Clinical trial NCT03447470: Study to Evaluate the Safety and Tolerability of RXC004 in Advanced Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Solid Tumor
Keywords: Biliary tract cancers
Thymus cancers
Lead sponsor: Redx Pharma Ltd
Sponsor class: INDUSTRY
First posted: 2018-02-27
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: (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.

Primary outcomes:
measure: 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:
timeFrame: 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.
measure: 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.
timeFrame: 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
measure: Module 3 - Safety and Tolerability of RXC004 at Intermittent Dosing Schedule.
timeFrame: 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.
Secondary outcomes:
measure: Module 1 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 1 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 1 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 1 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 96 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 2 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 2 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 2 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 2 - PK Profile - Half-life From PK Analysis on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 3 - PK Profile - AUC on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 3 - PK Profile - C24 on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 3 - PK Profile - Cmax on Cycle 0 Day 1 (C0D1)
timeFrame: Samples were analyzed from 0 - 48 hours after administration to evaluate PK parameters on Cycle 0 Day 1.
measure: Module 3 - PK Profile - Half-life on Cycle 0 Day 1 (C0D1)
timeFrame: Cycle 0 Day 1
Other outcomes:
Locations:
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital, Institute of Cancer Research
state: Surrey
city: London
country: United Kingdom
facility: Guys Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: Sir Bobby Robson Cancer Trials Research Centre
city: Oxford
country: United Kingdom
facility: Department of Oncology
Study officials:
affiliation: The Christie NHS Foundation Trust
name: Natalie Cook
role: PRINCIPAL_INVESTIGATOR
References: