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

Redx Pharma Ltd46 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Cancer Solid Tumor

Interventions

RXC004DRUG

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

NivolumabDRUG

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

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

(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.

Locations (5)

Royal Marsden Hospital, Institute of Cancer Research

Sutton, Surrey, United Kingdom

Guys Hospital

London, United Kingdom

The Christie NHS Foundation Trust

Manchester, United Kingdom

Sir Bobby Robson Cancer Trials Research Centre

Newcastle, United Kingdom

Outcomes

Primary Outcomes

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.

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

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

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.

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.

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.

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.