Advanced Solid Tumours
Conditions
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
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.
Interventions
DRUGRXC004
RXC004 will be administered orally, 2 mg QD; Dose Formulation: 0.5 mg or 1 mg capsules.
BIOLOGICALDenosumab
Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month; Use: Prophylactic
BIOLOGICALpembrolizumab
Pembrolizumab will be administered via intravenous infusion, 400 mg dose once every 6 weeks
Sponsors
Merck Sharp & Dohme LLC
Redx Pharma Ltd
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Monotherapy (Modules 1 and 2): Progression Free Survival Rate at 6 Months | At 6 months | The anti-tumour activity of RXC004 was assessed. Progression free survival rate at 6 months was defined as the percentage of patients who remained alive and free of progression at 6 months according to Kaplan-Meier estimates. |
| Combination Therapy (Module 3): Objective Response Rate (ORR) | Up to 23 months | The anti-tumour activity of RXC004 as a combination therapy was assessed. ORR was defined as the percentage 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
| Measure | Time frame | Description |
|---|---|---|
| Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): PFS | Up to 23 months | The preliminary efficacy of RXC004 as a monotherapy and as a combination therapy was assessed. PFS was 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 withdrew from the assigned study treatment or received another anticancer prior to progression. |
| Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Best Percentage Change in Tumor Size | Up to 23 months | The preliminary efficacy of RXC004 as a monotherapy and as a combination therapy was assessed. The best percentage change in tumour size was determined at a patient level. For each patient, it represents the largest decrease (or smallest increase) in tumour size. Percentage change in tumour size was derived at each visit by the percentage change from baseline in the sum of diameters of all target lesions. |
| Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Overall Survival (OS) | Up to 23 months | The preliminary efficacy of RXC004 as a monotherapy and as a combination therapy was assessed. OS was defined as the time from first day of study treatment until death due to any cause. |
| Maximum Observed Plasma Concentration (Cmax) | At Cycle 0 Day 1 and Cycle 1 Day 15 (Each cycle was 21 days in length) | The pharmacokinetics (PK) of RXC004 as a monotherapy and as a combination therapy was assessed. |
| Time to Cmax (Tmax) | At Cycle 0 Day 1 and Cycle 1 Day 15 (Each cycle was 21 days in length) | The PK (tmax) of RXC004 as a monotherapy and as a combination therapy was assessed. |
| Minimum Observed Concentration Across the Dosing Interval (Cmin) | At Cycle 1 Day 15 (The cycle was 21 days in length) (Up to 23 months) | The PK (Cmin) of RXC004 as a monotherapy and as a combination therapy was assessed. |
| Monotherapy (Modules 1 and 2): ORR | Up to 23 months | The preliminary efficacy of RXC004 was assessed. ORR was defined as the percentage 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. |
| Terminal Half-life (t½) | At Cycle 0 Day 1(The cycle was 21 days in length) | The PK (t½) of RXC004 as a monotherapy and as a combination therapy was assessed. |
| Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞) | At Cycle 0 Day 1 (The cycle was 21 days in length) | The PK (AUC0-∞) of RXC004 as a monotherapy and as a combination therapy was assessed. |
| Total Plasma Clearance After Oral Administration (CL/F) | At Cycle 0 Day 1 (The cycle was 21 days in length) | The PK(CL/F) of RXC004 as a monotherapy and as a combination therapy was assessed. |
| Apparent Volume of Distribution After Oral Administration (Vz/F) | At Cycle 0 Day 1 (The cycle was 21 days in length) | The PK (Vz/F) of RXC004 as a monotherapy and as a combination therapy was assessed. |
| Number of Patients With Adverse Events (AEs) | 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) | The safety, and tolerability profile of RXC004 as a monotherapy and as a combination therapy was assessed. The grading scales found in the revised National Cancer Institute CTCAE latest version was utilized for all events with an assigned CTCAE grading. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening, urgent intervention required; Grade 5: Death related to AE. |
| Terminal Rate Constant (λz) | At Cycle 0 Day 1 (The cycle was 21 days in length) | The PK (λz) of RXC004 as a monotherapy and as a combination therapy was assessed. |
| Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Disease Control Rate (DCR) | Up to 23 months | The preliminary efficacy of RXC004 as a monotherapy and as a combination therapy was assessed. DCR was defined as the percentage of patients with a best overall response of either CR, PR or stable disease (SD) for at least 6 weeks. |
Countries
Australia, United Kingdom
Participant flow
Recruitment details
This study was conducted from 10 December 2021 to 22 Nov 2023 at multiple centers in Australia, and United Kingdom.
