Colorectal Cancer
Conditions
Keywords
Open label, RXC004, Nivolumab, Ring finger protein 43, R-spondin, Efficacy, Safety, Pharmacokinetics
Brief summary
This is a Phase II, open label, multicentre, multi-arm, study to evaluate the preliminary efficacy and safety of RXC004 as monotherapy and in combination with nivolumab in patients with Ring finger protein 43 (RNF43) or R-spondin (RSPO) aberrated, microsatellite stable (MSS), colorectal cancer (CRC), that have progressed following current standard of care treatment.
Detailed description
The study is composed of two arms, RXC004 monotherapy (Arm A) and RXC004 in combination with nivolumab (Arm B). 20 evaluable patients will be enrolled in Arm A and 20 eligible patients in Arm B. The study initially opened with Arm A; Arm B will be opened once a recommended Phase II dose (RP2D) for RXC004 in combination with nivolumab is established in the phase I dose escalation study (NCT03447470). Once Arm B is opened, patients who are eligible for both Arm A and Arm B will be randomised 2:1 to Arm B: Arm A in an open-label manner. Patients in Arm A may be treated with RXC004 + nivolumab if they have progressive disease on the 8 week scan, as long as they are eligible for Arm B and have Sponsor approval.
Interventions
DRUGRXC004
RXC004 will be administered orally, 2 mg QD (Monotherapy); and 1.5 mg QD (Combination therapy) Dose Formulation: 0.5 mg or 1 mg capsules.
BIOLOGICALNivolumab
Nivolumab will be administered via IV infusion, 480 mg q4w.
BIOLOGICALDenosumab
Denosumab will be administered via subcutaneous (SC) injection, 120 mg once every month. Use: Prophylactic
Sponsors
Redx Pharma Ltd
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological documentation of metastatic (Stage IV) Colorectal cancer (CRC) and 1. Documented tumour tissue aberration in RNF43 and/or RSPO 2. Documented confirmation of microsatellite stable (MSS) status * Patients must have had documented radiological progression following a minimum of 1 prior SOC treatment regimen for metastatic disease * Eastern Cooperative Oncology Group performance status 0 or 1 * At least one lesion that is measurable by RECIST 1.1 at baseline * Patients must have at least one lesion suitable for biopsy at screening and be willing to provide mandatory tumour biopsy samples * Patients with adequate organ functions * 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 and for at least 5 months after the last dose of study drug. For patients on RXC004 monotherapy treatment (Arm A) the following inclusion criteria will also apply to enter the RXC004 + nivolumab treatment phase: * Patients must have had documented RECIST1.1 defined radiological progression on RXC004 monotherapy treatment on the first scheduled scan (week 8 +/- 1 week) * Patients must receive Cycle 1 Day 1 of combination study treatment within 28 days of the first scheduled scan (week 8 +/- 1 week).
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, immunosuppressants and other investigational drugs * Patients with a known hypersensitivity to any RXC004 excipients * Patients with a contra-indication for denosumab treatment * Patients who are pregnant or breast-feeding * 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 * Patients with a mean resting corrected QTcF \>470 ms, obtained from triplicate electrocardiograms performed at screening For patients on RXC004 + nivolumab combination treatment (Arm B or Arm A RXC004 + nivolumab treatment phase): * Patients with any contraindication to the use of nivolumab * Patients with active or prior documented autoimmune or inflammatory disorders within the past 5 years * Patients with active infections, including tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus * Patients with a history of allogeneic organ transplant or active primary immunodeficiency * Patients with a known hypersensitivity to nivolumab or any of the excipients of the product
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| RXC004 Monotherapy (Arm A): Disease Control Rate (DCR) Using Each Patient's Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1) | Up to 28 months | The anti-tumour activity of RXC004 monotherapy was evaluated. DCR is defined as the percentage of patients with a BOR of either complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks post baseline. |
| RXC004+Nivolumab Combination Therapy (Arm B): Objective Response Rate (ORR) Using Each Patient's BOR According to RECIST 1.1 | Up to 28 months | The anti-tumour activity as a combination therapy of RXC004 +nivolumab was evaluated. ORR is defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment, as defined in RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Up to 28 months | The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. The DOR is as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. DOR was not calculated as 1 patient had PR, and 0 patient had CR. As pre-specified in the SAP that after the review of the available data, DOR would not be summarized and listed. |
