Back to resultsA 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)
Primary Purpose
Colorectal Cancer
Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
RXC004
Nivolumab
Denosumab
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Cancer focused on measuring Open label, RXC004, Nivolumab, Ring finger protein 43, R-spondin, Efficacy, Safety, Pharmacokinetics
Eligibility Criteria
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
Sites / Locations
- Community Health Network Cancer Center North - Community Hospital NetworkRecruiting
- UT MD Anderson Cancer CenterRecruiting
- Lumi ResearchRecruiting
- National Cancer Center
- Seoul National University HospitalRecruiting
- Severance Hospital, Yonsei University Health System - Medical OncologyRecruiting
- Asan Medical Center - OncologyRecruiting
- Samsung Medical Center - Hematology-OncologyRecruiting
- Hospital del MarRecruiting
- Hospital Universitario Vall d'HebrónRecruiting
- Hospital Clìnic de BarcelonaRecruiting
- Hospital Universitario 12 de OctubreRecruiting
- Hospital Universitario Virgen del RocioRecruiting
- Beatson West of Scotland Cancer Centre - OncologyRecruiting
- Queen Elizabeth Hospital - Clinical ReasearchRecruiting
- University College of London (UCL)Recruiting
- The Royal Marsden NHS Foundation Trust - Royal Marsden HospitalRecruiting
- Christie HospitalRecruiting
- Oxford Cancer Centre
- The Royal Marsden Hospital (Surrey)Recruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Arm A: RXC004 monotherapy
Arm B: RXC004 + nivolumab
Arm Description
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).
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).
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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.
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).
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.
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.
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.
Maximum observed plasma concentration (Cmax)
To assess the pharmacokinetic (PK) of RXC004 in monotherapy and in combination with nivolumab.
Time to Cmax (tmax)
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Minimum observed concentration across the dosing interval (Cmin)
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Terminal rate constant (λz)
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Terminal half-life (t½)
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
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.
Total plasma clearance after oral administration (CL/F)
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Apparent volume of distribution after oral administration (Vz/F)
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Number of patients with adverse events (AEs)
To assess the safety and tolerability profile of RXC004 monotherapy and RXC004 + nivolumab combination
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04907539
Brief Title
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)
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)
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 8, 2021 (Actual)
Primary Completion Date
August 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Redx Pharma Plc
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
Open label, RXC004, Nivolumab, Ring finger protein 43, R-spondin, Efficacy, Safety, Pharmacokinetics
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
50 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Arm A: RXC004 monotherapy
Arm Type
Experimental
Arm Description
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).
Arm Title
Arm B: RXC004 + nivolumab
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
RXC004
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Intervention Description
Nivolumab will be administered via IV infusion, 480 mg q4w.
Intervention Type
Biological
Intervention Name(s)
Denosumab
Intervention Description
Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month.
Use: Prophylactic
Primary Outcome Measure Information:
Title
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)
Description
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.
Time Frame
Up to 20 months
Title
RXC004 + nivolumab Combination: Objective response rate (ORR) using each patients BOR according to RECIST 1.1
Description
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.
Time Frame
Up to 20 months
Secondary Outcome Measure Information:
Title
Percentage change in the sum of target lesions
Description
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.
Time Frame
Up to 24 months
Title
Duration of response (DoR)
Description
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.
Time Frame
Up to 24 months
Title
Progression free survival (PFS)
Description
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).
Time Frame
From first dose of study treatment until the date of disease progression or death (Up to 24 months)
Title
RXC004 Monotherapy: ORR using investigator assessments according to RECIST 1.1
Description
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.
Time Frame
Up to 24 months
Title
RXC004 + nivolumab Combination: DCR using investigator assessments according to RECIST 1.1
Description
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.
Time Frame
Up to 24 months
Title
Overall survival (OS)
Description
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.
Time Frame
Up to 24 months
Title
Maximum observed plasma concentration (Cmax)
Description
To assess the pharmacokinetic (PK) of RXC004 in monotherapy and in combination with nivolumab.
