Study to Evaluate the Safety and Tolerability of RXC004 in Advanced Malignancies

A Modular Multi-Arm, Phase 1, Adaptive Design Study to Evaluate the Safety and Tolerability of RXC004, Alone and in Combination With Anti-cancer Treatments, in Patients With Advanced Malignancies

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03447470

Enrollment

Registered

2018-02-27

Start date

2019-03-18

Completion date

2023-09-29

Last updated

2025-01-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cancer, Solid Tumor

Keywords

Biliary tract cancers, Thymus cancers

Brief summary

The purpose of this study is to determine the safety and tolerability of RXC004 as monotherapy and in combination with Nivolumab in patients with advanced malignancies. In order to define the doses and schedules for further clinical evaluation.

Detailed description

The study will consist of an ascending monotherapy dose, the doses are pre-defined. The decision to escalate will be made upon the assessment of safety and tolerability data in the first cycle of treatment. Module 1 will commence with a 3+3 dose escalation design up to a recommended Phase 2 monotherapy dose. Patients being monitored for dose limiting toxicities at each dose level. Characterisation of the PK profile, MTD and/or recommended Phase 2 dose will be defined on the emerging data. Module 2: RXC004 and Nivolumab - Follows a similar 3+3 dose escalation design using RXC004 plus Nivolumab. The MTD and/or Phase 2 dose will be defined based on the PK profile, emerging safety and the appearance of any dose limiting toxicities. Module 3: Intermittent dose schedules of RXC004 will be investigated. The intermittent schedules will utilize the module 1 dose which was shown to be safe and tolerated when used continuously. Characterisation of the PK profile; Wnt pathway inhibition; incidence/severity of Wnt pathway related AEs and anti-tumor activity will be evaluated at 2 different dosing schedules.

Interventions

DRUGRXC004

RXC004 is taken orally, inhibits porcupine (PORCN) and interacts with the wnt signalling pathway.

DRUGNivolumab

RXC004 is taken orally, inhibits porcupine (PORCN) and interacts with the wnt signalling pathway. Nivolumab is a fully human monoclonal immunoglobulin G4 antibody to PD-1

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Masking description

Open label design

Intervention model description

Module 1 monotherapy Dose escalation in those patients with advanced solid tumors while being monitored for safety and dose-limiting toxicity. This module will provide information on dosing and schedules for further module(s). Module 2 will commence by enrolling patients with advanced solid tumors into a monotherapy dose escalation, in combination with a fixed dose of nivolumab (a known anti-cancer treatment). This module will provide information and safety and tolerability of the study drug or in combination with the anti-cancer treatment. Module 3 will investigate the pharmacokinetic, Wnt pathway inhibition, incidence/severity of Wnt pathway related adverse events and anti-tumour activity of RXC004 when given at 2 different intermittent dosing schedules in selected patients with Wnt ligand dependent advanced tumours.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

(Summarized due to limitation of characters) Inclusion Criteria: * Written informed consent * Aged at least 18 years * Histological or cytological confirmation of advanced malignancy not considered to be appropriate for further conventional treatment * Patients must use adequate contraception measures for the duration of the study and for 6 months after the study * Patients must have adequate organ functions * Ability to swallow and retain oral medication

Exclusion criteria

* Prior treatment with a compound of the same mechanism of action as RXC004 * No other anti-cancer therapy or investigational product throughout the study * Patients with persistent grade 2 or higher diarrhoea * Patients at high risk of bone fractures * QTc prolongation * Known uncontrolled intercurrent illness * Known severe allergies to any active or inactive ingredients In addition for Module 2 * Patients with any contraindication/hypersensitivity to Nivolumab of excipients * Patients with active or prior documented autoimmune of inflammatory disorders within the past 5 years * Patients with active infections, including tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus * Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks (28 days) of initiation of study treatment * Patients with body weight \<40kg * Patients with a history of allogeneic organ transplant or active primary immunodeficiency In addition to Module 3 Patients with Wnt ligand-dependent solid tumours, defined as: * Biliary tract cancers * Thymus cancers (thymic and thymoma WHO classification) * Any solid tumour with documented aberration in RNF43 and/or RSPO from central pre-screening or from a recognised panel approved by the Sponsor * Patients willing to have mandatory skin biopsies at baseline and on one occasion while on study treatment.

