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)

A Multi-arm, Phase II, Open-Label, Multicentre Study to Assess the Preliminary Efficacy of RXC004 in Monotherapy and in Combination With Nivolumab, in Patients With Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer Who Have Progressed Following Therapy With Current Standard of Care (PORCUPINE)

This is a Phase II, open label, multicentre, multi-arm, study to evaluate the preliminary efficacy and safety of RXC004 as monotherapy and in combination with nivolumab in patients with Ring finger protein 43 (RNF43) or R-spondin (RSPO) aberrated, microsatellite stable (MSS), colorectal cancer (CRC), that have progressed following current standard of care treatment.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: RXC004; Biological: Denosumab; Biological: Nivolumab

Detailed Description

The study is composed of two arms, RXC004 monotherapy (Arm A) and RXC004 in combination with nivolumab (Arm B). 20 evaluable patients will be enrolled in Arm A and 20 eligible patients in Arm B.

The study initially opened with Arm A; Arm B will be opened once a recommended Phase II dose (RP2D) for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470).

Once Arm B is opened, patients who are eligible for both Arm A and Arm B will be randomised 2:1 to Arm B: Arm A in an open-label manner.

Patients in Arm A may be treated with RXC004 + nivolumab if they have progressive disease on the 8 week scan, as long as they are eligible for Arm B and have Sponsor approval.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 5505
    • Asan Medical Center - Oncology
  • Seoul, Korea, Republic of, 3722
    • Severance Hospital, Yonsei University Health System - Medical Oncology
  • Seoul, Korea, Republic of, 6351
    • Samsung Medical Center - Hematology-Oncology
  • Gyeonggido [Kyonggi-do]
    • Goyang-si, Gyeonggido [Kyonggi-do], Korea, Republic of, 10408
      • National Cancer Center
• Spain
  • Barcelona, Spain, 08003
    • Hospital Del Mar
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
• United Kingdom
  • Birmingham, United Kingdom, B152TH
    • Queen Elizabeth Hospital - Clinical Reasearch
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust - Royal Marsden Hospital
  • London, United Kingdom, NW1 2PG
    • University College of London (UCL)
  • Manchester, United Kingdom, CB2 0QQ
    • Christie Hospital
  • Oxford, United Kingdom, OX3 7LJ
    • Oxford Cancer Centre
  • Surrey Quays, United Kingdom, SM25PT
    • The Royal Marsden Hospital (Surrey)
  • Scotland
    • Glasgow, Scotland, United Kingdom, G12 0YN
      • Beatson West of Scotland Cancer Centre - Oncology
• United States
  • California
    • Santa Rosa, California, United States, 95403
      • Providence Medical Foundation
  • Indiana
    • Indianapolis, Indiana, United States, 46250
      • Community Health Network Cancer Center North - Community Hospital Network
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • OptumCare Cancer Care
  • Texas
    • Houston, Texas, United States, 77030-4000
      • UT MD Anderson Cancer Center
    • Kingswood, Texas, United States, 77339
      • Lumi Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histological documentation of metastatic (Stage IV) Colorectal cancer (CRC) and

