| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with Advanced Malignancies
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced cancer with tumours. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Part A
o To assess the safety and tolerability of RXC004 when given orally as a single agent to patients with advanced malignancies, and to define the doses and schedules for further clinical evaluation.
• Part B
o To assess preliminary signs of monotherapy anti-tumour activity of RXC004 in patients with selected advanced solid malignancies, by evaluation of tumour response using RECIST v1.1.; objective response rate (ORR), duration of response (DRR) and disease control rate (DCR) (monotherapy ‘proof of concept’ [PoC]). |
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| E.2.2 | Secondary objectives of the trial |
• To characterise the PK profile of RXC004, following a single dose and at steady state after multiple dosing, when given orally alone or in combination with anti-cancer treatments.
• To obtain a preliminary assessment of RXC004 activity by evaluation of PD biomarker changes which may include, but are not limited to, Wnt pathway inhibition, gene expression signatures, and ctDNA levels.
• To obtain a preliminary assessment of the anti-tumour activity of RXC004 as a single agent or in combination with anti-cancer treatments (to include assessment of ORR, DCR, DoR and PFS)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability to give written informed consent prior to any study-specific screening procedures, sampling and analyses; including access to all archival tumour tissue taken within the last 18 months, with the understanding that the consent may be withdrawn by the patient at any time without prejudice.
2. Capable of understanding the protocol requirements, is willing and able to comply with the study protocol procedures, restrictions and has signed and dated the informed consent document.
3. Patients must have histological or cytological confirmation of advanced malignancy not considered to be appropriate for further conventional treatment.
4. Aged at least 18 years at the time of screening.
5. Evaluable disease, either measurable on imaging, or with informative tumour marker(s), as assessed by RECIST 1.1 or other relevant response assessment criteria for tumour type. For RECIST 1.1, patients should have at least 1 lesion that qualifies as a RECIST 1.1 target lesion at baseline (within 28 days of the first dose). The use of scans obtained as part of standard clinical practice, prior to informed consent, will be accepted if they comply with RECIST 1.1 criteria and have been performed within the 28-day screening period.
6. Patients must have recovered from toxicities of prior therapies. (i.e. to CTCAE ≤ grade 2) apart from alopecia.
7. Eastern Cooperative Oncology Group (ECOG) or World Health Organisation (WHO) performance status 0 or 1 with no deterioration over the previous 2 weeks and an estimated life expectancy of greater than 12 weeks.
8. Ability to swallow and retain oral medication.
9. Organ Function Requirements - Subjects must have adequate organ functions as defined below:
AST/ALT ≤ 2X ULN (upper limit of normal; with no underlying Liver Metastasis)
AST/ALT ≤ 3X ULN [with underlying Liver Metastasis]
Total Bilirubin within normal range
Serum Creatinine ≤ 1.5X ULN
ANC ≥ 1500 /μL
Platelets > 100,000/μL
Hb >9g/dL
10. Females must be using adequate contraceptive measures, must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
Post menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution
Module 1 Part B Monotherapy Expansion Specific Inclusion Criteria:
11. Patients must have histological or cytological confirmed, advanced or metastatic
gastric, pancreatic, colorectal or biliary cancer, not considered to be appropriate for
further conventional treatment
12. Patients in gastric, pancreatic or colorectal tumour expansion cohorts must have a
genetic alteration in the upstream Wnt signaling pathway (e.g. RNF43 mutation or
RSPO fusions). Patients in a biliary tumour expansion cohort will not have any genetic
selection.
13. Archival tumour material will be required (the provision of a fresh biopsy at screening
is also acceptable)
14. For entry into the colorectal expansion cohort patients will have a genetic alteration in
the upstream Wnt signaling pathway (e.g. RNF43 mutation and/or RSPO fusion) and
at least 1 lesion suitable for biopsy at screening. Patients must also be willing to
provide a mandatory tumour biopsy sample at baseline (pre first dose of RXC004) (this
may also be a screening biopsy) and in cycle 2. |
|
| E.4 | Principal exclusion criteria |
1. Prior therapy with a compound of the same mechanism of action as RXC004.
2. No other anti-cancer therapy or other investigational product (bisphosphonates are acceptable) is permitted other than the agent(s) described in the relevant study module
- During the study period, patients using allowed hormonal therapy should maintain a constant dose and should not change existing regimen.
- If a change in hormonal therapy is indicated, e.g. due to intolerable adverse effects, the regimen may be modified but change should be minimized thereafter.
3. Patients with persistent grade 2 or higher diarrhoea (any cause) that has not resolved or improved with appropriate treatment prior to study enrolment
4. Patients at higher risk of bone fractures, including;
• Patients with bone metastases
• Patients with beta-CTX (bone turnover marker) of > 1000 pg/mL
• Patients with Vitamin D [25(OH)D3] deficiency defined as < 30nmol/L (<12ng/mL). [Note - Patients who fail on this criteria alone can be retested within the screening window]
• Patients with a corrected total serum calcium level of <2 mmol/L and serum magnesium level of < 0.60 mmol/L
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 and any ≥ grade 2 vertebral fracture on VFA)
• 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.
• 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.
• Patients who have received oral or intravenous (i.v.) glucocorticoids for > 4weeks at daily doses equivalent to 7.5 mg of oral (p.o.) prednisolone within 6 weeks prior to study drug dosing
5. Patients receiving radiation to more than 30% of the bone marrow, direct radiation to their spine or pelvis, or with a wide field of radiation within 4 weeks of the first dose of study treatment.
6. Female patients who are pregnant or breast-feeding at entry
7. QTcF prolongation (> 470 msec or 60 msec above baseline)
8. Patients with any known uncontrolled inter-current illness including ongoing or active clinically significant infections, symptomatic congestive heart failure (with an Ejection Fraction (EF) ≤ 50% or the institutional lower limit of normal whichever is lower), hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
9. Patients with any of the following medications within 4 weeks prior to enrollment:
Anti-neoplastic agents
Immunotherapy [mAbs, Interferons, Cytokines (except GCSF)]
Immunosuppressants (e.g., cyclosporin, rapamycin, tacrolimus, rituximab, alemtuzumab, natalizumab, etc.).
Another investigational drug
10. Patients with any known severe allergies (e.g., anaphylaxis) to any active or inactive ingredients in the study drugs
In addition to the core exclusion criteria, patients must not enter Module 2 if any of the following exclusion criteria are fulfilled;
11. Patients with any contraindication to the use of Nivolumab as per approved county label (Summary of Product Characteristics or equivalent)
12. Patients with active or prior documented autoimmune of inflammatory disorders within the past 5 years
13. Patients with active infections, including tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus
14. Use of any live vaccines against infectious diseases (eg, influenza, varicella) within 4 weeks (28 days) of initiation of study treatment
15. Patients with body weight <40kg
16. Patients with a history of allogeneic organ transplant or active primary immunodeficiency
17. Patients with a known hypersensitivity to Nivolumab or any of the excipients of the product |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability: Characterisation of dose limiting toxicities, Minimally Biological Active Dose (MBAD), Maximum Tolerated Dose (MTD), Maximum Feasible Dose (MFD), and safety profile.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to protocol. |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to protocol. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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