Pre-assignment details
Patients who met the inclusion criteria, and none of the exclusion criteria were enrolled to the study. All study assessments were performed as per the Schedule of Assessment.
Participants by arm
| Arm | Count |
|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) Patients (Karnofsky performance status ≥70) were recruited and dosed with RXC004 (2 mg QD orally) within 6 weeks of progression following 1st line SoC treatment. | 6 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) Patients (ECOG performance status 0-1) were recruited and dosed with RXC004 within 6 weeks of progression following 1st line SoC treatment. | 20 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy Patients (ECOG performance status 0-1) were 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. | 19 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Consent withdrawn | 1 | 2 | 0 |
| Overall Study | Death | 5 | 15 | 10 |
Baseline characteristics
| Characteristic | Total | Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy |
|---|---|---|---|---|
| Age, Continuous | 58.1 years STANDARD_DEVIATION 12.61 | 65.7 years STANDARD_DEVIATION 7.94 | 55.8 years STANDARD_DEVIATION 14.72 | 58.1 years STANDARD_DEVIATION 10.85 |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 41 Participants | 5 Participants | 17 Participants | 19 Participants |
| Race/Ethnicity, Customized Not Stated | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 39 Participants | 3 Participants | 19 Participants | 17 Participants |
| Sex: Female, Male Female | 25 Participants | 3 Participants | 10 Participants | 12 Participants |
| Sex: Female, Male Male | 20 Participants | 3 Participants | 10 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 15 / 20 | 10 / 19 |
| other Total, other adverse events | 6 / 6 | 20 / 20 | 19 / 19 |
| serious Total, serious adverse events | 3 / 6 | 6 / 20 | 11 / 19 |
Outcome results
Primary
Combination Therapy (Module 3): Objective Response Rate (ORR)
The anti-tumour activity of RXC004 as a combination therapy was assessed. ORR was defined as the percentage of patients with a best overall response of complete response or partial response based on local investigator assessment as defined in RECIST 1.1.
Time frame: Up to 23 months
Population: Full analysis set included all patients who were enrolled and received at least one dose of RXC004 in Modules 1 and 2, and at least one dose of RXC004 or pembrolizumab in Module 3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Combination Therapy (Module 3): Objective Response Rate (ORR) | 0 percentage of participants |
Primary
Monotherapy (Modules 1 and 2): Progression Free Survival Rate at 6 Months
The anti-tumour activity of RXC004 was assessed. Progression free survival rate at 6 months was defined as the percentage of patients who remained alive and free of progression at 6 months according to Kaplan-Meier estimates.
Time frame: At 6 months
Population: Full analysis set included all patients who were enrolled and received at least one dose of RXC004 in Modules 1 and 2, and at least one dose of RXC004 or pembrolizumab in Module 3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2): Progression Free Survival Rate at 6 Months | NA percentage of participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2): Progression Free Survival Rate at 6 Months | 6.1 percentage of participants |
Secondary
Apparent Volume of Distribution After Oral Administration (Vz/F)
The PK (Vz/F) of RXC004 as a monotherapy and as a combination therapy was assessed.
