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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced Solid Tumours

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


Participation Criteria
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Eligibility Criteria
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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

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1 - RNF43 Mutated Advanced (unresectable)/Metastatic Pancreatic Cancer (Stage III/IV)<br>Patients (Karnofsky performance status ≥70) will be recruited and dosed with RXC004 (2 mg once daily [QD], orally) within 6 weeks of progression following 1st line SoC treatment. | Drug: RXC004<br>* RXC004 will be administered orally, 2 mg QD; 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: Module 2 -Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV)<br>Patients (Eastern Cooperative Oncology Group [ECOG] performance status 0-1) will be recruited and dosed with RXC004 within 6 weeks of progression, following 1st line SoC treatment. | Drug: RXC004<br>* 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.<br>Biological: Denosumab<br>* Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month; Use: Prophylactic<br>|
| Experimental: Module 3-Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy<br>Patients (ECOG performance status 0-1) will be recruited and dosed with RXC004 (1.5 mg QD, orally) in combination with pembrolizumab 400 mg IV infusion every 6 weeks (q6w) within 6 weeks of progression, following 1st line Soc treatment. | Drug: RXC004<br>* RXC004 will be administered orally, 1.5 mg QD; 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>Biological: Pembrolizumab<br>* Pembrolizumab will be administered via intravenous infusion, 400 mg dose once every 6 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 19 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 25 months | 
| 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 25 months | 
| 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 25 months | 
| 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 25 months | 
| 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 25 months | 
| 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) | 
| 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) | 
| 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 25 months | 
| Terminal rate constant (λz) | 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) | 
| 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) | 
| Area under the plasma concentration-time curve from zero to infinity (AUC0-∞) | 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) | 
| 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) | 
| 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) | 
| 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 25 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open-Label, RXC004, Ring finger protein 43, Pancreatic ductal adenocarcinoma, Biliary tract cancer, Efficacy, Safety, Pharmacokinetics, Pancreatic cancer, Cholangiocarcinoma, Gallbladder, Ampullary Cancer, Ampulla of Vater, MK-3475-E86