A Study to Assess RXC004 Efficacy in Advanced Solid Tumours After Progression on Standard of Care (SoC) Therapy (PORCUPINE2)

Advanced Solid Tumours Clinical Trial

— KEYNOTE-E86  

Official title:

A Modular, Phase II, Open-Label, Multicentre Study to Assess the Preliminary Efficacy and Safety of RXC004, in Patients With Advanced Solid Tumours That Have Progressed Following Therapy With Current Standard of Care

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04907851
• Other study ID #: RXC004/0003
• Secondary ID: MK-3475-E86KEYNO
• Status: Completed
• Phase: Phase 2
• Start date: December 10, 2021
• Est. completion date: November 30, 2023

Study information

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

Clinical Trial Summary

This study is to evaluate the preliminary efficacy and safety of RXC004 monotherapy and in combination with pembrolizumab in advanced solid tumours that have progressed following SoC treatment.

Description:

This Phase II, modular, open label, multicentre study initially opened with ring finger protein 43 (RNF43) loss of function (LoF) mutation-positive pancreatic ductal adenocarcinoma (PDAC) (Module 1) and molecularly unselected biliary tract cancer (BTC) (Module 2) modules. Module 3 will investigate RXC004 in combination with pembrolizumab in BTC. Modules 1 and 2 are monotherapies and Module 3 is the combination therapy.

The primary objective of the study is to assess the preliminary efficacy of RXC004 in each module. This will be evaluated in terms of progression free survival (PFS) at 6 months in Modules 1 and 2, and in terms of Objective response rate (ORR) in Module 3. Following radiological progression, patients will be followed-up for survival.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: November 30, 2023
• Est. primary completion date: November 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Core Inclusion Criteria:

• At least one lesion that is measurable by RECIST 1.1 at baseline (within 6 weeks prior to start of study treatment).

• Mandatory paired biopsies; Patients must have at least one lesion suitable for biopsy at screening

• Adequate organ and marrow function

• 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 from the time of treatment initiation, and for at least 5 months after the last dose of study drug.

Module 1 (PDAC) Specific Inclusion Criteria

• Histological documentation of advanced (unresectable)/metastatic (Stage III/IV) PDAC, with documented loss of function tumour mutation in RNF43

• Patients must have received one prior systemic treatment for advanced (unresectable)/metastatic PDAC (Stage III/IV), with clear evidence of radiological disease progression

• Patients must be enrolled and receive first dose of study treatment within 6 weeks of radiologically confirmed progression

• Karnofsky performance status =70.

Module 2 and Module 3 (BTC) Specific Inclusion Criteria

• Histological documentation of advanced (unresectable)/metastatic (Stage III/IV) BTC (intrahepatic or extrahepatic cholangiocarcinoma, ampulla of Vater, or gallbladder cancer)

• Patients must have received one prior systemic treatment for advanced (unresectable)/metastatic BTC, with clear evidence of radiological disease progression

• Patients must be enrolled and receive first dose of study treatment within 6 weeks of radiologically confirmed progression

• ECOG status 0 or 1.

Core 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

• Patients with a known hypersensitivity to any RXC004 excipients

• Patients with a contra-indication for denosumab treatment

• Patients who are pregnant or breast-feeding

• Known active human immunodeficiency viruses (HIV), hepatitis B (HBV), or hepatitis C (HCV) infections

• 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

• Mean resting corrected QTcF >470 ms, obtained from triplicate ECGs performed at screening.

There are no exclusion criteria specific to Modules 1 and 2.

Module 3 Specific Exclusion Criteria:

• Patients with any contraindication to the use of pembrolizumab as per approved label

• Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor, and was discontinued from that treatment due to a Grade 3 or higher AE

• Has received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of pembrolizumab in this study

• Has severe hypersensitivity (= Grade 3) to pembrolizumab and/or any of its excipients

• Has an active autoimmune disease that has required systemic treatment in past 2 years

• Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease

• Has an active infection requiring systemic therapy

• Patients with a history of allogeneic tissue/solid organ transplant

• Patients with active infections, including tuberculosis, HIV, HBV, or HCV

Related Conditions & MeSH terms

• Advanced Solid Tumours
• Neoplasms

Intervention

Drug:
• RXC004
RXC004 will be administered orally, 2 mg QD; Dose Formulation: 0.5 mg or 1 mg capsules.
• RXC004
RXC004 will be administered orally, 2 mg QD (Cohort 1, Module 2) and 1 mg QD (Cohort 2, Module 2); Dose Formulation: 0.5 mg or 1 mg capsules.
• RXC004
RXC004 will be administered orally, 1.5 mg QD; 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
• pembrolizumab
Pembrolizumab will be administered via intravenous infusion, 400 mg dose once every 6 weeks