Time frame: At Cycle 0 Day 1 (The cycle was 21 days in length)
Population: PK Analysis Set included all patients in the safety analysis set who have had at least one blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Apparent Volume of Distribution After Oral Administration (Vz/F) | 29700 milliliter (mL) | Geometric Coefficient of Variation 28.9 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Apparent Volume of Distribution After Oral Administration (Vz/F) | 41400 milliliter (mL) | Geometric Coefficient of Variation 31 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Apparent Volume of Distribution After Oral Administration (Vz/F) | 44800 milliliter (mL) | Geometric Coefficient of Variation 40.4 |
Secondary
Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞)
The PK (AUC0-∞) of RXC004 as a monotherapy and as a combination therapy was assessed.
Time frame: At Cycle 0 Day 1 (The cycle was 21 days in length)
Population: PK Analysis Set included all patients in the safety analysis set who have had at least one blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞) | 891 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 21.8 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞) | 690 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 43.5 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞) | 511 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 47 |
Secondary
Maximum Observed Plasma Concentration (Cmax)
The pharmacokinetics (PK) of RXC004 as a monotherapy and as a combination therapy was assessed.
Time frame: At Cycle 0 Day 1 and Cycle 1 Day 15 (Each cycle was 21 days in length)
Population: PK Analysis Set included all patients in the safety analysis set who have had at least one blood sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Maximum Observed Plasma Concentration (Cmax) | Cycle 0 Day 1 | 107 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31.4 |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 15 | 140 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 50.8 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Maximum Observed Plasma Concentration (Cmax) | Cycle 0 Day 1 | 78.7 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 43.9 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 15 | 99.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 50.7 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Maximum Observed Plasma Concentration (Cmax) | Cycle 0 Day 1 | 57.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 44.1 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 15 | 67.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 56.8 |
Secondary
Minimum Observed Concentration Across the Dosing Interval (Cmin)
The PK (Cmin) of RXC004 as a monotherapy and as a combination therapy was assessed.
Time frame: At Cycle 1 Day 15 (The cycle was 21 days in length) (Up to 23 months)
Population: PK Analysis Set included all patients in the safety analysis set who have had at least one blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Minimum Observed Concentration Across the Dosing Interval (Cmin) | 22.0 ng/mL | Geometric Coefficient of Variation 37.5 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Minimum Observed Concentration Across the Dosing Interval (Cmin) | 19.5 ng/mL | Geometric Coefficient of Variation 110 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Minimum Observed Concentration Across the Dosing Interval (Cmin) | 9.79 ng/mL | Geometric Coefficient of Variation 153 |
Secondary
Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Best Percentage Change in Tumor Size
The preliminary efficacy of RXC004 as a monotherapy and as a combination therapy was assessed. The best percentage change in tumour size was determined at a patient level. For each patient, it represents the largest decrease (or smallest increase) in tumour size. Percentage change in tumour size was derived at each visit by the percentage change from baseline in the sum of diameters of all target lesions.
Time frame: Up to 23 months
Population: Full analysis set included all patients who were enrolled and received at least one dose of RXC004 in Modules 1 and 2, and at least one dose of RXC004 or pembrolizumab in Module 3.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Best Percentage Change in Tumor Size | 41.67 Percentage change in tumour size |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Best Percentage Change in Tumor Size | 20.06 Percentage change in tumour size |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Best Percentage Change in Tumor Size | 30.61 Percentage change in tumour size |
Secondary
Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Disease Control Rate (DCR)
The preliminary efficacy of RXC004 as a monotherapy and as a combination therapy was assessed. DCR was defined as the percentage of patients with a best overall response of either CR, PR or stable disease (SD) for at least 6 weeks.
Time frame: Up to 23 months
Population: Full analysis set included all patients who were enrolled and received at least one dose of RXC004 in Modules 1 and 2, and at least one dose of RXC004 or pembrolizumab in Module 3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Disease Control Rate (DCR) | 16.7 percentage of participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Disease Control Rate (DCR) | 25.0 percentage of participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Disease Control Rate (DCR) | 31.6 percentage of participants |
Secondary
Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Overall Survival (OS)
The preliminary efficacy of RXC004 as a monotherapy and as a combination therapy was assessed. OS was defined as the time from first day of study treatment until death due to any cause.
