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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Cancer, Solid Tumor

Intervention / Treatment
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* Drug: RXC004
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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(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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy RXC004 - Module 1<br>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. | Drug: RXC004<br>* RXC004 is taken orally, inhibits porcupine (PORCN) and interacts with the wnt signalling pathway.<br>|
| Experimental: Combination RXC004 plus Nivolumab - Module 2<br>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. | Drug: RXC004<br>* RXC004 is taken orally, inhibits porcupine (PORCN) and interacts with the wnt signalling pathway.<br>Drug: Nivolumab<br>* 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<br>|
| Experimental: Intermittent schedules of monotherapy RXC004 - Module 3<br>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. | Drug: RXC004<br>* RXC004 is taken orally, inhibits porcupine (PORCN) and interacts with the wnt signalling pathway.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 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. | The DLT period will be assessed from the first dose until the end of 21 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 | 
| 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 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 | 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 | 
| Module 3 - Safety and Tolerability of RXC004 by assessment of anti-tumor activity and reduced treatment related Dose Limiting Toxicities by intermittent dosing for 21 days. | 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. | The assessment period will be from the first dose until the end of 21 days of intermittent dosing. Estimated time 12 Months in total | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Module 1 | Characterise the PK profile of RXC004 following single dose and at steady state and after multiple dose. | Throughout the study and at study completion (approximately 1 year) | 
| Module 2 | Characterise the PK profile of RXC004 in combination with Nivolumab to following single dose and at steady state and after multiple dose. | Throughout the study and at study completion (approximately 1 year) | 
| Module 3 | Characterise the PK profile of RXC004 following intermittent dosing schedule. | Throughout the study and at study completion (approximately 1 year). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biliary tract cancers, Thymus cancers