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

Phase 1

Completed

Conditions: Cancer
Solid Tumor

Interventions: Drug: RXC004
Drug: Nivolumab

Registration Number: NCT03447470

Lead Sponsor: Redx Pharma Ltd

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 46

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Module 1 Arm 1 - Monotherapy RXC004 (0.5 mg)	RXC004	Patients were given 0.5 mg RXC004 and monitored for Dose Limiting Toxicities.
Module 2 Arm 1 - RXC004 (1.0 mg) plus Nivolumab	RXC004	Patients were given 1.0 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.
Module 2 Arm 1 - RXC004 (1.0 mg) plus Nivolumab	Nivolumab	Patients were given 1.0 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.
Module 3 - Intermittent schedules of monotherapy RXC004	RXC004	Patients were given 2.0 mg RXC004. The patients were treated for 2 weeks at the same dose, followed by 1 week off for a 21 day cycle.
Module 1 Arm 3 - Monotherapy RXC004 (1.5 mg)	RXC004	Patients were given 1.5 mg RXC004 and monitored for Dose Limiting Toxicities.
Module 2 Arm 2 - RXC004 (1.5 mg) plus Nivolumab	Nivolumab	Patients were given 1.5 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.
Module 1 Arm 2 - Monotherapy RXC004 (1.0 mg)	RXC004	Patients were given 1.0 mg RXC004 and monitored for Dose Limiting Toxicities.
Module 1 Arm 6 - Monotherapy RXC004 (10.0 mg)	RXC004	Patients were given 10.0 mg RXC004 and monitored for Dose Limiting Toxicities.
Module 1 Arm 4 - Monotherapy RXC004 (2.0 mg)	RXC004	Patients were given 2.0 mg RXC004 and monitored for Dose Limiting Toxicities.
Module 1 Arm 5 - Monotherapy RXC004 (3.0 mg)	RXC004	Patients were given 3.0 mg RXC004 and monitored for Dose Limiting Toxicities.
Module 2 Arm 2 - RXC004 (1.5 mg) plus Nivolumab	RXC004	Patients were given 1.5 mg RXC004 in combination with a standard dose of Nivolumab and monitored for Dose Limiting Toxicities.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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 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 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..
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 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.

Trial Locations

Locations (5): Royal Marsden Hospital, Institute of Cancer Research
🇬🇧
Sutton, Surrey, United Kingdom
Department of Oncology
🇬🇧
Oxford, United Kingdom
Sir Bobby Robson Cancer Trials Research Centre
🇬🇧
Newcastle, United Kingdom
Guys Hospital
🇬🇧
London, United Kingdom
The Christie NHS Foundation Trust
🇬🇧
Manchester, United Kingdom