Time frame: Up to 23 months
Population: Full Analysis Set included all patients who enrolled and received at least one dose of RXC004 in Modules 1 and 2, and at least one dose of RXC004 or pembrolizumab in Module 3.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Overall Survival (OS) | 5.3 Months |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Overall Survival (OS) | 7.1 Months |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): Overall Survival (OS) | 4.7 Months |
Secondary
Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): PFS
The preliminary efficacy of RXC004 as a monotherapy and as a combination therapy was assessed. PFS was 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 withdrew from the assigned study treatment or received another anticancer prior to progression.
Time frame: Up to 23 months
Population: Full analysis set included all patients who were enrolled and received at least one dose of RXC004 in Modules 1 and 2, and at least one dose of RXC004 or pembrolizumab in Module 3.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): PFS | 1.4 months |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): PFS | 1.4 months |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Monotherapy (Modules 1 and 2) and Combination Therapy (Module 3): PFS | 1.41 months |
Secondary
Monotherapy (Modules 1 and 2): ORR
The preliminary efficacy of RXC004 was assessed. ORR was defined as the percentage 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.
Time frame: Up to 23 months
Population: Full analysis set included all patients who were enrolled and received at least one dose of RXC004 in Modules 1 and 2, and at least one dose of RXC004 or pembrolizumab in Module 3.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2): ORR | 16.7 percentage of participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Monotherapy (Modules 1 and 2): ORR | 5.0 percentage of participants |
Secondary
Number of Patients With Adverse Events (AEs)
The safety, and tolerability profile of RXC004 as a monotherapy and as a combination therapy was assessed. The grading scales found in the revised National Cancer Institute CTCAE latest version was utilized for all events with an assigned CTCAE grading. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening, urgent intervention required; Grade 5: Death related to AE.
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 23 months)
Population: Safety Set included all patients who enrolled and received at least one dose of RXC004 in Modules 1 and 2, and at least one dose of RXC004 or pembrolizumab in Module 3.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to interruption of RXC004 | 0 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Related Serious TEAE | 0 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Grade >=3 TEAE | 4 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to reduction of RXC004 | 0 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to death | 0 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Related TEAE | 4 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation of RXC004 | 1 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation or reduction or interruption of RXC004 | 3 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation or 0 6 interruption of Pembrolizumab | 0 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Related grade>=3 TEAE | 1 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to interruption of Pembrolizumab | 0 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Treatment-Emergent Adverse Event (TEAE) | 6 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Serious TEAE | 3 Participants |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation of 0 5 Pembrolizumab | 0 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to interruption of RXC004 | 9 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Treatment-Emergent Adverse Event (TEAE) | 20 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Related TEAE | 17 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Grade >=3 TEAE | 8 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Related grade>=3 TEAE | 3 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Serious TEAE | 6 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | Related Serious TEAE | 1 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to death | 0 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation or reduction or interruption of RXC004 | 10 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation of RXC004 | 2 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to reduction of RXC004 | 2 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation or 0 6 interruption of Pembrolizumab | 0 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation of 0 5 Pembrolizumab | 0 Participants |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Number of Patients With Adverse Events (AEs) | TEAE leading to interruption of Pembrolizumab | 0 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation of 0 5 Pembrolizumab | 5 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | TEAE leading to reduction of RXC004 | 1 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | Serious TEAE | 11 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | Related grade>=3 TEAE | 5 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | TEAE leading to interruption of RXC004 | 7 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | Grade >=3 TEAE | 10 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | Treatment-Emergent Adverse Event (TEAE) | 19 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation or 0 6 interruption of Pembrolizumab | 6 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | Related TEAE | 18 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation or reduction or interruption of RXC004 | 11 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | TEAE leading to death | 1 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | TEAE leading to interruption of Pembrolizumab | 1 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | TEAE leading to permanent discontinuation of RXC004 | 6 Participants |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Number of Patients With Adverse Events (AEs) | Related Serious TEAE | 4 Participants |
Secondary
Terminal Half-life (t½)
The PK (t½) of RXC004 as a monotherapy and as a combination therapy was assessed.