  1. Documented tumour tissue aberration in RNF43 and/or RSPO
  2. 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).

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, immunosuppressants and other investigational drugs
• Patients with a known hypersensitivity to any RXC004 excipients
• Patients with a contra-indication for denosumab treatment
• Patients who are pregnant or breast-feeding
• 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 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
• Patients with active or prior documented autoimmune or inflammatory disorders within the past 5 years
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: RXC004 monotherapy; Patients will receive RXC004 (2 mg once daily [QD], orally). Patients in Arm A may crossover to Arm B treatment if they have progressive disease on the first Response Evaluation Criteria in Solid Tumours, (RECIST) scan (if Arm B is open at the time of progression).	Drug: RXC004; RXC004 will be administered orally, 2 mg QD (Monotherapy); and 1.5 mg QD (Combination therapy) Dose Formulation: 0.5 mg or 1 mg capsules.; Biological: Denosumab; Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month. Use: Prophylactic
Experimental: Arm B: RXC004 + nivolumab; Patients will receive RXC004 (1.5 mg QD, orally) in combination with nivolumab (480 mg every 4 weeks [q4w], intravenous [IV] infusion). Arm B will be opened once a RP2D for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470). RXC004 dose to be used in combination with nivolumab will be based on data from the phase 1 study (NCT03447470).	Drug: RXC004; RXC004 will be administered orally, 2 mg QD (Monotherapy); and 1.5 mg QD (Combination therapy) Dose Formulation: 0.5 mg or 1 mg capsules.; Biological: Denosumab; Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month. Use: Prophylactic; Biological: Nivolumab; Nivolumab will be administered via IV infusion, 480 mg q4w.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
RXC004 Monotherapy (Arm A): Disease Control Rate (DCR) Using Each Patient's Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1)	The anti-tumour activity of RXC004 monotherapy was evaluated. DCR is defined as the percentage of patients with a BOR of either complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks post baseline.	Up to 28 months
RXC004+Nivolumab Combination Therapy (Arm B): Objective Response Rate (ORR) Using Each Patient's BOR According to RECIST 1.1	The anti-tumour activity as a combination therapy of RXC004 +nivolumab was evaluated. ORR is defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment, as defined in RECIST 1.1.	Up to 28 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Percentage Change in Tumor Size	The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. The best percentage change in tumour size was determined at a patient level. Percentage change in tumour size was derived at each visit by the percentage change from baseline in the sum of diameters of target lesions. The best percentage change in tumour size was the patients value representing the largest decrease (or smallest increase) from baseline in tumour size.	Up to 28 months
Progression Free Survival (PFS)	The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. PFS is defined as the time from first dose of study treatment until the date of disease progression or death (by any cause in the absence of progression).	Up to 28 months
Duration of Response (DOR)	The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. The DOR is as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. DOR was not calculated as 1 patient had PR, and 0 patient had CR. As pre-specified in the SAP that after the review of the available data, DOR would not be summarized and listed.	Up to 28 months
RXC004 Monotherapy (Arm A): Objective Response Rate (ORR) Using Investigator Assessments According to RECIST 1.1	The preliminary efficacy of RXC004 monotherapy was evaluated. ORR is defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment as defined in RECIST 1.1.	Up to 28 months
RXC004 + Nivolumab Combination Therapy (Arm B): Disease Control Rate Using Investigator Assessments According to RECIST 1.1	The preliminary efficacy of combination therapy of RXC004 + nivolumab was evaluated. DCR is defined as the percentage of patients with a BOR of either CR, PR or SD for at least 16 weeks post baseline.	Up to 28 months
Overall Survival (OS)	The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. OS is defined as the time from first day of study treatment until death due to any cause.	Up to 28 months
Maximum Observed Plasma Concentration (Cmax)	The pharmacokinetic (PK) (Cmax) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.	On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length)
Time to Maximum Plasma Concentration (Tmax)	The PK (Tmax) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.	On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length)
Minimum Observed Concentration Across the Dosing Interval (Cmin)	The PK (Cmin) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.	On Cycle 1 Day 15 (28 days cycle in length)
Terminal Rate Constant (λz)	The PK (λz) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.	On Cycle 0 Day 1 (3-7 days cycle in length)
Terminal Half-life (t½)	The PK (t½) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.	On Cycle 0 Day 1 (3-7 days cycle in length)
Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞)	The PK (AUC0-∞) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.	On Cycle 0 Day 1 (3-7 days cycle in length)
Total Plasma Clearance After Oral Administration (CL/F)	The PK (CL/F) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.	On Cycle 0 Day 1 (3-7 days cycle in length)
Apparent Volume of Distribution After Oral Administration (Vz/F)	The PK (Vz/F) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.	On Cycle 0 Day 1 (3-7 days cycle in length)
Number of Patients With Adverse Events (AEs)	The safety and tolerability profile of RXC004 monotherapy and RXC004 + nivolumab combination was evaluated. The grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse events (CTCAE) latest version was utilized for all events with an assigned CTCAE grading. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening, urgent intervention required; Grade 5: Death related to AE.	From time of signature of informed consent form throughout the treatment period and until 30 days after the last dose of RXC004 (for RXC004 monotherapy only) or 90 days after the last dose of Nivolumab (for RXC004 + nivolumab) (up to 28 months)

Collaborators and Investigators

• Sponsor: Redx Pharma Ltd

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2021
• Primary Completion (Actual): April 2, 2024
• Study Completion (Actual): April 2, 2024

Study Registration Dates

• First Submitted: May 25, 2021
• First Submitted That Met QC Criteria: May 25, 2021
• First Posted (Actual): May 28, 2021

Study Record Updates

• Last Update Posted (Actual): April 16, 2025
• Last Update Submitted That Met QC Criteria: March 26, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Safety; Nivolumab; Efficacy; Pharmacokinetics; Open label; RXC004; Ring finger protein 43; R-spondin
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Bone Density Conservation Agents; Nivolumab; Denosumab
• Other Study ID Numbers: RXC004/0002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No