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Patients will be given RXC004 at a specified dose level and reviewed for Dose Limiting Toxicities. Once the DLT period is complete RXC004 will be given at a higher dose until MTD is reached.

Patients will be given RXC004 at specific doses in combination with a standard dose of Nivolumab and reviewed for Dose Limiting Toxicities. Once the DLT period is complete, RXC004 will be given at a higher dose until MTD is reached.

Patients will be given RXC004 at specific doses. One group will be treated for 4 days, followed by 3 days off; repeated weekly for 21 days. A second group will be treated for 2 weeks at the same dose, followed by 1 week off for 21 days.

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

RXC004

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

Natalie Cook

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.

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.

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.

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

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

A DLT is defined as an adverse event or abnormal laboratory value. Haematological toxicity of CTCAE grade 4 for more than 4 consecutive days. Grade 3 neutropenia of any duration accompanied by fever \>38.5 degrees Celsius. Grage 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity \>CTCAE grade 4. Non-haematological toxicity \>CTCAE grade 3. 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

A DLT is defined as an adverse event or abnormal laboratory value. Haematological toxicity of CTCAE grade 4 present for more than 4 consecutive days.

Grade 3 neutropenia of any duration accompanied by fever \>38.5 degrees Celsius. Grade 3 thrombocytopaenia with bleeding. Any other confirmed haematological toxicity CTCAE \>grade 4. Non-haematological toxicity CTCAE \>grade 3. 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.

Characterise the PK profile of RXC004 following single dose and at steady state and after multiple dose.

Characterise the PK profile of RXC004 in combination with Nivolumab to following single dose and at steady state and after multiple dose.

Characterise the PK profile of RXC004 following intermittent dosing schedule.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study to Evaluate the Safety and Tolerability of RXC004 in Advanced Malignancies	NCT03447470	Cancer Solid Tumor	RXC004 Nivolumab	18 Years -	Redx Pharma Plc
Study to Evaluate the Safety and Tolerability of RXC004 in Advanced Malignancies	NCT03447470	Cancer Solid Tumor	RXC004 Nivolumab	18 Years -	Redx Pharma Plc

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