Design outcomes

Primary

Measure	Time frame	Description
Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	AE data was collected after each cycle and until 30-day follow-up visit after study exit. The DLT period were assessed from the first dose until the end of 21 days of continuous dosing in each cycle until a Maximum Tolerated Dose (MTD) was identified.	A DLT was defined as an adverse event or abnormal laboratory value. Haematological toxicity of CTCAE grade 4 or higher for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days.
Module 2 - Safety and Tolerability of RXC004 in Combination With Nivolumab by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 28 Days of Continuous Dosing.	The DLT period will be assessed from the first dose until the end of 28 days of continuous dosing. This will be completed for each dose level until a Maximum Tolerated Dose (MTD) is identified. Estimated time 12 Months in total	A DLT is defined as an adverse event or abnormal laboratory value. Haematological toxicity of CTCAE grade 4 or higher for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days. Any grade 3 or higher immune-related adverse events
Module 3 - Safety and Tolerability of RXC004 at Intermittent Dosing Schedule.	The assessment period will be from the first dose until the end of 21 days of intermittent dosing or within 7 days of IP discontinuation.	Haematological toxicity of CTCAE grade 4 or higher present for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days. Any grade 3 or higher immune-related adverse events.

Secondary

Measure	Time frame	Description
Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Half-life of RXC004 following single dose on Cycle 0 Day1 calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 96 hours following single dose on Cycle 0 Day1..
Module 2 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	AUC was calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 48 hours following single dose of RXC004 in combination with Nivolumab on Cycle 0 Day1.
Module 2 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Mean Plasma concentration of RXC004 at 24 h post-dose when given in combination with Nivolumab.
Module 2 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Maximum plasma concentration (Cmax) of RXC004 following single dose on Cycle 0 Day1 when given in combination with Nivolumab..
Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Area under the Curve, AUC (0-24) for RXC004 was calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 96 hours following single dose on Cycle 0 Day1.
Module 3 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	AUC was calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 48 hours following single dose of RXC004
Module 3 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Mean Plasma concentration of RXC004 at 24 h post-dose
Module 3 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Maximum plasma concentration (Cmax) of RXC004 following single dose
Module 3 - PK Profile - Half-life on Cycle 0 Day 1 (C0D1)	Cycle 0 Day 1	Half-life of RXC004 following single dose.
Module 2 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Half-life of RXC004 following single dose on Cycle 0 Day1 when given in combination with Nivolumab.
Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Mean Plasma concentration of RXC004 at 24 h post-dose calculated from the measurement of mean RXC004 concentrations at various time points from 0 - 96 hours following single dose on Cycle 0 Day1..
Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.	Maximum plasma concentration (Cmax) of RXC004 following single dose calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 96 hours following single dose on Cycle 0 Day1..

Countries

United Kingdom

Participant flow

Recruitment details

Participants were enrolled into one of the modules of the study.

Pre-assignment details

In Module 1, participants enrolled, into 6 arms at different dose levels: 0.5 mg; 1 mg; 1.5 mg; 2 mg; 3 mg; 10 mg. In Module 2, participants enrolled, into 2 arms at different dose levels (1.0 mg and 1.5 mg) of RXC004 in combination with Nivolumab. In Module 3, the enrolled participants received a dose of 2.0 mg of RXC004 at 2 weeks on/1 week off.

Participants by arm

Arm	Count
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg) Patients were given 0.5 mg RXC004 monitored for Dose Limiting Toxicities.	4
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg) Patients were given 1.0 mg RXC004 monitored for Dose Limiting Toxicities.	3
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg) Patients were given 1.5 mg RXC004 and monitored for Dose Limiting Toxicities.	7
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg) Patients were given 2.0 mg RXC004 and monitored for Dose Limiting Toxicities.	6
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg) Patients were given 3.0 mg RXC004 and monitored for Dose Limiting Toxicities.	4
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg) Patients were given 10.0 mg RXC004 and monitored for Dose Limiting Toxicities.	1
Module 2 Arm 1 - RXC004 (1.0 mg) Plus Nivolumab Patients were given 1.0 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.	6
Module 2 Arm 2 - RXC004 (1.5 mg) Plus Nivolumab Patients were given 1.5 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.	8
Intermittent Schedules of Monotherapy RXC004 - Module 3 Patients were given RXC004 at 2 mg once a day (QD). Patients were treated for 2 weeks at the same dose, followed by 1 week off for 21 day treatment cycles.	7
Total	46