Time Frame
At Cycle 0 and Cycle 1 (Each cycle is 28 days in length)
Title
Time to Cmax (tmax)
Description
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Time Frame
At Cycle 0 and Cycle 1 (Each cycle is 28 days in length)
Title
Minimum observed concentration across the dosing interval (Cmin)
Description
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Time Frame
At each treatment cycle (Each cycle is 28 days in length)
Title
Terminal rate constant (λz)
Description
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Time Frame
At Cycle 0 and Cycle 1 (Each cycle is 28 days in length)
Title
Terminal half-life (t½)
Description
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Time Frame
At Cycle 0 and Cycle 1 (Each cycle is 28 days in length)
Title
Area under the plasma concentration-time curve from zero to infinity (AUC0-∞)
Description
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Time Frame
At Cycle 0 and Cycle 1 (Each cycle is 28 days in length)
Title
Total plasma clearance after oral administration (CL/F)
Description
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Time Frame
At Cycle 0 and Cycle 1 (Each cycle is 28 days in length)
Title
Apparent volume of distribution after oral administration (Vz/F)
Description
To assess the PK of RXC004 in monotherapy and in combination with nivolumab.
Time Frame
At Cycle 0 and Cycle 1 (Each cycle is 28 days in length)
Title
Number of patients with adverse events (AEs)
Description
To assess the safety and tolerability profile of RXC004 monotherapy and RXC004 + nivolumab combination
Time Frame
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Craig Tilston
Phone
+44(0) 1625 469908
Email
c.tilston@redxpharma.com
First Name & Middle Initial & Last Name or Official Title & Degree
Richard Armer
Phone
+44 (0)7733 361689
Email
r.armer@redxpharma.com
Facility Information:
Facility Name
Community Health Network Cancer Center North - Community Hospital Network
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46250
Country
United States
Individual Site Status
Recruiting
Facility Name
UT MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-4000
Country
United States
Individual Site Status
Recruiting
Facility Name
Lumi Research
City
Kingswood
State/Province
Texas
ZIP/Postal Code
77339
Country
United States
Individual Site Status
Recruiting
Facility Name
National Cancer Center
City
Goyang-si
State/Province
Gyeonggido [Kyonggi-do]
ZIP/Postal Code
10408
Country
Korea, Republic of
Individual Site Status
Not yet recruiting
Facility Name
Seoul National University Hospital
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Severance Hospital, Yonsei University Health System - Medical Oncology
City
Seoul
ZIP/Postal Code
3722
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Asan Medical Center - Oncology
City
Seoul
ZIP/Postal Code
5505
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Samsung Medical Center - Hematology-Oncology
City
Seoul
ZIP/Postal Code
6351
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Hospital del Mar
City
Barcelona
ZIP/Postal Code
08003
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hospital Universitario Vall d'Hebrón
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hospital Clìnic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Individual Site Status
Recruiting
Facility Name
Hospital Universitario Virgen del Rocio
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Individual Site Status
Recruiting
Facility Name
Beatson West of Scotland Cancer Centre - Oncology
City
Glasgow
State/Province
Scotland
ZIP/Postal Code
G12 0YN
Country
United Kingdom
Individual Site Status
Recruiting
Facility Name
Queen Elizabeth Hospital - Clinical Reasearch
City
Birmingham
ZIP/Postal Code
B152TH
Country
United Kingdom
Individual Site Status
Recruiting
Facility Name
University College of London (UCL)
City
London
ZIP/Postal Code
NW1 2PG
Country
United Kingdom
Individual Site Status
Recruiting
Facility Name
The Royal Marsden NHS Foundation Trust - Royal Marsden Hospital
City
London
ZIP/Postal Code
SW3 6JJ
Country
United Kingdom
Individual Site Status
Recruiting
Facility Name
Christie Hospital
City
Manchester
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom
Individual Site Status
Recruiting
Facility Name
Oxford Cancer Centre
City
Oxford
ZIP/Postal Code
OX3 7LJ
Country
United Kingdom
Individual Site Status
Terminated
Facility Name
The Royal Marsden Hospital (Surrey)
City
Surrey Quays
ZIP/Postal Code
SM25PT
Country
United Kingdom
Individual Site Status
Recruiting
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
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)
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