| RXC004 Monotherapy (Arm A): Objective Response Rate (ORR) Using Investigator Assessments According to RECIST 1.1 | Up to 28 months | The preliminary efficacy of RXC004 monotherapy was evaluated. ORR is defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment as defined in RECIST 1.1. |
| RXC004 + Nivolumab Combination Therapy (Arm B): Disease Control Rate Using Investigator Assessments According to RECIST 1.1 | Up to 28 months | The preliminary efficacy of combination therapy of RXC004 + nivolumab was evaluated. DCR is defined as the percentage of patients with a BOR of either CR, PR or SD for at least 16 weeks post baseline. |
| Overall Survival (OS) | Up to 28 months | The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. OS is defined as the time from first day of study treatment until death due to any cause. |
| Maximum Observed Plasma Concentration (Cmax) | On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length) | The pharmacokinetic (PK) (Cmax) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. |
| Time to Maximum Plasma Concentration (Tmax) | On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length) | The PK (Tmax) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. |
| Best Percentage Change in Tumor Size | Up to 28 months | The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. The best percentage change in tumour size was determined at a patient level. Percentage change in tumour size was 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 was the patients value representing the largest decrease (or smallest increase) from baseline in tumour size. |
| Terminal Rate Constant (λz) | On Cycle 0 Day 1 (3-7 days cycle in length) | The PK (λz) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. |
| Terminal Half-life (t½) | On Cycle 0 Day 1 (3-7 days cycle in length) | The PK (t½) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. |
| Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞) | On Cycle 0 Day 1 (3-7 days cycle in length) | The PK (AUC0-∞) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. |
| Total Plasma Clearance After Oral Administration (CL/F) | On Cycle 0 Day 1 (3-7 days cycle in length) | The PK (CL/F) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. |
| Apparent Volume of Distribution After Oral Administration (Vz/F) | On Cycle 0 Day 1 (3-7 days cycle in length) | The PK (Vz/F) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. |
| Number of Patients With Adverse Events (AEs) | From time of signature of informed consent form throughout the treatment period and until 30 days after the last dose of RXC004 (for RXC004 monotherapy only) or 90 days after the last dose of Nivolumab (for RXC004 + nivolumab) (up to 28 months) | The safety and tolerability profile of RXC004 monotherapy and RXC004 + nivolumab combination was evaluated. The grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse events (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. |
| Minimum Observed Concentration Across the Dosing Interval (Cmin) | On Cycle 1 Day 15 (28 days cycle in length) | The PK (Cmin) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated. |
| Progression Free Survival (PFS) | Up to 28 months | The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. 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). |
Countries
South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted from 08 November 2021 to 02 April 2024 at multiple centers in 4 countries (South Korea, Spain, United Kingdom and United States of America).
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 |
|---|---|
| Arm A: RXC004 Monotherapy Patients received 2 mg of RXC004 monotherapy once daily orally. | 17 |
| Arm B: RXC004+Nivolumab Patients received 1.5 mg of RXC004 once daily along with the combination of 480 mg of Nivolumab every 4 weeks orally. | 8 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent withdrawn | 1 | 0 |
| Overall Study | Death | 14 | 3 |
Baseline characteristics
| Characteristic | Arm A: RXC004 Monotherapy | Arm B: RXC004+Nivolumab | Total |
|---|---|---|---|
| Age, Continuous | 53.4 Year STANDARD_DEVIATION 13.87 | 64.8 Year STANDARD_DEVIATION 7.78 | 57.0 Year STANDARD_DEVIATION 13.24 |
| Race/Ethnicity, Customized Not Hispanic or Latino | 14 Participants | 6 Participants | 20 Participants |
| Race/Ethnicity, Customized Not Stated | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 9 Participants | 3 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 14 / 17 | 3 / 8 |
| other Total, other adverse events | 17 / 17 | 8 / 8 |
| serious Total, serious adverse events | 3 / 17 | 5 / 8 |
Outcome results
Primary
RXC004 Monotherapy (Arm A): Disease Control Rate (DCR) Using Each Patient's Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1)
The anti-tumour activity of RXC004 monotherapy was evaluated. DCR is defined as the percentage of patients with a BOR of either complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks post baseline.