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008
Overall Study	Death	0	1	3	0	1	0	3	3	1
Overall Study	Treatment discontinued	3	2	4	6	2	1	2	4	3
Overall Study	Withdrawal by Subject	1	0	0	0	1	0	1	1	3

Baseline characteristics

Characteristic	Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 2 Arm 1 - RXC004 (1.0 mg) Plus Nivolumab	Module 2 Arm 2 - RXC004 (1.5 mg) Plus Nivolumab	Intermittent Schedules of Monotherapy RXC004 - Module 3	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	3 Participants	4 Participants	3 Participants	0 Participants	3 Participants	2 Participants	4 Participants	3 Participants	22 Participants
Age, Categorical Between 18 and 65 years	3 Participants	4 Participants	2 Participants	1 Participants	1 Participants	1 Participants	4 Participants	4 Participants	4 Participants	24 Participants
Age, Continuous	57 Years	62 Years	67 Years	68.5 Years	59 Years	73 Years	46.5 Years	64.5 Years	63 Years	63.2 Years
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	2 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	3 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	2 Participants
Race (NIH/OMB) White	3 Participants	6 Participants	4 Participants	3 Participants	1 Participants	4 Participants	5 Participants	7 Participants	7 Participants	40 Participants
Sex: Female, Male Female	1 Participants	3 Participants	2 Participants	3 Participants	0 Participants	2 Participants	5 Participants	2 Participants	4 Participants	22 Participants
Sex: Female, Male Male	2 Participants	4 Participants	4 Participants	1 Participants	1 Participants	2 Participants	1 Participants	6 Participants	3 Participants	24 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk
deaths Total, all-cause mortality	0 / 4	1 / 3	3 / 7	0 / 6	1 / 4	0 / 1	3 / 6	3 / 8	1 / 7
other Total, other adverse events	0 / 4	0 / 3	0 / 7	0 / 6	0 / 4	0 / 1	0 / 6	0 / 8	0 / 7
serious Total, serious adverse events	0 / 4	1 / 3	5 / 7	1 / 6	3 / 4	1 / 1	4 / 6	4 / 8	4 / 7

Outcome results

Primary

Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:

A DLT was defined as an adverse event or abnormal laboratory value. Haematological toxicity of CTCAE grade 4 or higher for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days.

Time frame: AE data was collected after each cycle and until 30-day follow-up visit after study exit. The DLT period were assessed from the first dose until the end of 21 days of continuous dosing in each cycle until a Maximum Tolerated Dose (MTD) was identified.

Population: RXC004 monotherapy was evaluated at 6 increasing doses.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Enteritis	0 Participants
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Colitis	0 Participants
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Patients with any DLT	0 Participants
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Pancreatitis	0 Participants
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Diarrhoea	0 Participants
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Colitis	0 Participants
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Enteritis	0 Participants
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Patients with any DLT	0 Participants
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Pancreatitis	0 Participants
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Diarrhoea	0 Participants
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Colitis	0 Participants
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Enteritis	0 Participants
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Pancreatitis	0 Participants
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Diarrhoea	0 Participants
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Patients with any DLT	0 Participants
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Diarrhoea	0 Participants
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Patients with any DLT	1 Participants
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Colitis	0 Participants
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Enteritis	0 Participants
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Pancreatitis	1 Participants
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Enteritis	1 Participants
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Patients with any DLT	2 Participants
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Pancreatitis	0 Participants
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Colitis	1 Participants
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Diarrhoea	0 Participants
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Patients with any DLT	1 Participants
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Enteritis	0 Participants
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Colitis	0 Participants
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Pancreatitis	0 Participants
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - Safety and Tolerability of RXC004 by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 21 Days of Continuous Dosing:	Diarrhoea	1 Participants

Primary

Module 2 - Safety and Tolerability of RXC004 in Combination With Nivolumab by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 28 Days of Continuous Dosing.