Time frame: At Cycle 0 Day 1(The cycle was 21 days in length)
Population: PK Analysis Set included all patients in the safety analysis set who have had at least one blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Terminal Half-life (t½) | 10.5 hour (h) | Geometric Coefficient of Variation 36.5 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Terminal Half-life (t½) | 9.90 hour (h) | Geometric Coefficient of Variation 27.6 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Terminal Half-life (t½) | 10.6 hour (h) | Geometric Coefficient of Variation 29 |
Secondary
Terminal Rate Constant (λz)
The PK (λz) of RXC004 as a monotherapy and as a combination therapy was assessed.
Time frame: At Cycle 0 Day 1 (The cycle was 21 days in length)
Population: PK Analysis Set included all patients in the safety analysis set who have had at least one blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Terminal Rate Constant (λz) | 0.0660 one per hour (1/h) | Geometric Coefficient of Variation 36.5 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Terminal Rate Constant (λz) | 0.0660 one per hour (1/h) | Geometric Coefficient of Variation 32.4 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Terminal Rate Constant (λz) | 0.0655 one per hour (1/h) | Geometric Coefficient of Variation 28 |
Secondary
Time to Cmax (Tmax)
The PK (tmax) of RXC004 as a monotherapy and as a combination therapy was assessed.
Time frame: At Cycle 0 Day 1 and Cycle 1 Day 15 (Each cycle was 21 days in length)
Population: PK Analysis Set included all patients in the safety analysis set who have had at least one blood sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Time to Cmax (Tmax) | Cycle 0 Day 1 | 1.49 hour (h) | Geometric Coefficient of Variation 36.3 |
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Time to Cmax (Tmax) | Cycle 1 Day 15 | 1.49 hour (h) | Geometric Coefficient of Variation 36.3 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Time to Cmax (Tmax) | Cycle 0 Day 1 | 1.44 hour (h) | Geometric Coefficient of Variation 51.3 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Time to Cmax (Tmax) | Cycle 1 Day 15 | 1.44 hour (h) | Geometric Coefficient of Variation 51.3 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Time to Cmax (Tmax) | Cycle 0 Day 1 | 1.66 hour (h) | Geometric Coefficient of Variation 45.9 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Time to Cmax (Tmax) | Cycle 1 Day 15 | 1.66 hour (h) | Geometric Coefficient of Variation 45.9 |
Secondary
Total Plasma Clearance After Oral Administration (CL/F)
The PK(CL/F) of RXC004 as a monotherapy and as a combination therapy was assessed.
Time frame: At Cycle 0 Day 1 (The cycle was 21 days in length)
Population: PK Analysis Set included all patients in the safety analysis set who have had at least one blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Module 1-RNF43 Mutated Advanced (Unresectable)/Metastatic Pancreatic Cancer (Stage III/IV) | Total Plasma Clearance After Oral Administration (CL/F) | 2250 milliliter per hour (mL/h) | Geometric Coefficient of Variation 21.8 |
| Module 2-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage III/IV) | Total Plasma Clearance After Oral Administration (CL/F) | 2900 milliliter per hour (mL/h) | Geometric Coefficient of Variation 43.5 |
| Module 3-Advanced (Unresectable)/Metastatic Biliary Tract Cancer (Stage Ill/IV) Combination Therapy | Total Plasma Clearance After Oral Administration (CL/F) | 2940 milliliter per hour (mL/h) | Geometric Coefficient of Variation 47 |