Time frame: Up to 28 months
Population: Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may have impacted outcome were excluded from the population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: RXC004 Monotherapy | RXC004 Monotherapy (Arm A): Disease Control Rate (DCR) Using Each Patient's Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1) | 18.2 Percentage of patients |
Primary
RXC004+Nivolumab Combination Therapy (Arm B): Objective Response Rate (ORR) Using Each Patient's BOR According to RECIST 1.1
The anti-tumour activity as a combination therapy of RXC004 +nivolumab was evaluated. ORR is defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment, as defined in RECIST 1.1.
Time frame: Up to 28 months
Population: Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may have impacted outcome were excluded from the population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: RXC004 Monotherapy | RXC004+Nivolumab Combination Therapy (Arm B): Objective Response Rate (ORR) Using Each Patient's BOR According to RECIST 1.1 | 14.3 Percentage of patients |
Secondary
Apparent Volume of Distribution After Oral Administration (Vz/F)
The PK (Vz/F) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.
Time frame: On Cycle 0 Day 1 (3-7 days cycle in length)
Population: The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: RXC004 Monotherapy | Apparent Volume of Distribution After Oral Administration (Vz/F) | 32300 milliliter (mL) | Geometric Coefficient of Variation 89.6 |
| Arm B: RXC004+Nivolumab | Apparent Volume of Distribution After Oral Administration (Vz/F) | 35800 milliliter (mL) | Geometric Coefficient of Variation 22 |
Secondary
Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞)
The PK (AUC0-∞) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.
Time frame: On Cycle 0 Day 1 (3-7 days cycle in length)
Population: The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: RXC004 Monotherapy | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞) | 733 hour*nanogram/milliliter (h*ng/mL) | Geometric Coefficient of Variation 48.9 |
| Arm B: RXC004+Nivolumab | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC0-∞) | 749 hour*nanogram/milliliter (h*ng/mL) | Geometric Coefficient of Variation 45 |
Secondary
Best Percentage Change in Tumor Size
The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. The best percentage change in tumour size was determined at a patient level. Percentage change in tumour size was 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 was the patients value representing the largest decrease (or smallest increase) from baseline in tumour size.
Time frame: Up to 28 months
Population: Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may have impacted outcome were excluded from the population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: RXC004 Monotherapy | Best Percentage Change in Tumor Size | 9.34 Percentage change in tumor size |
| Arm B: RXC004+Nivolumab | Best Percentage Change in Tumor Size | 0.00 Percentage change in tumor size |
Secondary
Duration of Response (DOR)
The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. The DOR is as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. DOR was not calculated as 1 patient had PR, and 0 patient had CR. As pre-specified in the SAP that after the review of the available data, DOR would not be summarized and listed.
Time frame: Up to 28 months
Population: Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1) received at least 4 weeks of treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may impact outcome were excluded from population.
Secondary
Maximum Observed Plasma Concentration (Cmax)
The pharmacokinetic (PK) (Cmax) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.
Time frame: On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length)
Population: The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: RXC004 Monotherapy | Maximum Observed Plasma Concentration (Cmax) | Cycle 0 Day 1 | 65.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 62 |
| Arm A: RXC004 Monotherapy | Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 15 | 80.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 66.8 |
| Arm B: RXC004+Nivolumab | Maximum Observed Plasma Concentration (Cmax) | Cycle 0 Day 1 | 56.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 56.4 |
| Arm B: RXC004+Nivolumab | Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 15 | 79.4 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 42.7 |
Secondary
Minimum Observed Concentration Across the Dosing Interval (Cmin)
The PK (Cmin) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.
