A Study to Assess Efficacy of RXC004 +/- Nivolumab in Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer After Progression on Standard of Care (SOC)

Prior treatment

• Prior therapy with a compound of the same mechanism of action as RXC004
• Any known uncontrolled inter-current illness or persistent clinically significant toxicity related to prior anti-cancer treatment
• Use of anti-neoplastic agents, immunosuppressants and other investigational drugs
• Patients with active or prior documented autoimmune or inflammatory disorders within the past 5 years

Other illness

• Patients who have any history of an active (requiring treatment) other malignancy within 2 years of study entry
• Patients with a known hypersensitivity to any RXC004 excipients
• 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
• Patients with active infections, including tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus
• Patients with a history of allogeneic organ transplant or active primary immunodeficiency
• Patients with a known hypersensitivity to nivolumab or any of the excipients of the product

Other

• Patients at higher risk of bone fractures
• Patients with known or suspected brain metastases
• Patients with a contra-indication for denosumab treatment
• Patients who are pregnant or breast-feeding
• Patients with a mean resting corrected QTcF \>470 ms, obtained from triplicate electrocardiograms performed at screening
  • For patients on RXC004 + nivolumab combination treatment (Arm B or Arm A RXC004 + nivolumab treatment phase):
• Patients with any contraindication to the use of nivolumab

• Histological documentation of metastatic (Stage IV) Colorectal cancer (CRC) and
  • Documented tumour tissue aberration in RNF43 and/or RSPO
  • Documented confirmation of microsatellite stable (MSS) status
• Patients must have had documented radiological progression following a minimum of 1 prior SOC treatment regimen for metastatic disease
• Eastern Cooperative Oncology Group performance status 0 or 1
• At least one lesion that is measurable by RECIST 1.1 at baseline
• Patients must have at least one lesion suitable for biopsy at screening and be willing to provide mandatory tumour biopsy samples
• Patients with adequate organ functions
• 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 and for at least 5 months after the last dose of study drug.
  • For patients on RXC004 monotherapy treatment (Arm A) the following inclusion criteria will also apply to enter the RXC004 + nivolumab treatment phase:
• Patients must have had documented RECIST1.1 defined radiological progression on RXC004 monotherapy treatment on the first scheduled scan (week 8 +/- 1 week)
• Patients must receive Cycle 1 Day 1 of combination study treatment within 28 days of the first scheduled scan (week 8 +/- 1 week).