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)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: RXC004
* Biological: Nivolumab
* Biological: Denosumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: RXC004 monotherapy<br>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<br>* 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.<br>Biological: Denosumab<br>* Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month. Use: Prophylactic<br>|
| Experimental: Arm B: RXC004 + nivolumab<br>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<br>* 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.<br>Biological: Nivolumab<br>* Nivolumab will be administered via IV infusion, 480 mg q4w.<br>Biological: Denosumab<br>* Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month. Use: Prophylactic<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RXC004 Monotherapy: Disease control rate (DCR) using each patients Best Overall Response (BOR) according to Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1) | To assess the anti-tumour activity of RXC004 monotherapy. DCR is defined as the proportion 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 20 months | 
| RXC004 + nivolumab Combination: Objective response rate (ORR) using each patients BOR according to RECIST 1.1 | To assess the anti-tumour activity of RXC004 +nivolumab. ORR is defined as the proportion of patients with a BOR of CR or PR, based on local investigator assessment, as defined in RECIST 1.1. | Up to 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage change in the sum of target lesions | To further assess the preliminary efficacy of RXC004 monotherapy and RXC004 + nivolumab. Percentage change in tumour size will be 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 will be the patients value representing the largest decrease (or smallest increase) from baseline in tumour size. | Up to 24 months | 
| Duration of response (DoR) | To further assess the preliminary efficacy of RXC004 monotherapy and RXC004 + nivolumab. The DoR will be defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. If a patient does not progress following a response, then their DOR will be censored at the progression free survival (PFS) censoring time. | Up to 24 months | 
| Progression free survival (PFS) | To further assess the preliminary efficacy of RXC004 monotherapy and RXC004 + nivolumab. 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). | From first dose of study treatment until the date of disease progression or death (Up to 24 months) | 
| RXC004 Monotherapy: ORR using investigator assessments according to RECIST 1.1 | To further assess the preliminary efficacy of RXC004 monotherapy. ORR is defined as the proportion of patients with a BOR of CR or PR, based on local investigator assessment, as defined in RECIST 1.1. | Up to 24 months | 
| RXC004 + nivolumab Combination: DCR using investigator assessments according to RECIST 1.1 | To further assess the preliminary efficacy of RXC004 + nivolumab. DCR is defined as the proportion of patients with a BOR of either CR, PR or SD for at least 16 weeks post baseline. | Up to 24 months | 
| Overall survival (OS) | To further assess the preliminary efficacy of RXC004 monotherapy and RXC004 + nivolumab. OS is defined as the time from first day of study treatment until death due to any cause. | Up to 24 months | 
| Maximum observed plasma concentration (Cmax) | To assess the pharmacokinetic (PK) of RXC004 in monotherapy and in combination with nivolumab. | At Cycle 0 and Cycle 1 (Each cycle is 28 days in length) | 
| Time to Cmax (tmax) | To assess the PK of RXC004 in monotherapy and in combination with nivolumab. | At Cycle 0 and Cycle 1 (Each cycle is 28 days in length) | 
| Minimum observed concentration across the dosing interval (Cmin) | To assess the PK of RXC004 in monotherapy and in combination with nivolumab. | At each treatment cycle (Each cycle is 28 days in length) | 
| Terminal rate constant (λz) | To assess the PK of RXC004 in monotherapy and in combination with nivolumab. | At Cycle 0 and Cycle 1 (Each cycle is 28 days in length) | 
| Terminal half-life (t½) | To assess the PK of RXC004 in monotherapy and in combination with nivolumab. | At Cycle 0 and Cycle 1 (Each cycle is 28 days in length) | 
| Area under the plasma concentration-time curve from zero to infinity (AUC0-∞) | To assess the PK of RXC004 in monotherapy and in combination with nivolumab. | At Cycle 0 and Cycle 1 (Each cycle is 28 days in length) | 
| Total plasma clearance after oral administration (CL/F) | To assess the PK of RXC004 in monotherapy and in combination with nivolumab. | At Cycle 0 and Cycle 1 (Each cycle is 28 days in length) | 
| Apparent volume of distribution after oral administration (Vz/F) | To assess the PK of RXC004 in monotherapy and in combination with nivolumab. | At Cycle 0 and Cycle 1 (Each cycle is 28 days in length) | 
| Number of patients with adverse events (AEs) | To assess the safety and tolerability profile of RXC004 monotherapy and RXC004 + nivolumab combination | 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 24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Open label, RXC004, Nivolumab, Ring finger protein 43, R-spondin, Efficacy, Pharmacokinetics