Time frame: On Cycle 1 Day 15 (28 days cycle in length)
Population: The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: RXC004 Monotherapy | Minimum Observed Concentration Across the Dosing Interval (Cmin) | 12.8 ng/mL | Geometric Coefficient of Variation 65.8 |
| Arm B: RXC004+Nivolumab | Minimum Observed Concentration Across the Dosing Interval (Cmin) | 17.2 ng/mL | Geometric Coefficient of Variation 49.4 |
Secondary
Number of Patients With Adverse Events (AEs)
The safety and tolerability profile of RXC004 monotherapy and RXC004 + nivolumab combination was evaluated. The grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse events (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 informed consent form throughout the treatment period and until 30 days after the last dose of RXC004 (for RXC004 monotherapy only) or 90 days after the last dose of Nivolumab (for RXC004 + nivolumab) (up to 28 months)
Population: The safety analysis set consisted of all patients who were enrolled and received at least one dose of study drug (RXC004).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | RXC004 Related Grade >=3 TEAE | 3 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | TEAE Leading to Death | 0 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | Nivolumab Related TEAE | 1 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | TEAE Leading to Permanent Discontinuation or Reduction or Interruption of RXC004 | 10 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | RXC004 Related TEAE | 14 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | TEAE Leading to Permanent Discontinuation of RXC004 | 2 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | Serious TEAE | 3 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | TEAE Leading to Reduction of RXC004 | 3 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | Grade >=3 TEAE | 9 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | TEAE Leading to Interruption of RXC004 | 8 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | RXC004 Related Serious TEAE | 2 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | TEAE Leading to Permanent Discontinuation or Interruption of Nivolumab | 0 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | Nivolumab Related Grade >=3 TEAE | 0 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | TEAE Leading to Permanent Discontinuation of Nivolumab | 0 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | Nivolumab Related Serious TEAE | 0 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | TEAE Leading to Interruption of Nivolumab | 0 Participants |
| Arm A: RXC004 Monotherapy | Number of Patients With Adverse Events (AEs) | Treatment emergent adverse event (TEAE) | 17 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | TEAE Leading to Interruption of Nivolumab | 3 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | Treatment emergent adverse event (TEAE) | 8 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | RXC004 Related TEAE | 8 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | Nivolumab Related TEAE | 5 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | Grade >=3 TEAE | 5 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | RXC004 Related Grade >=3 TEAE | 4 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | Nivolumab Related Grade >=3 TEAE | 2 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | Serious TEAE | 5 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | RXC004 Related Serious TEAE | 4 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | Nivolumab Related Serious TEAE | 2 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | TEAE Leading to Death | 1 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | TEAE Leading to Permanent Discontinuation or Reduction or Interruption of RXC004 | 7 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | TEAE Leading to Permanent Discontinuation of RXC004 | 3 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | TEAE Leading to Reduction of RXC004 | 4 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | TEAE Leading to Interruption of RXC004 | 3 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | TEAE Leading to Permanent Discontinuation or Interruption of Nivolumab | 5 Participants |
| Arm B: RXC004+Nivolumab | Number of Patients With Adverse Events (AEs) | TEAE Leading to Permanent Discontinuation of Nivolumab | 3 Participants |
Secondary
Overall Survival (OS)
The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. OS is defined as the time from first day of study treatment until death due to any cause.
Time frame: Up to 28 months
Population: Full analysis set consisted of all patients who were enrolled and received at least one dose of study drug (RXC004).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: RXC004 Monotherapy | Overall Survival (OS) | 4.8 Months |
| Arm B: RXC004+Nivolumab | Overall Survival (OS) | NA Months |
Secondary
Progression Free Survival (PFS)
The preliminary efficacy of RXC004 monotherapy and combination therapy of RXC004 + nivolumab was evaluated. 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).
