| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067946 |
| E.1.2 | Term | Renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Dose-escalation phase:
● To determine the safety, tolerability, dose-limiting toxicities (DLTs) of EXS21546 in combination with nivolumab.
Dose-expansion phase:
● To evaluate the preliminary anti-tumour activity of EXS21546 in combination with nivolumab.
● To further evaluate the safety, tolerability, and treatment adherence of EXS21546 in combination with nivolumab. |
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| E.2.2 | Secondary objectives of the trial |
Dose-escalation phase:
● To estimate the maximum tolerated dose (MTD) of EXS21546 in combination with nivolumab.
● To further characterise the safety, tolerability and treatment adherence of EXS21546 in combination with nivolumab.
● To characterise the plasma PK of EXS21546 following oral (PO) administration in combination with nivolumab.
Dose-expansion phase:
● To further evaluate the preliminary anti-tumour activity of EXS21546 in combination with nivolumab.
● To further evaluate the PK of EXS21546 in combination with nivolumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the entry criteria below at Screening and prior to dosing on Day 1.
1. Aged ≥18 years at time of informed consent.
2. Able and willing to provide written informed consent prior to start of any study specific procedures.
3. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1.
4. Previous histologically confirmed diagnosis of RCC or NSCLC having received previously checkpoint inhibitors as part of a SoC regimen.
5. Prior treatment with a regimen containing immune checkpoint inhibitor (ICI) and radiological determination of disease progression occurring after at least 12 weeks of that prior therapy.
6. Consent to mandatory paired tumour biopsies of at least one tumour site accessible for repeat biopsies. Planned sites for tumour biopsies must not have been previously irradiated and could be a target lesion of >2 cm diameter according to RECIST v1.1 and must be approved on a case-by-case basis by the Sponsor.
7. Ability to swallow and retain oral medication.
8. Estimated life expectancy > 3 months.
9. Adequate haematological, liver and renal function defined below (repeat measurement of borderline values permitted):
a. Haemoglobin ≥ 9 g/dL
b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
c. Platelet count ≥ 100 x 109/L.
d. Adequate coagulation function for all patients with prothrombin time (PT)/ international normalised ratio (INR)/ partial thromboplastin time (PTT) ≤ 1.5 x upper limit of normal range (ULN)
e. Total bilirubin ≤ 1.5 ULN
f. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3x ULN (≤ 5 x ULN if liver metastases)
g. Estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 (calculated by site laboratory or using chronic kidney disease epidemiology collaboration [CKDEPI] formula).
10. Measurable disease as per RECIST v1.1 and documented by computed tomography (CT) and/or magnetic resonance imaging (MRI).
11. A male participant with female partners of reproductive potential must agree to use contraception during the treatment period even if vasectomized, and for at least 6 months after the final dose of study treatment and must refrain from donating sperm during this period.
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
Not a woman of childbearing potential as defined in Appendix 3, OR
A woman of childbearing potential who agrees to follow the contraceptive guidance in Appendix 3 during the Treatment Period and for at least 6 months after the final dose of study treatment.
Women of childbearing potential must have a negative serum pregnancy test at Screening and a negative serum or urine pregnancy test within 48 hours before each new cycle of EXS21546 and must not be breast feeding.
12. Ability to adhere to study visit schedule and comply with study requirements. |
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| E.4 | Principal exclusion criteria |
1. Any anti-tumour therapy, including investigational therapies, within 4 weeks prior to the first dose of EXS21546.
2. Unresolved or unstable serious toxic side-effects of prior chemotherapy or radiotherapy, i.e., ≥ Grade 2 per CTCAE v5.0.
3. Concurrent other malignancy that could interfere with response evaluation.
4. Symptomatic central nervous system (CNS) malignancy or metastases. Screening of symptomatic participants without history of CNS metastases is not required. Participants with asymptomatic CNS lesions should have completed standard therapy for their CNS lesions 60 days prior to study enrolment.
5. Any other concurrent severe and/or uncontrolled medical, surgical or psychiatric and/or social condition which, in the view of the Investigator, could compromise the patient’s safety or ability to participate in the study.
6. Active clinically significant autoimmune disease requiring systemic treatment.
7. History of primary immunodeficiency, bone marrow transplantation or solid organ transplantation.
8. Active hepatitis B or C or human immunodeficiency virus (HIV) infection.
9. Active infection requiring systemic antibacterial, antiviral or antifungal therapy ≤7 days of first scheduled dose of study treatment.
10. Administration of a live or attenuated vaccine within 28 days of starting study treatment and for up to 3 months after the final dose of EXS21546 or anticipation that such vaccine will be required during the study.
11. Uncontrolled symptomatic malignant effusion(s) or those requiring recurrent drainage procedures (as defined as once monthly or more frequently). N.B patients with indwelling catheters (e.g., PleurX) are eligible.
12. Symptomatic interstitial lung disease and/or prior immunotherapy-related pneumonitis.
13. Confirmed baseline QTcF > 480 ms (single ECG) or history of torsades de pointes or history of congenital long QT syndrome.
14. Women who are pregnant or breast-feeding or planning to become pregnant during the study.
15. Patients who have had or are scheduled to have major surgery < 28 days prior to the first dose of study drug.
16. Prior surgery or gastrointestinal abnormality (e.g., gastric bypass) likely to affect absorption of oral medication on an ongoing basis.
17. Clinically significant cardiovascular disease within 4 months prior to first dose of study drug, including Symptomatic heart failure (New York Heart Association classes II-IV), unstable angina, myocardial infarction, unstable cardiac arrhythmia, cerebral vascular accident, coronary/peripheral artery bypass graft surgery, pulmonary embolism.
18. Patient is subject to any of the following procedures: ward of court, trusteeship, supervision order, applied mandate of future protection.
19. Known hypersensitivity to any study medications or components of the study medications or comparable drugs (e.g., A2A receptor antagonists, nivolumab, PD-1 inhibitors). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Dose-escalation phase:
● Incidence of DLTs during Cycle 1 (initial 28 days) of treatment with escalating doses of EXS21546 in combination with an approved dose of nivolumab.
● Incidence of treatment-emergent adverse events (TEAEs) characterised by type, incidence, severity (graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0), seriousness, timing and relationship to EXS21546 dosing.
Dose-expansion phase:
● ORR per RECIST v1.1.
● To further evaluate the safety, tolerability, and treatment adherence of EXS21546 in combination with nivolumab.
● Safety - Incidence and severity of treatment-emergent AEs and SAEs.
● Tolerability – Frequency of dose interruptions, dose reductions and dose intensity achieved.
● Adherence – treatment diary. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Dose-escalation phase:
● The MTD will be estimated based on safety, PK data, selected and available PD response and preliminary anti-tumour activity.
● Laboratory abnormalities characterised by type, frequency, severity (by CTCAE v5.0) and timing.
● Clinically significant changes in electrocardiogram (ECG) results and vital signs.
● Tolerability – Frequency of dose interruptions, dose reductions and dose intensity achieved.
● Adherence – treatment diary.
● PK parameters for EXS21546 derived from plasma concentration vs time profiles, including but not limited to area under plasma-concentration time curve (AUC), Cmax, time to peak plasma concentration.
Dose-expansion phase:
● DCR, PFS, DOR, TTR assessed using RECIST v1.1.
● PK profile of EXS21546 plasma concentrations for selected cycles. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| France |
| Spain |
| United Kingdom |
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| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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