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)

Colorectal Cancer Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04907539
• Other study ID #: RXC004/0002
• Status: Completed
• Phase: Phase 2
• Start date: November 8, 2021
• Est. completion date: April 2, 2024

Study information

• Verified date: April 2024
• Source: Redx Pharma Plc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: April 2, 2024
• Est. primary completion date: April 2, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

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:
• Nivolumab
Nivolumab will be administered via IV infusion, 480 mg q4w.
• Denosumab
Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month. Use: Prophylactic

Locations

Country	Name	City	State
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggido [Kyonggi-do]
Korea, Republic of	Asan Medical Center - Oncology	Seoul
Korea, Republic of	Samsung Medical Center - Hematology-Oncology	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System - Medical Oncology	Seoul
Spain	Hospital Clìnic de Barcelona	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitario Vall d'Hebrón	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
United Kingdom	Queen Elizabeth Hospital - Clinical Reasearch	Birmingham
United Kingdom	Beatson West of Scotland Cancer Centre - Oncology	Glasgow	Scotland
United Kingdom	The Royal Marsden NHS Foundation Trust - Royal Marsden Hospital	London
United Kingdom	University College of London (UCL)	London
United Kingdom	Christie Hospital	Manchester
United Kingdom	Oxford Cancer Centre	Oxford
United Kingdom	The Royal Marsden Hospital (Surrey)	Surrey Quays
United States	UT MD Anderson Cancer Center	Houston	Texas
United States	Community Health Network Cancer Center North - Community Hospital Network	Indianapolis	Indiana
United States	Lumi Research	Kingswood	Texas
United States	OptumCare Cancer Care	Las Vegas	Nevada
United States	Providence Medical Foundation	Santa Rosa	California

Sponsors (1)

Lead Sponsor	Collaborator
Redx Pharma Plc

Countries where clinical trial is conducted

United States,  Korea, Republic of,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 29 months
Primary	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 29 months
Secondary	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 29 months
Secondary	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 29 months
Secondary	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 29 months)
Secondary	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 29 months
Secondary	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 29 months
Secondary	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 29 months
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Terminal rate constant (?z)	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)
Secondary	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)
Secondary	Area under the plasma concentration-time curve from zero to infinity (AUC0-8)	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)
Secondary	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)
Secondary	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)
Secondary	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 29 months)