Time frame: Up to 28 months
Population: Full analysis set consisted of all patients who were enrolled and received at least one dose of study drug (RXC004).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: RXC004 Monotherapy | Progression Free Survival (PFS) | 2.0 Months |
| Arm B: RXC004+Nivolumab | Progression Free Survival (PFS) | 3.9 Months |
Secondary
RXC004 Monotherapy (Arm A): Objective Response Rate (ORR) Using Investigator Assessments According to RECIST 1.1
The preliminary efficacy of RXC004 monotherapy was evaluated. ORR is defined as the percentage of patients with a BOR of CR or PR based on local investigator assessment as defined in RECIST 1.1.
Time frame: Up to 28 months
Population: Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may impact outcome were excluded from the population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: RXC004 Monotherapy | RXC004 Monotherapy (Arm A): Objective Response Rate (ORR) Using Investigator Assessments According to RECIST 1.1 | 0 Percentage of patients |
Secondary
RXC004 + Nivolumab Combination Therapy (Arm B): Disease Control Rate Using Investigator Assessments According to RECIST 1.1
The preliminary efficacy of combination therapy of RXC004 + nivolumab was evaluated. DCR is defined as the percentage of patients with a BOR of either CR, PR or SD for at least 16 weeks post baseline.
Time frame: Up to 28 months
Population: Evaluable set consisted of all patients who received radiographic assessment at baseline (with measurable disease according to RECIST 1.1), received at least 4 weeks of study treatment and at least 1 post-dose radiographic tumour assessment or progressed or died ahead of the first radiographic assessment. Patients with important protocol deviations that may impact outcome were excluded from the population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: RXC004 Monotherapy | RXC004 + Nivolumab Combination Therapy (Arm B): Disease Control Rate Using Investigator Assessments According to RECIST 1.1 | 57.1 Percentage of patients |
Secondary
Terminal Half-life (t½)
The PK (t½) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.
Time frame: On Cycle 0 Day 1 (3-7 days cycle in length)
Population: The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: RXC004 Monotherapy | Terminal Half-life (t½) | 9.02 hour (h) | Geometric Coefficient of Variation 73.3 |
| Arm B: RXC004+Nivolumab | Terminal Half-life (t½) | 12.2 hour (h) | Geometric Coefficient of Variation 27.7 |
Secondary
Terminal Rate Constant (λz)
The PK (λz) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.
Time frame: On Cycle 0 Day 1 (3-7 days cycle in length)
Population: The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: RXC004 Monotherapy | Terminal Rate Constant (λz) | 0.0769 1/hour | Geometric Coefficient of Variation 73.3 |
| Arm B: RXC004+Nivolumab | Terminal Rate Constant (λz) | 0.0540 1/hour | Geometric Coefficient of Variation 29.8 |
Secondary
Time to Maximum Plasma Concentration (Tmax)
The PK (Tmax) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.
Time frame: On Cycle 0 Day 1 (3-7 days cycle in length) and Cycle 1 Day 15 (28 days cycle in length)
Population: The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A: RXC004 Monotherapy | Time to Maximum Plasma Concentration (Tmax) | Cycle 0 Day 1 | 2.07 Hour (h) |
| Arm A: RXC004 Monotherapy | Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 1.35 Hour (h) |
| Arm B: RXC004+Nivolumab | Time to Maximum Plasma Concentration (Tmax) | Cycle 0 Day 1 | 1.95 Hour (h) |
| Arm B: RXC004+Nivolumab | Time to Maximum Plasma Concentration (Tmax) | Cycle 1 Day 15 | 1.98 Hour (h) |
Secondary
Total Plasma Clearance After Oral Administration (CL/F)
The PK (CL/F) of RXC004 in monotherapy and in combination therapy with nivolumab was evaluated.
Time frame: On Cycle 0 Day 1 (3-7 days cycle in length)
Population: The PK Analysis Set included all patients in the full analysis set with at least 1 blood sample.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: RXC004 Monotherapy | Total Plasma Clearance After Oral Administration (CL/F) | 2730 milliliter per hour (mL/h) | Geometric Coefficient of Variation 48.9 |
| Arm B: RXC004+Nivolumab | Total Plasma Clearance After Oral Administration (CL/F) | 2000 milliliter per hour (mL/h) | Geometric Coefficient of Variation 45 |