A DLT is defined as an adverse event or abnormal laboratory value. Haematological toxicity of CTCAE grade 4 or higher for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days. Any grade 3 or higher immune-related adverse events

Time frame: The DLT period will be assessed from the first dose until the end of 28 days of continuous dosing. This will be completed for each dose level until a Maximum Tolerated Dose (MTD) is identified. Estimated time 12 Months in total

Population: RXC004 (at 2 doses) was evaluated in combination with Nivolumab.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 2 - Safety and Tolerability of RXC004 in Combination With Nivolumab by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 28 Days of Continuous Dosing.	Patients with any DLT	0 Participants
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 2 - Safety and Tolerability of RXC004 in Combination With Nivolumab by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 28 Days of Continuous Dosing.	Drug-induced Liver Injury	0 Participants
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 2 - Safety and Tolerability of RXC004 in Combination With Nivolumab by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 28 Days of Continuous Dosing.	Patients with any DLT	1 Participants
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 2 - Safety and Tolerability of RXC004 in Combination With Nivolumab by Assessment of Whether Any Dose Limiting Toxicities (DLT) Arise From First Dose Until the End of 28 Days of Continuous Dosing.	Drug-induced Liver Injury	1 Participants

Primary

Module 3 - Safety and Tolerability of RXC004 at Intermittent Dosing Schedule.

Haematological toxicity of CTCAE grade 4 or higher present for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever 38.5 degrees Celsius or higher. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE grade 4 or higher. Non-haematological toxicity CTCAE grade 3 or higher. Any other toxicity that is judged to be a DLT by the Safety Review Committee. An AE resulting in disrupted dosing \>14 days. Any grade 3 or higher immune-related adverse events.

Time frame: The assessment period will be from the first dose until the end of 21 days of intermittent dosing or within 7 days of IP discontinuation.

Population: RXC004 was evaluated at a dose of 2 mg monotherapy administered as an intermittent schedule of 2 weeks on/1 week off dosing

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 3 - Safety and Tolerability of RXC004 at Intermittent Dosing Schedule.	0 Participants

Secondary

Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)

Area under the Curve, AUC (0-24) for RXC004 was calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 96 hours following single dose on Cycle 0 Day1.

Time frame: Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.

Population: PK parameter AUC (0-24) was analyzed at various dose levels ranging from 0.5 - 10 mg.

Arm	Measure	Value (MEAN)	Dispersion
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	138.8 h*ng/ml	Standard Deviation 27.9
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	334.8 h*ng/ml	Standard Deviation 118.8
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	464.9 h*ng/ml	Standard Deviation 223.2
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	552.5 h*ng/ml	Standard Deviation 215.3
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	1350.6 h*ng/ml	Standard Deviation 217.8
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)	2702.2 h*ng/ml	—

Secondary

Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)

Mean Plasma concentration of RXC004 at 24 h post-dose calculated from the measurement of mean RXC004 concentrations at various time points from 0 - 96 hours following single dose on Cycle 0 Day1..

Time frame: Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.

Population: PK parameter, C24, was analyzed at various dose levels ranging from 0.5 - 10 mg.

Arm	Measure	Value (MEAN)	Dispersion
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	1.74 ng/ml	Standard Deviation 0.86
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	5.28 ng/ml	Standard Deviation 3.66
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	7.26 ng/ml	Standard Deviation 4.67
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	6.55 ng/ml	Standard Deviation 4.62
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	16.05 ng/ml	Standard Deviation 4.71
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)	49.5 ng/ml	—

Secondary

Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)

Maximum plasma concentration (Cmax) of RXC004 following single dose calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 96 hours following single dose on Cycle 0 Day1..

Time frame: Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.

Population: PK parameter Cmax was analyzed at various dose levels ranging from 0.5 - 10 mg.

Arm	Measure	Value (MEAN)	Dispersion
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	20.58 ng/ml	Standard Deviation 3.07
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	47.77 ng/ml	Standard Deviation 18.68
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	69.59 ng/ml	Standard Deviation 33.1
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	84.03 ng/ml	Standard Deviation 36.83
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	198.50 ng/ml	Standard Deviation 57.81
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)	369 ng/ml	—

Secondary

Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)

Half-life of RXC004 following single dose on Cycle 0 Day1 calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 96 hours following single dose on Cycle 0 Day1..

Time frame: Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.

Population: PK parameter Half-life was analyzed at various dose levels ranging from 0.5 - 10 mg.

Arm	Measure	Value (MEDIAN)
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)	16.77 hours
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)	15.04 hours
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)	16.88 hours
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)	15.37 hours
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)	14.44 hours
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)	20.0 hours

Secondary

Module 2 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)

AUC was calculated from the measurement of mean plasma concentration of RXC004 at various time points from 0 - 48 hours following single dose of RXC004 in combination with Nivolumab on Cycle 0 Day1.