Locations

Country	Name	City	State
Australia	The Alfred Hospital - Alfred Health	Melbourne	Victoria
Australia	Wollongong Hospital	Wollongong	New South Wales
United Kingdom	Cambridge University Hospital NHS Foundation Trust	Cambridge
United Kingdom	Beatson West of Scotland Cancer Care	Glasgow
United Kingdom	St James University Hospital	Leeds
United Kingdom	Barts Cancer Institute - Haemato-Oncology	London
United Kingdom	Imperial College Healthcare NHS Trust - Hammersmith Hospital	London
United Kingdom	Royal Free London Foundation NHS Trust	London
United Kingdom	University College Hospitals NHS Foundation Trust	London
United Kingdom	The Christie NHS Foundation Trust - Medical Oncology	Manchester
United Kingdom	Oxford Cancer and Haematology Centre Churchill Hospital	Oxford
United Kingdom	Weston Park Hospital	Sheffield
United Kingdom	The Royal Marsden Hospital (Surrey)	Sutton

Sponsors (2)

Lead Sponsor	Collaborator
Redx Pharma Plc	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

Australia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Monotherapy (Modules 1 and 2): Progression free survival (percent) rate at 6 months using Investigator assessment according to Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1)	To assess the anti-tumour activity of RXC004. Progression free survival rate at 6 months is defined as the proportion of patients who remain alive and free of progression at 6 months.	At 6 months
Primary	Combination therapy (Module 3): Objective response rate (ORR) using each patient's best overall response (BOR) according to RECIST 1.1	To assess the anti-tumour activity of RXC004 as combination therapy. ORR, defined as the proportion of patients with a best overall response of complete response or partial response, based on local investigator assessment, as defined in RECIST 1.1.	Up to 23 months
Secondary	Monotherapy (Modules 1 and 2): Objective Response Rate (ORR) using Investigator assessments according to RECIST 1.1	To further assess the preliminary efficacy of RXC004. ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR), based on local Investigator assessment, as defined in RECIST 1.1.	Up to 23 months
Secondary	Monotherapy (Modules 1 and 2) and Combination therapy (Module 3): Disease Control Rate (DCR) using Investigator assessments according to RECIST 1.1	To further assess the preliminary efficacy of RXC004 as monotherapy and as combination therapy. DCR is defined as the proportion of patients with a best overall response of either CR, PR or stable disease (SD) for at least 6 weeks.	Up to 23 months
Secondary	Monotherapy (Modules 1 and 2) and Combination therapy (Module 3): PFS using Investigator assessments according to RECIST 1.1	To further assess the preliminary efficacy of RXC004 as monotherapy and as combination therapy. 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), regardless whether the patient withdraws from the assigned study treatment or receives another anticancer prior to progression.	Up to 23 months
Secondary	Monotherapy (Modules 1 and 2) and Combination therapy (Module 3): Percentage change in the sum of target lesions using Investigator assessments according to RECIST 1.1	To further assess the preliminary efficacy of RXC004 as monotherapy and as combination therapy. 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 23 months
Secondary	Monotherapy (Modules 1 and 2) and Combination therapy (Module 3): Overall survival (OS)	To further assess the preliminary efficacy of RXC004 as monotherapy and as combination therapy. OS is defined as the time from first day of study treatment until death due to any cause.	Up to 23 months
Secondary	Maximum observed plasma concentration (Cmax)	To assess the pharmacokinetic (PK) of RXC004 as monotherapy and as combination therapy.	At Cycle 0 and Cycle 1 (Each cycle is 21 days in length)
Secondary	Time to Cmax (tmax)	To assess the PK of RXC004 as monotherapy and as combination therapy.	At Cycle 0 and Cycle 1 (Each cycle is 21 days in length)
Secondary	Minimum observed concentration across the dosing interval (Cmin)	To assess the PK of RXC004 as monotherapy and as combination therapy.	At each treatment cycle (Each cycle is 21 days in length), up to 23 months
Secondary	Terminal rate constant (?z)	To assess the PK of RXC004 as monotherapy and as combination therapy.	At Cycle 0 and Cycle 1 (Each cycle is 21 days in length)
Secondary	Terminal half-life (t½)	To assess the PK of RXC004 as monotherapy and as combination therapy.	At Cycle 0 and Cycle 1 (Each cycle is 21 days in length)
Secondary	Area under the plasma concentration-time curve from zero to infinity (AUC0-8)	To assess the PK of RXC004 as monotherapy and as combination therapy.	At Cycle 0 and Cycle 1 (Each cycle is 21 days in length)
Secondary	Total plasma clearance after oral administration (CL/F)	To assess the PK of RXC004 as monotherapy and as combination therapy.	At Cycle 0 and Cycle 1 (Each cycle is 21 days in length)
Secondary	Apparent volume of distribution after oral administration (Vz/F)	To assess the PK of RXC004 as monotherapy and as combination therapy.	At Cycle 0 and Cycle 1 (Each cycle is 21 days in length)
Secondary	Number of patients with adverse events (AEs)	To assess the safety and tolerability profile of RXC004 as monotherapy and as combination therapy.	From time of signature of main study informed consent form throughout the treatment period and until the 30 days after last dose of RXC004 (Up to 23 months)