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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cancer; Solid Tumor
• Intervention / Treatment: Drug: RXC004; Drug: Nivolumab

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Dr Jane Robertson CMO; Phone Number: 44(0)1625 469900; Email: j.robertson@redxpharma.com

Study Locations

• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Guys Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust
  • Newcastle, United Kingdom, NE77DN
    • Sir Bobby Robson Cancer Trials Research Centre
  • Oxford, United Kingdom, OX3 7LE
    • Department of Oncology
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital, Institute of Cancer Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

(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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: Redx Pharma Plc
• Investigators: Principal Investigator: Natalie Cook, The Christie NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2019
• Primary Completion (Estimated): September 29, 2023
• Study Completion (Estimated): September 29, 2023

Study Registration Dates

• First Submitted: February 14, 2018
• First Submitted That Met QC Criteria: February 26, 2018
• First Posted (Actual): February 27, 2018

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 5, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Biliary tract cancers; Thymus cancers
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: RXC004/0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No