinoma, ampulla of Vater, or gallbladder cancer) * Patients must have received one prior systemic treatment for advanced (unresectable)/metastatic BTC, with clear evidence of radiological disease progression * Patients must be enrolled and receive first dose of study treatment within 6 weeks of radiologically confirmed progression * ECOG status 0 or 1. Core Exclusion Criteria: * Prior therapy with a compound of the same mechanism of action as RXC004 * Patients at higher risk of bone fractures * Any known uncontrolled inter-current illness or persistent clinically significant toxicity related to prior anti-cancer treatment * Patients who have any history of an active (requiring treatment) other malignancy within 2 years of study entry * Patients with known or suspected brain metastases * Use of anti-neoplastic agents * Patients with a known hypersensitivity to any RXC004 excipients * Patients with a contra-indication for denosumab treatment * Patients who are pregnant or breast-feeding * Known active human immunodeficiency viruses (HIV), hepatitis B (HBV), or hepatitis C (HCV) infections * Use of any live or live-attenuated vaccines against infectious diseases (e.g., influenza nasal spray, varicella) within 4 weeks (28 days) of initiation of study treatment * Mean resting corrected QTcF \>470 ms, obtained from triplicate ECGs performed at screening. There are no exclusion criteria specific to Modules 1 and 2. Module 3 Specific Exclusion Criteria: * Patients with any contraindication to the use of pembrolizumab as per approved label * Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor, and was discontinued from that treatment due to a Grade 3 or higher AE * Has received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of pembrolizumab in this study * Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients * Has an active autoimmune disease that has required systemic treatment in past 2 years * Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease * Has an active infection requiring systemic therapy * Patients with a history of allogeneic tissue/solid organ transplant * Patients with active infections, including tuberculosis, HIV, HBV, or HCV