Patients with Ring Finger Protein 43 (RNF43) or R-spondin (RSPO) Aberrated, Metastatic, Microsatellite Stable, Colorectal Cancer MedDRA version: 21.0 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864
Conditions
Interventions
Product Name: RXC004
Product Code: RXC004
Pharmaceutical Form: Capsule
INN or Proposed INN: RXC004
Current Sponsor code: RXC004
Other descriptive name: small molecule inhibitor of PORCN
Concentration
Sponsors
Redx Pharma Plc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Participant must be >/=18 years of age at the time of signing the informed consent. 2. Ability to give written informed consent and capable of understanding the protocol requirements listed in the informed consent form (ICF). Written informed consent must be obtained prior to performing any protocol-related procedures, including screening and pre-screening evaluations Participants must be willing and able to comply with the study protocol procedures and restrictions. 3. Histological documentation of metastatic (Stage IV) CRC and; (a) documented tumour tissue aberration in RNF43 and/or RSPO from a central lab or from a recognised panel approved by the sponsor. Please see Appendix F for a list of allowed aberrations. (b) documented confirmation of MSS status. 4. Patients must have had documented RECIST1.1 defined radiological progression following a minimum of 1 prior standard of care treatment regimen for metastatic disease. Note: The last 2 imaging scans (done before and after the last immediate systemic treatment prior to study entry) confirming progressive disease (PD) and/or their reports should be available for central/sponsor review. 5. ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks and an estimated life expectancy of greater than 16 weeks. 6. At least one lesion that is measurable by RECIST 1.1 at baseline (within 28 days prior to start of study treatment). The measurable lesion must not be chosen for the mandatory paired biopsies. 7. Mandatory paired biopsies*; Patients must have at least one lesion suitable for biopsy at screening (which must not be a target lesion for RECIST 1.1) and be willing to provide mandatory tumour biopsy samples as follows: Arm A: Baseline*; C1D15 (+ up to 7 days) and during Cycle 3 of monotherapy treatment (3 biopsies). Arm A combination treatment phase patients: Baseline*, C1D15 (+ up to 7 days) and during Cycle 3 of combination treatment (3 biopsies). Arm B: Baseline**, C1D15 (+ up to 7 days) and during Cycle 3 of combination treatment (3 biopsies). *Baseline biopsy is mandatory except in exceptional circumstances where biposy is not technically feasiable. All patients without a baseline sample must be approved by Sponsor before starting study treatment. On treatment biopsies are also mandatory unless deemed not be be technically or clinically feesible by Investigator. 8. Patients with adequate organ functions as described below: - AST/ALT /= 1.5 x 10^9/L. - Platelets > 100 x 10^9/L. - Hb >8.5g/dL (with or without transfusional support). 9. Female patients of childbearing potential must have a negative pregnancy test prior to start of dosing. 10. Female patients of childbearing potential and male patients with female partners of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 90 days after the last dose of study drug. Please refer to protocol section 5.3.1 for details of acceptable methods of contraception. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 30
Exclusion criteria
Exclusion criteria: 1. Prior therapy with a compound of the same mechanism of action as RXC004. 2. Patients at higher risk of bone fractures, including; (a) Patients with Vitamin D [25(OH)D3] deficiency defined as < 30nmol/L (<12ng/mL). [Note - Patients who fail on this criteria can be retested within the screening window]. (b) Patients with a corrected total serum calcium level of <2 mmol/L and serum magnesium level of < 0.60 mmol/L. (c) Patients with osteoporosis (as defined by a T-score of < -2.5 at L/R total hip, L/R femoral neck, or lumbar spine (L1-4) by DEXA scan) or history of fragility fractures (any fracture occurring with low-level trauma or as a result of falling < standing height). (d) Patients with ongoing or a history of clinically significant hyperparathyroidism, Pagets disease or Osteomalacia. Patients with a prior diagnosis of hyperparathyroidism, Pagets disease or Osteomalacia, considered to have no increased bone fragility risk, may be included only after consultation with the Sponsor’s Medical Monitor. (e) Patients who have received treatment for type 2 Diabetes Mellitus with a Thiazolidinedione peroxisome proliferator-activated receptor gamma agonist (e.g. pioglitazone or rosiglitazone) within 4 weeks prior to study drug dosing. 3. Any known uncontrolled inter-current illness or persistent clinically significant toxicity related to prior anti-cancer treatment (as assessed by the Investigator) which in the investigator's opinion makes it undesirable for the patient to participate in the study. 4. Patients who have any history of an active (requiring treatment) other malignancy (except any in-situ carcinoma, non-melanoma skin carcinoma and early prostate cancer with a normal PSA) within 2 years of study entry. 5. Patients with known or suspected brain metastases. 6. Use of anti-neoplastic agents (including immunotherapy), immunosuppressants and other investigational drugs within 4 weeks prior to the first dose of study treatment. 7. Patients with a known hypersensitivity to any RXC004 excipients. 8. Patients with a contra-indication for denosumab treatment including: • Known hypersensitivity to Denosumab or any of the excipients. • Severe untreated hypocalcaemia. • Unhealed lesions from dental or oral surgery. 9. Patients who are pregnant or breast-feeding. 10. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements. For patients on RXC004 + Nivolumab combination treatment (Arm B or Arm A RXC004 + Nivolumab treatment phase) the following exclusion criteria will also apply. 11. Patients with any contraindication to the use of Nivolumab as per approved label (Summary of Product Characteristics or equivalent). 12. Patients with active or prior documented autoimmune or inflammatory disorders within the past 5 years, including inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis, Grave’s disease, lupus and celiac disease. The following are exceptions to this criterion: (a) Patients with vitiligo or alopecia. (b) Patients with type I diabetes mellitus. (c) Patients with residual hypothyroidism due to autoimmune condition only requiring hormone replacement. (d) Patients with psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. (e) Patients with celiac disease controlled by diet alone. 13. Patients with active infections, including tubercu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the anti-tumour activity of RXC004 monotherapy and RXC004 + Nivolumab.;Secondary Objective: - To further assess the preliminary efficacy of RXC004 monotherapy and RXC004 + Nivolumab. - To assess the PK of RXC004 in monotherapy and in combination with Nivolumab. - To assess the safety and tolerability profile of RXC004 monotherapy and RXC004 + Nivolumab combination.;Primary end point(s): Monotherapy : Disease control rate (DCR) using each patients Best Overall Response (BOR) according to RECIST 1.1 Combination : Objective response rate (ORR) using each patients BOR according to RECIST 1.1;Timepoint(s) of evaluation of this end point: Throughout trial treatment/follow-up period | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - % change in the sum of target lesions, duration of response (DoR), PFS, ORR (monotherapy) and DCR (combination) using investigator assessments according to RECIST 1.1 and OS. - Maximum plasma concentration (Cmax) after Dose 1, Cmax at steady state, minimum observed plasma concentration (Cmin) at steady state as well as other relevant parameters (e.g. tmax, t½, ?z, AUC0-8, CL/F, and Vz/F). - Incidence of AEs SAEs, dose reductions, interruptions and discontinuation.;Timepoint(s) of evaluation of this end point: Throughout trial treatment/follow-up period | — |
Countries
Spain
Contacts
Public ContactRichard Armer
Redx Pharma plc
Outcome results
None listed