Clinical trial NCT04907851: A Study to Assess RXC004 Efficacy in Advanced Solid Tumours After Progression on Standard of Care (SoC) Therapy (PORCUPINE2)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced Solid Tumours
Keywords: 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
zamaporvint
Lead sponsor: Redx Pharma Ltd
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2021-06-01
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Monotherapy (Modules 1 and 2): Progression Free Survival Rate at 6 Months
timeFrame: At 6 months
measure: Combination Therapy (Module 3): Objective Response Rate (ORR)
timeFrame: Up to 23 months
Secondary outcomes:
measure: Monotherapy (Modules 1 and 2): ORR
timeFrame: Up to 23 months
measure: Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Disease Control Rate (DCR)
timeFrame: Up to 23 months
measure: Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): PFS
timeFrame: Up to 23 months
measure: Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Best Percentage Change in Tumor Size
timeFrame: Up to 23 months
measure: Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Overall Survival (OS)
timeFrame: Up to 23 months
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: At Cycle 0 Day 1 and Cycle 1 Day 15 (Each cycle was 21 days in length)
measure: Time to Cmax (Tmax)
timeFrame: At Cycle 0 Day 1 and Cycle 1 Day 15 (Each cycle was 21 days in length)
measure: Minimum Observed Concentration Across the Dosing Interval (Cmin)
timeFrame: At Cycle 1 Day 15 (The cycle was 21 days in length) (Up to 23 months)
measure: Terminal Rate Constant (λz)
timeFrame: At Cycle 0 Day 1 (The cycle was 21 days in length)
measure: Terminal Half-life (t½)
timeFrame: At Cycle 0 Day 1(The cycle was 21 days in length)
measure: Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞)
timeFrame: At Cycle 0 Day 1 (The cycle was 21 days in length)
measure: Total Plasma Clearance After Oral Administration (CL/F)
timeFrame: At Cycle 0 Day 1 (The cycle was 21 days in length)
measure: Apparent Volume of Distribution After Oral Administration (Vz/F)
timeFrame: At Cycle 0 Day 1 (The cycle was 21 days in length)
measure: Number of Patients With Adverse Events (AEs)
timeFrame: 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)
Other outcomes:
Locations:
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Melbourne
country: Australia
facility: The Alfred Hospital - Alfred Health
state: Victoria
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospital NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Care
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: London
country: United Kingdom
facility: Barts Cancer Institute - Haemato-Oncology
city: London
country: United Kingdom
facility: University College Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Free London Foundation NHS Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust - Hammersmith Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust - Medical Oncology
city: Oxford
country: United Kingdom
facility: Oxford Cancer and Haematology Centre Churchill Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Sutton
country: United Kingdom
facility: The Royal Marsden Hospital (Surrey)
Study officials:
References: