Clinical trial NCT04907539: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: Open label
RXC004
Nivolumab
Ring finger protein 43
R-spondin
Efficacy
Safety
Pharmacokinetics
Lead sponsor: Redx Pharma Ltd
Sponsor class: INDUSTRY
First posted: 2021-05-28
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: Up to 28 months
measure: RXC004+Nivolumab Combination Therapy (Arm B): Objective Response Rate (ORR) Using Each Patient's BOR According to RECIST 1.1
timeFrame: Up to 28 months
Secondary outcomes:
measure: Best Percentage Change in Tumor Size
timeFrame: Up to 28 months
measure: Progression Free Survival (PFS)
timeFrame: Up to 28 months
measure: Duration of Response (DOR)
timeFrame: Up to 28 months
measure: RXC004 Monotherapy (Arm A): Objective Response Rate (ORR) Using Investigator Assessments According to RECIST 1.1
timeFrame: Up to 28 months
measure: RXC004 + Nivolumab Combination Therapy (Arm B): Disease Control Rate Using Investigator Assessments According to RECIST 1.1
timeFrame: Up to 28 months
measure: Overall Survival (OS)
timeFrame: Up to 28 months
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length)
measure: Time to Maximum Plasma Concentration (Tmax)
timeFrame: On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length)
measure: Minimum Observed Concentration Across the Dosing Interval (Cmin)
timeFrame: On Cycle 1 Day 15 (28 days cycle in length)
measure: Terminal Rate Constant (λz)
timeFrame: On Cycle 0 Day 1 (3-7 days cycle in length)
measure: Terminal Half-life (t½)
timeFrame: On Cycle 0 Day 1 (3-7 days cycle in length)
measure: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞)
timeFrame: On Cycle 0 Day 1 (3-7 days cycle in length)
measure: Total Plasma Clearance After Oral Administration (CL/F)
timeFrame: On Cycle 0 Day 1 (3-7 days cycle in length)
measure: Apparent Volume of Distribution After Oral Administration (Vz/F)
timeFrame: On Cycle 0 Day 1 (3-7 days cycle in length)
measure: Number of Patients With Adverse Events (AEs)
timeFrame: 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)
Other outcomes:
Locations:
city: Santa Rosa
country: United States
facility: Providence Medical Foundation
state: California
city: Indianapolis
country: United States
facility: Community Health Network Cancer Center North - Community Hospital Network
state: Indiana
city: Las Vegas
country: United States
facility: OptumCare Cancer Care
state: Nevada
city: Houston
country: United States
facility: UT MD Anderson Cancer Center
state: Texas
city: Kingswood
country: United States
facility: Lumi Research
state: Texas
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggido [Kyonggi-do]
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System - Medical Oncology
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - Oncology
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center - Hematology-Oncology
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón
city: Barcelona
country: Spain
facility: Hospital Clìnic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre - Oncology
state: Scotland
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital - Clinical Reasearch
city: London
country: United Kingdom
facility: University College of London (UCL)
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust - Royal Marsden Hospital
city: Manchester
country: United Kingdom
facility: Christie Hospital
city: Oxford
country: United Kingdom
facility: Oxford Cancer Centre
city: Surrey Quays
country: United Kingdom
facility: The Royal Marsden Hospital (Surrey)
Study officials:
References: