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A Study to Assess RXC004 Efficacy in Advanced Solid Tumours After Progression on Standard of Care (SoC) Therapy (PORCUPINE2) (KEYNOTE-E86)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04907851
Recruitment Status : Recruiting
First Posted : June 1, 2021
Last Update Posted : April 28, 2023
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Redx Pharma Plc

Study Description
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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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumours Drug: RXC004 Biological: Denosumab Biological: Pembrolizumab Phase 2

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 10, 2021
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : December 30, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Module 1 - RNF43 Mutated Advanced (unresectable)/Metastatic Pancreatic Cancer (Stage III/IV)
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
RXC004 will be administered orally, 2 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
Experimental: Module 2 -Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV)
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
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.

Biological: Denosumab
Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month; Use: Prophylactic
Experimental: Module 3-Advanced (unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy
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
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

Biological: Pembrolizumab
Pembrolizumab will be administered via intravenous infusion, 400 mg dose once every 6 weeks


Outcome Measures
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Primary Outcome Measures :
  1. 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) [ Time Frame: At 6 months ]
    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.

  2. Combination therapy (Module 3): Objective response rate (ORR) using each patient's best overall response (BOR) according to RECIST 1.1 [ Time Frame: Up to 19 months ]
    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.


Secondary Outcome Measures :
  1. Monotherapy (Modules 1 and 2): Objective Response Rate (ORR) using Investigator assessments according to RECIST 1.1 [ Time Frame: Up to 25 months ]
    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.

  2. Monotherapy (Modules 1 and 2) and Combination therapy (Module 3): Disease Control Rate (DCR) using Investigator assessments according to RECIST 1.1 [ Time Frame: Up to 25 months ]
    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.

  3. Monotherapy (Modules 1 and 2) and Combination therapy (Module 3): PFS using Investigator assessments according to RECIST 1.1 [ Time Frame: Up to 25 months ]
    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.

  4. 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 [ Time Frame: Up to 25 months ]
    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.

  5. Monotherapy (Modules 1 and 2) and Combination therapy (Module 3): Overall survival (OS) [ Time Frame: Up to 25 months ]
    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.

  6. Maximum observed plasma concentration (Cmax) [ Time Frame: At Cycle 0 and Cycle 1 (Each cycle is 21 days in length) ]
    To assess the pharmacokinetic (PK) of RXC004 as monotherapy and as combination therapy.

  7. Time to Cmax (tmax) [ Time Frame: At Cycle 0 and Cycle 1 (Each cycle is 21 days in length) ]
    To assess the PK of RXC004 as monotherapy and as combination therapy.

  8. Minimum observed concentration across the dosing interval (Cmin) [ Time Frame: At each treatment cycle (Each cycle is 21 days in length), up to 25 months ]
    To assess the PK of RXC004 as monotherapy and as combination therapy.

  9. Terminal rate constant (λz) [ Time Frame: At Cycle 0 and Cycle 1 (Each cycle is 21 days in length) ]
    To assess the PK of RXC004 as monotherapy and as combination therapy.

  10. Terminal half-life (t½) [ Time Frame: At Cycle 0 and Cycle 1 (Each cycle is 21 days in length) ]
    To assess the PK of RXC004 as monotherapy and as combination therapy.

  11. Area under the plasma concentration-time curve from zero to infinity (AUC0-∞) [ Time Frame: At Cycle 0 and Cycle 1 (Each cycle is 21 days in length) ]
    To assess the PK of RXC004 as monotherapy and as combination therapy.

  12. Total plasma clearance after oral administration (CL/F) [ Time Frame: At Cycle 0 and Cycle 1 (Each cycle is 21 days in length) ]
    To assess the PK of RXC004 as monotherapy and as combination therapy.

  13. Apparent volume of distribution after oral administration (Vz/F) [ Time Frame: At Cycle 0 and Cycle 1 (Each cycle is 21 days in length) ]
    To assess the PK of RXC004 as monotherapy and as combination therapy.

  14. Number of patients with adverse events (AEs) [ Time Frame: 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) ]
    To assess the safety and tolerability profile of RXC004 as monotherapy and as combination therapy.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04907851


Contacts
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Contact: Craig Tilston c.tilston@redxpharma.com

Locations
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Sponsors and Collaborators
Redx Pharma Plc
Merck Sharp & Dohme LLC
More Information
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Responsible Party: Redx Pharma Plc
ClinicalTrials.gov Identifier: NCT04907851    
Other Study ID Numbers: RXC004/0003
First Posted: June 1, 2021    Key Record Dates
Last Update Posted: April 28, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Redx Pharma Plc:
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
Additional relevant MeSH terms:
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Neoplasms
Denosumab
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
 Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Bone Density Conservation Agents
Physiological Effects of Drugs